C4.Cardiovascular system

In the West, cardiovascular disease is the most common cause of premature death in men, and 

a frequent cause of disability. Factors such as smoking and diet are strongly implicated, so much 

of this illness is preventable. If health professionals understand the mechanisms of the various 

disease processes it is easier for them to help patients avoid or cope with these illnesses. 

Cardiovascular disease (CVD) and its treatment frequently causes considerable confusion because there are a number of closely related conditions and a wide range of drugs, many of which can be used in more than one condition. It is the aim of this chapter to explain how an understanding of the principles of haemodynamics in particular can clarify not only the relationship  between  various  cardiovascular  diseases  but  also  common  threads  running through their pharmacotherapy. 

The first section discusses some important general principles of the normal function of the 

cardiovascular system. We will first consider the cardiovascular system simply as a closed system 

of pump, tubes and fluid designed to perfuse the tissues. We then discuss energy handling in 

cardiac muscle, its oxygen demand and its oxygen supply. The physiology of the vascular 

endothelium and the neurohormonal control of cardiovascular function must also be considered. 

This approach allows predictions to be made about how the cardiovascular system responds to 

normal and abnormal circumstances, and how drugs can affect its function.

Physiological principles of theViscosity

cardiovascular systemResistance ÷(4.2)

r4

 This section assumes a basic understanding of 

the physiology of the CVS. Appropriate back-

ground material for revision of the anatomy, 

physiology and pharmacology of the CVS is 

suggested in the References and further reading 

section.

Haemodynamics

Haemodynamics is the term used to describe the interactions of the physiological parameters that govern the behaviour of the CVS.

Blood flow and blood pressure

The  purpose  of  the  CVS  is  to  provide  an adequate perfusion of blood to all body tissues in response to a wide variety of sometimes swiftly changing  demands.  The  ability  of  the  heart to act as a pump to maintain this perfusion may be   called   the   pump   performance,   usually expressed as cardiac output.

Fluid flow through a rigid tube depends on the 

pressure gradient and inversely on the resistance 

to flow:

Pressure gradient

Flow ÷(4.1)

Resistance

Because blood vessels are not strictly rigid this 

relationship does not precisely describe blood 

flow, but it is a useful approximation. The pres-

sure gradient is generated by the heart during 

contraction, i.e. when doing work and using 

energy. It is equivalent to the blood pressure, or 

more  precisely  the  mean  arterial  pressure, 

which is approximately equal to diastolic pres-

sure plus one-third of the systolic-diastolic pres-

sure difference. Note that pressure is merely a 

means to an end: the goal is output.

Blood pressure is required to overcome the 

peripheral resistance, which depends predomi-

nantly on the radius of the blood vessels (r) and the viscosity of the blood (Poiseuille’s law):

Blood  viscosity  is  approximately  constant, 

although it may be altered pathologically, e.g. by 

increased RBC mass or acute dehydration. Thus 

variations in resistance usually reflect changes 

in the calibre of blood vessels. Not all vessels 

contribute equally. The arterioles are the main 

resistance vessels; together with the arteries they 

represent about 70% of the peripheral resistance.

Thus changes in systemic blood pressure, or perfusion of any particular region of the body, are readily achieved by altering the calibre of the resistance vessels, especially because the resis-

tance depends on the fourth power of the vessel radius. From Equations 4.1 and 4.2:

Flow ÷ pressure    r4(4.3)

Thus very small changes in vessel diameter will produce large changes in flow if pressure is unaltered.   For   example,   a   small   sustained constriction of all the body’s resistance vessels will mean that a considerable increase in blood pressure is required if the same flow is to be 

maintained. This may be relevant to the aeti-

ology of hypertension. Conversely, vasodilata-

tion will permit increased flow.

Regional control of resistance and flow: autoregulation

The CVS exploits the flow/resistance relation-

ship to increase the perfusion of specific areas 

temporarily at no extra cost in cardiac work. 

Blood is diverted from areas of lesser need, such 

as the skin, to those of greater need, such as 

muscle, by constricting vessels in the former and 

dilating those in the latter. Because the overall 

peripheral resistance does not change, cardiac 

output   and   blood   pressure   also   remain 

unchanged and there is no requirement for extra 

cardiac work.

How  are  these  adjustments  made?  When 

activity  in  a  tissue  or  organ  increases,  more 

oxygen is required. Initially blood flow does not 

increase,  so  oxygen  demand  outstrips  supply and the tissue becomes hypoxic; consequentlyresistance but have two other important roles in

metabolic  by-products,  including  acids  and carbon   dioxide,   accumulate   extracellularly. These have a direct dilating effect on local resis-

tance  vessels,  facilitating  increased  perfusion. Conversely, when a tissue is receiving too much blood  for  its  needs,  the  reverse  mechanism mediates local vasoconstriction.

Here is an elegant example of the economy of 

the body, a sensitive self-regulating system that 

continuously monitors blood flow through all 

tissues and redistributes it according to need. 

Note that, initially at least, no interventions 

from  the  nervous  or  hormonal  systems  are 

required.

The lung is an important exception to this 

general  rule  of  hypoxic  vasodilatation.  Lung 

arterioles constrict when hypoxic, and it is not 

difficult to see why. Hypoxia (low tissue oxygen) 

in an area of lung implies inefficiency in gas 

transport, possibly as a result of local disease. 

Blood perfusing that area will be inadequately 

oxygenated  and  thus  it  will  dilute  the  total 

pulmonary oxygen output. Consequently, blood 

is directed away from damaged areas of lung by 

local vasoconstriction. However, this mechanism 

becomes  counterproductive (i.e.  maladaptive) 

when  large  areas  of  lung  are  involved (see 

Chapter 5).

Other local influences on blood vessel calibre 

include  injury (causing  constriction  to  limit 

blood   loss)   and   numerous   local   hormones 

and    mediators,    including    prostaglandins 

(prostacyclin is a vasodilator), thromboxanes 

(predominantly  constrictor),  endothelins  and 

angiotensin (constrictor) and nitric oxide (NO; 

vasodilator).  Most  are  released  from  vascular 

endothelial cells and some may also have a 

crucial influence on blood vessel growth and 

proliferation, which has a bearing on vascular 

obstructive disease (see p. 235).

Distribution of blood volume

The amount of blood contained in different 

components  of  the  circulation  is  in  inverse 

proportion  to  their  resistance.  Low-resistance 

veins and venules contain up to 75% of blood 

volume  and  are  referred  to  as  capacitance 

vessels. They have little effect on peripheral

circulatory regulation. Firstly, they exert a crucial 

influence on cardiac output (discussed below). 

Secondly, being both compliant and muscular, 

veins can dilate or constrict to accommodate 

sudden changes in blood volume (e.g. IV infu-

sions,  fluid  depletion),  buffering  potentially 

destabilizing   effects   on   venous   return   and 

cardiac output (p. 189).

Conversely,  resistance  vessels  (arteries  and arterioles) contain only a small proportion of the blood; thus changes in their calibre alter the 

blood volume only slightly. Their primary func-

tion is the maintenance of the blood pressure via control of the peripheral resistance.

Cardiac output and blood pressure

Equation 4.1 can be expressed more familiarly 

as:

Blood pressure

Cardiac output(4.4)

Peripheral resistance

This   illustrates   important   relationships 

between the main haemodynamic parameters. 

For example, any rise in resistance requires an 

increased  blood  pressure,  generated  by  the 

heart, if cardiac output is be maintained. If this 

situation is sustained, the extra work required 

will take its toll and eventually this may lead to 

heart failure. An increased peripheral resistance 

is  commonly  found  in  most  hypertensive 

patients, but rather than always being the cause 

of  the  condition  this  could  be  a  secondary 

autoregulation  in  response  to  an  excessive 

cardiac output (p. 213). Thus in treating hype-

tension, although reducing peripheral resistance 

is the most obvious therapeutic target, strategies 

to  reduce  cardiac  output  are  equally  appro-

priate. Indeed one of the ways that both beta-

adrenergic blockers (beta-blockers) and diuretics 

are  thought  to  act  is  by  initially  reducing 

cardiac output.

Pump performance

It  is  crucial  to  appreciate  how  the  heart 

behaves as a pump. To understand the patho-

genesis  of  heart  failure  in  particular,  and  the 

rationale for treating CVD generally, the factors 

that  influence  cardiac  performance  must  be 

considered.   Three   variables   determine   the 

performance of a pump: (i) its initial priming 

with  fluid  to  be  pumped; (ii)  its  intrinsic 

power; and (iii) the resistance it must overcome 

in  expelling  fluid.  In  cardiac  terms  these  are 

known as preload, intrinsic contractility and 

afterload respectively.

Cardiac cycle

A  brief  summary  of  the  main  stages  in  the cardiac cycle is given in the text accompany-

ing Figure 4.1, and will be referred to in the 

subsequent discussion.

Preload

The force of contraction of a muscle is propor-

tional to the degree to which it is stretched 

before contracting - this is the preload. In the 

heart it is equivalent to the degree of distension 

of a chamber at the end of diastole, the end-

diastolic volume (EDV). This is the basis of the 

well-known   Starling’s   law,   which   is   often 

simply stated as: ‘the cardiac output equals the 

venous return’. It may be restated more precisely 

as: ‘the stroke volume is proportional to the 

EDV’, where the stroke volume is the volume 

expelled in one systolic beat. Some readers may 

find the mechanical analogy given in Figures 4.2 

and 4.3 helpful in understanding this concept 

(see also References and further reading).

An important implication of Starling’s law is 

that the heart is driven by the venous return. 

This  is  another  example  of  economical  self-

regulation. Consider what happens when exer-

tion  such  as  running  is  initiated.  The  leg 

muscles need extra blood immediately, and the 

leg  arterioles  rapidly  dilate  as  the  tissue 

becomes  hypoxic.  But  even  as  this  happens 

there will be an increased venous return, owing 

to the peripheral muscle pump. As deep-lying 

peripheral veins in the leg are compressed by 

contracting muscles, an increased blood flow is 

immediately delivered to the right side of the 

heart (one-way  flow  being  ensured  by  the 

non-return  valves  in  veins).  Thus  immedi-

ately  vigorous  activity  starts,  the  preload  is

system

increased,  raising  the  cardiac  output  by  the Starling mechanism.

This does not require the intervention of any 

hormonal or neural mechanisms, the increased 

venous return and cardiac output being directly 

proportional to the increased activity. It also 

explains  the  benefit  of  raising  the  legs  of 

someone who has fainted (it certainly does not 

‘increase the blood supply to the head’ directly).

Filling pressure

The preload on a cardiac chamber can also be 

expressed as the pressure within it at the end of 

diastole,   the   end-diastolic   pressure (EDP), 

which is approximately the filling pressure of 

the blood flowing into that chamber. A sustained 

rise in either of these factors implies that a 

normal heart is being overloaded or that an inef-

fective  heart  requires  an  elevated  preload  to 

maintain normal output. The right atrial pres-

sure (RAP) and the left ventricular EDP (LVEDP), 

measured by cardiac catheterization via periph-

eral arteries, give important information about 

the degrees of right- and left-sided heart func-

tion respectively. The RAP also indicates whether 

the systemic circulatory volume is appropriate, 

and so can be used to monitor IV infusions and 

prevent the heart, and the circulation generally, 

becoming overloaded.

The right heart preload may be determined 

more   conveniently   and   less   invasively   by 

measuring the pressure in the great veins as they 

enter  the  right  atrium.  The  central  venous 

pressure (CVP) is measured by passing an IV 

catheter percutaneously in the neck region so 

that its tip rests in the superior vena cava.

Filling is not a passive process; it is energy-

dependent. This energy is derived partly from 

relaxation of the compressive deformation of the 

previous   systolic   contraction,   elastic   recoil 

aiding  the  restoration  of  diastolic  shape.  An 

important determinant of filling is ventricular 

compliance (distensibility, the inverse of stiff-

ness). If it is reduced, a higher preload will 

be needed, possibly leading to diastolic failure 

(p. 189).

Ejection fraction

The ratio of the stroke volume to the EDV repre-

sents  the  effectiveness  of  cardiac  emptying Figure 4.1Important components of the heart. (a) The main internal structural components of the heart. This diagram 

(not anatomically precise or to scale) also shows the blood flow through the different chambers, emphasizing the origins 

and destinations of blood on each side. (b) The main centres of electrical excitation and pathways of electrical conduc-

tion in the heart. NB All given pressures are approximate and typical of a healthy young adult. AV, aortic valve; AVN, 

atrioventricular node; BB, bundle branches (right and left); BH, bundle of His; LA/RA, left/right atrium; LV/RV, left/right 

ventricle; MV, mitral valve; PA, pulmonary artery; PF, Purkinje fibres; PV, pulmonary valve; PVn, pulmonary vein; SAN, 

sinoatrial node; TV, tricuspid valve.

CIRCULATION (starting with return of blood to the heart from the peripheral circulation)

• Deoxygenated blood returns to the right side of the heart from 

venae cavae during diastole (relaxation)

• It enters the right atrium at a pressure of 0-10 mmHg

• Right atrial contraction increases pressure until the tricuspid valve

• Blood flows through the tricuspid valve into the right ventricle 

during diastole, partially assisted by atrial contraction (the ‘atrial

kick’)

• As right atrial pressure rises, the tricuspid valve closes and the 

pulmonary valve opens

• Right ventricular systole (contraction) sends blood via 

pulmonary arteries to the lungs at a pressure of about 30 mmHg

• Blood is oxygenated in the lungs and returns to the left atrium via

the pulmonary veins

• Left atrial systole increases pressure until the mitral valve opens

• Blood flows through the mitral valve into the left ventricle during

diastole

• Left ventricular contraction during systole

• As pressure rises, the mitral valve closes (‘lub’) and the aortic 

valve opens

• Left ventricular contraction during systole sends blood via the 

aorta to the body at a maximum pressure of about 120 mmHg

• Ventricular pressure falls and the aortic valve closes (‘dup’)

• Blood perfuses the periphery and oxygenates tissues

• Mean pressure falls to 30 mmHg at the arterial end of capillaries

and 15 mmHg at the venous end

• Deoxygenated blood returns to the heart via the veins; flow is 

facilitated by the peripheral muscle pump, and back flow is

prevented by one-way venous valves

CARDIAC CYCLE (starting at end of diastole)

• Impulses originate in the sino-atrial node, which controls rhythm 

and causes atrial systole

• Impulses spread across the atrium to the atrioventricular node

• Impulses traverse the bundle of His and bundle branches in the

septum (between Left and Right heart)

• Ventricular systole starts from the apex of the ventricles

• Intraventricular pressure rises, initially without change of size

because the aortic and pulmonary valves are closed (isovolumic 

phase)

• Impulse spreads towards the base of the ventricles (valves) via 

Purkinje fibres

• Mitral and tricuspid valves close as pressure rises

• Aortic and pulmonary valves open as pressure exceeds systemic

or pulmonary

• Blood propelled towards the aortic and pulmonary valves by 

contractile wave spreading from the apex and twisting

deformation of the ventricles due to asymmetric myocardial muscle sheets (ejection phase)

• Blood flows to the lungs from the right ventricle, and to the rest of 

body from the left ventricle

• Pressure in the ventricles falls and the aortic and pulmonary valves 

close

• Blood flows from the aorta into the coronary arteries as the 

ventricles relax;  ventricular diastole 

Figure 4.2Spring model of the loading on a pump. (a) Spring in resting position. (b) Spring stretched (primed) by preload P. The degree of stretch, and therefore the energy stored for subsequent recoil, is proportional to the magni-

tude of preload. (c) Afterload A applied to spring. (d) Spring recoils (contracts). Resistance to recoil depends on magni-

tude of afterload, and force of recoil depends on physical properties of spring (‘contractility’).

during systole. It is thus a good index of cardiac efficiency and is used as a quantitative measure of the degree of heart failure:

Stroke volume

Ejection(4.5)

fractionEnd-diastolic volume

The   average   ejection   fraction   in   health, measured by echocardiography, is 60-70%.

Intrinsic contractility

The  biochemical  and  metabolic  condition  of 

heart  muscle  will  influence  its  performance 

regardless  of  preloading.  Variable  contractility 

is a property not found in other smooth muscle 

or  in  skeletal  muscle.  It  is  affected  by  the 

autonomic nervous system, systemic hormones 

(e.g. adrenaline [epinephrine]), and disease (e.g. 

ischaemia due to obstructed coronary vessels), 

so that the same preload may produce a greater 

or   lesser   performance.   Contractility   also 

increases with increased heart rate (the force-

frequency effect). These represent further adap-

tive mechanisms available to the CVS.

Afterload

This is the resistance that the heart meets in 

contracting  and  doing  work  to  drive  blood 

through the arteries. A raised peripheral resis-

tance   will   at   first   reduce   cardiac   output, 

although normally a reflex increase in contrac-

tility will promptly restore it, at the expense of 

extra cardiac work. For most purposes the after-

load is approximately equivalent to the blood 

pressure.

Summary

Within the normal physiological range, cardiac 

performance    is    directly    proportional    to 

preloading (EDV or filling pressure) and contrac-

tility, and inversely proportional to afterload 

(vascular  resistance).  These  relationships  are 

illustrated and explained further in Figure 4.4.

Factors affecting pump performance

Preload

This, the most complex of all determinants of 

cardiac performance, is usually taken as equiva-

lent to the venous return. However, the more 

precise concept of filling pressure must be used 

to understand how preload varies (Figure 4.5). 

The filling pressure at the right atrium is usually 

about 10 mmHg.  It  depends  on  three  main 

factors:

1. The degree to which the circulatory system as 

a whole is ‘filled’ with blood, i.e. the blood

volume.

2. The   pressure   exerted   by   the   veins   to 

accommodate this, i.e. the venous tone.

3. The  contribution  of  muscular  activity  to

venous  return,  i.e.  the  peripheral  muscle pump (p. 168).

Blood volume

Fluid and electrolyte clearance by the kidney 

is varied to defend blood pressure. In partic-

ular,  fluid  is  retained  if  renal  perfusion  is 

threatened.  This  is  achieved  through  a  var-

iety  of  endocrine  mechanisms  including  the 

renin-angiotensin-aldosterone   system (RAAS), vasopressin/antidiuretic   hormone,   PGs   and kinins. Urine output also varies with renal perfu- sion. The renal control of body fluid volume is discussed in detail in Chapter 14.

Figure 4.3Stages in the cardiac cycle to illustrate loading, using the analogy of the spring. The effects of preload and 

afterload may be grasped more easily if it is imagined that there are springs in the ventricular wall that behave in a similar 

way to those in the previous figure. The right side is shown during diastole (a, b) to illustrate preload and the left side 

during systole to illustrate afterload (c, d). This is because changes in preload (systemic filling pressure) usually affect the 

right side, while the left side is usually affected by changes in afterload (systemic vascular resistance). However, similar 

considerations apply to both sides and they fill and empty simultaneously. (Volumes given below apply to average resting 

cardiac cycle, i.e. no exertion.) (a) Right side of heart at the end of systole (ESV, end-systolic volume; about 50 mL). 

Myocardial fibres are contracted (‘springs’ recoiled). Venous return starts to fill right atrium and then right ventricle, 

producing preload. (b) Right side at the end of diastole (EDV, end-diastolic volume; about 120 mL). Myocardial fibres are 

stretched, to a degree proportional to preloading (equivalent to volume of venous return). The potential force of subse-

quent contraction is proportional to the degree of myocardial stretch (equivalent to EDV). (c) Left side of heart at end of 

diastole. Myocardial fibres now start to contract. The afterload is equivalent to the resistance of the systemic arterioles 

(peripheral resistance) against which the left ventricle must eject the stroke volume (approx. 70 mL). The stroke volume will 

also be determined by the condition of the myocardium (contractility, perfusion, etc.). (d) Left side at end of systole; position 

is similar to (a). RV starting to fill. Stroke volume (SV) = EDV - ESV. Ejection fraction = SV/EDV (usually approx. 60%).

Figure 4.4Variation of pump performance with preload, afterload and contractility. (a) Preload. Assuming afterload and 

contractility remain constant, the preload/output curve is normally steep up to a maximum M (which depends on fitness). 

M is seldom reached and above it performance declines steeply with increasing preload. Note that the average resting 

cardiac output is 5 L/min. These ‘contractility curves’ or Frank-Starling curves clearly show how cardiac output is driven 

by venous return. They are useful to illustrate variations in cardiac performance resulting from changes in other parame-

ters. (b) Afterload. If contractility and preload remain constant, increases in afterload (usually peripheral resistance) reduce 

performance almost linearly, as shown in curve F. However, a curve such as this would only be found in heart failure. 

Normally, preload and contractility do not remain constant but increase reflexly to defend cardiac output (curve N), 

producing an almost flat relationship over a wide range. Comparison of curves F and N shows why arterial vasodilators, 

which reduce afterload, have little effect on output in health but can considerably improve it in failure. (c) Contractility. 

This family of contractility curves shows how different intrinsic contractilities affect the response of the heart to preload 

(assuming afterload is constant). Curve N is as in (a). Curve S, showing positive inotropic stimulation (e.g. sympathetic 

nervous system) is steeper and goes higher. Curve I shows the inhibitory effect of negative inotropic influences (e.g. 

parasympathetic nervous system). Curves S, N and I represent normal physiological variation. In compensated heart 

failure (C) the curve may barely rise above the minimum resting output. In decompensated failure (F), output actually falls 

with increases in preload beyond a certain point. This explains why preload reduction in heart failure can actually improve 

output (see p. 199).

The most recently identified mediators are the 

natriuretic  peptide (NP)  hormones,  released 

from a variety of tissues. The most important are 

atrial natriuretic peptide (ANP) (from the atria) 

and  brain  natriuretic  peptide (BNP) (from 

brain  and  cardiac  ventricles)  and  they  are 

proving  useful  as  markers  for  heart  failure 

because they are released when the circulation is 

failing. They have both vasodilator and natri-

uretic actions, and serve as counter-regulatory 

influences to limit excessive cardiac dilatation, 

peripheral   vasoconstriction   and   renal   fluid 

retention,   and   as   protection   against   fluid 

overloading.

Venous tone

The balance between the volume of fluid within blood vessels and its pressure is controlled by the 

tone of the vessels. If fluid volume is increased, 

e.g. by renal fluid retention, the pressure will 

tend to rise. The veins, being more compliant 

than arteries, will then dilate to accommodate 

the extra volume and hence buffer what may 

otherwise generate a dangerous rise in filling 

pressure and cardiac drive. Without this compli-

ance the heart could rapidly be overloaded and 

fail. Conversely, sudden falls in blood volume, 

e.g. as a result of severe haemorrhage, can be 

partially compensated by venoconstriction.

However, venous compliance is limited and large rises in blood volume do increase filling pressure at first, although further compensatory mechanisms  eventually  come  into  play,  e.g. increased renal fluid clearance.

Venous tone, like arterial tone, is under auto-

nomic control. Adrenergic drugs or stimulation of the sympathetic nervous system cause veno-

constriction, which is consistent with the stress response (‘fight  or  flight’):  it  increases  the venous return and filling pressure and so cardiac output. Conversely, extensive venodilatation is implicated in the pathogenesis of circulatory 

shock because it causes a profound reduction in cardiac output and blood pressure.

Ventricular compliance

Resistance to filling is determined by the ease 

with which the shape and size of the ventricle 

are restored during diastole. The hypertrophy of 

ventricular muscle that accompanies hyperten-

sion, some forms of cardiomyopathy (diseased 

heart muscle) and the diffuse fibrosis of chronic 

ischaemic  heart  disease  can  produce  a  stiff 

myocardium that significantly reduces ventric-

ular  compliance,  preventing  adequate  filling 

(p. 188).

Afterload

The afterload is determined mainly by arteriolar 

tone, which is affected by both normal physio-

system

logical mechanisms and disease (Table 4.1). In 

health, the overall tone is kept within narrow 

limits because there is rarely any physiological 

advantage in raising afterload. In hypertension, 

afterload is persistently raised, so the heart must 

work harder to maintain normal output; the ulti-

mate result may be left ventricular failure (LVF).

In health, blood viscosity is also constant. 

Persistent hypoxaemia (reduced blood oxygen 

level, e.g. in COPD), causes a reflex rise in RBC 

count (polycythaemia). The resulting increase in 

blood viscosity increases the afterload, which 

can contribute to right ventricular failure (RVF; 

see Chapter 5).

Contractility

Agents or circumstances that increase or decrease 

contractility are termed positively or negatively 

inotropic, respectively (Table 4.2). Small changes 

in perfusion demands are normally accommo-

dated by changes in preloading and the Starling 

effect rather than in contractility. However, if 

necessary,   positive   inotropic   effects   can   be 

activated rapidly by the sympathetic nervous 

system,   and   more   slowly   under   hormonal 

influences, e.g. thyroxine.

The myocardial adrenergic receptors are mainlyperfusion, i.e. ischaemic heart disease. However,

beta1.  However,  the  existence  of  a  small  but 

significant population of beta2-receptors means 

that beta2 selectivity among agonists such as the 

bronchodilators  can  never  entirely  free  them 

from cardiac effects. This contrasts with highly 

selective beta1-adrenergic blocking drugs, which 

will spare the lung and other beta2-populated 

sites. The parasympathetic nervous system has 

negatively  inotropic  effects  via  muscarinic 

receptors, restricted mainly to the atria.

Among drugs, two main groups affect contrac-

tility: the beta-adrenergic agents (stimulants and blockers) act via their normal autonomic recep-

tors,  while  the  cardiac  glycosides  and  other agents,  e.g.  the  phosphodiesterase  inhibitors, affect myocardial cells directly.

Myocardial pathology

Numerous  conditions  cause  deterioration  in 

myocardial  contractility,  hypoxia (low  tissue 

oxygen level) being one of the most important. 

It   usually   results   from   impaired   coronary

reduced blood oxygenation (hypoxaemia) will have a similar effect, e.g. severe chronic anaemia (Chapter 11) or COPD (Chapter 5).

Subtle  problems  can  result  from  excessive 

myocardial hypertrophy. A modest increase in 

myocardial mass is usually a beneficial adaptive 

response to chronically increased cardiac loading, 

as in any well-exercised muscle. However, if the 

myocardium grows too quickly it may outpace 

the formation of new coronary vessels, causing 

relative   ischaemia.   In   addition,   a   thick 

myocardium is less compliant (impairing filling), 

and the extra cardiac work required to contract it 

during systole will also reduce efficiency.

Overloading,   e.g.   excessive   afterload   in 

chronic hypertension, or excessive preload in 

fluid retention, can damage the myocardium by 

forcing  it  to  operate  beyond  its  ability  to 

compensate, causing heart failure. This and the 

various other pathological processes that directly 

affect the myocardium are discussed in more 

detail on pp. 188-193.

Heart rate

This represents yet another compensatory option for the CVS because cardiac output can quickly be changed  without  necessarily  changing  stroke volume or intrinsic contractility:

Cardiac

output

Stroke volume    heart rate

Heart  rate  is  under  broadly  similar  physio-

logical  influences  to  contractility.  However, 

while  the  sympathetic  nervous  system  exerts 

an  excitatory  influence  on  contractility,  the 

predominant  physiological  control  on  resting 

rate is inhibitory parasympathetic tone via the 

vagus nerve, slowing the heart (i.e. negatively 

chronotropic).   When   the   heart   rate   is 

increased the diastolic interval is reduced but 

the systolic time is mostly unchanged. Gener-

ally speaking, the CVS will use changes in rate 

only  to  produce  rapid  temporary  changes  in 

output.  Medium-term  output  changes  require 

altered   contractility,   and   chronic   changes

involve   renal   compensation   and   possibly myocardial hypertrophy.

Summary

The relationships between the factors discussed above   are   summarized   in   Figure 4.6.   This emphasizes  the  multifactorial  nature  of  CVS 

adjustments, involving coordination of haemo-

dynamic, neural and endocrine feedback loops and control paths.

Coronary circulation

Because the heart pumps continuously and has 

little reserve energy substrate (e.g. glucose), its 

blood  supply  is  critical.  Moreover,  it  has  the 

highest oxygen extraction of any organ in the 

body  (i.e.  its  coronary  arteriovenous  oxygen 

difference is greatest). This means that increases 

in oxygen demand need to be met mainly by 

increases in perfusion. Many common cardiac 

diseases result from impaired coronary perfusion.

Coronary perfusion

elastic recoil of the aorta immediately following systole, as the myocardium relaxes (Figure 4.7). Perhaps surprisingly, ventricular muscle is effec-

tively  perfused  only  during  diastole,  because myocardial  contraction  during  systole  com-

presses the coronary vessels, especially in the inner layer (endocardium).

The perfusion pressure driving blood into the 

coronary arteries is the difference between the 

pressure in the aorta and the pressure within 

the heart chamber during diastole (Equation 4.7).

CoronaryMeanEnd-

perfusionarterial-   diastolic

pressurepressurepressure

(4.7)

Thus  both  low  blood  pressure  and  a  raised 

EDP,  e.g.  during  heart  failure,  can  compro-

mise coronary perfusion. Note also that blood 

has   to   change   direction   and   flow   back 

towards the heart during diastole to enter the 

coronary  arteries,  which  branch  off  the  aorta 

just  after  the  aortic  valve.  This  tends  to 

produce turbulence, which may be a factor in 

the   particular   sensitivity   of   the   coronary 

arteries to atherosclerosis.

Control and compensation

The principal physiological controls on coronary vasculature  are  autoregulatory,  with  dilatation 

occurring in response to increased demand as 

metabolic   by-products   accumulate   in   the 

stimulated  myocardium.  Autonomic  control 

plays a minor role via alpha-adrenergic constrictor 

and beta2-adrenergic dilator nerves. These may 

however  play  a  role  in  coronary  vasospastic 

diseases such as variant angina (p. 249).

The heart does not normally have a well-

developed system of collateral vessels; thus it is more compromised by vascular obstruction than other tissues. Therefore atheromatous plaques that occlude coronary arteries in ischaemic heart disease (p. 236) will have a disproportionately large   effect.   However,   regular   exercise   and chronic vascular obstruction both stimulate the development of coronary collaterals.

A fixed obstruction such as an atheroma (see 

below) not only reduces the lumen but also 

impairs the vessel’s ability to dilate, and may 

abolish   it   completely.   Furthermore,   during 

ischaemia,  autoregulated  dilatation  normally 

occurs in vessels adjacent to the obstructed one; 

this may actually divert blood away from the 

area served by the obstructed vessel if that area 

does not have a collateral supply. This phenom-

enon, known as coronary steal, is sometimes 

seen when vasodilators are used in acute angina; 

the pain actually increases as blood is redirected 

away from the ischaemic area.

Myocardial energetics

Oxygen demand

The work done by the heart is given approxi-

mately by the product cardiac output    blood 

pressure. Clearly, oxygen demand is related to 

the work done. This relationship is governed by 

several variables. One way of expressing it is:

O2 demand    contractility 

myocardial wall tension

time in tension(4.8)

Contractility depends on the contractile state 

of the myocardium (p. 174), time in tension is 

related to heart rate, and wall tension is related to mean arterial pressure (for the left ventricle). 

Thus  adrenaline (epinephrine),  hypertension 

and   tachycardia(increased   heart   rate)   all 

increase oxygen demand if other factors remain 

unchanged.  This  is  particularly  important  to 

remember when the coronary supply is compro-

mised, because increases in such factors may 

precipitate acute angina.

If  contractility  is  approximately  constant, Equation 4.8 simplifies to:

O2 demand ÷ heart rate    blood pressure 

(4.9)

This semi-quantitative approximation, known as the ‘rate-pressure product’, is convenient for clinical studies because the variables are easily measured. It can be used to predict the effect of various strategies or drugs on oxygen demand. In the treatment of certain conditions the aim 

is to reduce the rate-pressure product, e.g. in 

ischaemic heart disease, where oxygen supply to the myocardium is restricted.

Efficiency

This may be taken as the work the heart does in relation to its oxygen consumption. Although absolute values do not concern us here, relative changes  do.  A  number  of  important  conse-

quences  affecting  efficiency  follow  from  the heart being a hollow chamber.

First,  ‘volume work’ is more efficient than 

‘pressure work’. That is, work done to increase 

cardiac output requires a smaller increase in 

oxygen demand than does the same amount of 

work done to raise blood pressure. Thus volume 

overloading is less harmful to the heart than 

sustained  high  blood  pressure.  Consequently, 

heart failure or angina develop far more readily 

from hypertension or aortic stenosis (narrowing 

of the aortic valve) than from fluid retention or 

aortic   incompetence (incomplete   closure   of 

aortic valve). Conversely, strategies to reduce 

afterload might be expected to be more effective 

at  reducing  cardiac  workload  than  strategies 

reducing preload.

A  more  important  consequence  relates  to 

myocardial wall tension, a major determinant of 

oxygen  demand.  The  ability  to  expel  blood 

during systole depends on the tension generated

system

in the ventricular wall and this is determined by 

the  diastolic  stretch  imparted  by  preloading. 

However, the effect is not linear and as preload 

increases  there  are  disproportionately  greater 

increases in oxygen demand. Thus doubling the 

preload  will  require  more  than  double  the 

oxygen demand if output is also to be doubled.

The  explanation  is  given  by  Laplace’s  law. 

Clearly, the walls of a hollow container need to 

develop (or  maintain)  tension  in  order  to 

generate (or withstand) pressure within. Laplace’s 

law states that this tension is proportional not 

only to the magnitude of the required pressure 

but also to the size of the container. In the cardio-

vascular context the ‘containers’ we are interested 

in are blood vessels and heart chambers:

Wall tension ÷ internal pressure    radius 

(4.10)

This explains, among other things, why large arteries need much thicker walls than smaller 

ones,   despite   their   internal   pressure   being similar. (Similarly, thin bicycle tyres, because of their small radius, can withstand much higher pressures than much thicker car tyres.)

Thus the larger the size from which a heart has 

to contract, i.e. the greater the EDV, the greater 

will be the wall tension required to generate the 

same internal pressure needed to overcome the 

afterload.   This   means   an   increased   oxygen 

demand for the same output (Equation 4.8). So 

for a given individual, the larger the heart, the 

less efficient it is. ‘Larger’ in this context means 

an increase in chamber size and should be distin-

guished from ‘hypertrophy’, which is an increase 

in muscle mass (p. 181).

The significance of this may be gauged when 

we  recall  that  cardiac  enlargement  by  the 

Starling  mechanism  is  a  prime  strategy  for 

accommodating extra haemodynamic demands. 

Normally  it  causes  no  problem  because  there 

is   sufficient   cardiac   reserve.   However,   in 

the  failing  or  ischaemic  heart  this  reduced 

efficiency  can  mean  the  difference  between 

compensation (i.e.  coping)  and  decompensa-

tion. It also explains the rationale for the use 

of  vasodilators  in  heart  failure,  which  reduce 

preload  or  afterload  and  therefore  ventricular 

wall tension.

Cardiovascular reserveriorates the patient will eventually be unable to

sustain an adequate cardiac output for normal

The cardiovascular (cardiac) reserve is the degreeactivity, or may even be breathless at rest; this is

to which the CVS can increase its performance to 

meet  additional  circulatory  demands,  or  can 

maintain performance in the face of increased 

afterload or impaired contractility. Changes in 

cardiovascular   demand   are   detected   by   a 

comprehensive system of receptors (Figure 4.6). 

Baroreceptors  in  the  aortic  arch,  the  carotid 

body, the atria and the ventricles detect changes 

in  intravascular  or  intracardiac  pressure  and 

relay   these   to   the   cardiovascular/vasomotor 

centre in the medulla. This then mediates an 

appropriate response via adjustments in sympa-

thetic and parasympathetic outflow, principally 

to the vasculature and myocardium, and also 

via  antidiuretic  hormone (ADH,  vasopressin) 

secretion. Chemoreceptors in the carotid body 

and the aortic arch detect oxygen tension, which 

would fall if lung perfusion were compromised. 

Intracardiac   baroreceptors   also   mediate   NP 

secretion.

The   renal   juxtaglomerular   apparatus   is 

another important detector of reduced perfu-

sion, mediating its response principally via the 

RAAS. In chronic situations, the kidney may 

increase erythropoietin secretion, expanding RBC 

numbers.

At rest, the average cardiac output is approxi-

mately 5 L/min. Because it depends on body size, 

the cardiac output is sometimes adjusted for 

body surface area: the resting cardiac index is 

approximately 3 L/min/m2. In a fit adult, cardiac 

output  can  be  increased  on  demand  up  to 

20-25 L/min; there may also be a rise in blood 

pressure.  The  difference  between  resting  and 

maximum cardiac output is the cardiac reserve. 

With a diseased heart, the cardiac reserve is 

reduced. In mild heart failure the reduction may 

be  small  and  therefore  only  noticeable  on 

vigorous exertion, when the patient will become 

unusually fatigued. As heart function deterio-

rates, the degree of exertion that produces the 

same  level  of  fatigue  becomes  progressively 

smaller. This reduced exercise tolerance  is a 

measure of diminishing cardiac reserve.

As  long  as  the  patient  can  maintain  an 

adequate cardiac output at rest the heart failure 

is compensated. However, as the condition dete-

decompensation.

The   various   haemodynamic,   neural   and 

endocrine mechanisms and strategies of cardio-

vascular compensation are summarized in Table

4.3; many have already been discussed. They are 

classified according to the speed with which the 

CVS can mobilize them. Note that medium- and 

long-term compensation mechanisms resemble 

normal   physiological   responses   to   exercise 

training.

Acute compensation

The CVS can respond very rapidly to acutely 

increased demand. Cardiac output may be raised 

through   the   Starling   mechanism   following 

increased venous return and/or venoconstric-

tion. The cardiovascular centre and sympathetic 

nervous system also contribute by acting on the 

myocardium  and  pacemaker,  giving  positive 

inotropic and chronotropic responses. Falls in 

blood pressure are also compensated by a sympa-

thetic nervous system vasoconstrictor response.

ANP may be secreted by the right atrium when 

atrial baroreceptors detect an increase in atrial 

filling, as a counter-regulatory response to limit 

or buffer these actions. This counters excessive 

activity of the sympathetic nervous system.

Medium-term compensation

If  the  stress  is  more  prolonged,  many  acute 

compensatory  mechanisms  may  persist,  but 

others also come into play. Renal compensation 

(see Chapter 14, p. 881) involves the RAAS and 

fluid retention to expand or maintain circulating 

fluid volume. There may also be secretion of 

ADH. More directly, if renal perfusion pressure is 

reduced  there  will  be  reduced  urine  output 

owing   to   reduced   filtration   and   increased 

reabsorption.

Long-term compensation

Chronically increased demand induces myocar-

dial  hypertrophy,  an  increase  in  myocardial 

muscle mass that increases contractility (note that this differs from ‘cardiac enlargement’, which means an increased EDV). If there is persistent hypoxaemia as a result of poor pulmonary perfu-

sion, an increased red cell count will eventually be induced, possibly resulting in polycythaemia. The kidneys continue to retain fluid.

Constraints on cardiac reserve

There are limits to most of these mechanisms; 

the   CVS   cannot   accommodate   increasing 

demands  indefinitely (Table 4.4).  Eventually 

these primarily beneficial haemodynamic and 

neuroendocrine   mechanisms   come   to   be 

deployed in circumstances beyond their design 

limits: they then become maladaptive (counter-

productive).  This  accounts  for  many  of  the 

features of heart failure.

Renal/Starling

The kidneys will attempt to support a failing 

circulation  by  retaining  fluid,  increasing  the 

filling   pressure   and   thus   cardiac   output. 

However,  because  of  the  Laplace  limitation 

(p. 178), a failing myocardium cannot benefit 

indefinitely  from  this.  As  the  heart  becomes 

progressively more stretched, not only does it 

become less oxygen efficient but the cells also 

become fatigued and unable to respond. There is 

a limit to the degree of stretch (cardiac enlarge-

ment) that the muscle fibres can tolerate, depen-

dent at the ultracellular level on the degree of 

interdigitation  of  the  actin  and  myosin  fila-

ments.  Beyond  this,  fluid  retention  becomes 

maladaptive. There is also the more obvious 

anatomical  constraint  of  the  pericardial  sac 

around the heart.

Sympathetic nervous system

Adrenergic receptors on myocardial or vascular smooth muscle eventually become desensitized (accommodated)  to  prolonged  and  unrelieved stimulation,andthereforelessresponsive,possibly through  down-regulation  or  post-receptor  un-

coupling. This may induce reflex sympathetic over-activity that, among other things, produces an unsustainable increase in myocardial oxygen demand and promotes arrhythmia.

At this stage, which is found in early chronic 

(compensated) heart failure, a further protective 

mechanism   is   activated.   Atrial   and   arterial 

baroreceptors (stretch receptors) signal the CVS 

centre to limit sympathetic activity and promote 

increased vagal activity. This reduces myocardial 

wall stress by reducing excessive cardiac stimula-

tion and peripheral vasoconstriction; arrhyth-

mias are also inhibited. Thus as cardiac function 

declines the heart is protected against excessive 

demands. As we will see below, this mechanism 

later   becomes   blunted;   baroreceptor   failure 

signals the onset of decompensation and over-

whelming maladaptive stimulation of heart and 

arteries.

Renal/endocrine

Renin  secretion  may  also  become  excessive, 

partly  mediated  by  the  sympathetic  nervous 

system,  and  angiotensin  then  contributes  to

the  decompensation.  Failure  in  the  counter-

regulatory  NP  and  nitric  oxide  mechanisms 

exacerbates the situation. This will allow exces-

sive fluid retention and vasoconstriction by no 

longer attenuating the actions of aldosterone 

and angiotensin.

If the heart rate increase is excessive, coordi-

nation   becomes   disrupted   and   arrhythmias 

develop   that   compromise   the   efficiency   of 

ventricular  ejection.  The  practical  maximum 

heart rate in a young fit person is about three 

times the resting rate, but is reduced to double 

the resting rate at age 80 years. Even before this 

stage efficiency may be reduced because of inad-

equate time for complete emptying or refilling 

within each cardiac cycle.

Finally,   myocardial   hypertrophy   is   not without disadvantages (Figure 4.8):

•  The heart becomes stiffer, i.e. less compliant, 

and  so  more  work  and  more  oxygen  are

required for each contraction.

•  The muscle growth will be partly inwards, 

reducing the chamber size.

•  The   thicker   walls   will   produce   unequal 

stresses at different levels within the thickness

during contraction, so more energy will be 

expended in deforming them.

•  Muscle   development   may   outstrip   new 

coronary vessel growth (angiogenesis). 

It must be remembered that the main function 

of the Starling mechanism is to maintain stroke 

volume under conditions of increased loading. 

Even under maximal exercise stimulation stroke 

volume rarely increases by more than about 

25%.  The  increase  in  cardiac  output  during 

exercise is principally due to increased heart rate. 

The  main  cardiovascular  effect  of  training  is 

to increase resting stroke volume and EDV and 

reduce resting heart rate. This increases cardiac 

reserve by allowing greater latitude for increased 

heart rate and ejection fraction.

Thus although the CVS is beautifully designed 

to  compensate  most  economically  for  wide 

variations in physiological demands, there are 

certain stresses with which it cannot cope and 

these can lead to CVD, particularly heart failure.

Clinical features of cardiovascular disease

Symptoms

Because the CVS supplies all organs, symptoms 

may arise in any one of these, and the cause may 

not be obviously cardiovascular, especially to a 

patient. Further, because most CVD is chronic, 

symptoms may at first be noticeable only on 

exertion. As the disease progresses, the point at 

which  symptoms  develop  comes  earlier.  The 

severity of many acute cardiovascular symptoms 

can be graded empirically by applying the widely 

used functional scale of the New York Heart 

Association (NYHA):

•  Grade  I.  Asymptomatic.  No  symptoms  at 

ordinary physical activity.

•  Grade   II.   Mild.   Symptoms   evident   on 

strenuous exertion.

•  Grade III. Moderate. Symptoms evident on 

moderate exertion.

•  Grade IV. Severe. Symptoms at rest.

Fatigue

Impaired perfusion to body skeletal muscle due 

to reduced myocardial function (heart failure) 

will cause patients to tire easily. Reduced exercise 

tolerance can be estimated empirically by asking 

how far a patient can walk, climb stairs, etc. or 

quantified by formal exercise testing on a tread-

mill or exercise bicycle (with ECG monitoring). 

Of course, fatigue can have many other causes, 

both physical and mental. Common iatrogenic 

causes include beta-blocker therapy and, in the 

elderly especially, diuretic-induced sodium and 

potassium imbalance.

Dizziness; fainting (syncope)

Temporarily  interrupted  CNS  perfusion  (tran-

sient ischaemic attacks, TIAs) commonly result 

from, among other causes, sudden temporary 

ventricular  arrhythmias  or  postural  hypoten-

sion. It is usually reversible within a few minutes 

(contrast this with epilepsy, stroke, etc.). Possible 

iatrogenic causes of syncope are CNS depres-

sants,  vasodilator  therapy  or  diuretic-induced  hypovolaemia.   Simple   faints   in   otherwiseorigin, and such symptoms should not be used

healthy  individuals  are  not  uncommon  and 

usually are due to increased parasympathetic 

activity  causing  transient  hypotension (vaso-

vagal attack).

Dyspnoea

Shortness of breath or difficulty in breathing is a 

subjective  feeling  that  may  or  may  not  be 

associated   with   objectively   reduced   blood 

oxygenation. Possible causes are mainly cardio-

vascular (i.e.  pulmonary  oedema  from  LVF), 

primary  pulmonary  disease (Chapter 5)  and 

anaemia.   Postural   variation   is   common   in 

cardiovascular   dyspnoea:   it   is   worse   when 

supine, so that the patient breathes more easily 

when  erect  or  sitting (orthopnoea).  This  is 

because intrathoracic pressure is increased when 

the  patient  is  recumbent,  raising  pulmonary 

venous pressure and thus promoting the forma-

tion of alveolar oedema (see below).

Palpitations

An  abnormal  awareness  of  the  heartbeat  is usually caused by an arrhythmia, particularly an extrasystole.  Patients  may  also  notice  severe tachycardia or bradycardia.

Pain

Pain arising in the chest region can have many 

origins, including the upper GIT, the lungs and 

the chest wall, as well as acute anxiety. The 

typical cardiac ischaemic pain associated with 

coronary   artery   disease   is   characteristically 

described as ‘crushing’ or ‘choking’, but seldom 

as ‘sharp’ or ‘momentary’. Patients may illustrate 

it by making a fist against their sternum or 

describing it as “like someone bear-hugging you 

from behind”. The pain may radiate up to the 

jaw or down the left arm. The most important 

differential   diagnosis   for   a   pharmacist   is 

dyspeptic pain from the oesophagus, or from the 

stomach or duodenum, which may be described 

as sharp (“like a knife”) and patients illustrate by 

pointing (see Chapter 3). However, it may not be 

possible from the patient’s description to distin-

guish between cardiac pain and that of epigastric

in isolation to diagnose cardiac events.

Examination: signs and history

Pulse

Palpating the pulse indicates cardiac rate and 

rhythm.   If   vascular   obstructive   disease   is 

suspected, it is customary to take the pulse at 

several sites on either side of the body (both 

wrists,  elbows,  ankles,  knees)  to  check  for 

possible impaired or asymmetric perfusion. For 

example, a diabetic may have normal pulses at 

the knee but weak ones at the ankle owing to 

angiopathy. The pulse pressure, the difference 

in pressure between systole and diastole, can be 

estimated by palpation and yields useful semi-

quantitative information (e.g. both the arterial 

rigidity of arteriosclerosis in the aged, and an 

incompetent aortic valve, cause a sharp differ-

ence with each beat, i.e. wide pulse pressure).

Palpation of the left chest at the fouth or fifth intercostal space, about halfway between the 

sternum and side of body, will reveal the apex beat. This is where the left ventricle impacts on the chest wall during systole, yielding informa-

tion about the rhythm and strength of the heart beat. In an enlarged heart this point is shifted 

leftwards (away from the sternum).

Blood pressure

Measurement of systemic arterial blood pres-

sure is discussed on pp. 214-216. The pressure is 

at or near systolic level for only a short part of 

the cardiac cycle: for most of the cycle, pressure 

is nearer diastolic. Thus mean arterial pressure 

(MAP), which gives an indication of the average 

stress put on the arterial system, is not a simple 

average: it is calculated by giving greater weight 

to the diastolic:

Mean

arterialdiastolic1/3 (systolic - diastolic)

pressure(4.11)

In   developed   countries,   blood   pressure 

increases with age. Systolic pressure is affected 

more   than   diastolic,   and   continues   rising, possibly to  180-200 mmHg at age 80 (which 

indicates the need for treatment) as arterioscle-

rosis (p. 235) reduces arterial compliance. Dias-

tolic   pressure   rises   less   steeply   to   around

90 mmHg at age 60, and then flattens out. Thus, 

the pulse pressure widens on ageing, reflecting 

decreasing aortic compliance. Between the ages 

of 20 and 60, the approximate normal values are 

given by:

Systolic blood pressure1002/3 age

(4.12)

Diastolic blood pressure671/3 age

(4.13)

Blood  pressure  is  normally  a  little  lower  in 

younger  women  than  men  but  tends  to  rise 

faster   postmenopausally   so   that   pressures 

converge,   and   older   women   have   higher 

systolic pressures than men. In less developed 

and rural areas there is little change with age, 

but migrants from rural areas to industrialized 

ones  tend  to  acquire  the  rising  pattern, 

suggesting the existence of strong environmental 

factors.

The  central  venous  pressure  (CVP)  is  the 

blood  pressure  at  the  point  where  the  great 

veins  enter  the  right  atrium  and  is  normally 

between 0 and 10 mmHg. The CVP represents 

the  RAP  or  preload  and  is  a  good  index  of 

cardiac  performance,  because  reduced  ventric-

ular performance will cause it to rise. It may be 

used to monitor possible fluid overload in heart 

failure or IV fluid therapy. The jugular venous 

pressure (JVP) is a non-invasive external indi-

cator,  detectable  by  examining  for  possible 

swelling of the jugular vein in the neck. It is 

measured  by  estimating  the  height  of  this 

swollen portion above the line of the clavicle 

(with  the  patient  sitting  with  their  thorax  at 

45º). Normally it is undetectable but in right 

heart failure it is raised.

Cyanosis

This  blue  coloration  of  blood  is  caused  by 

reduced  oxygen  saturation (increased  deoxy-

haemoglobin level). It is noticeable clinically in 

highly vascular areas such as lips, tongue or 

nailbeds. The terms central and peripheral in

system

relation to cyanosis refer to its origin and not 

where it is observed - a common source of 

confusion. Central cyanosis is caused by gener-

alized arterial hypoxaemia, due for example to 

pulmonary oedema. In peripheral cyanosis the 

arterial oxygen saturation may be normal but 

perfusion of a particular area (usually fingers or 

toes)  is  compromised.  In  heart  failure  this 

commonly occurs in the skin as vasoconstriction 

there diverts blood to more important areas. 

Local  blood  flow  is  slowed,  more  oxygen  is 

extracted, the arteriovenous oxygen difference is 

raised,   and   the   blood   becomes   abnormally 

deoxygenated and blue-tinged. The area will be 

cold,  but  if  it  is  massaged  to  improve  local 

perfusion then normal colour may be restored 

(contrast this with central cyanosis).

Oedema

The origins of oedema are complex. The conven-

tional explanation is illustrated in Figure 4.9, 

although recent evidence has questioned the 

completeness of this. On this model the oedema 

of heart failure is primarily caused by a combi-

nation of raised total body water (owing to renal 

fluid retention) and the preferential redistribu-

tion of an abnormal amount of this water to the 

extravascular   extracellular   compartment,   i.e. 

tissue fluid (owing to raised peripheral venous 

pressure). As will be discussed below, hydrostatic 

factors  also  contribute.  Generally,  pulmonary 

oedema  results  from  left  heart  failure,  and 

peripheral oedema (in ankles, sacrum, abdom-

inal  organs)  from  right  heart  failure.  If  the 

oedematous area is compressed firmly with the 

thumb for about 10 s (this is usually painless 

for the patient), the impression remains as a pit 

for very much longer than would be the case for 

normal skin - hence the term pitting oedema.

Investigation

Electrocardiogram

An ECG reveals to the trained eye both qualita-

tive  and  quantitative  information  about  the 

heart’s activity and electrical conduction system. 

The multiplicity of leads enables localization of  certain  lesions;  e.g.  where  an  infarction 

has  occurred.  Exercise  provocation  and 24-h 

recording may be useful modifications. The trace 

as it most commonly appears in generic ECG 

illustrations (similar to lead II) is shown in Figure

4.10, together with an account of the origin of each component. A number of basic ECG traces will be used in the relevant sections below to 

illustrate some typical abnormalities.

Imaging

A plain chest X-ray (see Figure 4.12(a)) will show the size of the heart and whether or not the lung fields are clear. Shadowing at the base of the 

lungs along the lower margin (defined by the 

diaphragm) usually indicates accumulation of fluid (i.e. pulmonary oedema).

Undoubtedly the most generally useful tech-

nique is echocardiography, which uses ultra-

sound.   This   is   relatively   inexpensive   and 

completely non-invasive. It provides a contin-

uous timed record of all the movements and 

dimensions of cardiac structures (including wall 

thickness,   chamber   size,   shape   and   valve 

movements), and can measure ejection fraction. 

Magnetic   resonance   imaging(MRI)   and 

computed tomography (CT) scanning of the 

thorax may also sometimes be required.

In  ventricular  angiography,  heart  move-

ment throughout the cardiac cycle can be visu-

alized by injecting radio-opaque material into 

the  general  circulation.  In  coronary  angiog-

raphy,  much  smaller  quantities  of  contrast 

medium are precisely injected via a catheter at 

the  root  of  a  coronary  artery  to  visualize 

possible obstructive lesions. This is becoming a 

standard investigation and diagnosis of cardiac 

ischaemic symptoms, and for deciding whether 

bypass or angioplasty (p. 253) is indicated, and 

if so where.

Nuclear  imaging  is  used  in  two  ways.  In 

radionuclide   ventriculography,   thallium-201 

taken  up  from  coronary  blood  by  healthy 

myocardial   tissue   leaves‘cold’   spots   that 

identify under-perfused (ischaemic) areas. Tech-

netium-99-labelled RBCs enable visualization of 

the heart chambers and their movement; the 

ejection fraction can be measured accurately.

Catheterization

A fine plastic catheter may be introduced into the heart via a peripheral artery to access the left side of the heart or a vein (right side) so as to lie with its tip in a heart chamber or great vessel. Radiocontrast medium may then be injected, 

pressure at that point measured or blood with-

drawn for gas analysis. It is particularly useful to measure the RAP (equivalent to CVP or preload), pressure drop across a valve, and pressure in the pulmonary vein (pulmonary ‘wedge’ pressure, equivalent to left atrial pressure).

Heart failure

Heart failure (cardiac failure) is not a disease but a syndrome, with many possible aetiologies and a complex pathogenesis, yet it may be simply defined as the failure of the heart to meet the 

normal perfusion demands of the body. Many diseases can impair cardiac performance and all are   usually   serious.   Consequently,   chronic cardiac failure has a poor prognosis, comparable with that for many forms of cancer.

Whatever  the  cause  of  failure,  the  clinical 

picture resulting from reduced contractility is similar. This is due to a combination of the 

consequences  of  impaired  perfusion  and  the 

secondary consequences of maladaptive attempts 

by the CVS to compensate (p. 180; Table 4.3). 

The cardiac failure syndrome may also involve 

peripheral organ damage not directly caused by 

reduced  blood  supply,  especially  in  skeletal 

muscle.

Terminology

Terms  commonly  used  to  describe  different 

aspects of heart failure are given in Table 4.5. 

Most cases of heart failure would be classified as 

‘chronic compensated low-output left ventric-

ular systolic failure’. The clinical features of left 

and right failure differ in certain crucial aspects, 

but many patients, especially the elderly, present 

with bilateral failure. The distinction between 

acute and chronic is important for management. 

The difference between systolic and diastolic 

failure is discussed below.

Heart failure187

Epidemiology

Determining  the  prevalence  of  heart  failure 

depends upon which grade, ejection fraction 

cut-off point and population are being consid-

ered. Estimates for symptomatic heart failure 

vary between 0.5% and 2%, but among those 

aged over 80 this rises to over 10%. If asympto-

matic cases (Class 1) are included, overall preva-

lence is almost 10%. The annual incidence in the 

UK is approximately 0.3%, representing over 

150000 cases.

Aetiology

The causes of heart failure may be considered in two broad groups:

1. Pump  failure,  with  primary  reduction  in 

myocardial contractility.

2. Overloading, with either excessive afterload 

(pressure   overload)   or   excessive   preload (volume overload), which arise outside the heart and reduce contractility secondarily.

Specific causes within these groups may give rise to failure acutely or chronically and may initially affect one specific chamber or side of the heart. However, in chronic heart failure both sides are usually affected eventually. Table 4.6 shows the common causes in each group.

Despite this wide range of possible aetiologies, 

in  industrialized  countries  by  far  the  most 

common cause of LVF is ischaemic heart disease, 

causing  over  half  of  cases;  the  second  most 

common is cardiomyopathy (see below) and the 

third  is  valvular  disease.  Untreated  systemic 

hypertension used to be a common cause but is 

no longer a major factor. Valve disease secondary 

to childhood rheumatic fever is now uncommon 

as a result of improved public health and sanita-

tion.  However,  in  developing  countries  the 

picture  is  quite  different,  with  infective  and 

nutritional causes predominating.

system

Pathogenesis

Primary pump failure

Damage to the myocardium usually results in 

systolic failure. Ischaemic heart disease (IHD, 

restriction  of  the  coronary  blood  supply)  is 

the most common cause; it usually affects just 

one  chamber,  most  often  the  left  ventricle. 

Ischaemic   failure   may   develop   suddenly 

following myocardial infarction (MI), with no 

prior warning signs of ischaemic chest pain over 

the  preceding  weeks  or  months.  Alternatively 

there may be slowly progressive diffuse fibrosis 

with multiple minor and possibly asymptomatic 

infarcts,  especially  in  the  elderly.  Chronic 

ischaemia   may   also   induce   asymptomatic 

myocardial   hibernation,   with   progressive 

decline  in  systolic  function,  although  poten-

tially  this  is  reversible  by  revascularization. 

However, it must be remembered that IHD is a 

separate  disease  entity  from  heart  failure  and 

does  not  invariably  lead  to  it.  Heart  failure rarely results from stable angina pectoris.

The  cardiomyopathies  are  a  miscellaneous 

group   in   which   diffuse   damage   occurs 

throughout  the  myocardium.  They  are  either 

idiopathic or secondary to conditions such as 

infection, toxins (e.g. alcohol), inflammation or 

autoimmune  disease.  In  dilated  cardiomy-

opathy the myocardium becomes thin, weak and 

excessively enlarged, with a raised EDV and a low 

ejection fraction. This may arise as a consequence 

of,  for  example,  infection,  thyroid  disease  or 

alcohol  abuse.  In  hypertrophic  cardiomy-

opathy  there  is  excessive  thickening  of  the 

myocardium, leading to poor ventricular filling 

and obstructed ejection, particularly due to struc-

tural distortion around the valves, whereas in 

restrictive cardiomyopathy there is increased 

ventricular stiffness but little hypertrophy.

In the ageing heart a diffuse (‘senile’) fibrosis 

can occur and a number of systemic diseases 

such  as  sarcoid  and  amyloidosis  may  have 

diffuse cardiac complications that lead to even-

tual failure. Arrhythmias may also cause pump 

failure. Interestingly, cardiac tumours are rare.

While  most  forms  of  pump  failure  cause 

reduced contractility and systolic failure, some 

diffuse diseases of the myocardium can lead to 

it  becoming  fibrosed  and  stiff,  with  reduced 

compliance. This results in difficulty in filling 

the heart adequately during diastole, and leads 

to diastolic failure. This has been recognized 

in about one-fifth of patients with symptoms 

of  failure (i.e.  low  cardiac  output),  but  a 

normal  heart  size  and  ejection  fraction (and 

thus  normal  systolic  function),  and  may  be 

present in up to half of all heart failure cases. 

Causes  include  patchy  ischaemic  or  senile 

fibrosis, restrictive cardiomyopathy and hyper-

trophic   cardiomyopathy(e.g.owing   to 

untreated hypertension).

Overloading

Both over-work and over-stretch cause structural 

and  biochemical  abnormalities  in  myocardial 

cells, such as the deposition of fibrils and impaired 

calcium  utilization.  The  result  is  a  decreased 

force and velocity of contraction and delayed 

relaxation. These effects are usually irreversible.

Heart failure189

Excessive afterload

If the systemic vascular resistance is abnormally 

high, causing systemic hypertension, the raised 

afterload on the left ventricle may eventually 

cause  it  to  fail,  but  the  right  ventricle  will 

initially  be  unaffected.  The  heart  is  far  more 

prone  to  damage  from  pressure  overloading 

than  from  volume  overloading,  although  the 

former  is  now  relatively  uncommon  because 

hypertension  is  detected  earlier  and  treated 

better. However, it is possible that failure diag-

nosed  as  ischaemic  or  cardiomyopathic  may 

have  been  aetiologically  related  to  chronic 

undetected hypertension.

Similarly,   sustained   rises   in   pulmonary vascular resistance, causing pulmonary hyper-

tension (e.g. secondary to many chronic lung 

diseases), can eventually lead to RVF, known as cor pulmonale, although it may be secondary to many other conditions.

Theoretically,  the  afterload  on  both  sides 

may  be  increased  by  abnormally  high  blood 

viscosity, such as in polycythaemia, but this is 

unlikely to cause failure in the absence of other 

abnormalities.

Excessive preload

This is an uncommon general cause of failure. 

Whether or not excessive increases in venous 

return lead to failure depends on the cause and 

other factors. The heart tolerates volume over-

load well, and because the output initially is 

high, symptoms are not at first evident. The left 

side of the heart receives the same volume of 

venous return as the right, at approximately the 

same preloading, because the lungs usually offer 

little resistance. Because the left ventricle is by 

far the more powerful, if decompensation is 

caused by raised systemic filling pressure the 

right side will be first to fail.

If   moderate   hypervolaemia   develops,   the 

initially raised output will be surplus to the 

perfusion needs of the body. Owing to autoregu-

lation there will be vasoconstriction throughout 

the body and a rise in peripheral resistance: 

blood  pressure  will  increase  and  output  will 

return to normal (remember, blood pressure 

cardiac outputperipheral resistance). Thus, 

the raised preload is converted to a raised after-

load and, if not corrected, this may itself lead to

failure. This could also have a bearing on the 

pathogenesis of essential hypertension (p. 213).

Precisely the opposite occurs in diseases where 

widespread vasodilatation results in a severely 

reduced peripheral resistance, e.g. in septicaemic 

shock. This produces an obligatory requirement 

for raised cardiac output to maintain blood pres-

sure, leading eventually to what is known as 

high-output   failure(although   this   is   a 

misleading term because by definition it does 

not become failure until the myocardium can no 

longer  sustain  the  output).  Other  conditions 

create  an  excessive (hyperdynamic)  systemic 

demand for output, stimulating the heart via the 

usual CVS reflexes. Examples include chronic 

severe anaemia, low blood oxygen being the 

stimulus,   and   thyrotoxicosis,   where   basal 

metabolic rate is increased.

Although not usually primary causes of heart 

failure, anaemia, severe infection, fluid retention 

(including that from drugs such as NSAIDs and 

corticosteroids) or over-enthusiastic IV infusion 

can be causes of decompensation in patients 

with otherwise stable compensated heart failure.

Valve disease

Stenosis  (narrowing  or  failure  to  open  fully) 

causes an outflow obstruction, which increases

system

afterload;  thus  mitral  stenosis  can  cause  left 

atrial failure. Alternatively, valve incompetence 

(failure to close fully) will permit regurgitation, 

which causes volume overload in the chambers 

both upstream and downstream of the valve: 

upstream, because of the back-flow and down-

stream  because  there  will  eventually  be  an 

abnormally   large   ingress   as   the   upstream 

chamber overfills. On this basis we can predict 

the consequences of stenosis or incompetence of 

the  mitral,  tricuspid,  aortic  and  pulmonary 

valves,  i.e.  which  chamber(s)  will  fail  and 

whether this is the result of excessive afterload or 

preload.

Pathophysiology

Haemodynamic changes

Heart failure is a dynamic process rather than a 

single event, even when acute. Whatever the 

aetiology, the process is similar and the reduc-

tions in cardiac effectiveness can be represented 

by pump performance curves (Figure 4.11).

As  contractility  falls  the  stroke  volume  is 

reduced; this leaves a higher EDV after ejection. 

This means an increased preload for the next 

contraction  so  that  contractility  is  increased 

appropriately (by   the   Starling   mechanism). 

Consequently output is restored, but as long as 

the  myocardium  is  impaired  then  output  is 

being   maintained   only   at   the   expense   of 

increased diastolic size, i.e. the EDV is increased. 

Because the heart is now ‘larger’ it is less effi-

cient, according to Laplace’s law. In health this is 

usually insignificant, but in heart failure this 

compensation eventually reduces efficiency and 

erodes the cardiac reserve.

In  Figure  4.11,  curve  N  represents  normal 

contractility.  Point  n  represents  the  resting 

cardiac output of 5 L/min (that which is suffi-

cient to maintain resting organ function and 

renal fluid clearance); the difference between n 

and  n-max  represents  the  cardiac  reserve.  If 

output falls much below 5 L/min there will be 

symptoms  of  hypoperfusion,  notably  fatigue. 

Alternatively, should perfusion demands exhaust 

the cardiac reserve by requiring preload to rise 

beyond point P-max, output will not increase 

and may fall. Consequently venous pressure will 

rise, causing congestive symptoms (i.e. oedema). 

On the left side of the heart this will result in 

pulmonary oedema and breathlessness.

Acute failure

Suppose that a patient with normal cardiac func-

tion suddenly were to suffer a moderate MI. 

Contractility immediately drops and output may 

quickly fall below the normal resting minimum, 

to point f on a new, less steep, contractility curve

(F). The patient experiences fatigue even at rest, among other symptoms, and the CVS initiates compensation.

The heart enlarges until a new equilibrium is 

attained  at  a  higher  preload (point  f ).  The 

cardiac  reserve  is  now  reduced,  as  is  the 

maximum  output  that  can  be  reached  by 

maximal preload (f ). At rest, the patient may 

be unaware of any disability but he or she will 

have  reduced  exercise  tolerance,  becoming 

breathless earlier than before the MI. This situ-

ation (n ➞ f ➞ f) is termed compensated 

failure. Note that a higher preload than before 

is needed to sustain even resting cardiac output 

(f ), so the heart is permanently less efficient.

If the infarction is very severe, the output may 

drop precipitately to point d, putting the patient

Heart failure191

on curve D, and they would probably collapse. 

After  maximum  compensation  to  point  d , 

normal resting output can only just be attained 

at maximal preload; the patient may even be 

beyond this, on the falling arm of the curve. 

There is now zero cardiac reserve and the patient 

will be fatigued at the slightest exertion and may 

be breathless even at rest: this is decompensated 

failure.

Chronic failure

A  gradual  reduction  in  cardiac  contractility produces  a  similar  pattern,  except  that  the patient’s haemodynamics would be represented by a series of progressively declining contrac-

tility curves, rather than a sudden fall.

A patient could remain in chronic compen-

sated failure indefinitely if the disease progres-

sion is arrested or is sufficiently slow. However, 

a supervening severe stress (e.g. a serious infec-

tion, sudden fluid overload, excessive exertion 

or  chronic  anaemia)  often  drives  them  into 

decompensation.

A plain chest X-ray (CXR) dramatically visual-

izes severe heart failure. Figure 4.12(a) shows a 

normal chest: the heart shadow occupies about 

half the width of the thorax, i.e. the cardiotho-

racic  index  is 0.5.  In  Figure 4.12(b) (severe 

failure) the cardiac enlargement is easily seen; 

the index is nearer 0.7. The increased size is not 

due  to  cardiac  hypertrophy,  which  does  not 

show up on plain X-ray (the absolute increase in 

size in hypertrophy being relatively modest and 

growth predominantly inwards). What is shown 

is the result of an increased diastolic volume.

Compensation and consequences: decompensation

Heart failure is more than simply a reduction in 

cardiac output and accompanying tissue hypop-

erfusion. As was shown above (p. 180), when the 

cardiac  reserve  is  mobilized  in  circumstances 

where its main effector system - the heart itself -

cannot respond, it soon becomes maladaptive. 

Cardiac enlargement, driven in part by excessive 

fluid retention and possibly by venoconstriction, 

brings inefficiency and over-stretch as muscle 

fibres lose mutual adherence. Excessive hyper-

trophy  interferes  with  ventricular  filling  and 

 ejection. The maladaptive changes in ventricular 

shape caused by dilatation and hypertrophy are 

termed   remodelling,   especially   when   they 

follow MI. Angiotensin may contribute to this 

process.

These   changes   are   accompanied   by   the 

neuroendocrine   mechanisms   we   met   in 

discussing cardiac reserve. In heart failure these 

can exacerbate the situation as one or more 

components fail to respond satisfactorily, e.g. a 

failure   to   increase   myocardial   contractility 

following increased sympathetic nervous system 

activity.

The    normally    protective    baroreceptor-

mediated  inhibition  of  sympathetic  outflow 

becomes blunted, and unrestrained sympathetic 

drive results in excessive inotropic stimulation 

of the myocardium and widespread peripheral 

vasoconstriction. Both conditions place further 

loads on the heart. In addition, renal perfusion is 

reduced  and  atrial  pressures  rise.  Thus  circu-

lating levels of noradrenaline (norepinephrine),

angiotensin, aldosterone, ADH (vasopressin) and NP all rise.

Decompensation follows as these mechanisms 

combine to reduce cardiac output, rather than to 

increase or even just maintain it. The heart has 

passed the maximum on its contractility curve 

(see  Figure 4.4).  Irreversible  myocardial  cell 

damage and necrosis follow. The sequence of 

events is illustrated in Figure 4.13. Clearly, treat-

ment must target not only low cardiac output 

but also these maladaptive mechanisms.

Cardiogenic shock

If contractility falls below that which can sustain 

the  resting  cardiac  output,  producing  wide-

spread  hypoperfusion,  this  counterproductive 

cycle deteriorates rapidly. Peripheral arterioles 

throughout the body respond to local hypoxia 

by  autoregulatory  dilatation,  overcoming  the 

centrally    mediated    vasoconstriction    that 

attempts to defend blood pressure. The result is a 

disastrous fall in blood pressure, low venous return and poor coronary perfusion; together(dyspnoea) and oedema. However, the clinical

these result in even worse contractility and lower cardiac output. At the same time, hypoxic lung vessels   constrict,   thereby   increasing   right ventricular  afterload.  The  entire  syndrome  is termed cardiogenic shock.

Despite the most aggressive management, the 

whole devastating vicious cycle can be rapidly 

fatal,   especially   if   irreversible   multi-organ 

damage occurs before circulation is restored.

Clinical features

The classical symptom triad of heart failure is 

exercise limitation (fatigue), shortness of breath

picture, although fairly consistent, is often more 

complex. Many of the clinical features result 

from   impaired   flow   ahead   of   the   affected 

chamber;  this  hypoperfusion  is  termed  the 

forward  component  of  heart  failure.  Other 

symptoms are caused by an increase in pressure 

in the veins draining into the affected chamber; 

this results in congestion or oedema, termed 

the backward component (Figure 4.14). Both 

components usually coexist - they are different 

aspects  of  failure,  not  different  forms  of  it. 

However, the symptoms may vary according to 

which side of the heart is primarily affected, and 

the   picture   is   further   complicated   by   the 

neuroendocrine compensatory mechanisms A   feature   that   commonly   accompanies 

chronic failure is the anaemia of chronic disease, 

which contributes to the fatigue and also exacer-

bates the failure by putting an extra load on the 

heart owing to increased circulatory demands.

Forward component (hypoperfusion)

The effects of hypoperfusion are independent of 

which side of the heart fails because the outputs 

from either side are always equal, even when 

reduced. The principal feature is fatigue, but 

numerous other symptoms follow from poor 

peripheral perfusion. The extremities will be cold 

and pale as the CVS attempts to redirect the 

reduced  cardiac  output  away  from  skin  and 

muscle to the brain, heart and kidney by periph-

eral vasoconstriction. Reduced renal perfusion 

pressure will cause fluid and electrolyte reten-

tion,   partly   via   activation   of   the   RAAS, 

contributing  to  oedema.  Over-activity  of  the 

sympathetic nervous system produces symptoms 

such as tachycardia and tachypnoea (increased 

respiratory rate).

It is possible that fatigue is not due just to 

skeletal muscle hypoperfusion but is part of a 

generalized   myopathy   secondary   to   heart 

failure.  It  may  result  from  impaired  energy

system

handling and subsequent atrophy, or rises in 

catabolic cytokines, possibly of cardiac origin, 

such as TNF. Both myocardial and respiratory 

muscles are affected, exacerbating the cardiac 

problems and contributing to the breathlessness.

Backward component (congestion/oedema)

Right-sided failure. The raised pressure within 

the great veins draining into the right side of the 

heart (i.e. systemic venous congestion) will be 

communicated  back  to  the  venous  end  of 

systemic capillaries where it impairs the venous 

drainage   of   tissue   fluid,   causing   peripheral 

oedema (p. 184). A further factor in acute failure 

is the haemodilution caused by expansion of the 

blood  volume.  This  reduces  plasma  protein 

concentration   and   thus   oncotic   pressure, 

contributing to further loss of fluid from the 

vascular compartment.

Not all areas of the body are affected equally. 

The   additional   effect   of   gravity   will   make 

oedema  first  noticed  in  the  ankles  of  erect 

patients, or in the sacral area of the bed-bound. 

The liver, being highly vascular, is affected early, 

causing hepatomegaly (enlarged liver), and the 

patient may then feel bloated, nauseous and 

anorexic.   Congestion   of   the   stomach   and duodenum   may   impair   nutrient   and   drug absorption. Later, ascites (free oedema fluid in the abdominal cavity) may develop.

A raised JVP (p. 184), seen as distension and pulsation of the external jugular veins in the 

neck, gives an accessible, approximate clinical index of the severity of right-heart failure. The CVP (p. 184) is a more precise indicator for 

monitoring the progress of severe failure, but 

measuring it is invasive. The raised systemic 

venous pressure reduces the arteriovenous pres-

sure difference, slowing peripheral blood flow and causing peripheral cyanosis.

In the kidney, raised venous pressure has more 

far-reaching   consequences.   It   reduces   the 

glomerular   filtration   rate (owing   to   raised 

efferent arteriolar pressure; see Chapter 14) thus 

exacerbating the fluid and electrolyte retention. 

This   is   maladaptive   because   the   resultant 

increased  intravascular  volume  further  raises 

venous pressures, exacerbating excessive preload 

and oedema.

In summary, right-sided failure causes fatigue, fluid retention, peripheral oedema, abdominal congestion and peripheral cyanosis.

Left-sided failure. This is more common and 

usually more serious. The rise in pulmonary 

venous pressure causes pulmonary congestion 

and pulmonary oedema by a similar mecha-

nism to that causing peripheral oedema in right-

sided failure. However, unlike most other tissues, 

lungs do not normally have any tissue fluid and 

the equivalent of the extravascular space is the 

normally dry alveolar space. Thus even a small 

imbalance in transcapillary pressure can allow 

fluid into the alveoli, which seriously interferes 

with gas diffusion and also reduces pulmonary 

compliance (thereby  increasing  the  work  of 

breathing).  The  resulting  hypoxaemia  causes 

severe  breathlessness (dyspnoea)  and  central 

cyanosis.  Severe  pulmonary  oedema  can  be 

rapidly fatal (see also Chapter 5).

The  dyspnoeic  effects  of  mild  pulmonary 

oedema  are  particularly  noticeable  when  the 

patient is supine because the oedema fluid then 

spreads throughout the lungs. When erect, i.e. 

sitting  or  standing,  venous  filling  pressure  is 

reduced as intravascular fluid is redistributed to 

lower parts of the body; this reverses the condi-

tions that produce pulmonary oedema. This is

Heart failure195

orthopnoea,  breathing  adequately  only  when 

erect. Even a moderate change in posture, such 

as propping a patient up in bed with pillows, 

promotes  redistribution  of  the  fluid,  which 

collects at the lung bases to leave the apexes 

relatively clear and permitting adequate ventila-

tion at rest. This is easily visualized by X-ray 

(Figure 4.12). However, in all but the mildest 

pulmonary oedema, changes in posture alone 

are insufficient and drug therapy is needed. In 

addition to oxygen and diuretics, opiates may be 

used  in  severe  cases;  they  work  in  part  by 

venodilatation,  causing  a  rapid  reduction  in 

filling pressure.

A  typical  history  given  by  patients  with 

untreated left-heart failure is of waking breath-

less, wheezy and coughing after a few hours’ 

sleep. They go to the window for a ‘breath of 

fresh air’, and quite soon feel better: not because 

of the air, plainly, but owing to the change in 

posture. This phenomenon, because it may recur 

throughout  the  night,  is  called  paroxysmal 

nocturnal  dyspnoea  (PND). It is a classical, 

almost   pathognomonic   sign   of   LVF.   Such 

patients are advised to sleep with three or four 

cushions, or in a chair, which usually improves 

matters at least in the early stages.

To   summarize,   left-sided   failure   causes severe   fatigue,   pulmonary   oedema,   severe breathlessness and central cyanosis.

Predominant pathophysiological pattern

The backward and forward components can occur 

to different extents in the same patient. Which 

predominates - congestion or hypoperfusion -

depends on the shape of the patient’s contractility 

curve and the position of its maximum. Figure

4.15 shows left ventricular contractility curves in 

heart failure. The ‘dyspnoea threshold’ represents 

the preload above which pulmonary venous pres-

sure is so high as to cause breathlessness. Below the 

‘fatigue threshold’, output is so low as to cause 

severe tiredness.

If the maximum output attainable is below the dyspnoea  threshold (curve  H,  hypoperfused pattern), fatigue will occur after even moderate exertion, but before breathlessness. On the other hand, the patient whose heart is on curve C will become breathless before their muscles actually become fatigued (congestive pattern). Bilateral (biventricular) failure

Unilateral chronic failure is uncommon. Usually, 

patients present with bilateral failure and have 

mixed symptoms because failure of one side 

eventually compromises function on the other: 

this is the classical ‘congestive cardiac failure’. 

The hypoperfusion that follows failure of either 

side affects the pulmonary and systemic circu-

lations  equally.  Coronary  hypoperfusion  will 

ensue, leading eventually to chronic ischaemic 

ventricular   failure   on   the   opposite   side. 

Following unilateral LVF, pulmonary congestion 

will increase the afterload on the right ventricle 

and if this is untreated, the result will be RVF.

Asymptomatic left ventricular dysfunction

The early stages in slowly deteriorating chronic heart failure are initially fully compensated and therefore asymptomatic (Class I on the NYHA scale; p. 197). It can only be detected by investi-

gation, but there is evidence that early detection and  treatment,  before  irreversible  myocardial damage develops, improves prognosis.

Presentation

A few common examples of heart failure patients 

will serve to illustrate typical presentations. One 

might be an undiagnosed hypertensive male in

his   mid-forties,   probably   somewhat   obese, 

possibly living a stressful life, perhaps starting to 

suffer from angina pectoris. His heart failure may 

be precipitated acutely by MI or may develop 

slowly   along   with   ventricular   hypertrophy. 

Another  example  might  be  an  older  smoker 

with COPD (Chapter 5), slowly developing cor 

pulmonale. A third example might be an elderly 

patient with underlying asymptomatic IHD and 

developing  valve  disease,  perhaps  following 

childhood rheumatic fever.

Most  will  complain  at  first  of  increasing 

fatigue   and   a   reduced   exercise   tolerance: 

climbing stairs, running for a bus, working or 

going shopping, etc. They will find breathing 

particularly  difficult  at  night  and  may  have 

obvious ankle oedema after a day on their feet. 

They may complain of palpitations. Eventually 

they will see their GP, when a provisional diag-

nosis will usually be straightforward. However, 

NICE recommends definitive investigation.

Investigation and grading

Investigations   are   used   in   heart   failure   to 

confirm the diagnosis and exclude other possi-

bile diagnoses, to determine the cause and any 

exacerbating or precipitating factors, to grade 

the extent of dysfunction, and to monitor the 

progress of treatment. It is important to try to 

determine the cause of heart failure because it may be reversible or correctable.

Extensive investigation is not usually required. 

A CXR will show the extent of cardiac enlarge-

ment and the existence of lung congestion, i.e. 

pulmonary oedema. The stethoscope may reveal 

the characteristic sounds of valve disease or the 

crackles  on  breathing (crepitations)  that  are 

characteristic of pulmonary oedema. The pulse 

may  indicate  an  arrhythmia.  An  ECG  will 

reveal any cardiac hypertrophy (usually from 

long-standing   hypertension),   ischaemia,   the 

possibility of MI and any arrhythmia.

Echocardiography is becoming mandatory as 

the single most useful non-invasive indicator of 

ventricular function and the best predictor of 

prognosis,  through  measurement  of  ejection 

fraction.  Other  routine  investigations  would 

include urea and electrolytes, full blood count, 

and liver, renal and thyroid function tests.

More sophisticated tests and instruments are available for the few cases that present diag-

nostic  problems,  including  isotope  imaging, cardiac  catheterization  and  coronary  angiog-

raphy. These can also be used to measure the 

extent of myocardial damage. Except in acute severe failure, invasive haemodynamic measure-

ments are rarely indicated.

Currently the potential of measuring a natri-

uretic peptide precursor, N-terminal pro-BNP 

(NT proBNP) as a diagnostic marker and index 

severity  and  progress  is  being  evaluated.  At 

present its use is restricted to ruling out signifi-

cant heart failure if its level is low or normal.

Grading

A variety of semi-quantitative bedside methods 

and scales are employed for grading. The patient 

is asked about limitations on daily activities such 

as walking distance or stair climbing before the 

onset  of  fatigue  or  dyspnoea,  or  how  many 

pillows they sleep with. These questions may be 

supplemented by formal exercise testing. Exami-

nation of the JVP and the extent of oedema are 

important.

Such observations can be used to grade the 

patient on the NYHA scale for heart failure, and 

although symptoms do not always correlate with 

objective functional impairment, it is useful to

Heart failure197

indicate the approximate ejection fraction (EF) of each class:

•  Class  I.  Asymptomatic.  No  symptoms  at 

ordinary physical activity (EF 40-50%).

•  Class  II.  Mild.  Breathlessness  and  fatigue

evident on strenuous exertion (EF 35-40%). 

•  Class III. Moderate. Breathlessness and fatigue

evident on moderate exertion (EF 30-35%). 

•  Class IV. Severe. Breathlessness at rest (EF

30%)

Symptomatic   improvement   also   correlates poorly with changes in haemodynamic indices. Thus  for  monitoring  therapy  and  progress 

generally, subjective assessments by the patient, global measures of exercise tolerance and esti-

mations  of  the  ‘quality  of  life’  are  often  the most useful methods. For patients on medica-

tion  these  must  be  supplemented  by  regular clinical biochemistry monitoring.

Prognosis

The seriousness of heart failure can be judged 

from its poor prognosis, which the advent of 

ACEI therapy has improved only modestly. For 

NYHA Class IV heart failure the median survival 

is only 1 year, while for Classes II and III it is 3-5 

years. The annual mortality rate from asympto-

matic left ventricular disease (Class I) is about 5%.

Management

The   management   of   heart   failure   involves 

correcting the consequences of low cardiac out-

put and congestion, and addressing the various 

maladaptive pathophysiological responses that 

have   complicated   the   clinical   picture.   The 

general approaches will be reviewed first, before 

discussion of the management strategies. A fuller 

account of many of the drugs mentioned in this 

section is given on pp. 224-232 in the section on 

Hypertension. Only properties pertinent to heart 

failure are covered here.

Aims

The various aims in managing heart failure are 

listed   below.   They   overlap   in   sequence, objectives and methods and are not in order of precedence.

•  Identify   and   correct   any   causative   or 

contributory factors.

•  Improve cardiac efficiency and effectiveness. •  Reduce cardiac workload.

•  Counteract maladaptive responses. •  Increase cardiac output.

•  Relieve symptoms.

•  Reduce progression and prolong survival.

Ideas about improving declining cardiac perfor-

mance have changed. Rather than attempting to force the heart to maintain an unrealistic output while impaired and under maximal physiolog-

ical stimulation, current practice favours two 

alternative strategies:

1. Reduce the load on the heart to match its 

reduced pumping ability.

2. Limit  the  counterproductive  compensatory 

mechanisms.

Stimulation, unloading or cardioprotection?

The traditional treatment for heart failure has 

been to use inotropic agents, notably cardiac 

glycosides. However, there is little evidence for the benefit of this approach.

Careful   trials   have   shown   that   simple inotropic agents do not improve prognosis, and indeed  most  worsen  mortality.  The  possible exception is digoxin, the value of which probably rests on various actions other than its inotropic activity (see below).

Unloading  is  theoretically  more  attractive than simple stimulation because it is more phys-

iological. If the heart cannot sustain an adequate output to meet current demands, it is appro-

priate  to  reduce  those  demands.  Put  more 

prosaically, in order to open a stiff door on rusty hinges, a few drops of oil are preferable to brute force. However, although this approach often 

produces   haemodynamic   improvement,   it 

confers little survival benefit, so has now been augmented by cardioprotection.

Thus  attention  has  focused  on  the  failing 

myocardium and the high level of endogenous 

stimulation   it   undergoes   via   compensatory 

mechanisms.   Particularly   important   are   the 

neuroendocrine   mechanisms   involving   the

system

RAAS,  the  sympathetic  nervous  system  and 

cardiac beta-receptors. In heart failure there is 

excessive   sympathetic   drive   to   which   the 

myocardium can no longer respond, and also 

high renin and aldosterone levels. It has been 

shown that blocking these mechanisms with 

ACEIs   and   beta-blockers   protects   the   heart 

against further damage, retards progression of 

the failure, and significantly improves prognosis.

These new insights could also explain why 

extra stimulation by inotropic drugs might be 

superfluous  and  possibly  harmful.  Moreover, increasing   contractility   inevitably   increases oxygen demand, which is counterproductive, 

particularly in ischaemic failure.

Correct causative or contributory factors

Although attending to the underlying cause of 

the failure would seem to be a priority, it may 

not be immediately feasible, whether obvious 

(e.g. MI) or only revealed on investigation (e.g. 

valve  disease,  coronary  artery  disease).  Both 

causal and potential contributory factors (e.g. 

hypertension, anaemia) may have to wait until 

the  patient  is  stabilized  before  appropriate, 

possibly long-term, corrective measures are initi-

ated. These might include attention to CVS risk 

factors, salt restriction, stopping smoking, anti-

hypertensive therapy, weight reduction, valve 

replacement and haematinics.

Reduce cardiac workload

A basic form of unloading has always been prac-

tised. Rest is imposed by the exercise limitation 

of the condition and patients are often fatigued. 

Bedrest has been the traditional advice, but if 

excessive  it  can  be  detrimental  to  exercise 

tolerance,   predisposing   to   muscle   atrophy, 

deconditioning, and possibly thromboembolic 

complications.   Moreover,   moderate   aerobic 

physical  training  has  now  been  shown  to 

improve quality of life even if it does not benefit 

survival. Thus it is strongly encouraged, under 

supervision, in all patients with stable failure in 

Classes II and III.

Further, our better understanding of haemody-

namics now enables us to intervene positively to 

reduce   the   myocardial   workload,   either   by 

reducing preload with venodilators or diuretics, or by reducing afterload with arterial dilators 

(Figure 4.16).

Preload reduction

Starling’s law predicts that reducing preload will 

reduce cardiac output. If so, would reducing the 

preload   not   exacerbate   the   hypoperfusion 

(forward  component)  of  heart  failure?  This 

would be true if the failing myocardium were 

not operating on the falling limb of its contrac-

tility curve (see Figure 4.3(a)) and therefore no 

longer governed by Starling’s law. In this situa-

tion  reducing  preload  may  actually  increase 

output, as well as decreasing oxygen demand by 

reducing diastolic volume (Laplace’s law, p. 178).

Diuretics. Dietary sodium and fluid restriction 

and natriuresis are the first-line strategy in all 

patients   with   evidence   of   fluid   retention. 

Diuretics have several diverse but interdepen-

dent  effects.  They  mobilize  the  excess  fluid 

retained by the kidneys, reducing intravascular 

fluid (i.e. blood volume), which reduces preload. 

Consequently, venous end-capillary pressure is 

lowered, an effect enhanced by the venodilator

 action  of  diuretics  (Table  4.7).  This  reduces oedema by facilitating the return of oedema 

fluid to the circulation, to be cleared by the 

kidneys.  Kidney  function  benefits  from  the improved cardiac function.

The  principal  danger  is  dehydration,  espe-

cially if loop diuretics are needed, because this 

would  further  compromise  cardiac  and  renal 

function. Clearly, diuretics are contra-indicated in hypovolaemic, low-output states. Potassium, 

and perhaps magnesium, plasma levels need to 

be monitored carefully because of the arrhyth-

mogenic effects of hypokalaemia and hypomag-

nesaemia on the myocardium, especially in the 

presence  of  cardiac  glycosides. (For  a  more 

detailed discussion of diuretics, see pp. 226-227.)

Venodilators. Dilating veins increases venous 

capacitance, which leads to reduced pressure in 

the venous system, lowering filling pressure and 

venous end-capillary pressure, as with diuretics. 

Either nitrates (predominantly venodilator) or 

venous-arteriolar dilators, e.g. alpha-adrenergic 

blockers, ACEIs or angiotensin receptor antago-

nists (ARAs) may be used. The main problems 

with nitrates are tolerance and acute falls in 

cardiac   output   and   blood   pressure   causing 

syncope. Nitrates may be used alone or in combi-

nation with arterial dilators in both acute and 

chronic failure, but nowadays are most often 

used in acute failure.

Afterload reduction

Almost invariably, as cardiac output and blood 

pressure fall, the body responds by increasing 

sympathetic drive and renin/angiotensin levels. 

This may defend blood pressure, but only at the 

expense of raised peripheral resistance, further 

overloading  an  impaired  myocardium.  If  the 

blood pressure continues to fall, attempts to 

restore it with vasoconstrictor drugs will have 

the same effect.

Although  changes  in  peripheral  resistance 

have little effect on the output of the normal 

heart(see  Figure4.3(b))  owing  to  reflex 

compensation, the performance of the diseased 

heart  can  be  markedly  improved  by  reducing 

afterload.  Thus  ideally,  if  afterload  is  reduced 

output will rise while blood pressure is main-

tained. Moreover, because pressure work is the 

most energy-consuming component of cardiac 

performance,  reducing  the  afterload  is  a  very 

effective  way  to  reduce  myocardial  oxygen 

demand. This may be particularly important in 

ischaemic failure.

Balancing the benefits of reduced resistance against the possible problems of hypoperfusion of vital organs may be very difficult, and in acute severe   failure   this   strategy   is   restricted   to specialist units.

system

Arterial vasodilators  (p.  225). These are a 

heterogeneous  group (Table 4.7)  that  act  by 

several  different  mechanisms.  In  theory,  this 

group  is  most  appropriate  for  patients  with 

hypoperfusion  or  heart  failure  secondary  to 

hypertension. However, they are often helpful in 

any severe or resistant failure.

Although   the   older   sympatholytic(e.g. 

prazosin)   and   direct-acting (e.g.   hydralazine) 

agents are still used, the ACEIs are now first-

line   vasodilators,   having   both   arterial   and 

venodilator  effects  as  well  as  several  other 

actions (p. 225). Further, the ACEIs are free from 

adverse effects of postural hypotension, toler-

ance and reflex compensation. The specific arte-

rial and/or venodilators do not have a beneficial 

long-term  effect,  probably  because  of  reflex 

activation  of  the  RAAS,  which  ACEIs  block. 

Thus combined dilator therapy (e.g. hydralazine 

plus nitrates) has been replaced by monotherapy 

with ACEIs unless contra-indicated. However, 

vasodilators may be added if severe failure is not 

controlled with diuretics and ACEIs.

CCBs have not been found helpful and are 

generally   avoided,   especially   the   negatively inotropic ones like verapamil. However, those with a predominant vasodilator action (dihy-

dropyridines,   DHPs,   particularly   amlodipine; Table 4.25) may be useful in ischaemic failure or where there is hypertension.

Counteract maladaptive responses

We have seen that the consequences of maladap-

tive neurohumoral activation include excessive 

sympathetic   drive,   vasoconstriction,   raised 

aldosterone secretion, renal fluid retention and 

cardiac hypertrophy with ventricular dilatation. 

Several of the agents already discussed mitigate 

these effects; the following are directed more 

specifically at them.

Angiotensin-converting enzyme inhibitors

The action of angiontensin-converting enzyme 

inhibitors (ACEIs) is complex. Inhibition of the 

production  of  circulating  angiotensin  causes 

both venous and arterial dilatation and reduced 

aldosterone levels. They also reduce the local 

production  of  angiotensin  in  many  tissues, 

notably the kidney, where it normally inhibits glomerular filtration, and the heart and blood 

vessels, where it has growth-promoting action. The action of ACEIs is not reduced by tolerance or reflex sympathetic compensation.

The  renal  action  of  ACEIs  counteracts  the 

aldosterone hypersecretion found in some heart 

failure patients and reduces fluid retention in 

most,  with  no  risk  of  hypokalaemia.  Indeed 

there is a risk of hyperkalaemia, especially when 

used with potassium supplements or potassium-

sparing diuretics. It is also likely that reduced 

local  tissue  angiotensin  production  leads  to 

reduced vascular and myocardial hypertrophy 

(remodelling),  including  that  which  usually 

follows MI.

Most importantly, several large trials such as 

SOLVD, CONSENSUS and V-HeFT have demon-

strated that in adequate doses after careful titra-

tion ACEIs prolong survival by up to 50% even 

in mild heart failure. They also reduce disease 

progression, hospitalization and MI. (For further 

discussion of ACEI therapy generally, see p. 229).

Angiotensin receptor antagonists (ARAs) have 

a more specific pharmacological action. They 

provide  similar  but  no  greater  benefits  than 

ACEIs  and  are  useful  where  patients  cannot 

tolerate the cough caused by ACEIs. Combina-

tions of ACEIs and ARAs may provide a small 

additional benefit, presumably owing to a more 

complete block, but are not currently widely 

used.

Beta-blockers and partial sympathetic agonists

Trials have convincingly, if rather unexpectedly, 

demonstrated beneficial effects of conventional 

beta-blockers such as metoprolol in most classes 

of heart failure. Newer beta-blockers also shown 

to be beneficial include bisoprolol and carvedilol; 

the latter also has an alpha-blocking vasodilator 

action. These drugs have been shown to reduce 

hospitalization, disease progression and symp-

toms,   and   to   reduce   significantly   all-cause 

mortality. The resultant increase in survival is 

greater than that conferred by ACEIs and addi-

tional to it. Possible mechanisms include reduc-

tion of sympathetic stimulation, heart rate and 

oxygen demand, and up-regulation of receptors.

The best evidence is for use in NYHA Classes II 

to III failure. In chronic severe heart failure 

(Class IV) or acute severe decompensation the

Heart failure201

myocardium relies on sympathetic drive, so the 

well-known negative inotropic problem of beta-

blockers in heart failure could be hazardous. 

However, there is even evidence of benefit in this 

class  too.  They  are  particularly  indicated  in 

failure  associated  with  IHD.  At  present  their 

value in the elderly, and in failure with normal 

systolic function, has not been demonstrated.

Beta-blockers should usually be initiated by 

specialists, at low doses and with great care, and 

there may be an initial transient worsening of 

symptoms. Thus at present most primary care 

prescribers would seek consultant cardiological 

opinion before starting patients on them.

The seemingly anomalous use of beta-blockers 

in heart failure, although it goes against conven-

tional teaching, which has always warned of the 

danger in this situation, is not without prece-

dent. Beta-blockers are indicated in hypertrophic 

cardiomyopathy,  in  which  grossly  thickened, 

fibrosed  ventricular  walls  obstruct  outflow  if 

systolic contraction is too vigorous. Inotropic 

agents    and    venodilators    exacerbate    this 

condition.

The realization that beta-blockers can improve 

the prognosis of most cases of mild to moderate 

heart failure has changed clinical practice and 

heart failure management protocols significantly 

(see  p. 206).  Because  both  ACEIs  and  beta-

blockers are effective only in systolic dysfunc-

tion, it is important that suspected failure is 

always   investigated   echocardiographically   to 

confirm a reduced ejection fraction. As yet, it is 

unclear whether beta-receptor cardioselectivity 

(see p. 229) is preferable for heart failure, because 

myocardial beta-2 receptors may be involved. 

Evidence of benefit has been shown by both 

selective(metoprolol)and     non-selective 

(carvedilol) agents. (For a general discussion of 

beta-blocker therapy, see p. 227.)

Aldosterone antagonists

In addition to its role in promoting fluid clear-

ance, aldosterone has vasoconstrictor action and 

promotes  myocardial  fibrosis.  Therefore,  the 

raised levels in heart failure could be signifi-

cantly maladaptive. Both spironolactone and the 

newer eplerenone have been found to improve 

survival in large trials (RALES and EPHESUS, 

respectively). They are effective at low doses that 

have little diuretic effect and are currently third-

line agents for more severe failure. Surprisingly, 

combination  with  ACEIs  does  not  produce 

significant hyperkalaemia (which, like the use of 

beta-blockers in heart failure, is another tradi-

tional contra-indication discredited). The more 

expensive eplerenone lacks spironolactone’s adverse 

endocrine effects of gynecomastia, oligomenor-

rhoea  and  impotence,  and  appears  to  offer 

benefits in heart failure following MI. For both 

drugs, careful monitoring of serum potassium is 

essential, especially in renal impairment.

Digoxin

Recognition of the neuroendocrine complica-

tions in heart failure has indicated how the 

diverse   actions   of   digoxin (Table 4.8)   may 

contribute to its beneficial effect, independently 

of its inotropic action. The precise mechanisms 

have not been fully elucidated but an important 

component is the restoration of baroreceptor 

activity. As heart failure develops, baroreceptor 

responses to increased atrial and arterial pressure 

serve   to   dampen   sympathetic   outflow   and 

increase parasympathetic activity, protecting the 

heart from excessive stimulation and loading 

(p. 181). However, these responses eventually 

become blunted due to stretch receptor damage 

from  prolonged  activation,  permitting  excess

system

sympathetic activity. Digoxin appears to improve 

baroreceptor  function  and  thus  mitigate  this 

counterproductive development. Consequently, 

noradrenaline(norepinephrine)   levels   fall, 

vagal  activity  increases,  contributing  to  the 

negative chronotropic action, and myocardial 

wall stress and peripheral vasoconstriction are 

both  reduced.  The  activity  of  the  RAAS  is 

also  depressed,  limiting  fluid  retention  and 

vasoconstriction.

These observations may explain some possible actions of digoxin, but are not sufficient reason for  increasing  its  role,  which  is  still  mainly directed  at  improving  cardiac  output  and  is covered in more detail below.

Improve effectiveness: increase cardiac output

In severe heart failure, symptoms may persist 

despite the measures mentioned above, especially 

if shock has supervened. Inotropic drugs are 

then needed. The three main groups, each of 

which acts at a different site, are the traditional 

cardiac glycosides, the sympathomimetic amines 

and the phosphodiesterase inhibitors. They have 

different roles, advantages and drawbacks and 

none is regarded as a first agent. All can improve 

symptoms,  although  only  digoxin  has  been 

shown to reduce mortality. 

Cardiac glycosides

Action. The traditional role of digitalis glyco-

sides has been as inotropes, mediated by the 

action   in   increasing   intracellular   calcium 

through inhibition of membrane Na/K-ATPase. 

The observation that they improve contractility 

without   an   increase   in   myocardial   oxygen 

demand is probably explained partly by their 

multiple other actions (Table 4.8). These actions 

may  also  account  for  their  superiority  over 

conventional inotropes.

Digoxin  has a negative chronotropic effect, 

owing partly to increased vagal activity. This is 

invaluable when the failure is complicated by 

atrial fibrillation, and generally it tends to limit 

oxygen demand. The action on conduction is 

complex, and includes a negative dromotropic 

action (slowing conduction times). The negative 

chronotropic effect is distinct from the positive 

inotropic effect, the latter usually being observed 

first.

Note that by contrast the sympathomimetic 

amines are both positively inotropic and posi-

tively chronotropic and so almost always increase 

oxygen  demand.  For  detailed  accounts  of  the 

pharmacology of the cardiac glycosides, see the 

References and further reading section (p. 270). 

Side-effects. The principal drawback of glyco-

side  therapy is the narrow therapeutic index, 

with toxicity sometimes resembling the symp-

toms  being  treated,  i.e.  various  arrhythmias 

(Table 4.9). This problem is compounded by the 

sensitivity of plasma level and receptor activity 

to diverse pharmacokinetic and pharmacody-

namic factors (Table 4.10). Routine plasma level 

monitoring is not essential for safe and effective 

use if there is close monitoring of clinical and 

toxicological  signs.  However,  it  is  invaluable 

where the response is unexpected, or when renal 

impairment is known or suspected.

Digitoxicity is managed by drug withdrawal and use where appropriate of:

•  plasma   level   measurement   of   digoxin, 

potassium and creatinine;

•  oral potassium;

•  digoxin-specificantibodyfragment

(Digibind);

•  oral binding agents (e.g. cholestyramine); •  occasionally anti-arrhythmic drugs.

 The DIG trial demonstrated that digoxin is safer than was previously thought, which implies that previous fears about digoxin toxicity were exag-

gerated and that the toxicity that did occur 

previously could have been due to inadequate monitoring, or excessive plasma levels.

Role. Digoxin has seemed perennially to be on 

the verge of popular revival, without ever quite 

making it. Well-organized trials (e.g. RADIANCE, 

DIG) have improved its image, having demon-

strated significant reductions in signs and symp-

toms with fewer adverse effects than expected, 

definite deterioration when discontinued and a 

small reduction in heart failure deaths. However, 

there was no reduction in all-cause mortality.

Digoxin  has  a  first-line  indication  only  in 

heart failure associated with atrial fibrillation. 

Otherwise, its current role is third- or fourth-line 

in failure not controlled adequately with ACEIs, 

beta-blockers and spironolactone. Moreover, its 

target plasma level is now considerably lower 

than before ( 1 ng/ml). It is of no benefit in 

shock or cor pulmonale (possibly because of 

hypoxaemia) and has been superseded in severe 

acute heart failure and after MI by unloading 

strategies.

Sympathomimetic inotropic amines

Prolonged   reflex   stimulation   of   the   failing 

myocardium by the sympathetic nervous system 

may  become  counterproductive,  resulting  in 

depletion   of   catecholamines   and   down-

regulation of myocardial beta-receptors, with the 

paradoxical result that although beta-agonists 

are helpful in some situations, beta-blockers are 

preferred in others. 

Inotropic amines, usually given parenterally, 

have traditionally been a last resort in refractory 

failure and shock. They affect a variety of recep-

tors,  producing  a  mixed  spectrum  of  effects 

(Table 4.11). This is especially true of natural 

mediators such as adrenaline (epinephrine) and 

noradrenaline (norepinephrine),   which   cause 

unwanted    arterial    vasoconstriction    that 

increases afterload and reduces cardiac output.

Isoprenaline  (isoproterenol), an early synthetic 

agent, causes hypotension and arrhythmias. All 

raise heart rate and myocardial oxygen demand, 

sometimes   excessively,   although   this   may 

eventually be offset by increased efficiency.

Dopamine has dose-dependent receptor selec-

tivity. In low doses it has a vasodilator action on 

dopaminergic  receptors,  a  potentially  useful 

property in shock. At higher doses it also stimu-

lates inotropic beta1-receptors. However, further 

dose increases result in alpha receptor-mediated 

vasoconstriction,  raising  blood  pressure  and 

possibly  inducing  regional  ischaemia;  it  also 

liberates noradrenaline (norepinephrine). Dobuta-

mine only affects beta1-receptors and this pure

inotropic effect is sometimes preferable. Dopex-

amine has a greater affinity for both cardiac and 

peripheral beta2-receptors, and there is evidence 

that  in  chronic  failure,  although  beta1 myo-

cardial  receptors  may  be  down-regulated,  the 

beta2-receptors are not. Its main action is likely 

to be vasodilatory.

All these agents can only be given parenter-

ally and are limited to specialist use for severe 

resistant failure in a coronary care unit (CCU). 

Predominant  beta2-agonists,  more  commonly 

used in obstructive airways disease, e.g. salbu-

tamol, also have peripheral vasodilator actions, 

which is particularly useful in cor pulmonale. 

These agents offer more choice in their route 

of  administration,  including  oral  and  inhala-

tion, which is beneficial in chronic failure. A 

particular risk of these drugs is hypokalaemia.

Phosphodiesterase inhibitors

Aminophylline, a methylxanthine, has tradition-

ally been used in acute failure complicated by 

pulmonary oedema, where bronchoconstriction 

(‘cardiac asthma’) is common. As well as bron- chodilator activity it has inotropic, diuretic and respiratory   stimulant   properties.   However, xanthines are also arrhythmogenic and increase oxygen demand, and are no longer used.

The bipyridines have inotropic and vasodilator 

action. Milrinone, enoximone and related agents 

act by a novel mechanism, increasing cardiac 

output and reducing peripheral resistance with 

little or no increase in oxygen demand. They 

improve symptoms and exercise tolerance but 

increase  mortality.  They  can  only  be  used 

parenterally and have similar roles and restric-

tion to the sympathomimetic amines.

Calcium sensitizers

Levosimendan, not yet available in the UK, is the 

first in a new class of drugs that increase contrac-

tility   without   apparent   increase   in   oxygen 

requirement,   are   vasodilator   and   are   not 

arrhythmogenic. It is used parenterally in acute 

severe decompensated failure where other agents 

have failed.

Other methods

In severe heart failure that is resistant to drug 

treatment, an intra-aortic balloon pump (coun-

terpulsation) may be temporarily placed in the

thoracic aorta. Synchronized with the ECG, the 

balloon is inflated during diastole to improve 

systemic and coronary perfusion. Cardiac trans-

plantation is being seen increasingly as a realistic 

option in otherwise untreatable end-stage heart 

failure,  especially  that  caused  by  cardiomy-

opathy. Although a satisfactory completely artifi-

cial heart is yet to be developed, a number of 

sophisticated   ventricular   assist   devices   are 

proving useful on a temporary basis for patients 

awaiting  transplantation.  Alternatively,  these 

may relieve the damaged heart of its workload 

for few months, which in some cases may enable 

a degree of recovery to occur.

Alternative, potentially simpler surgical pro-

cedures are currently undergoing development. 

In   cardiac   myoplasty   a   muscular   pouch 

surrounding the heart is fashioned using local 

chest   wall   muscle   tissue.   Surprisingly,   this 

skeletal muscle acquires the structural character-

istics of cardiac muscle. Where there is gross 

ventricular dilatation (dilated cardiomyopathy) 

the Batista procedure involves remodelling (by 

excision of a wedge of ventricle), producing a 

smaller, less stressed chamber.

Another possibility is revascularization, either 

by bypass or angioplasty, which is becoming a 

 viable option and has shown benefits in patients with evidence of ischaemia even in the absence of angina symptoms.

Reduce symptoms

The above strategies will usually bring about 

symptomatic   improvement   such   as   reduced oedema,  fatigue  and  dyspnoea,  an  improved sense  of  well-being  and  quality  of  life,  and possibly an increased exercise tolerance.

In  mild  failure  the  main  aim  of  diuretic therapy may be simply to reduce uncomfortable or unsightly oedema.

The opioids are frequently used in pulmonary 

oedema,  having  venodilator,  anxiolytic  and 

respiratory depressant actions. This last action is 

useful in suppressing the inefficient, fast, shallow 

respiration (tachypnoea)  commonly  found  in 

pulmonary  oedema.  In  addition,  a  severely 

hypoxaemic  patient  will  be  given  oxygen, 

provided  care  is  taken  in  chronic  pulmonary 

disease present (see Chapter 5, p. 338).

Reduce progression and prolong survival

Nowadays it is realistic to expect retarded disease 

progression and increased survival. ACEIs and 

beta-blockers in particular improve survival in 

chronic heart failure patients, and this is due in 

part  to  a  cardioprotective  action  inhibiting 

further myocardial damage. Almost all patients 

with  symptomatic  heart  failure  should  take 

them, in the absence of contra-indications.

Drug selection

A summary of the current consensus for drug 

selection in systolic failure, as recommended by 

the European Society of Cardiology and NICE, is 

given in Figure 4.17 (see References and further 

reading).  The  main  criterion  is  severity,  the 

strategy being gradually to increase intervention 

with the addition of more drugs. Few patients 

are managed by monotherapy. Although most 

chronic cases can be managed in the community, 

particular  complications  such  as  arrhythmias 

and  pulmonary  oedema  will  require  specific 

additions,   while   acute   failure   may   require

system

management   in   a   specialist   CCU   where parenteral  therapy  and  close  haemodynamic and ECG monitoring are available.

Recent trends include the almost obligatory 

use  of  ACEIs  in  most  cases (unless  contra-

indicated), the recommendation for the wider 

if cautious use of beta-blockers, and the use of 

digoxin in severe cases (even in sinus rhythm).

Asymptomatic (Class I)

ACEIs should be used alone where evidence of systolic  dysfunction  is  discovered,  to  reduce progression. Systolic dysfunction is indicated by a dilated heart and an ejection fraction below 

45% (normal60%). ARAs can be sustituted where ACEIs are not tolerated.

Patients  with  atrial  fibrillation  should  be 

started  on  digoxin  straightaway,  usually  with 

warfarin  to  protect  against  stroke  from  an 

embolism  originating  in  the  atria.  Ventricular 

or  supraventricular  arrhythmia  may  require 

amiodarone,   but   care   must   be   taken   with 

potential digoxin/warfarin and digoxin/amiodarone 

interactions.

Mild-moderate (Class II)

Where there are no signs of fluid retention ACEIs 

can be used alone, titrating the dose up to an 

effective target level. Oedema is more usually 

present and diuretics are used in combination 

with ACEIs. Loop diuretics are routinely used, 

although thiazides can be used in mild failure, 

and in the elderly where they are less likely to 

cause dehydration than loop diuretics. Because 

diuretics are invariably combined with ACEIs, 

potassium-sparing adjuncts are not required and 

may be harmful.

Where fluid retention is particularly resistant, 

possibly due to a low glomerular filtration rate 

with  poor  delivery  of  diuretic  to  the  tubule, 

a   synergistic   diuretic   combination   may   be 

required for a few days. A loop diuretic with the 

thiazide metolazone is often successful (‘sequen-

tial nephron blockade’), although any thiazide 

should work as well. For pulmonary oedema, 

high doses of loop diuretic may be given with 

morphine and oxygen and the patient is nursed 

sitting almost erect. With high-dose and combi- nation diuretics, attention should be paid to the 

patient’s renal function and their serum potas-

sium level, and they require close monitoring.

As the patient improves, the diuretics may be stepped down, although ACEIs should always be continued.

Severe (Class III)

If symptoms persist or the patient deteriorates, a beta-blocker is added. Subsequently, if there is no   improvement   an   aldosterone   antagonist should also be added.

Very severe (Class IV)

This  stage  represents  irreversible  myocardial 

damage and the only curative measure is trans-

plantation. The prognosis is otherwise very poor, 

with  a  median  survival  of  less  than  a  year. 

Medical   therapy   is   mainly   palliative   while 

awaiting surgery. Various schemes have been 

devised   for   the   optimum   combination   of 

diuretics,   arterial   dilators   and   venodilators, 

based  on  haemodynamic  parameters  such  as 

filling pressure and pulmonary venous pressures 

(see References and further reading).

IV    sympathomimetic    or    dopaminergic 

inotropes, may be tried but their potential to 

increase   myocardial   oxygen   demand   must 

always be remembered. None is beneficial in 

long-term use but they may have a palliative 

role.

Diastolic failure

This form of heart failure is especially difficult to treat, and there is as yet no reliable trial 

evidence. Efforts to increase diastolic time with cardiodepressants such as beta-blockers, or with CCBs such as verapamil, may be tried. Drugs that reduce preload (and hence diastolic filling) need to  be  used  with  great  caution:  this  includes nitrates and diuretics. The only agents to have shown promise are the ARAs.

Hypertension

Definition and epidemiology

For most diseases a population can usually be 

divided into two fairly distinct groups, ‘normal’ 

or ‘ill’, on the basis of a defining characteristic or 

measurement. You are either diabetic or not, on 

the basis of blood glucose; you have airways 

obstruction or you do not, on the basis of peak 

expiratory flow. Unfortunately, it is less easy to 

define   normal   or   abnormal   blood   pressure 

because within a given population there is a 

continuous distribution of blood pressure about 

a single modal value, although this value varies 

with age, ethnic group, etc. Figure 4.18 shows

system

the  distribution  of  diastolic  pressure  for  a 

Western industrialized population: it is almost 

uniform, but is skewed towards the higher levels. 

Clearly,   the   oft-cited‘normal’   levels   of 

120 mmHg  systolic  blood  pressure  (SBP)  and

80 mmHg diastolic (DBP) are only a statistical 

approximation   for   a   majority   around   the 

modal value. The majority do lie between 70 and

90 mmHg   DBP,   but   there   is   a   substantial minority above 90 mmHg.

A clear distinction would be invaluable in 

identifying those who need treatment, because 

untreated high blood pressure is associated with 

long-term morbidity and premature mortality. 

Although the risk to an individual cannot be 

precisely predicted from their blood pressure, 

actuarial data confirm that excessive blood pres-

sure is harmful. We know that different popula-

tion groups with different mean blood pressures 

have different prevalences of diseases thought to 

be caused by hypertension. However, these risks 

are also graded continuously, and the challenge 

is  to  know  at  which  point  the  benefits  of 

treatment (reduced  long-term  complications) 

outweigh   the   harms   of   treatment (adverse 

effects, reduced quality of life, etc.). The balance will  vary  between  individuals  according  to numerous   other   factors   including   age   and comorbidity (Table 4.12). Generally, the cut-off point has tended to be reduced gradually over the years as less toxic drugs have been developed that reduce the harms of treatment.

Variations in blood pressure

Variations with age and gender were discussed 

on pp. 183-184. Monitoring of blood pressure 

over 24 h  shows  that  it  varies  continuously 

throughout  the  day  owing  to  both  regular 

diurnal variation (lower overnight and higher in 

the morning) and irregular physical and mental 

stress, as might be predicted from physiology. 

Thus it is important to standardize the condi-

tions of measurement (see below) if longitudal 

comparisons are to be made. Even so, large-scale

Hypertension209

epidemiological  studies  have  shown  a  close correlation between single random blood pres-

sure measurements and cardiovascular risk.

Definitions

The first important distinctions to be made are 

whether the cause of the hypertension is readily 

identifiable   or   not,   and   how   elevated   the 

pressure is.

Primary (essential) and secondary hypertension

In about 10% of cases of raised blood pressure 

there may be obvious reasons (Table 4.13). This 

is termed secondary hypertension; it is often 

associated  with  very  high  pressure  and  rapid 

progression,  but  appropriate  therapy  (possibly 

surgical)   will   often   correct   the   problem. However, in most cases there is usually only a mild or moderate elevation of blood pressure, for which no obvious cause can be found. More-

over,  the  body  resists  attempts  to  lower  the pressure. It seems that part of the body’s pres-

sure control mechanism (e.g. baroreceptors) has been  reset  at  a  higher  level:  hence  the  term essential hypertension.

Benign and malignant hypertension

Hypertension is called malignant or accelerated 

(terms not strictly synonymous but often used 

so)  when  the  DBP  is  above 120 mmHg  and 

usually rising rapidly. Urgent reduction of the 

pressure is essential to prevent stroke, cardiac 

failure or renal failure. The prognosis for the 5% 

or so of hypertensive patients who present with 

or who develop this form is much poorer than 

for the majority with benign (mild or moderate) 

hypertension.  This  is  a  rather  unfortunate, 

historical misnomer because no degree of hyper-

tension can be described as benign. Malignant 

hypertension   commonly   has   an   underlying

system

renal cause. Most of the following discussion concerns benign essential hypertension.

Diastolic or systolic?

Most attempts to distinguish high blood pressure 

from the normal range definitions of hyperten-

sion allow for the greater proportional rise in SBP 

than DBP and include intermediate classifica-

tions  to  recognize  the  continuous  variation. 

Because   increased   risk   is   associated   with 

pressures  sometimes  regarded  as  normal,  an 

‘optimal’ grade has been proposed (Table 4.14).

SBP   is   inversely   proportional   to   arterial 

compliance, which declines with age owing to 

smooth muscle fibrosis and calcification (arte-

riosclerosis). DBP by contrast reflects the periph-

eral resistance, a measure of the average size of 

blood   vessel   lumens   throughout   the   body, 

against which the heart has to develop and 

maintain a pressure.

Because the vasculature is exposed to diastolic 

pressure for the greater part of the cardiac cycle, 

it was formerly assumed that DBP was the main 

marker for the vascular damage that is the main 

complication of hypertension. Thus most early 

trials monitored DBP and aimed to reduce it. 

However, following more recent trials (e.g. Syst-

Eur),  systolic  pressure  is  increasingly  being 

accepted  as  an  equally  or  more  important 

prognostic indicator. Because both tend to be 

elevated   in   hypertension   this   is   not   so 

important.

However,   patients   with   isolated   systolic 

hypertension (ISH) and normal DBP are increas-

ingly recognized. Such patients are at greater 

risk, but also benefit more from treatment. These 

tend to be older patients and there was some 

doubt about the wisdom of aggressive treatment 

because   resultant   excessive   hypotension   or 

reduced perfusion to vital areas may increase 

mortality. However, the need to treat ISH is now 

established and it is recognized in the official 

classification (Table 4.14).   Furthermore,   the 

calculation  of  an  individual’s ‘cardiovascular 

risk’ (see p. 216) uses SBP not DBP.

Thus, the definition of hypertension is essen-

tially statistical and epidemiological. All that can 

be done is to mark off certain pressures on either 

side of the median as bounding the ‘normal’ 

limits, and class all others as ‘abnormal’. Exactly 

where this borderline is drawn has changed as 

understanding of the risks of untreated hyper-

tension has grown and as more effective, less 

toxic treatments have been developed. Formerly, 

active treatment was considered only if the DBP 

was consistently above 100 mmHg. Now, with 

better   and   safer   drugs   the   borderline   has 

dropped to 90 mmHg, or even 85 mmHg for

those  with  several  other  cardiovascular  risk factors, if not all patients.

Prevalence

Estimates of prevalence depend crucially on how 

hypertension is defined, i.e. what thresholds are 

assumed. Based on a definition of hypertension 

as   a   DBP   above 95 mmHg   or   SBP   above 

150 mmHg, it has been estimated that there may 

be 4 million hypertensives in the UK. If a level of 

140/90 mmHg is taken as the threshold, the 

figure will be nearer 20% of the population, i.e. 

up to 12 million. This shows the difficulty of 

defining a condition solely on the basis of a 

physiological measurement that varies continu-

ously   throughout   the   population.   There   is 

increasing concern over the potential labelling 

and ‘medicalizing’ of large numbers of people on 

the basis of probability alone, knowing many of 

them will never develop any complication but 

will have been made anxious by being diagnosed 

as ‘ill’ rather than healthy. A similar dilemma 

arises  with  falling  thresholds  for  acceptable 

cholesterol levels.

Hypotension

The definitions of blood pressure in Table 4.14 

imply that no harm is believed to be associated 

with pressures moderately below ‘normal’, i.e. 

70-80 mmHg diastolic. This is indeed the case in 

the  UK  and  the  USA.  In  mainland  Europe, 

however, a distinct diagnostic category of what is 

in effect essential hypotension is recognized, a 

condition  usually  treated  with  various  drugs including inotropic and pressor agents. Interest-

ingly, evidence is emerging of an adverse prog-

nosis for persons with low blood pressure, with vague   and   subjective   symptoms   including depression, tiredness, etc., although as yet it is not a recognized illness in the UK.

This phenomenon must be distinguished from 

blood  pressure  low  enough  to  affect  normal 

function   or   consciousness(as   in   postural 

hypotension or shock), and it is necessary to 

exclude specific pathologies that cause hypoten-

sion,   such   as   hypothyroidism   or   Addison’s 

disease.  Moreover  hypotension  needs  to  be 

considered as a potential result of over-treatment 

of borderline hypertension in the elderly (see 

below).

Course and prognosis

Hypertension is a chronic, life-long condition with a variable rate of progression and a highly variable prognosis. Being insidious in onset and initially symptomless, it may go undetected for years, and is often discovered incidentally. Yet if untreated the patient will eventually develop 

one or more of the complications, frequently 

leading to premature death.

What then are the risks of having too high a 

blood pressure? After all, if a person asked what 

blood pressure was for, you might reply that it 

drove blood round the body. They might then 

justifiably retort that surely then you could not 

have too much of it - the more the better. This 

credibility gap needs to be bridged when a diag-

nosis is first made, without causing undue alarm. 

It must be reinforced when adverse drug effects 

occur in a previously asymptomatic person who 

has now become a ‘patient’.

For  although  hypertension  is  almost  invari-

ably  symptomless  for  many  years  there  are 

subtle,  sinister  pathological  processes  at  work 

causing  long-term  damage  to  the  heart  and 

blood vessels, as well as to other vital organs, 

especially the kidney and eyes. A middle-aged 

patient with a DBP above 110 mmHg has a 1 in

5 chance of dying within 5 years; a 35-year-old

system

patient with DBP over 105 mmHg has their life 

expectancy reduced by 15 years compared to a 

normotensive.  The  list  of  conditions  from 

which hypertensives may ultimately suffer reads 

like a recitation of the ills of civilized man: MI, 

stroke, heart failure and renal failure. Death is 

usually from stroke or MI, far more commonly 

than in normotensives. These risks are related 

to  the  duration  and  severity  of  the  elevated 

blood  pressure.  Adequate  early  treatment  can 

reduce the incidence of complications by up to 

50%.

Aetiology

Heredity

Hypertension occurs about equally in men and 

women, although younger men in particular are 

more  prone  to  atherosclerotic  complications. 

There is often a family history, but it is probably 

a susceptibility to hypertension that is inherited 

and this is only expressed if certain environ-

mental factors are present. Immigrant popula-

tions with low mean blood pressures tend to 

assume  the  prevalence  of  the  host  country. 

However, certain races have a higher prevalence 

of hypertension even in mixed societies (e.g. 

African Americans in the USA), although envi-

ronmental variables such as diet and response to 

stress may still contribute to this. There are 

almost certainly several genes involved.

Many factors may complicate epidemiological 

studies. In making cross-cultural and interna-

tional  comparisons  it  is  difficult  to  ensure 

control for all environmental factors, and to reli-

ably  compare  blood  pressure  measurements. 

Nor, in following the fate of migrant communi-

ties, can we always assume that the migrant 

population is representative of the area of origin 

(for example, those who choose to migrate may 

include a higher proportion of those with higher 

blood  pressures).  On  the  other  hand,  even 

prenatal influences may be environmental (e.g. 

maternal diet or smoking), so that a positive 

family  history  does  not  necessarily  imply  a 

genetic mechanism.

Environmental factors

Whatever the genetic contribution to suscepti-

bility,   environmental   factors   are   extremely 

important in the manifestation of the disease 

(see Table 4.12) and these factors have to be 

addressed in the assessment, management and 

education of the hypertensive patient. Because 

the precise pathogenesis of hypertension is still 

unresolved, the way in which most aetiological 

factors contribute to raised blood pressure is 

usually unknown.

Controversy still surrounds the various ‘salt 

hypotheses’. Salt intake is difficult to measure 

accurately, and a general correlation both within 

and between populations is difficult to demon-

strate. Dietary salt restriction, although generally 

regarded as beneficial, usually produces disap-

pointingly small reductions in blood pressure. 

However, some individuals and some races (e.g. 

Black people) do have a ‘salt-sensitive’ hyperten-

sion, in which blood pressure is very responsive 

to changes in sodium intake.

Other factors, particularly smoking and hyper-

lipidaemia,   exacerbate   the   complications   of 

hypertension (especially atherosclerosis), but do 

not contribute significantly to a sustained eleva-

tion in blood pressure. Hyperlipidaemia, and by 

extension a high fat/cholesterol diet, has been 

implicated as a minor independent causal factor 

for  raised  blood  pressure,  possibly  through 

interaction  with  vascular  mediators  such  as 

endothelin at the vascular endothelium, but the 

popular idea of widespread cholesterol plaques 

causing  a  generalised  arterial  obstruction  is 

erroneous.

Certain  factors  contribute  to  both  hyper-

tension  and atherosclerosis,  e.g.  stress and  a sedentary  life.  Whether  glucose  intolerance, hyperinsulinaemia    and    insulin    resistance contribute directly to the raised blood pressure or merely exacerbate the potential for complica-

tions is unclear (see Chapter 9, p. 600).

Obesity  and  lack  of  exercise  are  important 

factors in modern life that have a significant 

hypertensive effect. Alcohol intake, considerably 

in excess of that providing the putative beneficial 

effect on reducing atheroma, is a major contrib-

utor to the overall hypertensive load. Also, many 

drugs are hypertensive agents (Table 4.13).

Hypertension213

Pathophysiology

Underlying haemodynamic defect

Blood pressure can be expressed as the product of cardiac output and peripheral resistance, so an elevated blood pressure means that one or both of these factors must also be raised. Attention has traditionally focused on the peripheral resis-

tance,  and  because  this  is  almost  invariably raised  in  hypertension,  most  early  theories tried to account for this increase through an 

underlying increased vascular tone.

More  recently,  the  possibility  of  a  raised 

cardiac  output  as  a  prime  cause  has  been 

explored. Fluid retention is known to be an occa-

sional cause of secondary hypertension. This is 

readily   explained   in   haemodynamic   terms: 

blood volume is increased, venous return and 

preload are raised and cardiac output rises, at 

least initially. However, systemic peripheral resis-

tance would then increase, as part of the normal 

autoregulation of blood flow. The aim of this is 

to  limit  the  resulting  excessive,  unnecessary 

perfusion of the body. As the peripheral resis-

tance rises, the cardiac output would then return 

to   normal.   When   the   patient   eventually 

presents, these compensations will have reached 

equilibrium and only a raised peripheral resis-

tance is found.

Pathogenesis

Most theories of essential hypertension implicate 

the kidney. This creates a difficulty because renal 

damage is also often a consequence of prolonged 

hypertension caused by damage to renal arteri-

oles. Thus renal damage found in a patient with 

hypertension of indeterminate duration could be 

either a cause or a consequence. Indeed, by that 

stage a vicious cycle will have been initiated: 

renal damage raises blood pressure, which in turn 

causes further renal damage. In early hyperten-

sion an identifiable renal lesion or functional 

impairment can rarely be found, but this does not 

mean that subclinical or microscopic damage has 

not already occurred. Figure 4.19 illustrates one 

theory of how renal damage can initiate, and 

then sustain, hypertension.

Other major theories are summarized in Table

4.15, and Figure 4.20 provides an overview of 

how some of these proposed mechanisms may 

interact to alter cardiac output or peripheral 

resistance. Figure 4.20 shows one possible way in 

which sodium is implicated, via a defect in the 

transmembrane sodium pump. In the kidney 

this  defect  would  impair  sodium  and  water 

clearance, and in blood vessel smooth muscle 

it  could  lead  to  calcium  accumulation  and 

vasoconstriction.

One approach to this, which is helpful for 

predicting  response  to  treatment,  categorizes 

hypertension on the basis of plasma renin levels, 

because  this  appears  to  correlate  with  the 

distinction discussed above between vasocon-

striction  and  expanded  blood  volume.  Some 

hypertensive patients have raised renin levels 

and  tend  to  have  primary  vasoconstriction; 

these patients tend to respond better to drugs 

that block the RAAS such as ACEIs and beta- blockers. Others have low renin levels, owing 

possibly to inhibition of the RAAS by salt and fluid  overload; these patients respond poorly

to   ACEIs   and   beta-blockers,   and   better   to 

diuretics and CCBs. This distinction is supported 

by the observation that Black people generally 

fall into the latter category in terms of both their 

renin levels and their response to antihyperten-

sives. As discussed below, this forms the basis 

is the British Hypertension Society treatment 

guidelines.

There may be several subgroups of hyperten-

sion, in each of which a different mechanism 

operates. Patients with high renin levels may perhaps  have  silent  renal  damage  caused  by 

subtle intrarenal ischaemia. On the other hand, 

a low renin level would be an expected response 

to hypertension if the renal mechanisms were 

intact, because of feedback inhibition. It has 

been   speculated   that   avid   salt   retention, 

permitted by low renin, might confer a survival 

advantage in hotter climates where salt loss can 

be a problem.

Further detail is not given here because there is still no firm evidence for the most likely 

mechanism. In the absence of a more defined 

pathogenesis,   the   management   of   essential hypertension  generally,  and  antihypertensive drug selection specifically, remain largely empir-

ical. The aim is simply to reduce pressure rather than target underlying pathologies.

Diagnosis and investigation

Measurement

Blood pressure should be measured in a consis-

tent and standardized manner. Semi-automatic 

electronic  manometers  are  rapidly  replacing 

mercury   manometers.   These   are   sufficiently 

accurate provided they are regularly recalibrated. 

In all cases care must be taken to use the correct 

cuff size for the patient’s arm girth, otherwise 

readings may be unreliable. The British Hyper-

tension   Society’s   recommendations   for   the 

procedure include:

•  The effects of stress, anxiety, time of day, 

smoking,   alcohol   and   room   temperature 

should be minimized or standardized.

•  The patient should have rested for 10 min 

beforehand, and the procedure should have

been explained (this is rare, but obviously 

sensible).

•  The patient may be sitting or lying, as long as 

the cuff is at heart height.

•  The average of two or three readings at any 

one time should be taken.

The so-called phase 5 recording is recommended to measure DBP; i.e. when sounds completely disappear, rather than just being muffled, as 

there can be a 5-10 mmHg pressure difference according to the method of recording.

Unless a very high pressure is discovered (i.e. 

DBP115-120 mmHg), little need be done at 

once, although this will depend on the patient’s 

age. Measurements as outlined above should be 

repeated twice, at intervals of a few weeks. Often 

the  pressure  will  settle  down  as  the  patient 

becomes familiar with the procedure and their 

‘white-coat hypertension’ subsides. Simply being 

labelled as hypertensive is stressful, so the diag-

nosis should not be made lightly, and care taken 

when explaining it to the patient.

In  certain  cases  where  the  pressure  seems erratic, borderline or resistant to therapy, or when a more objective and reproducible measurement is required, it may be helpful to arrange 24-h 

ambulatory monitoring. A cuff is connected to a portable, battery-powered electronic manometer that samples pressure over a period of 24 h at 

approximately hourly intervals to determine the diurnal pattern and compute a mean.

Investigation

There are three aims in investigating a newly 

diagnosed hypertensive:

1. To discover any primary, perhaps treatable, 

cause or contributory factor.

2. To identify significant risk factors.

3. To assess the extent of end organ damage.

Clinical examination, simple blood chemistry 

(urea, electrolytes, glucose and lipids), urinalysis 

(protein,  glucose,  cells),  CXR  and  ECG  will 

suffice in most patients. A basic grading derives 

simply  from  the  blood  pressure  itself (Table

4.14). However, a global grading that takes into

system

account not just elevation but also duration and 

possible extent of potential organ damage can be 

made by ophthalmoscopy (fundoscopy), which 

assesses the degree of retinal arterial damage. A 

drug history is also important. These data will 

serve as a baseline for subsequent monitoring 

and  also  reveal  clinical  signs  or  biochemical 

abnormalities suggestive of secondary hyperten-

sion. In such cases more invasive investigations 

would then be needed, including renal function 

tests and excretion urography, echocardiography 

and additional blood analysis for corticosteroids, 

aldosterone, catechols and renin.

At the same time an assessment is made of risk 

factors both for hypertension and for arterial 

complications,   e.g.   smoking,   alcohol,   body 

weight, exercise habits, diet, diabetes, stress and 

family history (Table 4.16), so that an initial plan 

of general advice for the patient may be devised.

A formal cardiovascular risk prediction can then be made. This uses an algorithm that takes into account risk factors such as:

•  gender;

•  smoking status; •  age;

•  SBP;

•  ratio    of    total    plasma    cholesterol    to 

high-density (HDL) cholesterol (p. 238).

This  has  been  constructed  on  the  basis  of 

epidemiological  data,  largely  from  the  USA 

Framingham  study.  A  number  of  algorithms 

have  been  published  but  the  one  currently 

recommended by NICE is that published by the 

Joint   British   Societies (BHS   IV, 2004).   An 

example is included at the back of the BNF, in 

the form of nomograms. A person’s status is 

usually expressed as the percentage risk of a 

cardiovascular   event (developing   angina,   or 

suffering or dying from MI or stroke) in a specific 

number of years; for example, a “10-20% risk 

over the next 10 years”. These are used for 

asymptomatic patients with moderately elevated 

blood pressure or cholesterol to guide the deci-

sion about starting drug therapy.

The aim is to move away from basing treat-

ment decisions solely on inflexible population-

based thresholds of a single parameter applicable 

to all patients (such as blood pressure or choles-

terol level), to one where all aspects of an indi- vidual’s  risk  are  considered.  It  thus  avoids 

treating possibly very large numbers of people at 

perhaps very low risk. The tables also help the 

patient to understand their personal risk, and 

which  aspects  of  their  life  or  behaviour  are 

affecting it. This enables them to make a more 

informed choice about whether or not to start 

drug therapy.

For patients with higher levels of blood pres-

sure or cholesterol there will usually be a guide-

line   that   recommends   mandatory   primary 

prevention. However, the tables or charts are not 

to be used without consideration of the patient’s 

full history. Patients with diabetes in particular, 

being at far greater risk, are not covered by this 

approach: any degree of hypertension in diabetics 

needs  vigorous  treatment.  Also,  the  data  on 

which they are based derive predominantly from 

Caucasians, so they are not directly applicable to 

other races. For example, South Asian immi-

grants to the UK appear to have a higher risk of 

CVD than natives for the same risk factor levels.

Clinical features and presentation

Moderate   essential   diastolic   hypertension   is 

symptomless. Complaints of nosebleeds, tired-

ness or vague headaches usually derive not from 

raised pressure but from popular misconceptions 

about hypertension, or possibly concern about

the diagnosis itself. However, malignant hyper-

tension certainly may cause severe headaches 

and other neurological phenomena, known as 

hypertensive   encephalopathy.   Consequently, 

essential   hypertension   is   usually   identified 

opportunistically during routine screening, or 

life insurance or employment medical examina-

tions. Increasingly, screening by GPs is identi-

fying cases much earlier. Any genuine presenting 

symptoms will usually have been caused by one 

of the complications of untreated hypertension 

(e.g. angina, visual problems). Thus all new cases 

of heart failure, IHD, etc. are investigated for 

hypertension.

Complications

The problems caused by a chronically elevated 

arterial pressure can be largely anticipated from a 

consideration of the disturbed haemodynamics 

(Table 4.17). In general, the extent of the damage 

will be proportional to the increase in pressure 

and its duration before detection. There are two 

broad groups of complications, depending on 

how much the pressure is raised. If pressure is 

greatly  raised  there  will  be  direct  organ  or 

vascular damage, including heart failure, reno-

vascular disease/malignant hypertension, hyper-

tensive  encephalopathy,  retinal  damage  and 

haemorrhagic  stroke.  The  benefits  of  blood  pressure-reducing interventions are most easily 

demonstrated in this group. For more modest 

elevations, most problems are caused indirectly 

and more chronically by the promotion and 

acceleration   of   atheroma   formation.   These 

complications are significantly exacerbated by 

interaction with other common atherogenic risk 

factors, notably smoking and hyperlipidaemia.

Heart failure

Hypertension  was  a  common  cause  of  heart 

failure   before   safe   and   effective   treatment 

became  available.  The  persistently  increased 

afterload on the left ventricle initially leads to 

compensatory hypertrophy (remodelling), often 

seen on the ECG of newly diagnosed hyperten-

sive patients as a higher R-wave (see Figure 4.10). 

Eventually there is left ventricular dilatation and 

decompensation.

Arteriosclerosis

Excessive stress on the walls of resistance vessels exposed  to  elevated  pressure  stimulates  the development of thicker muscular walls in order to  withstand  it (Laplace’s  law;  p. 178).  The resulting hypertrophy of arterial walls, especially arterioles, has several consequences:

system

•  It encroaches on the lumen, narrowing it 

(remodelling),   which   reduces   end-organ

perfusion, causing ischaemia, especially in the kidney.

•  Peripheral resistance is further raised (because 

all arteries throughout the body are affected). 

•  Arterial  compliance  falls,  which  increases

afterload and hastens ventricular failure. 

•  Damaged vascular walls are more prone to

aneurysm(bulging)    and    haemorrhage, especially cerebral vessels.

Atherosclerosis

Perfusion   problems   are   exacerbated   by   an 

increased tendency to arterial atheroma, which 

is encouraged by high pressure and associated 

blood turbulence. In atherosclerosis (not to be 

confused  with  arteriosclerosis),  there  is  focal 

deposition    of    lipid-rich    fibrous    lesions 

(atheromas) in the inner lining layer of certain 

arteries. Atheroma, atherosclerosis and throm-

bosis are all accelerated by hypertension.

Morbidity and mortality

Almost any organ can be affected by these prob-

lems, but the heart, brain, kidney, eyes and 

(particularly if the patient smokes) lower limbs 

 are especially prone. The results may be heart 

failure, angina, MI, stroke, renal failure, visual 

problems or possibly limb amputation: the most 

common causes of death among hypertensives 

are stroke and MI. These complications can be 

prevented or retarded by effective antihyperten-

sive therapy although stroke, heart failure and 

renal impairment seem to be far more effectively 

prevented   than   atheromatous   complications 

such as MI. Ventricular and possibly vascular 

hypertrophy are partially reversible with optimal 

treatment.

Assessments of the effect of different treat-

ments   on   prognosis   have   sometimes   been inconclusive,  perhaps  because  many  of  the complications are advanced at first diagnosis 

owing  to  the  silent  preclinical  progression. Moreover, some antihypertensive drugs, espe-

cially  beta-blockers  and  thiazides,  may  have adverse atherogenic effects.

Management

Decision to treat

In a patient with mild hypertension the most 

important decision to be made is at what point 

to initiate drug treatment. In addition to the 

level of the blood pressure itself, the patient’s age 

and  cardiovascular  risk  must  be  taken  into 

account in balancing the likely benefits of inter-

vention against the possible harms and reduced 

quality of life from lifelong drug therapy (Table

4.18).

Numerous  protocols  exist  for  determining 

the  threshold  for  starting  drug  treatment, 

notably  from  the  World  Health  Organization 

(WHO), the British Hypertension Society, and 

the   American   Joint   National   Committee. 

Figure 4.21 represents  a  consensus.  At  the 

borderlines of different grades the recommen-

dation is that the patient should be monitored 

closely over 1-3 months and treatment started 

or  amended  if  the  pressure  remains  high. 

Protocols are frequently updated so the reader 

is  urged  to  check  the  appropriate  sources  in 

the References and further reading section for 

the latest recommendations.

 Severe hypertension

Very    severe    hypertension(i.e.above 

210/120 mmHg)  represents  a  medical  emer-

gency, with the risk of encephalopathy, renal 

damage or haemorrhagic stroke. Nevertheless, 

this is not corrected too aggressively because a 

rapid fall in blood pressure can compromise cere-

bral perfusion. Parenteral therapy is generally 

avoided, a smooth fall over a number of hours 

being preferred, and this can be attained effec-

tively with oral therapy (e.g. ACEI, hydralazine, 

labetalol). IV nitroprusside is reserved for estab-

lished hypertensive encephalopathy and other 

situations of immediate danger.

For pressures consistently above 110 mmHg 

diastolic and/or 180 mmHg systolic, the normal 

treatment protocol (see below) should always be 

initiated.

Moderate hypertension

A   DBP   of  100-110 mmHg   and/or   SBP   of 

160-180 mmHg   should   probably   always   be 

treated, but in the absence of risk factors obser-

vation over 4 weeks is suggested to see if the 

pressure   can   be   reduced   with   conservative general measures (see below). It must be remem-

bered that there is clear evidence that older 

patients  benefit  as  much  from  treatment  as 

younger  ones,  especially  in  the  reduction  of 

stroke.

Mild hypertension

The current UK consensus (British Hypertension Society) is that a DBP of 90-100 mmHg and/or SBP of 140-160 mmHg only need immediate 

attention in those already showing complica-

tions  or  with  specific  risk  factors,  and  drug treatment is rarely justified below this.

Some  cardiologists  caution  against  over-

vigilance.  Patients  with  marginal  or  illusory 

disease,  especially  the  elderly,  are  perhaps 

being over-diagnosed and over-treated. In older 

patients there may be less time for the compli-

cations to become significantly limiting, and in 

the meantime reduced pressure might compro-

mise  cerebral  or  coronary  perfusion.  Thus 

therapy  might  cause  more  problems  immedi-

ately than it might prevent in the future, and 

lowering  blood  pressure  below 80-85 mmHg 

may be associated with an increased mortality 

from  IHD.  There  is  some  evidence  for  a  J-

shaped mortality curve for blood pressure, with 

mortality  lowest  around 80 mmHg  diastolic 

and rising at pressures not only higher but also 

lower than this. This might explain the failure 

to demonstrate a reduction in IHD mortality in 

some  hypertension  trials.  However,  this  rela-

tionship  has  not  been  conclusively  demon-

strated  and  most  evidence  supports  similar 

treatment  of  the  elderly  to  younger  persons, 

with comparable benefit.

Isolated systolic hypertension

Although raised SBP without a raised DBP was 

formerly regarded as less dangerous, it has been shown to be associated with similarly increased 

mortality. In particular the Syst-Eur trial showed 

a  significant  benefit  in  treating  SBP  above 

150 mmHg in the elderly, with less stroke and 

less dementia.

Aim and strategy

From a community perspective the management 

of hypertension, although improving, is still far 

from ideal. Detection rates are increasing but it is 

still estimated that up to half of cases remain 

undiagnosed at any given time. Of those diag-

nosed, half may be sub-optimally treated. Of 

those prescribed optimal treatment perhaps no 

more  than  half  are  normotensive,  owing  to 

inadequate  compliance  or  other  problems. 

Thus active screening and follow-up monitoring 

are  crucial.  Furthermore,  pharmaceutical  care 

is important in ensuring optimal prescribing, 

patient comprehension and concordance.

Strategy

NICE has issued guidance to cover the manage-

ment of hypertension in primary care, and much 

of the following is based upon this. The general 

strategy   in   managing   hypertension   follows 

several stages:

•  Ensure   that   blood   pressure   is   genuinely 

elevated by repeat measurements.

•  Decide a target for reduced pressure. 

•  General    measures:    reassurance;    health

education; advice on lifestyle. •  Non-drug interventions.

•  Optimal drug monotherapy. •  Combined drug therapy.

•  Regular monitoring.

Target blood pressure

The recommended objective for hypertension 

treatment has gradually been reduced as the 

risk-benefit ratio changes, as already noted. New 

studies with safer drugs, such as the HOT (Hyper-

tension Optimal Treatment) trial, have produced 

greater reductions in morbidity and mortality 

by targeting lower pressures, with no signifi-

cant  increase  in  adverse  effects.  The  British 

Hypertension Society recommends aiming for 

140/85 mmHg  in  patients  without  complica-

Hypertension221

tions and 130/80 mmHg for those with a high CVD risk or renal damage.

General measures

Because hypertension is a chronic progressive 

disease,   lifelong   monitoring   and   usually   a 

progressively  increasing  level  of  intervention 

will be required. In such an insidious, symptom-

less  condition  the  patient’s  cooperation  and 

compliance are essential, and patient education 

is an important means of securing concordance. 

Ultimately the decision rests with the patient: 

imposed medical edicts are no longer acceptable. 

The initial plan should be to counsel and to 

educate  the  patient  about  their  disease,  but 

perhaps  suggest  nothing  positive  at  first.  A 

mildly elevated blood pressure, discovered inci-

dentally, will often return to normal within a 

few months and may remain so for several years.

The notion of a general change in habits and 

way of life should be introduced next. Simple 

psychotherapy or ‘brief counselling’ (an informal 

but structured targeted session of 5-10 min) is 

sometimes helpful, e.g. engendering the idea of a 

combined effort of health workers and patient to 

conquer the condition. Continuous encourage-

ment and reassurance are important. Scare tactics 

are almost invariably unhelpful: the history of 

anti-smoking propaganda teaches us this, even 

though the connection between smoking and its 

respiratory consequences is far more obvious.

Suitable advice and recommendations at this 

stage are summarized in Table 4.19. Measures are 

included to reduce both blood pressure and the 

risk of arterial complications. Alas, this is not a 

list  to  endear  the  clinician  to  an  otherwise 

healthy, apparently fit and symptomless patient.

A moderate reduction in sodium intake is a 

realistic goal, especially if done by simply cutting 

down on added salt. The ideal is about 6-9 g 

sodium chloride daily (100-150 mmol Na). By 

analogy with sugar intake and the ‘sweet tooth’, 

the subjective saltiness of food may be relative, 

determined  in  part  by  average  consumption. 

If  intake  is  reduced,  eventually  less  salt  will 

taste equally salty as the salt content of saliva 

is  reduced.  However,  very  low-salt  diets  are 

unappetizing,  result  in  poor  compliance  and 

are of arguable benefit, especially because salt 

reduction rarely produces blood pressure falls greater than about 5 mmHg (except in those 

patients with ‘salt-sensitive’ hypertension). An 

overall reduction in the salt added to processed 

foods  might  be  more  beneficial  in  reducing 

community hypertension prevalence than indi-

vidual targeting. A moderate increase in potas-

sium intake (e.g. in fresh fruit and vegetables) 

may also be helpful: the most important factor 

could be a lowering of the dietary Na/K ratio.

The  role  of  calcium  and  magnesium  sup-

plements is dubious. Diets low in fat and cho-

lesterol   may   be   both   anti-atherogenic   and 

hypotensive. Achieving the ideal body weight 

should be encouraged. The role of pharmacists 

in smoking cessation is well established. Exercise 

is important and a very efficient method of 

lowering blood pressure: even modest increases 

can be very beneficial. As few as three half-hour 

sessions a week at less than 50% maximum 

capacity can be enough to produce sustained 

falls of up to 10 mmHg. Cholesterol also falls 

and exercise capacity increases.

Non-drug interventions

Encouraging results have been obtained with 

non-invasive techniques to reduce blood pres-

sure.  Some  may  act  by  reducing  stress:  for 

example,   moderate   routine   aerobic   exercise 

(such as walking a few miles a day), biofeedback 

(where the patient monitors their own blood 

pressure and consciously tries to lower it), relax-

ation therapy, hypnotherapy and meditation. 

The effectiveness of these approaches very much

depends  on  patient  preferences  and  health 

beliefs.

Pharmacotherapy

Despite the best efforts of clinician and patient, 

the above measures rarely produce more than a 

modest fall of about 5-10 mmHg, even when 

combined,  and  the  effect  is  not  permanent. 

Blood pressure eventually starts to rise again and 

most  patients  then  require  active  treatment. 

Furthermore, many drug regimens, after working 

effectively  for  some  time,  gradually  fail  to 

control the condition. This may be because of 

poor compliance with drug therapy or general 

measures, progression of the condition, or the 

body’s reflex (though maladaptive) defence of 

the abnormal pressure.

General principles. The philosophy of ‘stepped 

care’ in treating hypertension means a progres-

sive   increase   in   intervention   to   maintain 

control. At one time it also implied a fairly rigid 

sequence  of  specific  drugs  at  specific  stages: 

nowadays a more tailored approach is used. The 

general   sequence   and   important   general 

considerations are summarized in Table 4.20.

Patients are likely to be taking antihyperten-

sive  drugs  for  the  rest  of  their  lives  so  it  is 

important  to  use  agents  with  the  fewest 

adverse effects first, at the minimum effective 

dose,   and   to   monitor   therapy   regularly. 

Compliance  can  be  increased  by  minimizing 

the  number  of  daily  doses  using  long-acting 

agents or modified-release formulations Any new dose level must be given for several 

weeks  to  achieve  both  pharmacokinetic  and, 

more importantly, biological steady state. Some 

drugs, notably the thiazide diuretics and the beta-

blockers, have a non-linear dose-response curve 

that plateaus early, so that maximum clinical 

effect is achieved at little above the minimum 

effective  dose.  In  contrast,  adverse  effects  are 

usually dose-dependent so it is counterproductive 

to increase the dose if adequate control with these 

drugs is not achieved.

Details of specific drug selection, indications and contra-indications are considered below.

Continuous   cover.   There   is   evidence   that 

complications are lessened if the antihyperten-

sive effect is as consistent as possible throughout 

the day. It is likely that variability in blood pres-

sure contributes to end-organ damage indepen-

dently of absolute pressure levels. For example, 

the diurnal morning surge in blood pressure is 

thought to be a trigger for CVS events such as MI 

and stroke. Thus during development of antihy-

pertensive drugs, particularly long-acting (once 

daily) ones, which are known to be desirable for 

improved compliance, the ability of a drug to 

sustain its effect is evaluated. One parameter 

used is the trough : peak (T/P) ratio, which is the 

blood pressure reduction recorded before the 

next dose compared to the maximum blood

dose. The ideal would be 1, but a minimum 

value of 0.5 is recommended by US FDA guide-

lines. Note that peak and trough in this context do not refer to plasma levels. Thus whatever 

dosage regimen is used, it should aim to produce a sustained reduction of blood pressure with 

minimal variability. This objective has not yet been incorporated into UK guidelines.

Combination therapy. Antihypertensive drugs 

act on many different sites or mechanisms that 

the body uses to maintain blood pressure (Figure

4.22). Thus, if control is not achieved by the 

optimal dose of one type there are several advan-

tages to combining two or failing that even three 

agents:

•  Additive or possibly synergistic effect. •  Reduced individual adverse effects.

•  Mutual antagonism of adverse effects.

When choosing a drug to be added, one from a 

different group should be added to the regimen 

to give an additive or possibly synergistic effect, 

ensuring that adverse interactions are avoided 

(see below).

Combinations can minimize adverse effects in 

two ways: firstly by keeping individual doses low 

and secondly by specific antagonism. In hyper-

tension the body’s blood pressure control mech-

anisms   have   been   reset   to   maintain   an 

abnormally high pressure, so that when a drug 

lowers pressure by interfering with one mecha-

nism, e.g. by dilating arterioles, the body even-

tually   responds   by   recruiting   another,   e.g. 

tachycardia or fluid retention, in an attempt to 

raise pressure again. Thus diuretics can cause 

palpitations (tachycardia) and renin release, and 

vasodilators  can  cause  fluid  retention (with 

possible  oedema)  and  tachycardia.  However, 

diuretics  will  counteract  oedema  and  beta-

blockers  will  prevent  tachycardia  and  renin 

release.  Furthermore,  vasodilators  will  coun-

teract   the   peripheral   vasoconstriction   that 

occurs with beta-blockers (causing cold hands 

and feet). Thus the combination of all three is 

logical if blood pressure warrants it.

Fixed-dose proprietary combination products 

are indicated only occasionally, owing to the 

usual problems of being unable to manipulate 

the doses of components independently, and 

the difficulty of ascribing adverse effects. One strategy is first to stabilize the patient on the 

individual components separately and then to 

introduce a combined product, if a suitable one is available, to aid compliance.

Monitoring

Regular follow-up is essential to monitor compli-

ance with therapy, possible adverse drug effects and disease progression, especially complications. Pharmacists have a role in promoting and re-

inforcing this process, through repeat prescribing, supplementary prescribing and involvement in chronic disease management programs.

Drugs used in hypertension

This section first discusses the properties of the 

various groups of antihypertensive agents and 

concludes by reviewing the rationale for drug 

selection.

Mode of action

Figure 4.22 shows the possible sites of action of 

common antihypertensive agents; their general 

haemodynamic actions are summarized in Table

4.21. However, their modes of action in hyper-

tension are often uncertain and some may act by more than one mechanism.

All antihypertensive agents, either directly or 

indirectly, affect cardiac output or peripheral 

resistance.  However,  cardiac  output  is  rarely 

raised in essential hypertension, and long-term 

reduction would compromise exercise tolerance 

or even resting systemic perfusion. So when we 

reduce cardiac output we rely on subsequent 

reflex vascular autoregulation to dilate vessels 

and  decrease  resistance  in  response  to  the 

reduced perfusion, thus restoring normal output. 

Recall  that  the  effect  on  cardiac  output  of 

reducing   the   afterload   varies   according   to 

whether the myocardium is unimpaired or in 

failure (Figure 4.4).

Diuretics

These cause a small sustained reduction in blood 

volume, and as a consequence also in cardiac 

output, but how far this contributes to their 

action  remains  unclear.  They  also  promote 

vasodilatation, partly due to autoregulation. The 

thiazides are more effective in hypertension than 

the more powerful loop diuretics, partly because 

they have a direct vasodilator action and partly 

because they generally have a longer duration of 

action (although loop diuretics may be given 

twice daily).

Angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists

Angiotensin-converting    enzyme    inhibitors 

(ACEIs) act at several sites crucial to blood pres-

sure maintenance, which probably accounts for 

their considerable success, although doubt still 

surrounds the principal antihypertensive mecha-

nism. The most likely explanation is that inhibi-

tion of angiotensin production causes both a 

direct reduction of arteriolar vasoconstriction 

and   a   secondary   reduction   of   aldosterone-

induced fluid retention. At least two other mech-

anisms may contribute. Angiotensin-converting 

enzyme (ACE) is also responsible for the break-

down of vasodilatory bradykinin, so kinin levels

rise when ACE is inhibited (causes the cough and angio-oedema associated with ACEIs; see below). There  may  also  be  a  direct  vascular  action inhibiting local angiotensin-induced vessel wall hypertrophy;  in  untreated  hypertension  this hypertrophy   contributes   to   the   long-term vascular complications.

Angiotensin receptor antagonists (ARAs) have very   similar   therapeutic   actions.   However, because  they  act  directly  on  the  angiotensin receptor rather than the converting enzyme that activates angiotensin, they do not inhibit the 

breakdown of bradykinin so do not cause a cough. Renin inhibitors are being evaluated.

Calcium-channel blockers

The mode of action of calcium-channel blockers 

(CCBs) is complex because the different calcium 

channels and associated receptors have not been 

fully characterized. There are at least two types 

of calcium channel, associated with different 

tissues: the L-type (in smooth muscle, including 

myocardium) and the T-type (in nodal/neuronal 

tissue). Existing agents block either the former 

only, or both.

A further distinction between target tissues 

is   in   the   post-receptor   excitation   coupling 

involving calcium. In cardiac muscle cells CCBs 

are  synergistic  with  beta-blockers.  Normally, 

adrenergic   stimulation   of   adjacent   beta-

adrenergic receptors opens the calcium channel, 

leading to an increase in intracellular calcium 

concentration. This promotes the Ca2  -troponin 

C interaction that eventually leads to contrac-

tion. Thus beta-blockers and CCBs have similar, 

synergistic inhibitory effects; in the heart, this 

negative inotropism and chronotropism can lead 

to severe depression of contractility. By contrast, 

in  peripheral  vascular  smooth  muscle,  intra-

cellular calcium interacts with calmodulin to 

promote contraction, whereas beta-stimulation 

inhibits this. Thus beta-blockers cause vasocon-

striction but CCBs promote relaxation; indeed, 

CCBs will antagonize the peripheral constriction 

sometimes experienced with beta-blockers.

The two main CCB groups, the dihydropy-

ridines (or DHPs, e.g. nifedipine, amlodipine) and 

the non-DHPs (diltiazem and verapamil), bind to 

different   receptor   sites   within   the   calcium 

channel. More importantly, they have different 

affinities for target tissues. The non-DHPs are 

more active on cardiac and nodal tissue, the 

DHPs   preferentially   target   vascular   smooth 

muscle.

Beta-blockers

By   inhibiting   the   intracellular   adenylate 

cyclase/kinase system, beta-blockers effectively 

prevent calcium entry into cells, so reducing 

sarcoplasmic    calcium    concentration.    This 

inhibits both smooth muscle contraction and 

tissue  conduction,  and  explains  their  similar

system

spectrum  of  activity  to  CCBs.  The  negative 

inotropic   action   of   the   beta-blockers   will 

certainly reduce cardiac output, but there are 

other possibilities. Thus beta-blockade reduces 

renin release and peripheral adrenergic (vaso-

constrictor) tone and there may also be central 

actions.   Long-term   reduction   in   peripheral 

resistance is an important overall effect.

Other vasodilators

This diverse and lesser used group of drugs acts 

on arteriolar tone at a variety of different sites, 

both locally and through the autonomic nervous 

system (Figure 4.22   and  Table 4.21).  Thus 

vasodilators with different modes of action may 

be combined.

Clinical use

Diuretics

Thiazide  diuretics  have  long  been  first-line 

drugs, owing principally to their low toxicity 

and the fact that they were among the first to 

have   been   convincingly   shown   to   reduce 

mortality in hypertension. They have numerous 

potentially  adverse  metabolic  or  biochemical 

effects  on  plasma  lipids,  glucose,  urate  and 

potassium (Table 4.22).  The  contribution  of 

these adverse effects to cardiovascular morbidity 

and mortality via arrhythmias, glucose intoler-

ance and atheroma is uncertain. In addition, 

they can cause impotence (erectile dysfunction) 

in males, seriously impairing quality of life.

Nevertheless, thiazides are still recommended 

by many authorities (e.g. NICE and the British 

Hypertension Society) as first-line drugs for mild 

to moderate hypertension (for certain patients, 

see below). One reason is that at low doses (e.g. 

bendroflumethiazide 1.25-2.5 mg daily), they are 

almost equally as effective as at the originally 

recommended  higher  dose  (5 mg),  but  cause 

significantly   fewer   adverse   effects.   This   is 

because the dose-response curve for an antihy-

pertensive effect reaches a plateau at quite low 

doses, whereas the dose-adverse effect curve is 

more linear (Figure 4.23); thus raising the dose 

increases the side-effects with no increase in 

therapeutic effect.

Potassium supplementation, which used to be 

routinely co-prescribed, although poorly toler-

ated and poorly complied with, is at this dose 

rarely needed. Besides, thiazides are increasingly 

used  in  combination  with  potassium-sparing 

diuretics or ACEIs. If potassium supplements are 

used in these circumstances the risk then is of 

hyperkalaemia rather than hypokalaemia.

Choice. There is little to choose between the 

available thiazides; bendroflumethiazide is among 

the cheapest. Most may be given once each 

morning. They seem particularly beneficial in 

Blacks,  whose  hypertension  is  often  volume-

dependent, and in the elderly because of their 

freedom from acute toxicity in low doses. In 

renal impairment loop diuretics are required, but 

these diuretics are otherwise avoided because 

they act briefly and so do not provide sustained control; they also lack the direct vasodilator 

effect of thiazides.

Beta-blockers

The  generally  mild  and  predictable  adverse 

effects and wide choice available within this 

group meant that for a long time they were 

usually first-line therapy for newly diagnosed 

hypertension. However, serious doubts were first 

raised by the ASCOT-BPLA and ALLHAT trials 

and   they   were   confirmed   by   subsequent 

meta-analysis. It was found that beta-blockers 

(particularly atenolol) were not as effective as 

ACEIs and CCBs in the primary prevention of 

cardiovascular   complications,   despite   having 

comparable   hypotensive   potency.   Moreover, 

beta-blockers have been shown to cause a rela-

tively high incidence of diabetes on long-term 

use. This prompted NICE in 2006, in collabora-

tion with the British Hypertension Society, to 

cease  recommending  beta-blockers  as  initial 

treatment.

Their precise role in multiple drug therapy for 

resistant  hypertension,  and  whether  certain 

beta-blockers are less acceptable than others, has 

yet to be decided. At present they still have an 

important role in hypertension associated with 

IHD (especially following MI) or stable heart 

failure. Further, patients already stabilized and 

well controlled on beta-blockers, experiencing 

no problems, should continue. On the other hand, patients taking beta-blockers who are not 

well controlled should be considered for step-

ping down and stopping them, converting the 

patient  to  the  scheme  discussed  below (see 

Figure 4.25).

Dose.   As with diuretics, recommended doses of 

beta-blockers  have  been  reduced  (e.g.  atenolol

50 mg daily) with no loss of antihypertensive 

action,  but  reduced  adverse  effects.  Once-  or 

twice-daily dosing is usually sufficient because 

the effect of beta-blockade is not directly related 

to plasma level. For once-daily dosing, to improve 

compliance, drugs with a longer half-life (e.g. 

atenolol), or modified-release formulations may 

be  used.  The  dose  should  start  low  and  be 

increased gradually. Should it be necessary to stop 

therapy, the dose must be tapered off equally 

slowly, especially in those with IHD, to reduce 

the risk of rebound adrenergic over-stimulation 

causing tachycardia, ischaemia, hypertension, etc.

system

Side-effects, contra-indications and cautions. 

The well-understood dose-related and physiolog-

ically predictable adverse effects are summarized 

in Table 4.23. Probably as a result of a combina-

tion  of  these,  beta-blockers  can  significantly 

reduce  the  quality  of  life  of  some  patients. 

Cautions and contra-indications can be antici-

pated  from  the  adverse  effect  profile.  Beta-

blockers must be used with extreme caution in 

obstructive airways disease, and probably not at 

all in asthma, although cardioselective ones can 

be cautiously introduced under specialist advice 

in mild asthma. They should also be avoided in 

peripheral vascular disease, Raynaud’s syndrome, 

bradycardia and heart block. Their use in heart 

failure is discussed on p. 201.

In patients with diabetes given beta-blockers, 

early  physiological  responses  to  developing 

hypoglycaemia (hunger, tachycardia, etc.) and 

the patient’s perception of these effects are dimin- ished,   with   potentially   serious,   though 

fortunately  rare,  results.  In  type 2 diabetes, 

insulin release may be inhibited, which aggra-

vates hyperglycaemia and impairs control (see 

Chapter 9, p. 586). Thus in general they should be 

avoided in hypertensive patients with diabetes. 

Choice. All beta-blockers have equivalent anti-

hypertensive  activity.  Three  main  properties 

yield  criteria  for  differentiating  beta-blockers 

(Figure 4.24).   Possible   adverse   effects   and 

precautions (Table 4.23) further qualify choice.

Cardioselectivity  is  conferred  by  a  greater 

affinity for beta1-receptors, located mainly on 

the myocardium, compared with beta2-receptors 

(most   other   beta-adrenergic   sites).   Cardio-

selectivity is relative and is less marked at higher 

doses. Nevertheless, selective agents are preferred 

in all but those few indications where infor-

mation  on  their  use  is  inadequate,  such  as 

hypertrophic   cardiomyopathy,   thyrotoxicosis, 

migraine and immediately after an MI. Respira-

tory, metabolic and peripheral vasoconstrictor 

effects (mediated via beta2-receptors), are still 

seen, and even selective agents are potentially 

hazardous in patients with severe asthma.

Intrinsic   sympathomimetic   activity(ISA, 

partial  agonist  activity)  may  offset  broncho- constriction,  peripheral  vasoconstriction  and 

myocardial  depression  in  some  patients.  The 

vasodilator action is perhaps the most useful. 

Pindolol  has  the  greatest  ISA.  A  similar  effect 

is  achieved  in  agents  that  have  additional 

alpha-blocking   activity(labetalol,   carvedilol). 

Celiprolol combines highly selective beta1-blocker 

with  selective  beta2-stimulant  activity,  which 

also   counteracts   peripheral   vasoconstriction. 

Nebivolol  has  vasodilating  activity  via  a  NO 

mechanism.

Lipophilic beta-blockers, as expected, cross the 

blood-brain barrier and require hepatic metabo-

lism before elimination. Central beta-blockade 

can cause CNS disturbances, most marked with 

propranolol. Hepatic clearance means potentially 

low bioavailability (owing to first-pass metabo-

lism) and a shorter half-life (unless there are 

active  metabolites).  Pindolol  and  timolol  are 

cleared  both  renally  and  hepatically,  making 

their elimination less susceptible to impairment 

of either system.

ACEIs

ACEIs seem to interfere with quality of life less 

than other antihypertensive agents, particularly 

important in lifelong treatment. They are now often used as first choice in moderate hyperten-

sion in combination with a diuretic, as well as in 

severe resistant hypertension regardless of renin 

levels because they effectively combat the raised 

renin levels induced by diuretics. Combination 

with CCBs or beta-blockers is also successful. 

ACEIs are especially useful in diabetic hyperten-

sion because they protect against nephropathy 

(see Chapter 9, p. 603). ACEIs have an undis-

puted  place  as  sole  therapy  in  renovascular, 

high-renin hypertension.

ACEIs are proving to be remarkably free of the 

adverse effects common with other potent anti-

hypertensive   agents,   both   serious(central, 

postural,   dysrhythmic   and   metabolic)   and 

simply troublesome (fatigue, sexual and mental 

impairment).  Most,  apart  from  lisinopril  and 

captopril, are prodrugs activated in the liver.

Side-effects,  contra-indications  and  precau-

tions  (Table 4.24).   The main problems with 

ACEIs are related to their potent antihyperten-

sive and anti-aldosterone actions. Severe first-

dose  hypotension  may  occur,  particularly  in 

volume- or salt-depleted patients such as those 

already on diuretic therapy. Sometimes patients 

are initiated on a low dose of the short-acting 

captopril  given  at  night  to  test  their  reaction, 

and switched to a longer-acting preparation if 

successful; alternatively low initial doses of long-

acting drugs such as perindopril or lisinopril, and 

careful titration, can minimize this problem. If 

possible,  diuretics  should  be  stopped  a  day 

before starting ACEI therapy, and reintroduced 

carefully if necessary under medical supervision. 

Significant   hyperkalaemia   may   follow   con-

comitant use of potassium-sparing diuretics or 

potassium supplements. Rarely, severe hypersen-

sitivity reactions (i.e. angio-oedema, with fatal 

laryngeal obstruction) have occurred.

The possibility of severe renal impairment is 

related to hypotension, especially if there is pre-

existing renal disease, owing to reduced renal 

perfusion pressure. A particular problem is bilat-

eral renal artery stenosis (usually atherosclerotic 

in origin). In such cases the blood pressure is 

being kept high by elevated renin levels in order 

to maintain renal perfusion. Inhibition of the 

RAAS may then produce a disastrous fall in blood 

pressure,   even   precipitating   acute   pre-renal 

failure. In the elderly, caution is even advised

with  ACEIs  in  unilateral  stenosis.  Peripheral vascular disease or other evidence of widespread atheroma would suggest the possibility of renal artery stenosis and indicate the need for avoid-

ance or careful monitoring.

Persistent  dry  cough  affects  up  to  20%  of patients. It is probably due to excess bradykinin (which  is  usually  metabolized  by  ACE),  and sometimes proves intolerable, in which case an ARA can be substituted.

Initial   reports   of   bone   marrow   toxicity (neutropenia) with captopril  resulted from the use of unnecessarily high doses. Moreover, these and some other adverse effects, e.g. taste distur-

bance and skin rash, may be immunologically based, and related to the sulphydryl group found in captopril but not later ACEIs (see also penicil-

lamine; Chapter 12, p. 772). Rarely, neutropenia can occur with any of the ACEIs.

The principal drug interaction of the ACEIs, 

apart    from    that    with    potassium-sparing 

diuretics, is with NSAIDs. Partly through their 

action on intrarenal PGs, NSAIDs used in combi- nation with ACEIs can result in a reduced anti-

hypertensive effect, increased renal toxicity and increased potassium retention.

Renin inhibitor. Recently released is aliskiren, a direct inhibitor of renin, which works upstream in the renin/angiotensin cascade.

Angiotensin-II receptor antagonists

At present, the only strong indication for this 

group is when ACEIs are not tolerated. They 

produce   far   less   cough   and   angio-oedema. Otherwise, they are equally effective antihyper-

tensive agents and yield equal improvements in cardiovascular  morbidity  and  mortality.  One recent analysis has suggested they may increase MI but this is not yet widely accepted.

Calcium-channel blockers

These are increasingly used as initial therapy in 

hypertension because they cause fewer adverse 

cardiovascular, bronchial and metabolic prob-

lems than the beta-blockers. Careful selection 

within the group is needed for specific indica-

tions (Table 4.25).  Predominantly  vasodilator 

agents are preferred in hypertension, but anti-

arrhythmic and negative inotropic activity is 

useful in hypertensive patients with IHD. The 

non-cardiodepressant CCBs (the DHPs) can be 

usefully  and  safely  combined  with  a  beta-

blocker.

Side-effects.   Most problems, such as flushing 

and  headaches,  are  minor  and  result  from 

vasodilatation, particularly with the DHPs. Simi-

larly, reflex tachycardia with possible palpita-

tions may occur. However, this is undesirable in 

ischaemic  patients  because  it  increases  myo-

cardial oxygen demand so, in the absence of 

ventricular dysfunction, the use of a non-DHP 

(e.g. verapamil), or combination with a beta-

blocker,  is  recommended.  Peripheral  oedema, 

usually in the ankles, is a common problem and 

is caused by leakage from precapillary vessels 

subjected to higher pressures owing to arteriolar 

dilatation.  Because  it  is  not  caused  by  fluid 

retention,  the  oedema  does  not  respond  to 

diuretics but may respond to an ACEI. Non-

DHPs have less effect on blood vessels but are 

cardiodepressant, with the risk of heart failure or 

bradycardia.

Cautions and contra-indications.   Discontinu-

ation  has  been  associated  with  exacerbated 

ischaemic events in those with IHD, and so 

should be performed gradually. Combination of 

the negatively inotropic agents verapamil, dilti-

azem  and nifedipine  with beta-blockers is best 

avoided or used with great care, especially where 

there is left ventricular dysfunction, because it 

can cause heart failure or heart block. Enzyme 

inhibition  by  grapefruit  juice  enhances  the 

action   of   most   CCBs,   except   amlodipine. 

Different modified-release preparations of CCBs 

are  not  interchangeable  and  should  not  be 

prescribed or supplied generically.

Vasodilators

This large heterogeneous group (Table 4.21) has 

had a chequered history in hypertension treat-

ment. Not surprisingly, the first antihypertensive 

agents used targeted the peripheral arterioles. 

Predominant arterial dilatation is preferred but 

this   can   cause   postural   hypotension   by 

inhibiting natural reflex vasoconstriction. Early 

sympatholytic vasodilators, including ganglion 

blockers (e.g. hexamethonium) and non-specific 

alpha-blockers (e.g. phentolamine), had limited 

effectiveness and serious adverse effects, chiefly 

postural  hypotension,  impotence  and  reflex 

tachycardia. Reserpine caused severe depression. 

The adrenergic neurone blockers (e.g. guanethi-

dine), although somewhat more successful, still 

have serious adverse effects and are reserved now 

for resistant hypertension.

Newer vasodilators cause fewer postural prob-

lems and most induce fewer lipid abnormalities 

than beta-blockers or thiazides. Other common 

vasodilator drawbacks, such as headaches, dizzi-

ness,  palpitations,  flushing  and  reflex  fluid 

retention, are less serious. One of the miscella-

neous‘reserve’   group   of   the   more   toxic 

direct-acting vasodilators (e.g. minoxidil) is still 

sometimes needed.

Centrally acting sympatholytics (e.g. methyl-

dopa, clonidine) have long been used as third- or 

fourth-line  drugs,  but  now  have  little  place 

owing  to  central  effects  such  as  impotence 

and  depression.  However,  methyldopa  remains 

a  useful  alternative  in  a  variety  of  special 

circumstances where standard drugs are contra-

indicated, e.g. in diabetes, in the hypertension of 

pregnancy and when postural hypotension is 

especially hazardous, such as in the elderly or in 

those with cerebrovascular disease. Clonidine is 

now known to act partly via central imidazoline 

receptors and has been associated with depres-

sion; the newer more specific moxonidine may 

have fewer adverse effects.

The direct-acting spasmolytic hydralazine lost 

favour  owing  to  its  tendency  to  precipitate  a 

lupus-like syndrome, especially in slow acetyla-

tors. However, at doses below 100 mg daily the 

risk is small. The selective (post-synaptic alpha2) 

adrenergic blockers, e.g. prazosin, terazosin, doxa-

zosin, seem to cause less tachycardia and, except 

for  the  first  dose,  less  postural  hypotension.

They   also   reduce   plasma   cholesterol   and 

produce a favourable change in the HDL/LDL 

ratio.

Drug selection

Diuretics, ACEIs, ARAs and CCBs have all been 

shown in long-term controlled trials to reduce 

overall mortality in hypertension. The first has 

long  been  known  to  be  effective,  but  more 

recently the HOT trial produced evidence in 

support of ACEIs and CCBs. Nevertheless, after 

the ALLHAT trial, diuretics still emerged as the 

cheapest and least toxic first drugs, and they are 

usually   recommended   as   effective   first-line 

therapy by many authorities in the absence of 

contra-indications.

Because almost all existing antihypertensive drugs   have   comparable   blood   pressure-

lowering  efficacy,  the  optimal  order  of  selec-

tion  in   an   individual   patient   is   governed primarily  by  adverse  effects,  precautions  and contra-indications. Factors that modify choice in common   conditions   or   patient   groups   are summarized in Table 4.26.

Numerous schemes have been devised to aid 

selection. The scheme favoured by the British 

Hypertension  Society  (2006)  shown  in  Figure

4.25represents  one  of  the  simplest  and 

clearest.  It  is  based  on  the  categorization  of 

hypertension into low-renin (fluid overloaded) 

and  high-renin (vasoconstricted)  forms,  and 

makes   the   primary   distinction   for   initial 

therapy  based  on  the  lesser  effectiveness  of 

ACEIs  in  black  people,  the  greater  suitability 

for  or  tolerance  to  diuretic  or  CCBs  in  older 

patients, and the greater likelihood of renovas-

cular  atheroma  in  the  elderly (thus  avoiding 

ACEIs).  Younger  patients  who  cannot  tolerate 

ACEIs, or women of childbearing age, should 

be  considered  for  beta-blockers.  It  may  be 

advisable to try several different monotherapies 

if control is not achieved with the first, before 

starting dual therapy. Logical combination dual 

therapy is the next step. A particular combina-

tion  that  should  be  avoided  is  diuretic  plus 

beta-blocker,  which  has  an  increased  risk  of 

inducing  diabetes.  Triple  therapy  is  the  third 

stage;  although  the  evidence  base  for  this  is 

poor,  it  represents  consensus  advice  and  has sound pharmacological and pathophysiological 

logic.

At  every  stage,  the  cautions  and  contra-

indications  of  each  drug  for  the  particular 

patient need to be considered. However, as the 

need for multiple therapy increases there is less 

room  for  manoeuvre  and  compromises  may 

have to be made.

Many other combinations are possible, partic-

ularly in refractory hypertension. If a patient is 

not controlled on three drugs, expert advice 

should usually be sought. The choice of a fourth 

drug would be an alpha-blocker, a potassium-

sparing diuretic (amiloride, spironolactone) or a 

beta-blocker.

Attention must also be paid to potential drug 

interactions  of  antihypertensive  agents.  Table

4.27 illustrates the general principles with some 

representative examples. Details will be found in 

standard   texts (see   References   and   further 

reading).

Additional  therapy.   Atherosclerosis  prophy-

laxis with antiplatelet drugs and a statin also 

need  to  be  considered  for  all  hypertensive 

patients, in the light of their overall CVD risk (p. 

216). For aspirin, the side-effect risk is not trivial 

and  the  current  recommendation  is  first  to 

ensure good blood pressure control then use 

aspirin, in the absence of contra-indications, i.e. 

for primary prevention:

•  in patients over  50 years with evidence of

hypertension-induced organ damage;

•  where the 10-year CVD risk is20%; •  in diabetes.

For secondary prevention, use aspirin in all cases, i.e. where there is existing ischaemic disease.

and vascular obstructive disease235

The use of statins also depends on CVD risk 

and is discussed in detail below (p. 247; Table

4.32),  but  the  considerations  are  similar  to 

aspirin without the age criterion. Thus use statins 

for primary prevention where the 10-year CVD 

risk is20% and in all cases for secondary 

prevention. 

Ischaemic heart disease

Ischaemia means literally ‘to hold back blood’. 

Ischaemic heart disease (IHD) is the collective 

name  for  a  number  of  conditions  in  which 

obstructive  lesions  of  the  coronary  arteries 

restrict myocardial blood flow. IHD is also called 

‘coronary  artery  disease’  or  simply‘heart 

disease’.  The  main  clinical  manifestations  are 

angina pectoris and MI, but heart failure and 

arrhythmias  also  occur.  IHD  is  the  greatest 

single  cause  of  death,  especially  premature 

death, in industrialized societies. In the UK it is 

responsible for about a third of all male deaths 

and  causes  considerable  morbidity.  This  is 

especially  significant  because  IHD  is  largely 

preventable.

There   are   wide   geographic,   ethnic   and 

national  variations  in  prevalence,  e.g.  male 

mortality   from   IHD   per100000varies 

between 400 in  Finland  and 30 in  Japan. 

However,  immigrant  groups  tend  to  assume 

the  same  prevalence  as  their  host  country 

when  fully  assimilated,  showing  the  impor-

tance of environmental risk factors. Epidemio-

logical and pathological studies and large-scale 

intervention  trials  strongly  suggest  that  the 

causes  lie  in  the  industrialised  or  developed 

way of life.

Atherosclerosis and vascular obstructive disease

The pathology and treatment of IHD can best be 

understood in the general context of vascular 

obstruction(partial   block)   and   occlusion 

(complete block), and so we will review this first.

Classification

The main processes responsible for chronic arte-

rial obstruction are arteriosclerosis and athero-

sclerosis. In addition, thrombosis may occur as 

an acute complication, in both veins and arteries 

(Figure 4.26).

Arteriosclerosis

Although   this   term   is   commonly   used   to 

describe all degenerative or proliferative arterial 

lesions, it should be reserved for the symmetrical 

thickening of the middle muscle layer (media) of 

arterioles throughout the body. It usually arises 

in response to hypertension, when it may be 

partially reversed by treatment, but it also seems 

to be a normal consequence of ageing. Because it 

is widely disseminated and invades the vessel 

lumen it increases peripheral resistance, thus 

aggravating  hypertension  and  perpetuating  a 

vicious circle. The media often becomes fibrosed 

and  calcified,  especially  in  the  elderly.  It  is 

popularly known as ‘hardened arteries’.

At first there may be no significant impair-

ment of perfusion. However, in the elderly there 

may be chronically reduced cerebral or renal 

perfusion.   Moreover,   the   stiffened,   non-

compliant vessels are weakened and eventually 

may bulge (aneurysm) and rupture, particularly 

in  cerebral  vessels  where  the  result  is  acute 

haemorrhagic stroke.

Arteriosclerosis is described here to differen-

tiate  it  from  atherosclerosis.  It  will  not  be considered further and all that follows will apply specifically to atheroma/atherosclerosis.

Atherosclerosis

In  this  condition,  fatty-fibrous  plaques  or 

atheromas are deposited asymmetrically within 

the innermost layer (intima) of certain, but not 

all,  arteries.  Sites  such  as  bends,  branches  or 

bifurcations seem especially prone. This patchy 

(focal)  distribution  means  that  there  is  little

system

effect  on  total  peripheral  resistance,  but  local perfusion  may  be  crucially  impaired.  Athero-

sclerosis  can  occur  in  many  different  organs, the  result  being  a  wide  spectrum  of  clinical manifestations (Figure 4.27).

Thrombosis

Thrombi result from abnormal triggering of the 

coagulation  process  within  intact  arteries  or 

veins (rather than, as is normal, after damage or 

rupture). This causes sudden occlusion. Small 

particles of thrombus may break off forming 

thromboemboli,  which  lodge  further  down-

stream, with similar outcome. Arterial thrombi 

frequently form at the sites of coronary or cere-

bral atherosclerotic lesions, with potentially fatal 

consequences (Figure 4.27). For a full discussion 

of thrombosis, see Chapter 11.

Aetiology

Classes of contributory factors

An understanding of the formation of atheroma and thrombosis is important for both prevention and treatment. At the most general level the 

contributory factors may be grouped into three categories:  histological (endothelial  damage), 

rheological(abnormal    blood    flow)    and

biochemical(abnormal    blood    or    tissue 

constituents). These may occur independently or 

together (Table 4.28). The response to injury 

theory proposes that atherosclerosis arises from a 

maladaptive chronic inflammatory reaction in 

which an attempt is made to repair the vascular 

wall or to limit chronic damage. This reaction 

persists at the expense of obstructing the vessel 

lumen and possibly promoting further damage.

Vascular endothelial damage

An atheroma is probably initiated by factors that 

breach   the   arterial   endothelial   defences, 

exposing   underlying   tissue.   Constituents   of 

tobacco smoke undoubtedly contribute to this. It 

is also possible that partially oxidized compo-

nents of the plasma lipid particle LDL irritate the 

endothelium, with more significant oxidation 

occurring within the wall. Recent findings have 

implicated chronic inflammatory damage from 

systemic microbial colonization, possibly with 

Chlamydia or Helicobacter species. Finally, hyper-

lipidaemia itself may be directly damaging to the 

vessel wall.

A  sudden   rupture   or   ulceration   of   a 

previously  stable  atheromatous  plaque  may 

triggerthrombosis,    with    acute    effects. 

Inflamed  venous  or  heart  valves  are  also  foci 

for thrombosis.

Abnormal flow

In arteries, atheromas are most commonly found 

where flow is turbulent and wall shear forces 

high. Presumably this causes endothelial cell 

dysfunction; possibly this is because it interferes 

with   shear-triggered,   nitric   oxide-mediated 

vascular   relaxation,   which   alters   LDL   flow 

through the vessel wall, or causes enlargement of 

intercellular gaps allowing abnormal access of 

irritants.  Atheromas  do  not  usually  form  in 

veins, although they are found in the normally 

low  pressure  pulmonary  arteries  in  cases  of 

pulmonary hypertension.

In veins, it is abnormally sluggish flow that 

causes problems, e.g. prolonged bedrest or long-

distance air travel predispose to venous (‘deep-

vein’) thrombosis, usually in the leg. This is one 

reason why patients are mobilized rapidly after 

surgery. In atrial fibrillation, static pools of blood 

develop within the heart and may clot. In either 

case  thrombi  may  be  carried  downstream  as 

emboli. From the leg the path taken by emboli 

follows widening veins to the right heart, ulti-

mately to lodge in a pulmonary artery. Thrombi 

originating from the right atrium also lodge in 

the lungs, while those from the left atrium lodge 

in the brain or coronary arteries.

Abnormal constituents

Endothelial damage can trigger platelet adhesion 

and aggregation or the clotting cascade, espe-

cially if there is an imbalance between platelet 

promoter and inhibitor factors. For example, 

certain  PGs (e.g.  prostacyclin  released  from 

vascular endothelium) tend to inhibit platelet 

activation and aggregation while others, notably 

the  thromboxane  series,  are  pro-aggregatory. 

Clotting factor abnormalities, e.g. high levels of 

fibrinogen, have been found in IHD patients. 

Coagulation is also disturbed following severe 

trauma, e.g. major surgery, and by certain drugs, 

e.g. oral hormonal contraceptives. Smoking may 

contribute   by   providing   irritants   or   local 

hypoxia.

Risk factors

The  major  international  INTERHEART  study 

(2004) of 15 000 individuals from all continents 

identified nine modifiable risk factors that could

system

account for 90% of all MIs (a condition that can 

act as a surrogate for atherosclerosis in general). 

Moreover five of these accounted for 80% of the 

risk: hyperlipidaemia (dyslipidaemia), smoking, 

diabetes, hypertension and abdominal obesity 

(Table 4.29). Dyslipidaemia is measured as the 

LDL/HDL ratio (see below); obesity is measured 

as the waist to hip ratio (found to be more 

closely linked to disease than the traditional 

body  mass  index);  diabetes  may  act  partly 

through the associated dyslipidaemia. These act 

synergistically, so that for example possessing 

any two poses more than twice the risk.

Many  other  less  critical  factors  have  been 

implicated, some of them associated with indus-

trialized societies and modifiable by changes to 

lifestyle, others not modifiable (Table 4.29). A 

possible protective effect of moderate alcohol 

intake  is  still  widely  debated.  There  is  also 

evidence of prenatal influences on the fetus. 

Maternal nutritional deprivation may cause not 

just low birthweight but also a predisposition in 

later life to atherosclerosis, hypertension and 

diabetes. The prevalence in younger males is 

about three times that in females, but the rates 

converge  later  in  life  because  the  incidence 

among   postmenopausal   women   is   greatly 

increased.

The lipid hypothesis

The lipid hypothesis of atherogenesis traces the 

causal links between dietary lipid, plasma lipid, 

atherosclerosis and IHD. An outline of the steps 

in the argument is given in Table 4.30. Patients 

with familial hyperlipidaemia have long been 

known to suffer a high incidence of premature 

atherosclerotic disease. A similar pattern is seen 

in  diabetics,  whose  lipid  metabolism  is  also 

disturbed. However, the relationship between 

dietary lipid and plasma lipid, especially choles-

terol,   and   the   mechanisms   controlling   the 

metabolism, transport and interconversions of 

lipid within the body, are incompletely under-

stood. Note that plasma cholesterol is only part 

of the body pool of cholesterol, 75% of which 

derives  from  hepatic  synthesis  and  only  a 

quarter directly from dietary cholesterol. This is 

why, although dieting often helps to reduce lipid 

levels moderately in many patients, even the 

most rigorous diet may not reduce plasma lipids sufficiently in some. Moreover, dietary saturated fat has more influence on plasma cholesterol 

than dietary cholesterol itself.

Saturated   fatty   acids(SFA,   from   animal sources) raise LDL levels, partly by stimulating cholesterol synthesis, and both cholesterol and saturated fats may stimulate the synthesis of 

aggregatory PGs. Of course, some dietary SFA intake is nutritionally essential.

By   contrast,   unsaturated   fats   in   general 

(mostly oils from plant sources and fish oils) 

appear to have a protective effect, possibly by 

increasing the breakdown of LDL. Polyunsatu-

rated fatty acids (PUFA) are thought to be bene-

ficial  in  both  reducing  LDL  and  increasing 

synthesis   of   antithrombotic   anti-aggregatory 

blood factors. PUFA, however, and particularly 

those of the n-6 series, are prone to oxidation 

and in large amounts may reduce HDL. Mono-

unsaturated fatty acids (MUFA; found especially 

in olive oil and rape seed oil) do not have these 

disadvantages. Polyunsaturates in the omega-3 

series (especially fish oils) appear to be protec-

tive, probably by an antithrombotic action. It is

known that fish-eating populations such as the Eskimos and the Japanese have a low incidence of atherosclerosis.

Other factors

Regular exercise is protective, partly by raising 

plasma HDL levels and possibly by encouraging 

the development of collateral blood vessels. Both 

exercise  and  low-fat  diets  may  reduce  blood 

pressure, and hypertension is an independent 

atheroma risk factor. A large number of other 

substances have been implicated in the aetiology 

and  pathogenesis  of  IHD,  including  dietary 

factors (e.g.  folic  acid,  flavinoids)  and  other 

plasma constituents (e.g. lipoprotein a, homo-

cysteine and fibrinogen), but the evidence is 

currently less convincing for these.

Evidence.   The  lipid  hypothesis  is  strongly 

supported  by  two  important  epidemiological 

observations. First, a correlation exists between 

the mean plasma cholesterol levels of different 

population groups (even those with relatively 

low   mean   levels)   and   their   prevalence   of atherosclerosis.   Secondly,   large   population groups who have reduced dietary lipid intake, e.g. in the USA and Finland, have achieved a 

decline in heart disease.

The role of pharmacological intervention with 

lipid-regulating drugs in secondary prevention is 

now well established, even in patients with what 

were formerly considered ‘normal’ lipid levels 

( 5.5 mmol/L  total  cholesterol).  Furthermore, 

their use in primary prevention is justified in 

harm/benefit terms for those with a high CVD 

risk.  Four  major  intervention  trials  reporting 

from different parts of the world have provided 

persuasive evidence of the benefits of reducing 

lipid levels pharmacologically on morbidity and 

mortality from IHD and stroke. They have also 

shown that using statin lipid-regulating drugs 

significantly improves the outcome, with very 

little added harm.

The Scandinavian 4S trial targeted secondary 

prevention   in4400   patients   with   hyper-

lipidaemia and existing IHD (angina or MI). The

CARE trial was similar, but the 4000 patients had 

near-average lipid levels. The Scottish WOSCOPS 

trial involved primary prevention in over 6500 

men  with  hyperlipidaemia  but  no  ischaemic 

symptoms. In the Heart Protection Study (HPS), 

20000 high-risk patients with cholesterol levels 

that would not at the time have mandated lipid-

lowering were treated. In all cases the beneficial 

effects were correlated with the reduction in 

lipid levels. A significant observation was that 

the degree of benefit depended more on the 

degree   of   reduction   than   on   the   initial 

cholesterol  level.  This  has  brought  about  a 

change in the approach to lipid lowering. Now 

the aim is to lower cholesterol based on overall 

cardiovascular  risk  rather  than  absolute  lipid 

level.

Recently the penultimate step in the lipid 

hypothesis received support in the ASTEROID 

clinical  trial,  which  showed  a  reduction  in 

atheroma lesions after 2 years of high-dose statin 

therapy (rosuvastatin). Statins may also have a role here beyond simply lowering plasma lipid, acting on platelets or directly on the vascular 

endothelium. However, evidence is still awaited that such plaque reduction produces significant improvement   in   clinical   outcomes   such   as ischaemic events in the long term.

Pathogenesis

The precise sequence of events leading to the 

development  of  an  atheromatous  plaque  is 

complex and incompletely understood. In an 

evolving  plaque  there  are  chronic  immuno-

inflammatory   cells   such   as   T-lymphocytes, 

macrophages and fibroblasts, together with a 

wide variety of mediators and cytokines with 

chemotactic, cytotoxic, growth-promoting, pro-

aggregatory and pro-inflammatory actions. This 

supports   the   concept   of   atheroma   being 

primarily a protective mechanism. In addition, 

in the latest modification to the lipid hypothesis, 

a primary causative role is given to an abnor-

mally  oxidized  form  of  LDL.  It  is  uncertain 

exactly   how   and   where   the   LDL   becomes 

oxidized, but it is likely to be after uptake into 

the  intima,  where  macrophages,  endothelial 

cells and smooth muscle cells may be involved.

The process may result in part from an imbal-

ance between pro-oxidant factors and natural 

antioxidant   substances   such   as   tocopherol 

(vitamin E), carotene (vitamin A) and ascorbate 

(vitamin C). However, no convincing benefit has 

yet  been  shown  to  result  from  regular  anti-

oxidant  vitamin  therapy.  Similarly,  although 

inflammation secondary to chronic low-grade 

infection with Clostridia or Helicobacter species 

has been proposed as a factor, trials of antibiotics 

have proved negative.

Figure  4.28 gives an overall picture of the 

process. It is necessarily a simplified summary of 

complex and poorly understood events, but will 

serve to identify potential targets for therapeutic 

intervention.

Following endothelial damage, LDL particles 

gain access to the intima. Here their components 

are oxidized by peroxidase enzyme and thereby 

rendered    immuno-active(particularly    the 

oxidized  apoprotein  component)  as  well  as 

perhaps doing further direct damage. Part of the

and vascular obstructive disease241

protective action of HDL may be in antagonizing 

this process, or removing oxidized LDL particles 

before they do harm. Otherwise, T-lymphocytes 

recognize the particles as foreign and secrete 

mediators that recruit other immune cells, as 

well   as   causing   further   local   inflammatory 

damage. Macrophages displaying receptors for 

oxidized   LDL   scavenge   it   by   phagocytosis, 

forming ‘foam cells’, some of which break down 

to release free lipid.

The   process   may   cease   at   this   point, 

resulting in relatively innocuous ‘fatty streaks’ 

of  little  haemodynamic  consequence  within 

arteries.  Such  lesions  are  often  found  in 

young,  otherwise  healthy  adults,  but  there  is 

still  debate  over  whether  they  are  early  signs 

of  clinical  atherosclerosis  or  a  separate  harm-

less phenomenon.

If the risk factors persist, the defence mecha-

nisms   may   be   overwhelmed.   Platelets   are 

attracted and secrete chemotaxins and platelet-

derived  growth  factor.  This  induces  smooth 

muscle cells to migrate from the media into the 

intima,   and   fibroblasts   to   start   producing 

collagen  fibres.  Locally  produced  angiotensin 

may   also   contribute   to   growth   promotion, 

providing  one  possible  prophylactic  role  for 

ACEIs. The connective tissue matrix of the devel-

oping atheroma is thus strengthened, and even-

tually a protective fibrous cap forms over the 

lipid and foam cells, which becomes overgrown 

by new endothelial cells. Some are almost unde-

tectable  and  have  been  classified  as ‘lurking 

future lesions’. A stable plaque will have a high 

proportion of fibrous components whereas an 

unstable one - which is liable to rupture and 

promote thrombosis - has more macrophages 

and lipid.

Progression and outcome

Chronic  vascular  obstruction  may  follow  a 

number  of  courses (Figure 4.29).  The  most 

benign outcome is repair. The atheroma remains 

small, and is overgrown by a tough fibrous cap. 

The  small  degree  of  residual  obstruction  is 

unlikely to cause symptoms. If the obstruction 

grows larger before it stabilizes, new blood chan-

nels  may  eventually  be  formed  through  it r(ecanalization). However, slow progression of the flow restriction is more usual, with gradually worsening symptoms, e.g. angina in the heart or intermittent   claudication  in  the  periphery 

(usually the legs).

Sometimes there will be an acute complica-

tion.  The  plaque  may  rupture,  followed  by 

platelet aggregation and possibly thrombosis; or 

perhaps a weakened atheroma cap may split and 

haemorrhage. Such an event does not necessarily 

result from a particularly large plaque: it seems 

to be not the size but the stability of the plaque 

that is critical.

In milder cases the result is a platelet aggregate 

with only a small degree of thrombosis, which is 

reversed   by   the   normal   plasma   defence

processes, e.g. plasmin, which dissolves small accidental   intravascular   clots.   This   could underlie unstable angina or TIAs, and there is minimal anoxic cell death (necrosis).

In other cases there is substantial rupture and 

a massive irreversible thrombus develops causing 

complete   occlusion   and   subsequent   anoxia 

downstream. This commonly occurs in coronary 

or cerebral vessels, resulting in myocardial or 

cerebral  infarction (MI  or  stroke).  It  is  even 

possible that relatively innocuous ‘lurking’ lesions 

could  rupture  and  cause  a  major  ischaemic 

event, in which case the patient would not have 

had any prior warning - nor would conventional 

angiography,   had   it   been   performed,   have 

revealed any significant abnormality. 

Figure 4.30 shows the transverse section of an 

artery severely obstructed by an atherosclerotic 

plaque.

Myocardial ischaemia

Why the heart?

The general clinical consequences of ischaemia 

were discussed in Chapter 2 (p. 58). The factors 

that make the heart particularly sensitive are:

•  The myocardium has a high O2  demand and 

high O2 extraction.

•  The heart works continuously.

•  There are relatively few coronary collateral 

vessels.

•  Myocardial   cells   regenerate   poorly   after 

damage.

•  The heart is an integrated organ.

Unlike the brain, the lung or the kidney - other 

important organs that are sensitive to ischaemia

- the whole heart functions in an integrated 

manner so that malfunction of any part will 

have a disproportionate effect on overall effi-

ciency. Because it is not composed of many 

identical functional subunits, the heart cannot 

divert function from damaged areas to healthy 

ones. The efficient ejection of blood requires 

coordinated contraction, and the process uses 

the whole myocardium to conduct the electrical 

excitation, so even small areas of ischaemia or 

necrosis can severely reduce pump performance.

Thus the heart is a prime target for circulatory 

insufficiency, and because it is such a vital organ 

the results are almost always serious. This is why 

IHD is such a problem. Furthermore, atheromas 

seem to be deposited preferentially in the coro-

nary circulation. This may be a consequence of 

the anatomy, because coronary flow is retrograde 

(backwards towards the heart) and thus poten-

tially turbulent. Because the left ventricle has the 

greatest oxygen demand and the most vascula-

ture, coronary atherosclerosis usually affects the 

left ventricle.

Myocardial oxygen balance

The degree of ischaemia in a tissue depends on 

the balance between oxygen supply (in blood) 

and   oxygen   demand.   Myocardial   oxygen 

demand varies according to circulatory require-

ments.   Assuming   that   blood   is   adequately 

oxygenated,   myocardial   oxygen   supply   is 

normally determined by the calibre of the coro-

nary vessels and coronary perfusion pressure. 

The calibre is altered mainly by reflex autoregu-

lation in response to local oxygen levels. The 

perfusion pressure is the difference between pres-

sure in the left ventricle at the end of diastole 

(LVEDP) and mean aortic pressure. This balance 

between supply and demand can be disturbed by 

either excessive demand or reduced supply.

Excessive myocardial demand

The fixed lesions of atherosclerosis limit the 

extent of the dilatation that can be induced by 

autoregulation (or drugs). Thus while coronary 

perfusion may be adequate at rest, at some point 

during escalating effort blood flow will be unable

system

to   increase   sufficiently   to   meet   the   rising demand. Because normally the myocardium has few collateral vessels, the area beyond a lesion will become ischaemic.

Symptoms become evident only after 75% of 

the  lumen  of  a  major  coronary  vessel  has 

become obstructed, at first only on strenuous 

exertion. There will be no permanent damage to 

the myocardium if effort, and thus cardiac work-

load,  is  promptly  reduced.  The  ischaemia  is 

partial and is reversed when oxygen demand 

falls. This produces the typical clinical picture of 

acute predictable onset and rapid reversibility 

that is characteristic of classical angina pectoris 

(often called ‘angina of effort’).

Restricted oxygen supply

If   an   event   such   as   rupture   followed   by 

thrombus formation produces complete occlu-

sion,  or  greater  than 90%  obstruction,  then 

myocardial  anoxia  occurs.  The  precipitating 

event may be unrelated to excessive effort or 

exertion. If this occlusion is not reversed within 

about 6 h the anoxic myocardial tissue will die: 

this is MI. Alternatively, there may be severe but 

transient,  reversible  spasm  of  one  or  more 

sections of either atheromatous or apparently 

normal coronary artery. This may account for 

‘variant’  or  Prinzmetal  angina.  Intermediate 

stages, known as the acute coronary syndrome, 

can also occur (see below).

Clinical consequences

Angina and MI, although similar pathologically, 

are two distinct clinical entities that can exist 

independently. MI is one extreme of a spectrum 

of acute conditions known collectively as acute 

coronary syndrome (ACS). Angina is not invari-

ably  a  precursor  of  MI  and  not  all  angina 

patients go on to suffer MI. Their differential 

pathogenesis is illustrated in Figure 4.31.

Other cardiac abnormalities may follow from 

myocardial  ischaemia,  possibly  asymptomati-

cally. Numerous small, subclinical infarcts can 

produce a widely disseminated patchy fibrosis of 

the myocardium leading to dilated cardiomy-

opathy and chronic heart failure, without the 

patient ever complaining of typical ischaemic 

pain.  Twenty-four-hour  ECG  monitoring  has shown that this so-called ‘silent ischaemia’ may 

be more common than was previously supposed. 

Heart failure also frequently follows frank MI.

Ischaemia may affect conducting tissue as well as cardiac muscle, either acutely (during MI), or chronically, leading to arrhythmias. Ventricular fibrillation  may  account  for  many  cases  of sudden cardiac death.

Less  commonly,  ischaemic  symptoms  may 

occur    unassociated    with    any    coronary 

obstruction,   not   even   vasospasm.   Examples 

include:

•  excessive   cardiac   oxygen   demand,   e.g. 

thyrotoxicosis;

•  severely reduced oxygen supply, e.g. severe 

anaemia;

•  reduced coronary perfusion pressure, as in 

hypertrophic cardiomyopathy, aortic stenosis

(raised   LVEDP)   and   cardiogenic   shock (inadequate aortic pressure).

Ischaemic pain is probably related to the accu-

mulation of the products of anaerobic metabo-

lism, e.g. acid or lactate. However, the picture of angina or MI pain as a type of muscle cramp, 

although   adequate   for   most   purposes,   is probably an oversimplification.

Prevention and treatment

Primary    prevention    theoretically    implies 

preventing   the   atherosclerotic   process   from 

starting, whereas secondary prevention means 

taking  measures  to  limit  or  perhaps  reverse 

damage  that  is  discovered  subsequently,  or 

prevent  symptomatic  recurrence.  In  practice 

however, primary prevention is usually extended 

to mean preventing the appearance of signs or 

symptoms of ischaemia, even though clinically 

silent atheromas may be present. Unfortunately, 

most patients only discover they have athero-

sclerosis when symptoms - which may not be 

cardiovascular, but usually are - first occur, in 

which case secondary prevention is the best that 

can be offered.

Hyperlipidaemia

The pathology of hyperlipidaemia in relation to 

atherosclerosis was discussed above (pp. 238 and 

240). The current non-drug prophylaxis recom-

mendations are summarized in Table 4.31, and 

the  reader  is  directed  to  the  References  and 

further  reading  section  for  detailed  reviews 

(p. 270).

Primary prevention

The major problem with interventions to reduce 

the lipid level lies in identifying the threshold of 

risk. As with blood pressure, total plasma choles-

terol varies unimodally throughout the popula-

tion (Figure 4.18), and an increased risk can be 

demonstrated at levels near or even below the 

population average (6 mmol/L for middle-aged 

males in the UK). Thus the same risk stratifica-

tion approach to that used for managing hyper-

tension has to be adopted (p. 216). A coronary 

heart disease risk evaluation looks at evidence-

based treatment thresholds for hyperlipidaemic 

patients of different ages with various combina-

tions of major coronary risk factors. The inter-

vention threshold for a given patient is based 

not solely on their lipid level but also on the

system

presence of other atherosclerosis risk factors and 

existing ischaemic symptoms, so this is balanced 

against the inherent risk of the intervention. 

However,   universal   lipid   screening   is   not 

currently    cost-effective    and    opportunistic 

screening  needs  to  be  targeted  on  high-risk 

groups (Table 4.29).

As with hypertension, the initial approach is 

for abnormal readings to be repeated; if hyper-

lipidaemia  is  confirmed,  possible  underlying 

primary causes must then be eliminated. Unless 

the   cholesterol   level   is   dangerously   high 

( 10 mmol/L  approx.),  the  total  cholesterol: 

HDL ratio is6, or there are other risk factors, 

the  first  step  is  to  initiate  non-drug  methods 

and to try them for 3-6 months. Simple risk 

factor reduction (lifestyle recommendations and 

dietary  measures)  would  be  suitable  for  an 

asymptomatic   younger   non-smoking   patient 

with normal blood pressure, no family history 

and a total cholesterol level below 6.5 mmol/L 

(7.8 mmol/L in younger women). If this fails or 

there are other risk factors, drug therapy is the 

next stage, as shown by the HPS trial. A choles-

terol level8 mmol/L will usually require drug 

treatment  eventually  in  all  patients.  Special 

consideration   applies   to   diabetic   patients, 

who  would  normally  be  started  earlier  (see Chapter 9).

Secondary prevention

The decision is simpler if a patient already has 

ischaemic symptoms or has suffered an MI or 

stroke.  There  is  now  ample  evidence  of  the 

benefits of lipid-regulating drugs in almost all 

patients after MI or unstable angina whether the 

lipid level is high (4S trial) or not (CARE trial).

The presence of disabling ischaemic symptoms would indicate the need for prompt surgical 

intervention (see below).

Risk factor reduction

Tables  4.29  and  4.31  indicate  the  general 

approach to identifying and addressing athero-

sclerotic risk factors. Of the primary modifiable 

risks,  diabetes  is  discussed  in  Chapter 9 and 

hypertension in this chapter. Smoking and its 

cessation are discussed in Chapters 5 and 10. 

The  focus  here  is  on  the  management  of 

hyperlipidaemia.

Targeting known risk factors through health 

promotion  and  regular  screening  in  general 

can reduce the individual risk and community 

load  of  IHD  in  particular  and  atherosclerosis. 

Most of the advice coincides with the general 

recommendations for a healthy life, and is in 

many  ways  similar  to  specific  recommenda-

tions  for  reducing  hypertension;  of  course 

keeping  blood pressure within normal limits 

itself reduces atherosclerosis. However, hyper-

tension screening and medication compliance 

are notoriously poor. The difficulties of smoking 

cessation are also well known. Dietary habits too 

are difficult to change, although average reduc-

tions of 10-15% in serum cholesterol can be 

achieved in this way.

Much   effort   is   therefore   being   put   into 

attempting  to  change  the  habits  of  whole 

communities so as to reduce the prevalence of 

the disease and its multi-system consequences. 

There is still far to go in changing public percep-

tions and practices regarding a healthy lifestyle, 

but there is epidemiological evidence from the 

USA and Finland that population-wide changes 

can produce significant falls in atherosclerosis 

prevalence. A prolonged population reduction of

and vascular obstructive disease247

no more than 0.6 mmol/L (which can be achieved 

by dietary means alone) has been shown to 

reduce the incidence of coronary disease by 30%.

Pharmacotherapy

Drug  therapy  is  indicated  in  secondary  pre-

vention and for primary prevention of IHD in high-risk individuals.

Lipid-regulating therapy

The statins (hydroxymethyl-glutaryl-CoA reduc-

tase inhibitors; HMGIs) are the drugs of choice. 

By inhibiting hepatic cholesterol synthesis, they 

reduce cholesterol levels, causing a significantly 

reduced  rate  of  coronary  events  and  slower 

progression (and possibly regression) of athero-

sclerotic  lesions.  Serious  adverse  effects  are 

uncommon, although liver and muscle damage 

are possible. Liver function should be checked 

before starting the drugs and after 1-3, 9 and 15 

months.  Patients  are  warned  to  report  any 

muscle pain or weakness. If the pain is associated 

with serum creatine kinase (CK) level greater 

than  five  times  normal  the  drug  should  be 

discontinued; if not and the pain is tolerable, it 

would be sensible to monitor CK levels as long as 

the pain persists. Statins need only be given once 

daily, and for the shorter-acting ones (including 

simvastatin) an evening dose is preferred because 

that is when most cholesterol is synthesized; for 

longer-acting ones (e.g. atorvastatin) timing is 

not critical.

Thresholds.   The decisions as to who should 

receive  drug  therapy  and  at  what  point  are 

always subject to debate and change. Current 

guidance by NICE and the Joint British Societies 

(JBS-2) recommends pharmacotherapy for three 

specific groups:

•  People   with   a  10-year   CVD   risk20%

(primary prevention).

•  All patients with pre-existing atherosclerotic 

CVD (secondary prevention).

•  All patients with diabetes.

In addition, people with certain specific risks 

should be covered, regardless of other criteria. 

These   are:   blood   pressure160/100;   total

cholesterol:HDL    ratio6;    and    familial hyperlipidaemia.

Targets.   As  with  hypertension,  target  levels 

have fallen as evidence accumulates of increased 

benefit with little increase in harm. The optimal 

targets are total cholesterol below 4 mmol/L and 

LDL cholesterol below 2 mmol/L. Alternatively, 

if it produces lower levels, the aim should be 

a 25% reduction in total cholesterol together 

with a 30% reduction in LDL. JBS also specify 

less stringent, perhaps more practical minimum 

targets of 5 mmol/L total and 3 mmol/L LDL. 

There is still debate as to how low is desirable or 

safe, with some authorities now recommending

3.5 mmol/L total cholesterol as optimal.

Other agents such as fibrates, nicotinic acid 

derivatives and bile-salt binding resins may be 

added if necessary. Fibrates are particularly useful 

for raised triglycerides. Useful adjuncts include 

ezetimibe, which impairs gastrointestinal absorp-

tion of cholesterol and is useful where lipid 

levels cannot be controlled by a statin alone. As 

target levels go down, increasing use will be 

made of combination lipid-regulating therapy. 

For the detailed pharmacotherapy of hyperlipi-

daemia, see the References and further reading 

section.

Antiplatelet therapy

Secondary prevention of MI and stroke routinely 

involves low-dose aspirin (see also Chapter 11). 

Recent understanding of the role of inflamma-

tion  in  atheroma  has  further  validated  this 

approach. However, less gastro-erosive platelet 

inhibitors  have  been  developed.  Clopidogrel  is 

more effective than aspirin, blocking a different 

pathway to platelet aggregatory factor synthesis, 

but is more expensive. It is a useful alternative 

for  aspirin-intolerant  patients  and  is  used  in 

combination with aspirin in ACS. Dipyridamole, 

an older antiplatelet, may be used in combination 

with aspirin for stroke or TIAs.

The   final   common   platelet   aggregation 

pathway   involves   glycoprotein   IIb/IIIa,   the 

fibrinogen receptor on the platelet membrane, 

and  blockers  of  this  have  been  developed. 

Chimeric glycoprotein receptor antibody frag-

ments such as abciximab, and small molecule 

direct inhibitors such as eptifibatide and tirofiban, 

are limited to specialist units because they are 

only available for parenteral use. These drugs are

system

at present used in association with angioplasty and in ACS.

The use of aspirin  as primary prevention is 

controversial, because of the small but signifi-

cant risk of gastrointestinal haemorrhage. While 

some  have  recommended  it  as  routine  for 

everyone over 50, the current view is that it 

should only be used where there is an increased 

CVD   risk.   A   comparison   of   primary   and 

secondary prevention of IHD is given in Table

4.32.

Polypill

With  the  increasing  number  of  medications 

being given to patients at even moderate CVD 

risk, supported by evidence of increased survival, 

the suggestion has been made that all people 

over 55 should be given a drug combination as 

primary prevention. The proposal is for everyone 

to take a low dose of a beta-blocker, an ACEI, 

aspirin, a statin, a thiazide and folic acid. The aim 

would be to benefit from an additive or even 

synergistic effect of each component. All except 

folate have been shown to reduce CVD risk as secondary  prevention,  and  some  as  primary prevention. Folate reduces levels of homocys-

teine, a minor atherosclerosis risk factor. There is no trial evidence that this combination will be effective, nor can there be any realistic calcula-

tion of the risk-benefit balance on a theoretical basis, but it remains an interesting idea.

Vascular surgery

Revascularization   is   indicated   in   secondary 

prevention when drug therapy fails or as emer-

gency treatment. Coronary bypass and angio-

plasty will be discussed in the sections on angina 

and MI below.

Angina pectoris

Definition and classification

Angina is both defined and diagnosed by clinical 

criteria. Typical ischaemic cardiac pain is retro-

sternal (behind the breastbone), intense, diffuse 

rather than sharp, and gripping, constricting or 

suffocating.  Patients  describe  the  sensation  of 

having their chest crushed by a bearhug, or they 

may clench their fist over their chest. Yet even 

when it radiates to the upper arms, neck or jaw on 

either side it may be difficult to distinguish from 

severe dyspepsia, ‘heartburn’ or oesophageal pain 

(see Chapter 3), or even pericarditis, so other 

signs must also be sought.

In classical angina pectoris pain comes on 

acutely following exertion, and is relieved within 

a few minutes by resting or by taking buccal or 

sublingual  GTN.  Attacks  occur  predictably  at 

the same level of effort. Coronary atherosclerosis 

is   almost   invariably   present.   A   minority 

(about 10%) of patients suffer from a variant 

(Prinzmetal)  form,  where  attacks  are  unpre-

dictable and may occur even at rest, although 

commonly under emotional stress. In such cases 

there may be no permanent coronary obstruc-

tion, the attacks being due to reversible vaso-

spasm. This section considers mainly chronic 

state angina. Unstable angina and ACSs will be 

covered below, after discussion of MI.

Angina pectoris249

Clinical features, investigation and diagnosis

Angina can be triggered by any circumstances 

that  acutely  increase  cardiac  workload (Table

4.33).  The  clinical  features  are  highly  sugges-

tive  and  rapid  relief  with  GTN  is  almost 

conclusive.  However,  in  ambiguous  cases  an 

exercise ECG (e.g. on a treadmill), will usually 

show reversible ST segment changes typical of 

myocardial  ischaemia  (Figure 4.32).  The  rest-

ing  ECG  is  usually  normal  but  may  provide 

evidence  of  a  past,  possibly  silent  MI  (Figure

4.32(d)), or of myocardial hypertrophy (usually 

resulting from untreated hypertension), which 

would show as an elevated R-wave. In variant 

angina, ST elevation is more common but the 

exercise  test  may  not  cause  an  attack,  and 

24-h  ambulatory  ECG  monitoring  can  be 

valuable.

More  invasive  tests  are  rarely  justified  in 

moderate  stable  disease.  Angiography (Figure

4.33)  or  isotope  scans  are  reserved  for  wors-

ening  disease,  unstable  angina  or  evaluation 

before  surgery  because  their  results  would 

otherwise  not  affect  management.  Moreover, 

patients  with  little  objective  obstruction  may 

have  severe  symptoms,  while  evidence  of 

extensive  atherosclerosis  is  sometimes  found 

in  patients  who  complain  little.  Angiography 

indicates  objective  severity  and  provides  a 

baseline for assessing progress. In general, the 

elderly   seem   less   likely   to   experience 

ischaemic  pain,  and  neuropathy  in  diabetics 

can disguise it.

A functional assessment is essential - at what point does the pain occur and what does it 

prevent the patient doing? Angina can be graded using the NYHA functional scale:

•  Grade I. Asymptomatic. No pain at ordinary 

physical activity.

•  Grade II. Mild. Pain evident on strenuous 

exertion.

•  Grade   III.   Moderate.   Pain   evident   on 

moderate exertion.

•  Grade  IV.  Severe.  Pain  unpredictable  and 

unrelated to exertion.

Course and prognosis

Many angina patients have such slowly progres-

sive disease that it causes little disability. Never-

theless, their mortality rate is on average about 

four  times  that  of  those  without  coronary 

disease, some eventually dying of MI. The rate of 

progression depends partly on how early the 

disease is detected and partly on what measures 

are then taken to reduce risk factors, although

the effectiveness of such measures once symp-

toms have become evident is uncertain. The 5-

year   mortality   rate   for   moderate   stable 

uncomplicated angina involving only one main coronary vessel is less than 10%, but this may be doubled if more risk factors are involved.

Some patients experience an acceleration of 

symptoms  with  a  rapidly  reducing  exercise 

tolerance and unpredictable attacks, often unas-

sociated   with   exercise   or   their   accustomed trigger factors. This is unstable angina, part of 

the ACS spectrum, considered in a later section 

(p. 266).

Management

Aims and strategy

The overall aim in the management of angina is to minimize myocardial ischaemia. There are 

three objectives:

1. To abolish the symptoms of an acute attack.

2. To  prevent  or  minimize  the  frequency  of

symptomatic or silent myocardial ischaemia.

3. To  halt  or  reduce  the  progression  of  the

underlying atherosclerosis.

In  acute  management  and  prophylaxis,  the main   strategy   is   to   readjust   the   oxygen supply/demand balance favourably (Table 4.34). For   long-term   management,   coronary   risk factors must also be reduced.

system

Reducing oxygen demand

As in heart failure, drug therapy is mainly aimed 

at ‘unloading’ the heart. Thus negative inotropes 

such as beta-blockers and non-DHP CCBs are 

used, although in heart failure the former are 

only used with great care and the latter avoided. 

Arterial dilators if used alone can produce reflex 

tachycardia, which will increase cardiac work, 

and so combination with beta-blockers is prefer-

able. A cardiodepressant (non-DHP) CCB may 

serve both functions. Both beta-blockers and the 

sinus node inhibitor ivabradine reduce cardiac 

rate.

Nitrates  act  indirectly,  through  peripheral 

venodilatation. By dilating the great veins they 

reduce  venous  return,  thus  rapidly  reducing 

cardiac  output  and  thus  cardiac  work  and 

oxygen  demand.  Although  they  also  dilate 

arteries, it is a common misconception that they 

act by coronary vasodilatation: coronary arteries 

obstructed   by   atherosclerosis   are   minimally 

dilatable. 

 It  is  equally  important  to  improve  overall 

cardiovascular efficiency. Regular moderate exer-

cise enables the best use to be made of reduced 

myocardial    capacity.Stopping    smoking 

improves  oxygen  carriage  in  the  blood  by 

reducing carboxyhaemoglobin levels, and this 

reduces   cardiac   output   requirements.   Thus 

despite drug treatment that apparently reduces 

cardiac performance, i.e. reducing preload, rate 

and  contractility,  there  may  be  no  fall  in 

absolute exercise capacity.

Improving oxygen supply

This is more difficult medically because most 

angina is caused by fixed lesions. If the atheroma 

occupies less than about 60% of the arterial 

circumference (which is uncommon in sympto-

matic angina), arterial dilators may be beneficial 

by direct action on the obstructed part of the 

coronary vessel. However, there will usually be 

maximal   natural   autoregulatory   dilatation 

anyway. Indeed, vessels near the diseased artery 

may be preferentially dilated by autoregulation 

or vasodilators, thereby diverting blood away

Angina pectoris253

from  the  deprived  region  and  exacerbating symptoms (coronary steal).

In the rarer variant angina, which is caused 

by vasospasm, vasodilators do work, mainly by 

direct action on the coronary arteries. Recent 

angiographic studies also suggest that transient 

vasospasm superimposed on fixed obstructions 

may contribute partially to classical angina pain, 

thus  providing  a  limited  role  for  coronary 

vasodilatation.

In   severe   advanced   angina,   with   almost 

complete blockage of one or more main coro-

nary  arteries,  surgery  becomes  necessary.  In 

coronary artery bypass graft (CABG) a length 

of vessel, taken from a leg vein or from the more 

conveniently located internal mammary artery, 

is grafted between the aorta and a site beyond 

the obstructing lesion (Figure 4.34). This can 

produce dramatic improvements in symptoms 

but unfortunately atherosclerosis at the same site 

tends to recur after 5-10 years.

Percutaneous transluminal coronary angio-

plasty (PCTA) is a far less invasive technique. In 

this method a coronary catheter is inserted via a

peripheral artery until a small balloon at its tip 

rests adjacent to the plaque. Inflation of the 

balloon   breaks   up   the   plaque,   flattens   or 

stretches it, or stretches the surrounding vessel 

wall (Figure 4.35). The patient is heparinized for 

the procedure, and it is followed by a short 

course  of  intensive  antiplatelet  therapy (e.g. 

aspirin   abciximab), then clopidogrel for a month 

and aspirin  indefinitely. Subsequent microem-

bolization occasionally causes further obstruc-

tions downstream ( 1% of cases). Angioplasty 

has few other complications and avoids the need 

for open-heart surgery. The technique is also 

used for other stenosed arteries, including the 

femoral and renal arteries.

Recurrence  of  obstruction  can  occur  in  up 

to 60%  of  cases  after  as  little  as 6 months. 

This is not from new plaque but from initial 

recoil and subsequent overgrowth of endothe-

system

lium  (endothelial  hypertrophy);  however  the 

procedure   may   be   repeated.   To   reduce   re-

occlusion   the   standard   procedure   following 

coronary angioplasty is to place a tubular mesh 

supporting structure (stent) intra-arterially at the 

site of the lesion after balloon expansion. Costing 

around £1000, these alloy devices are up to a few 

centimetres  long  and  about  the  diameter  of 

the vessel being remodelled. After insertion, the 

stent eventually becomes overgrown with new 

endothelium. The use of stents has led to a signif-

icant reduction in the restenosis rate. A recent 

innovation is the use of drug-eluting stents, 

which are coated with an anti-proliferative agent 

such as sirolimus or paclitaxel. The drug is slowly 

eluted and inhibits local growth. There are as yet 

no long-term data on these expensive devices 

but they are recommended by NICE for very 

narrow or very long lesions.

Preventing further obstruction

General  measures  such  as  stopping  smoking, losing weight, keeping fit, modifying diet, etc. are an essential part of initial angina manage-

ment, and are aimed at either directly inhibiting further atheroma or reducing other risk factors. The  onset  of  angina  symptoms  renders  the patient receptive to such advice.

As noted above (p. 247), the risk-benefit ratio 

at  present  also  favours  giving  life-long  lipid-

regulating  agents  and  aspirin  as  secondary 

prevention to all symptomatic angina patients. 

The HOPE trial has suggested that ACEIs might 

be beneficial for high-risk angina patients, e.g. 

those  with  diabetes,  even  in  the  absence  of 

heart failure.

Acute attack

Glyceryl trinitrate

The traditional GTN has yet to be bettered for 

rapid symptomatic relief (Table 4.35). Patients 

should be encouraged to anticipate situations 

that  will  provoke  an  attack,  and  use  GTN 

prophylactically immediately beforehand, which 

keeps  the  ischaemic  burden  to  a  minimum. 

The sublingual aerosol formulation is preferred 

because it has greater stability and thus a longer 

shelf-life after dispensing. It also has a more 

prompt action. Rapid falls in blood pressure may 

follow the dose so patients are advised to sit 

when taking it. Acute headache and flushing 

are other side-effects of the widespread vaso-

dilatation. The absence of side-effects such as 

headache and flushing is a marker for either 

non-compliance or inactive tablets.

GTN  tablets  have  a  short  shelf-life,  and 

careful  selection  of  the  bottle  closure  is 

needed. If a patient on GTN tablets complains 

of  worsening  or  accelerating  symptoms,  with 

declining  effectiveness,  poor  storage  rather 

than unstable angina may be to blame. Isosor-

bide  dinitrate  is  also  available  in  sublingual 

spray form.

Prophylaxis

Atherosclerosis   prophylaxis   was   covered   on pp. 245-249.

Beta-blockers.These  are  first  choice  unless contra-indicated (Table 4.23). In addition to the details  given  on  pp. 227-229,  a  number  of specific points about the use of beta-blockers in angina should be noted:

•  Their    action    in    secondary    protection 

following MI has been clearly demonstrated. 

•  They improve exercise capacity.

•  They are contra-indicated in coronary spasm 

(e.g.  variant  angina),  because  they  permit

unopposed coronary alpha-constrictor tone. 

•  Withdrawal, if necessary, should be slow (over

4 weeks), to avoid rebound exacerbation or even MI (owing to beta-receptors having been up-regulated).

•  Cardiospecific drugs are preferred.

•  Drugs  without  intrinsic  sympathomimetic 

activity are preferred because they have a

reduced likelihood of reflex tachycardia. 

•  A higher dose than used for hypertension is

usually required.

Formerly, a resting heart rate of about 60-70 

beats/min was the therapeutic target, but a more reliable predictor of effectiveness might be the limitation  of  exertional  tachycardia  to 100 beats/min. This permits higher doses.

Calcium-channel  blockers.   These  are  often 

successful if beta-blocker therapy fails or is inap-

propriate (see p. 231) and they are the first 

choice for variant angina. Those with consider-

able negative chronotropic and negative ino-

tropic action as well as vasodilatation, i.e the 

non-DHP agents such as verapamil and diltiazem, 

may  be  beneficial  provided  that  ventricular 

function is adequate and they are not combined 

with  a  beta-blocker.  Otherwise,  a  DHP (e.g. 

nifedipine)  is  used,  although  these  can  cause 

reflex tachycardia. CCBs are perhaps better toler-

ated than beta-blockers and are suitable for a 

wider variety of patients.

Nitrates.   These  act  as  in  angina  to  reduce 

preload, with a lesser effect on afterload and 

perhaps  a  small  effect  on  coronary  vessels. 

Various  formulations  of  organic  nitrates  are 

available to help counteract the problems of this 

group, which are related to systemic vasodilata-

tion or tolerance (Tables 4.35 and 4.36). Adverse 

effects may prevent up to a quarter of patients 

from   using   nitrates.   Preventing   tolerance 

requires a daily ‘washout’ period of low plasma 

level,  e.g.  overnight,  in  the  absence  of  noc-

turnal attacks. It occurs because sulfhydryl (-SH) 

groups on receptors become saturated and can 

no  longer  produce  NO  from  the  nitrate  for 

dilatation.

Topical GTN patches are expensive and offer 

little advantage except the psychological benefit 

of direct application to the chest. Unless used 

with care they may even exacerbate tolerance,

which is encouraged by a stable plasma level. 

Buccal modified-release preparations provide a 

combination of prompt and sustained action.

Because there is no convenient clinical index of  plasma  levels,  such  as  bradycardia  with beta-blockers, dose adjustment is imprecise.

Potassium channel activators.   These drugs, 

e.g. nicorandil, combine nitrate-like venodilator 

action (due to NO production) with CCB-like 

arterial   dilatation.   Theoretically   they   could 

replace a combination of nitrate and CCB, with 

the potential advantage that nitrate intolerance 

would be masked by the arterial dilator action. 

The IONIA trial suggests they may have superior 

outcomes to nitrates.

Sinus   node   inhibitors.   Ivabradine  reduces 

cardiac rate by acting directly on the sinus node, 

the result being reduced oxygen consumption. 

Experience is limited but it seems to have fewer 

side-effects  than  beta-blockers  but  a  similar 

clinical action, and so may prove to be a useful 

alternative  in  patients  who  cannot  tolerate 

beta-blockers.

ACEIs.   Evidence   is   accumulating  (e.g.   the 

HOPE (ramipril) and EUROPA (perindopril) trials) 

that ACEIs may be beneficial in stable angina 

even in the absence of heart failure. This makes 

their spectrum in CVD as broad as that of beta-

blockers. This should not be suprising in view 

of  their  widespread  unloading  properties.  At 

present they are used only for high-risk angina 

patients, though they are not licensed for this in 

the UK.

Drug selection

All  patients  should  have  regular  statin  and 

aspirin, and GTN as required. If prophylaxis is 

indicated, beta-blockers are the first choice if 

tolerated. For other drug choices see Figure 4.36, 

which shows most possible rational combina-

tions. It is rare that a patient is unable to take either beta-blockers or CCBs as initial mono-

therapy. If either of these alone fails, a variety of 

synergistic dual therapies is available. Some have 

particular advantages, e.g. a beta-blocker plus 

CCB counteracts the peripheral vasoconstriction 

induced  by  the  former,  and  the  tachycardia 

induced by the latter; a DHP CCB should be 

chosen to avoid excessive myocardial depres-

sion. The tendency to tachycardia induced by 

nitrates is countered by the bradycardia induced 

by diltiazem or beta-blockers. Hypotension can 

occur with a nitrate plus a CCB, in which case 

the DHPs should be avoided. The role of potas-

sium channel activators in combinations is not 

yet established.

Most patients will be well controlled on dual therapy, but triple therapy is sometimes needed. Otherwise,   failure   of   dual   therapy   is   an indication that the patient is a candidate for 

angioplasty or bypass surgery.

Myocardial infarction

Myocardial infarction (MI, ‘heart attack’, ‘coro-

nary thrombosis’) occurs when a coronary vessel 

becomes  occluded  for  more  than  about  6 h, 

whether or not the occlusion is subsequently 

relieved.

Angina and MI

Unlike for angina, exertion is not a trigger for 

MI, and although MI is frequently associated 

with current stress or general ‘life events’, the 

patient  may  be  unable  to  recall  a  particular 

precipitating event. MI is not simply an intensi-

fication of angina: it differs in a number of 

crucial respects (Table 4.37). Many patients have 

stable angina for many years and never develop 

an MI. For others a fatal MI is their first and last 

experience of heart disease - about 50% of MIs 

occur without previous ischaemic symptoms.

Acute coronary syndrome

Angina and MI stand at either end of a spectrum of ischaemic states referred to as acute coronary syndrome  (ACS).  In  between  are  a  range  of increasingly severe acute conditions. Therefore MI will be discussed in detail first, because doing so will bring in most of the features of the less serious conditions. ACS will then be discussed by comparison with MI.

Pathogenesis

Initiating event

Postmortem   examinations   after   MI   almost invariably show advanced coronary atheroscle-

rosis with a thrombotic occlusion in one vessel. ‘Sudden ischaemic death’ within an hour or so of the onset of symptoms, before infarction proper can develop, also occurs. This is probably due to ventricular fibrillation. However, these patients usually also have obstructive lesions.

Why should an apparently stable atheroma-

tous  plaque  suddenly  precipitate  thrombosis 

and occlusion? Stress-induced acute abnormal-

ities  in  both  clotting  factors  and  platelets 

have been proposed, but it is currently thought 

that a particularly lipid-rich plaque, with low 

amounts of smooth muscle and fibrous support, 

may fissure or rupture. This exposes lipid and 

subendothelial  structures,  triggering  massive 

platelet aggregation and subsequent thrombosis.

In   the   few   cases   where   no   substantial 

atheroma is found on angiography or at post-

mortem examination, the cause may be severe 

vasospasm  or  a  primary  platelet  or  clotting 

abnormality.

Severity

The   process   of   infarction   in   general   was 

described in Chapter 2 (pp. 58-61). If a tissue 

undergoes a period of anoxia, then irreversible 

damage occurs, followed by wound healing and 

organization of scar tissue. Scar tissue can never 

fulfil the functions of the tissue it replaces. In the 

heart this means that as well as being non-

contractile, the infarcted area is inelastic and 

poorly   conducting.   This   has   the   following potential consequences:

•  Poor contractility leads to poor ejection, i.e. 

systolic failure.

•  Poor elasticity (reduced compliance) leads to 

poor filling, i.e. diastolic failure.

•  Poor conductivity leads to arrhythmias.

The  consequences  in  individual  cases  depend 

primarily on the size of the area of myocardium 

served by the coronary vessel that is occluded. 

The  mildest  form  involves  a  small  arteriole, 

resulting  in  a  clinically  silent (symptomless) 

infarction. Moreover, dilatation of neighbouring 

vessels by autoregulation may protect the area 

adjacent to the ischaemic core from complete 

anoxia, thereby limiting infarct size. However, if 

this is repeated over a long period it results in 

widespread‘patchy   fibrosis’   and   eventual 

cardiac failure. Occlusion of larger arterioles will 

cause a classical presentation of MI, but if the 

area damaged is not too extensive the patient 

will survive, possibly with a degree of perma-

nent cardiac failure. At its most severe an MI 

may involve one of the main coronary arteries, 

often  the  left  anterior  descending,  which 

supplies most of the left ventricle (Figure 4.7), 

causing  an  anterior  infarct.  Death  is  likely  if 

more  than  about  50%  of  the  left  ventricle  is 

damaged.

One  important  factor  determining  outcome 

is how well developed the patient’s collateral 

coronary  vessels  are;  another  is  how  much 

conducting tissue is involved. Conduction across 

the whole myocardium is necessary for normal 

coordinated contraction, and ischaemic muscle 

may conduct erratically. In addition, ischaemic 

damage to nodal tissue or nerve tracts may have 

a disproportionate effect because arrhythmias 

can compromise the function of the entire heart.

Course and prognosis

About half of all patients suffering an MI in the 

UK die within a month; half dying in the first 

hour and three-quarters within the first 24 h. 

Deaths occurring in the first few hours, before 

medical help becomes available, are usually from 

ventricular fibrillation. Subsequent deaths are

Myocardial infarction259

mainly from heart failure. The 5-year survival rate among those who survive the first month is 76%, compared to people of a similar age 

without MI of 93%.

In the immediate post-infarction period the 

myocardium surrounding the developing lesion 

becomes hyperexcitable owing to excess sympa-

thetic tone and the high local levels of potas-

sium  released  from  the  damaged  cells.  The 

patient is then at great risk of a fatal arrhythmia. 

Some   community-based ‘coronary   first   aid’ 

programmes  have  significantly  reduced  mor-

tality. Lay people are instructed in elementary 

resuscitation, and the emergency services, e.g. 

ambulance staff and firemen, are taught the 

‘blind’  use  of  defibrillators,  parenteral  anti-

arrhythmics and in some cases thrombolytics. 

Defibrillators are now being placed in public 

spaces such as railway stations.

The patient who survives this critical period 

has  a  reasonable  prognosis:  ironically,  those 

who  get  to  hospital  include  those  who  least 

need it. Many patients with uncomplicated MI 

require,   after   emergency   treatment,   only 

supportive  therapy  and  are  soon  discharged. 

Such  patients  may  do  better  at  home  in 

familiar,  unthreatening  surroundings  rather 

than  in  a  stressful  high-technology  CCU. 

However,  the  consensus  view  is  that  all 

suspected  MI  patients  should  preferably  be 

assessed initially in a hospital. Poorer prognosis 

is  indicated  by  older  age,  history  of  IHD  or 

hypertension,  and  the  development  of  heart 

failure or arrhythmias.

Clinical features

Some MIs may be so mild as to be dismissed by 

the   patient,   relatives   and   sometimes   even 

doctors as indigestion, especially if the patient 

has not experienced ischaemia before. It may be 

some time before the persistent pain brings a 

patient to medical attention. Angina patients, 

however, will recognize an MI because although 

the pain is familiar it persists, tends to be more 

severe, and is not relieved by normal medication 

(i.e.  GTN).  With  large  areas  of  myocardial 

damage the patient may collapse from acute 

heart failure or cardiogenic shock.

On admission, patients are usually cold and 

pale (owing to central conservation of reduced 

cardiac output), clammy (due to sympathetic 

discharge), nauseated and breathless with rapid 

shallow breathing. Their great distress is due not 

only to severe pain but also to profound fear and 

anxiety. This heightens the perception of pain 

because  patients  are  literally  mortally  afraid. 

There   may   be   hypotension,   tachycardia   or 

profound bradycardia, and signs of pulmonary 

oedema(e.g.   crackles   heard   through   the 

stethoscope).

Investigation and diagnosis

All patients with suspected MI are closely moni-

tored for 72 h to confirm the diagnosis and 

anticipate   complications.   Precise   diagnostic 

criteria vary, but generally the diagnosis depends 

on significant findings in at least two of three 

crucial areas:

•  Clinical presentation and history. •  Progressive ECG changes.

•  Progressive serum cardiac marker changes.

In many cases the ‘classical’ clinical features are 

absent and it can be very difficult to ascribe a 

cardiac cause. This is especially true of milder 

attacks with minimal myocardial damage and no 

cardiac failure, and in diabetics and the elderly. 

Objective criteria then become important.

Electrocardiogram

Certain  characteristic  changes  occur  after  a 

typical  transmural  MI, i.e. affecting the full 

myocardial thickness. The ST segment quickly 

becomes markedly elevated, only settling down 

to normal after several weeks (Figure 4.32(c)). A 

‘pathological’ Q-wave occurs early and persists as 

a permanent marker of a past MI (Figure 4.32(d)). 

The  particular  ECG  leads  that  detect  these 

changes  indicate  the  position  of  the  infarct 

within the myocardium, while their magnitude 

indicates the severity of the MI. Less commonly, 

if the infarct does not affect the entire thickness 

of the cardiac wall, the Q-wave remains normal 

and the ST segment is depressed. This is non-Q-

wave or subendocardial infarction.

system

In hospital, these time-dependent changes can be followed by continuous monitoring. A more important reason for such monitoring is the 

early detection of serious arrhythmias, an alarm sounding automatically when these occur.

Cardiac serum markers

Measurement  of  the  serum  levels  of  certain 

enzymes typically found in myocardial cells, but 

released on injury or death, provides additional 

evidence (Figure 4.37). A particular range, quan-

tity and sequence of enzyme release is character-

istic of MI, an isoform or CK being the most 

specific. Elevation more than 15% above the 

normal  range  is  diagnostic.  An  even  more 

specific serum marker of myocardial damage is 

cardiac troponin-T (cTn). This component of 

cardiac   muscle   fibrils   is   detectable   within 

minutes of an MI, peaks at 12 h and persists for 

about 2 weeks.  Its  presence  during  unstable 

angina   indicates   a   greater   likelihood   of 

subsequent infarction.

Complications

About half the patients with MI who survive the 

first  few  hours  develop  one  or  more  of  the 

complications  shown  in  Table 4.38,  mostly 

within the first few days. The frequency and severity of these are the best arguments for the existence  of  CCUs,  where  continuous  moni-

toring and prompt attention are assured. If such complications do not develop, the patient is at less risk and may do better at home. The occur-

rence of heart failure is the single most accurate predictor of long-term outcome.

A transmural infarct may be overly compliant, 

bulging during systole (forming an aneurysm), 

which  reduces  ventricular  output  and  thus 

causes heart failure. A septal infarct may rupture 

into the right ventricle. Rupture into the pericar-

dial cavity is usually fatal but the risk is reduced 

by early beta-blockade. A ventricular aneurysm 

may persist after the infarction has healed. Non-

Q-wave infarction is initially less serious but has 

a poorer prognosis: there is a likelihood of a full 

MI in the near future with a higher overall 

mortality than normal.

Ventricular  remodelling  by  dilatation  and 

hypertrophy gradually compensates for the loss

of functional myocardium, a process that may 

continue for up to 6 months after the infarction. 

Although   this   may   be   beneficial   in   many 

patients,   progressive   dilatation   can   lead   to 

chronic ventricular failure, and cardiac enlarge-

ment is a poor prognostic factor. Early ACEIs 

limit this process.

Weeks or months after an infarct, and particu-

larly after a second or third such occurrence, an autoimmune reaction to necrotic cardiac tissue (Dressler’s  syndrome)  may  develop,  which  is managed with steroids.

Management

The aims in managing MI are, in sequence, to:

•  act   promptly   to   save   life   and   reduce 

complications;

•  treat acute symptoms;

•  restore   flow   through   the   affected   artery 

(revascularization);

•  minimize subsequent infarct size; •  treat complications;

•  rehabilitate;

•  ensure secondary prevention of subsequent 

attack.

Immediate management

The emergency management of MI is primarily 

symptomatic and supportive (Table 4.39). The IV 

route is preferred because reduced peripheral 

perfusion  delays  uptake  from  IM  sites,  and 

frequent injections are more conveniently given 

via an in situ IV line. Early revascularization by 

thrombolysis or PTCA is mandatory but is not 

always immediately available (see below).

Opioids  are  invaluable  as  analgesics,  tran-

quillizers and venodilators. Paradoxically, their 

respiratory depressant action is also useful: it 

reduces the ineffectual fast respiration associated 

with  panic.  In  the  UK,  diamorphine (heroin) 

is  routinely  used,  but  morphine  or  pethidine 

(meperidine) are also suitable; an anti-emetic 

(e.g. cyclizine or metoclopramide) may be required. 

A 300-mg aspirin tablet (for its antiplatelet effect, 

not analgesia) is chewed to promote more rapid 

absorption. A GTN tablet is taken sublingually or buccally.  High-concentration  oxygen  (40%  or 

more by mask, unless the patient is known to 

have chronic airways disease, see Chapter 5) is 

often   needed.   Heart   failure   and   shock   are 

discussed below.

Myocardial salvage: reducing infarct size

It was previously thought that after an MI little 

could be done to prevent myocardial damage, 

which  was  assumed  already  to  have  occurred 

irreversibly. However, several interventions have 

been developed. They are best initiated within 

3h  of  the  onset  of  symptoms,  although 

evidence  is  emerging  that  the  thrombotic 

process  in  some  infarctions  evolves  continu-

ously over the first 24 h, so that later interven-

tions  may  still  be  beneficial.  Broadly,  these 

techniques   involve   methods   of   improving 

oxygen supply and methods to reduce myocar-

dial  oxygen  demand  that  spare  less  severely 

hypoxic  areas.  Audit  criteria  for  this  phase 

include ‘pain to vein’ time - the time between 

onset of symptoms and start of treatment - and 

‘door to needle’ time - the speed with which 

patients  admitted  to  an  A&E  department  are 

started on treatment, ideally30 min.

Antithrombotics

Aspirin  is   given   as   soon   as   possible   and continued, with the aim of preventing extension of the existing thrombus or re-thrombosis. It 

does not reduce the size of the culprit thrombus. There is some evidence that clopidogrel enhances this action, but glycoprotein IIb/IIIa inhibitors probably do not. There is no evidence to support the routine use of heparin except in association with angioplasty or thrombolysis.

Reperfusion: thrombolysis

The key to improving outcome in MI is to restore 

blood flow to the ischaemic area by opening up 

the occluded coronary artery as soon as possible. 

In some areas (especially the USA), it is possible 

to organize balloon angioplasty or even bypass 

surgery sufficiently rapidly as a primary inter-

vention, and this is becoming more common in the UK. However, pharmacological throm-

bolysis (fibrinolysis)  is  the  usual  treatment. Angioplasty is also used where thrombolysis has failed (salvage angioplasty).

The natural endogenous fibrinolytic enzyme is 

plasmin (see Chapter 11). This lyses fibrin clots 

forming intermittently and accidentally within 

the normal circulation, or following repair of 

any vessel damage (Figure 4.38). It also destroys 

other clotting factors, inhibiting further throm-

bosis. Both blood and tissue factors activate its 

precursor,  plasminogen.  Normally  a  delicate 

equilibrium exists between clotting and anti-

clotting   factors   but   this   is   overwhelmed

Myocardial infarction263

following   pathological   thrombosis.   Throm-

bolytic drugs activate plasminogen artificially (Figure 4.38 and Table 4.40).

Indication and use.   Pharmacological throm-

bolysis is now considered for all patients with 

symptoms   strongly   suggestive   of   MI   and 

confirmed by ECG. Thrombolysis recanalizes up 

to 50% of patients and reduces mortality rate by 

25%. Patients with anterior infarcts benefit most, 

the  benefit  being  greatest  for  those  patients 

treated  earliest.  Ideally,  this  should  be  within 

2h of onset of symptoms (i.e. usually before 

reaching hospital), but 4-6 h is probably more realistic and 12 h is the maximum for significant 

benefit. There are only small gains after longer 

delays.

Heparin  is used routinely as an adjunct to 

alteplase therapy, because alteplase has a short half-life. It is also indicated in patients with a 

tendency   to   thrombosis,   to   reduce   venous thrombosis and pulmonary embolism. However, there is an increased chance of bleeding and 

heparin is not recommended routinely.

Side-effects,  contra-indications  and  precau-

tions.   Early  fears  that  thrombolysis  would 

cause massive haemorrhage proved unfounded, 

but bleeding is still the major risk. This may be 

at the site of injection, so that further venepunc-

ture  should  be  delayed  and  cautious.  More 

serious is internal bleeding, especially intracere-

brally (e.g. haemorrhagic stroke). Major contra-

indications  include  recent  surgery (including 

dental extraction), recent head injury, a history 

of cerebrovascular disease or if there is a risk of 

bleeding from a peptic ulcer. A more complete 

list is given in Table 4.41.

Choice.   Streptokinase (SK) is a foreign protein 

and therefore antigenic; it acts directly on plas-

minogen anywhere in the circulation. Alteplase (rt-PA) is a genetically engineered human tissue 

plasminogen activator that has a greater affinity 

than SK for fibrin. Reteplase and tenecteplase are 

similar but modified to be more clot-specific by 

being selective for plasminogen in the presence 

of fibrin. They also have a longer half-life.

SK is currently the cheapest agent. Because it is 

antigenic, antibodies form within 4 days. This 

may  cause  allergic  reactions,  but  fortunately 

anaphylaxis  is  uncommon.  The  outstanding 

problem is the lack of effect if treatment is 

repeated after 4 days, because the antibodies 

bind the drugs and prevent them from acting. 

Another thrombolytic must be used if a patient 

has a second infarct after SK treatment.

Alteplase and reteplase, although more expen-

sive,  permit  lower  doses  and  hence  reduce 

systemic bleeding by targeting the coronary clot. 

However, this property is generally exploited to 

use higher doses for a better vessel opening rate, 

thus vitiating the advantage. Used in this way 

the   clot-specific   agents   are   more   likely   to 

produce haemorrhagic stroke as a complication. 

Either way, the advantage of selectivity is not 

translated into as large an increase in survival as 

expected. Thus, despite the fact that reteplase and 

tenecteplase  produce   better   arterial   opening, 

neither produces a better clinical outcome.

Overall, differences in efficacy are small and 

of far less significance in survival terms than 

variations in the time between symptoms and 

thrombolysis  or  admission  and  thrombolysis. 

Thus  research  continues  for  a  thrombolytic 

agent closer to the ideal. In the UK at present, 

SK  is  the  drug  of  choice  in  the  absence  of 

contra-indications.

Primary   angioplasty.   There   is   increasing 

evidence that prompt angioplasty, if it can be 

arranged, produces better long-term outcomes 

than   thrombolysis.   It   is   indeed   becoming 

routine in some parts of the USA. However, the 

facilities do not yet exist in the UK for its wide-

spread use.

Cardiac workload reduction

Surrounding an evolving infarct there are rela-

tively hypoxic, but not completely anoxic, areas. 

Reducing the oxygen deficit of these might be 

expected to aid their recovery, reduce the size of 

the subsequent infarct, and thus improve prog-

nosis.   In   addition   this   contributes   to   the management of any heart failure. The strategies used are similar to those in angina:

•  Reduction of heart rate and contractility using 

beta-blockers.

•  Reduction of afterload using arterial dilators, 

e.g. ACEIs.

•  Reduction of preload using venodilators, e.g. 

nitrates, ACEIs.

Early  IV  beta-blockers  have  been  shown  to 

reduce  infarct  size,  arrhythmias  and  cardiac 

rupture.   Because   the   usual   cardiac   contra-

indications to beta-blockers are all common after 

MI (especially serious heart failure, bradycardia, 

heart  block  and  hypotension)  many  patients 

who might benefit would normally be excluded. 

However, cautious use of certain beta-blockers 

(e.g. carvedilol) in heart failure is now known to 

be   beneficial.   There   is   little   evidence   that 

cardioselectivity is to be preferred, but obviously 

non-selective   agents   would   on   theoretical 

grounds be expected to do more harm and those 

with intrinsic sympathomimetic activity, which 

increase heart rate, should be avoided. Therapy 

is continued orally for secondary prevention (see 

below).

Oral ACEIs started within 24 h of infarction 

have also been shown to improve outcome, espe-

cially  when  there  is  overt  failure,  impaired 

ventricular   function   or   hypertension.   They 

appear to counter the ventricular enlargement 

(remodelling) that occurs after infarction and 

worsens  ventricular  function  and  prognosis. 

They are particularly useful when beta-blockers 

are contra-indicated but may be used together 

with them. ACEIs are routinely used for at least

6 weeks if not contra-indicated, e.g. by hypoten-

sion, and are continued if heart failure persists. As usual, ARAs may be substituted where ACEIs are  not  tolerated.  Neither  beta-blockers  nor ACEIs should be started before the patient has been stabilized haemodynamically.

Other drugs that might be started very early 

but  for  which  there  is  either  insufficient 

evidence or lack of experience are eplerenone (in 

severe  heart  failure),  a  statin  and  clopidogrel. 

There  is  no  consensus  on  the  routine  use  of 

early  IV  nitrates  in  the  absence  of  ischaemic

Myocardial infarction265

pain or heart failure, although in addition to 

reducing oxygen demand they will counter any 

primary or reflex coronary spasm. CCBs are not 

beneficial.

Complications

Arrhythmias

Ventricular fibrillation needs prompt electrical 

defibrillation.   Early   prophylactic   lidocaine 

(lignocaine)  or  procaine  enjoyed  a  vogue,  but 

are  not  used  now  in  the  UK.  Other  specific 

arrhythmias  are  treated  as  usual  when  they 

occur. Early prophylactic magnesium infusions 

are not useful.

Heart failure and shock

These are managed as usual (pp. 197-208). They require   careful   haemodynamic   monitoring because   of   the   autonomic   imbalance   and unstable homeostatic control after MI.

Thromboembolic complications

These may be deep vein, pulmonary, cerebral or endocardial (mural) and are prevented by a short course of heparin, perhaps followed by warfarin for a few weeks. Long-term oral anticoagulation is not needed if aspirin is being given.

Rehabilitation

Patients  without  complications  are  mobilized 

within 2-3 days and discharged soon after. This 

reduces the chance of venous thrombosis, and is 

good for morale. Other aspects of rehabilitation 

are  summarized  in  Table 4.42.  Patients  may 

eventually  lead  near-normal  lives.  Although 

most do eventually die of IHD, nothing indicates 

that   a   life   of   self-imposed   semi-invalidism 

improves their chances and the quality of such a 

life  is  inferior.  By  following  simple  positive 

health   recommendations,   to   which   infarct 

survivors are especially receptive, by 6 months 

after their infarct many patients say that they 

feel better than for many years before.

Secondary prevention

Antiplatelet therapy

The long-term benefit of regular low-dose aspirin 

is   clear,   especially   following   thrombolysis. 

However, even large-scale trials have failed fully 

to resolve uncertainty over the optimal dose: 

recommendations range between 50 and 300 mg 

daily but the usual dose is 75 mg. If the patient 

is aspirin intolerant, clopidogrel is indicated.

Anticoagulants

Early  trials  of  anticoagulants  following  MI, 

usually using warfarin, were flawed and used 

imprecise  monitoring  methods,  and  toxicity 

seemed   to   outweigh   any   potential   benefit. 

However,   despite   re-analysis,   more   reliable 

monitoring methods and even revival of the 

thrombosis theory, these drugs are unlikely to be 

used routinely for the majority of patients after 

MI. Warfarin therapy is inconvenient and expen-

sive to manage, requiring regular blood moni-

toring (see Chapter 11), and there are risks of 

misdosing and interactions. The combination of 

aspirin and warfarin may have a superior effect 

but these problems count against its adoption. 

Nevertheless, there is much research into alter-

native types of antithrombotic, such as the oral 

ximelagatran, an oral thrombin inhibitor.

system

Beta-blockers

Routine    prophylactic    cardiospecific    beta-

blockade (for at least 2-5 years, and perhaps life-

long) is beneficial. Even patients with moderate 

heart failure can be treated. On the other hand, 

very low-risk patients seem unlikely to benefit. 

Pooled data suggest an overall 25% reduction in 

mortality rate.

ACE inhibitors

Regular ACEIs are recommended for all patients, 

in combination with beta-blocker or alone if 

beta-blockers are contra-indicated (about 25% of 

patients). The optimum duration of treatment is 

not yet clear, but is at least 5 years. However, 

high-risk patients will probably be on them for 

life.

Lipid-regulating agents

These have been clearly demonstrated to be of benefit in all at-risk patients, which obviously includes those post-MI, whatever the lipid level. Targets were discussed above (p. 248).

Figure 4.39 summarizes the various treatment options for a wide spectrum of possible presenta-

tions and clinical opinions. Note that this is not a flow chart for management, but an overall 

framework   for   comprehending   the   many possible eventualities and remedies.

Acute coronary syndrome

Classical angina and MI are clearly defined and 

diagnosed but there exist a range of intermediate 

conditions where patients present with atypical 

features. Their pain occurs at rest and it does not 

relent on resting or with GTN, but the ECG and 

serum marker signs do not fulfil the criteria for 

full MI. These conditions have been variously 

described as unstable, crescendo or pre-infarc-

tion angina, or acute coronary insufficiency, but 

the preferred term is acute coronary syndrome 

(ACS). There are a number of ways of defining 

the   intermediate   stages   that   comprise   this 

syndrome but all are characterized by identifying which of the criteria for full-blown MI are or are 

not  met  (p. 260).  Figure 4.40  summarizes  a 

common  classification,  with  a  summary  of 

treatment.

The primary criterion of ACS is the typical 

clinical  presentation  of  myocardial  ischaemia 

(chest  pain,  etc.)  but  which  is  unprovoked 

and/or prolonged and/or unrelieved by resting 

or GTN. If there are neither typical ECG nor 

cardiac serum marker changes it is described as 

unstable angina. That description would also

apply  if  there  were  atypical  ‘dynamic’  ECG 

changes, i.e. ST segment instability, associated 

with pain, but no consistent elevation. ECG 

changes typical of MI but with no serum markers 

is termed ST-elevation myocardial infarction 

(STEMI),   and   serum   markers   without   ECG 

changes is non-ST elevation myocardial infarc-

tion (NSTEMI).  If  all  three  criteria (clinical 

features,  ECG,  marker  changes)  are  met  the 

event is termed acute myocardial infarction 

(AMI); this may be considered the extreme end of the ACS spectrum. There also may be an atyp-

ical AMI without Q-wave changes, i.e. non-Q-

wave MI.

It is likely that all these situations start with 

the coronary plaque rupturing to some extent, 

and  platelet  aggregates  or  small  thrombi (or 

both) forming. Except in AMI these are probably 

cleared naturally before infarction supervenes, 

but   which   syndrome   eventually   develops 

depends on factors such as the size of the vessel 

affected, the maximum degree of obstruction 

and the time before resolution. All cases repre-

sent  a  medical  emergency,  because  without 

aggressive  prophylaxis  in  a  CCU,  half  such 

patients  would  go  on  to  develop  a  full  MI. 

Indeed, many AMIs are preceded by similar, if 

perhaps   accelerated   phenomena,   and   this

dynamic   process   continues   after   symptoms develop. Thus infarction is to be viewed not as a discrete event but as a process evolving over 

12-24 h, so that anti-thrombotic treatment may significantly minimize thrombus extension, and fibrinolytic therapy may be beneficial over a 

longer period than was at first thought.

The management of the various forms of ACS 

varies according to the criteria outlined above 

and also to the patient’s risk stratification. This is 

based  on  factors  such  as  continuing  pain, 

ventricular  failure,  ECG  instability,  age  and 

ischaemic event history. Moreover, the patient’s 

categorization can change quickly in the first 

12-24 h.

The routine immediate management of ACS 

is  much  as  for  a  suspected  MI  (Figure  4.40), 

involving  aspirin,  opioid,  oxygen  and  GTN.

Summary of cardiovascular aetiologies

Admission to a CCU should be rapidly arranged

so that the ECG and marker status can be deter-

mined,  the  risk  stratified  and  complications 

managed. Unstable angina and NSTEMI do not 

require   thrombolysis,   but   need   intensive 

antiplatelet  and  antithrombotic  therapy  with 

aspirin,  clopidogrel,  and  LMW  heparin.  Anti-

ischaemic therapy is also given, with IV beta-

blockers  and  nitrates  if  there  is  persistent 

ischaemic pain or heart failure. For NSTEMI a 

glycoprotein IIb/IIIa inhibitor is added. All cases 

of STEMI are treated as for AMI, with throm-

bolysis.  If  the  pain  does  not  respond  within

48 h of the onset of pain in any form of ACS, angiography with a view to revascularization by angioplasty/stenting is indicated.

CVD is potentially very confusing, with a variety 

of similar but distinct conditions affected by a 

range  of  overlapping  but  not  identical  risk 

factors, and which can affect one another. Thus 

IHD can lead to heart failure, but is itself acceler-

ated   by   hypertension;   hyperlipidaemia   can 

directly promote IHD but not hypertension; a 

sedentary lifestyle can promote both hyperten-

sion and IHD. In conclusion, therefore, it may be 

helpful to summarize some of the main points 

that link the conditions covered. Figure 4.41 

gives an overview of the main CVDs, the aetio-

logical  relationships  between  them  and  the 

various risk factors that affect them.