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Heart Failure: Epidemiology, Pathophysiology and Diagnosis

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TETC23 12/2/05 9:43 Page 685
Heart Failure: Epidemiology,
23 Pathophysiology and Diagnosis
John McMurray, Michel Komajda, Stefan Anker
and Roy Gardner
Summary
The term ‘heart failure’ describes the common clinical
syndrome arising when delivery of oxygen to the
metabolizing tissues is impaired because of defective
function of the heart as a pump (or, rarely, by
extracardiac disorders). The syndrome is characterized
by breathlessness, exercise intolerance and sodium and
water retention, often manifest as oedema. There are
numerous causes of heart failure, the most common of
which are myocardial disease and valvular disease. Left
ventricular myocardial damage is commonly caused by
hypertension, coronary artery disease (usually
myocardial infarction) or both. Those disease processes
can cause left ventricular systolic dysfunction, diastolic
dysfunction or both. The aim of investigation is to
establish the underlying cardiac cause of heart failure,
quantify ventricular and valvular function, estimate the
severity of symptoms and the degree of functional
Introduction
Heart failure is the term used to describe a common
clinical syndrome arising, in ways that are incompletely
understood, as a consequence of reduced cardiac pump
function. The term ‘syndrome’ merely describes a con-
stellation of symptoms and signs and, therefore, heart
failure is not a diagnosis as such. Unfortunately, the
typical symptoms (breathlessness and fatigue) and signs
(e.g. oedema) of heart failure are relatively non-specific,
making clinical confirmation of the syndrome difficult.
The syndrome of heart failure itself can arise as a result
of almost any abnormality of the structure, mechanical
function, or electrical activity of the heart, each of which
may require quite different treatments, emphasizing
limitation and identify relevant comorbidities. These
determine which treatments should and can or cannot
be used. A resting 12-lead ECG, transthoracic Doppler
echocardiogram, blood chemistry and haematological
measurements are essential basic investigations.
Investigations also provide information on prognosis
which is, to a large extent, determined by left ventricular
systolic function and comorbidity, as well as age. The
pathophysiology of one type of heart failure, that caused
by left ventricular systolic dysfunction, is partially
understood. Two key elements are neurohumoral
activity and left ventricular remodelling. Untreated,
patients with that type of heart failure demonstrate
chronic, sustained, neurohumoral activation and show
progressive enlargement of the left ventricle with an
associated decline in systolic function. The most
successful treatments, to date, alter these processes.
the importance of appropriate investigation of patients
with suspected heart failure. Many of the typical clinical
symptoms and signs of heart failure do not arise directly
as a result of the cardiac abnormality but rather from
secondary dysfunction of other organs and tissues, e.g.
the kidneys and muscles. These secondary consequences
of pump failure are myriad and their causes are not fully
elucidated. Dysfunction of tissues and organs remote
from the heart cannot, however, be explained solely
by reduced perfusion and it is generally believed that
other systemic processes (e.g. neurohumoral activation)
are involved. In other words, the pathophysiology of
heart failure is complex and incompletely understood
and, consequently, so is the pathophysiological basis of
treatment. It has even proved difficult to agree a simple
definition of heart failure (Table 23.1) [1]. The terms
used to describe different types of heart failure can also
685
TETC23 12/2/05 9:43 Page 686

686 Chapter 23

Table 23.1 Definitions of heart failure

1933 A condition in which the heart fails to discharge its contents adequately. (Lewis)
1950 A state in which the heart fails to maintain an adequate circulation for the needs of the body despite a satisfactory filling
pressure. (Wood)
1980 A pathophysiological state in which an abnormality of cardiac function is responsible for the failure of the heart to pump
blood at a rate commensurate with the requirements of the metabolizing tissues. (Braunwald)
1985 A clinical syndrome caused by an abnormality of the heart and recognized by a characteristic pattern of haemodynamic,
renal, neural and hormonal responses. (Poole-Wilson)
1987 . . . syndrome . . . which arises when the heart is chronically unable to maintain an appropriately high blood pressure
without support. (Harris)
1988 A syndrome in which cardiac dysfunction is associated with reduced exercise tolerance, a high incidence of ventricular
arrhythmias and shortened life expectancy. (Cohn)
1989 . . . ventricular dysfunction with symptoms . . . (Anonymous)
1993 Heart failure is the state of any heart disease in which, despite adequate ventricular filling, the heart’s output is decreased or
in which the heart is unable to pump blood at a rate adequate for satisfying the requirements of the tissues with function
parameters remaining within normal limits. (Denolin et al.)
1994 The principal functions of the heart are to accept blood from the venous system, deliver it to the lungs where it is
oxygenated (aerated), and pump the oxygenated blood to all body tissues. Heart failure occurs when these functions are
disturbed substantially. (Lenfant)
1996 Abnormal ventricular function, symptoms or signs of heart failure (past or current), and on treatment (? with a favourable
response to treatment). (Poole-Wilson)
2001 (1) Symptoms of heart failure (at rest or during exercise) and (2) objective evidence (preferably by echocardiography) of
cardiac dysfunction (systolic and/or diastolic) at rest (both criteria 1 and 2 must be fulfilled) and (3) in cases where the
diagnosis is in doubt, response to treatment directed towards heart failure. (ESC Task Force)

Adapted from Purcell and Poole-Wilson [1].

be confusing. Generally the term ‘heart failure’ is used to
describe the symptomatic syndrome, although a patient
can be rendered asymptomatic with treatment. A patient
who has never exhibited the typical signs or symptoms of
heart failure is better described as having asymptomatic
left ventricular systolic dysfunction (or whatever the
underlying cardiac abnormality is). Patients who have
had heart failure for some time are often said to have
‘chronic heart failure’. If chronic heart failure deteriorates
the patient may be described as ‘decompensated’ and
this may happen suddenly, i.e. ‘acutely’, usually leading
to hospital admission. New heart failure may also present
acutely, for example as a consequence of acute myocar-
dial infarction (or in a subacute or acute on chronic fash-
ion, for example in a patient who has had asymptomatic
cardiac dysfunction for an often indeterminate period)
and may resolve (the patient may become ‘compensated’)
or persist. ‘Congestive heart failure’ is a term still used
commonly in the United States and may describe acute
or chronic heart failure with evidence of congestion, i.e.
sodium and water retention. Congestion, though not
some symptoms of heart failure (e.g. fatigue), may resolve
with diuretic treatment. Many or all of these terms may be
accurately applied to the same patient at different times,
depending on what stage of their illness they are in.
Epidemiology
The epidemiology of symptomatic heart failure in de-
veloped countries is well understood, especially in Europe
(Fig. 23.1) [2–10]. Approximately 2% of the adult popu-
lation has heart failure, although the syndrome mainly
afflicts the elderly, affecting 6–10% of people over the
age of 65 years [2–11]. In Europe and North America, the
lifetime risk of developing heart failure is approximately
one in five for a 40-year-old [12,13]. The age-adjusted
incidence of heart failure appears to have remained
stable over the past 20 years [14,15]. Prevalence is thought
to be increasing, partly because survival is increasing
[16]. Approximately two in a thousand of the adult popu-
lation are discharged from hospital with heart failure
each year and heart failure accounts for about 5% of
TETC23 12/2/05 9:43 Page 687
Heart Failure: Epidemiology, Pathophysiology and Diagnosis
USA
(CHS)
10
9
8 preserved LV
7 systolic function
Prevalence
6
5
4
Figure 23.1 Prevalence of heart 3
failure in cross-sectional population 2
echocardiographic studies: proportion of 1
subjects with preserved left ventricular 0
systolic function. Adapted from Age range 66–103 75–86
McMurray and Pfeffer [173]. Mean age 78
all medical and geriatric admissions and is the single
most common cause of such admissions in those over
65 years [17–23]. Age at admission (and at death) seems
to be increasing, suggesting that preventive treatments,
such as antihypertensives, and secondary prevention after
myocardial infarction are delaying the development of
heart failure [17–23]. Hospital discharges include patients
developing heart failure suddenly, de novo, as a con-
sequence of another cardiac event (usually myocardial
infarction), patients presenting for the first time with
decompensation of previously unrecognized cardiac dys-
function and patients with established, chronic, heart
failure who have suffered worsening sufficiently severe
to lead to hospital admission (though it is recognized
that the ‘threshold’ for admission to hospital may vary
substantially between countries). Some of these admis-
sions are unavoidable, reflecting the progressive natural
history of heart failure (see below) whereas others may be
avoidable (e.g. as a result of non-adherence to treatment,
failure of prompt recognition and treatment of early
decompensation) [24]. After years of steady increase, age-
adjusted rates of admission for heart failure seem to
have reached a plateau, or even decreased, in Europe and
North America (Fig. 23.2) though absolute numbers of
admissions continue to increase and heart failure is still
an enormous burden on health services and a cost to
society, accounting for approximately 2% of all health-
care spending [17–23,25]. Hospital admissions account
for the main part of this expenditure, typically about
70%. Even in primary care, heart failure accounts for
more consultations than angina (Fig. 23.3), reflecting the
limiting symptoms and reduction in well-being experi-
enced by patients with heart failure [26]. Indeed, quality
of life has, consistently, been shown to be reduced more
by heart failure than by other chronic illnesses (Fig. 23.4)
[27].
687
Finland England Sweden Denmark Spain Portugal USA Nether.
(Helsinki) (Poole) (Vasteras) (Copen.) (Asturias) (EPICA) (Olmsted) (Rotter.)
Proportion with
70–84 75 –>50 >40 >25 >
– 45 55–95
– 76 75 – 60 68 63 65
Heart failure is deadly as well as disabling. Community-
based surveys indicate that 30–40% of patients die within
1 year of diagnosis and 60–70% die within 5 years, mainly
from worsening heart failure or suddenly (probably be-
cause of a ventricular arrhythmia) [11,13,15,28]. Thus an
adult living to age 40 has a one in five risk of developing
heart failure and, once apparent, a one in three chance
of dying within a year of diagnosis. Mortality is even
higher in patients requiring hospital admission, exceed-
ing that of most cancers (Fig. 23.5), though a number of
recent studies indicate that prognosis may be improving
(Fig. 23.6) [18–23,29,30].
Left ventricular function has also been measured in a
number of population-based echocardiographic studies,
notably in Europe, enabling estimation of the preval-
ence of heart failure with reduced and preserved systolic
function, as well as the prevalence of asymptomatic left
ventricular systolic and diastolic dysfunction (Fig. 23.6)
[31–39]. Synthesis of these epidemiological surveys sug-
gests that approximately half of patients with sympto-
matic heart failure in the community have reduced systolic
function (and half have preserved function) [31]. The
epidemiology of symptomatic heart failure with reduced
systolic function differs from that of heart failure with
preserved systolic function in that patients with preserved
function are, on average, older, are more often women,
have more comorbidity and have a better age-adjusted
survival (Fig. 23.7) [31–39]. The causes of heart failure in
patients with preserved systolic function also differ from
those with reduced systolic function (see below) [31–39].
Because about half of cases of left ventricular systolic
dysfunction are asymptomatic the argument has been
made for screening for symptomless cases although no
consensus has been reached on this point [40]. Recent
studies have reported very disparate prevalence rates of
diastolic dysfunction and proportions of symptomatic
TETC23 12/2/05 9:43 Page 688

688 Chapter 23

A Netherlands B Scotland

6500 Men

Number of hospitalizations
190 6000
Men
Women
170 5500
Per 100 000 per year

150 5000
4500
130
4000
110
3500
90
3000
70 2500
1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 1990 1991 1992 1993 1994 1995 1996
Year Year

C Leicestershire, England D Sweden

Incidence/ 100 000 inhabitants

350
Standardized rate per 10 000

60 300
50 250
40 200
30 150
20 100 Men
Women
10 50
0 0
1993/4 1994/5 1995/6 1996/7 1997/8 1998/9 1999/0 2000 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000

Year Year

Figure 23.2 Trends in hospital admissions for heart failure demonstrating recent plateau or decline. (A) Age-adjusted discharge rate
for heart failure in men and women. (B) Gender-specific trends in hospitalizations (principal diagnosis) for heart failure in men.
Squares, total episodes; triangles, number of individuals; circles, first-ever hospitalization. (C) Gender- and age-specific trends in
first-ever heart failure hospitalization rates (principal diagnosis) in individuals ≥ 40 years. Orange circles, men and women ≥ 65 years;
blue triangles, all men; red circles, all women; green squares, men and women < 65. (D) Age-adjusted annual incidence of
first-ever hospitalization for heart failure as the principal diagnosis. Reprinted with permission [174].

Angina Hypertension Heart failure

400
380 364.9
360
340
Consultation rate per 1000 males

320 304.7
300 288.4
280
260
240
220
200 191.2
180 171.3
160 141.9
140
120
100 86.8 90.8 86
80 65.1
60 Figure 23.3 Age-stratified primary-care
38.7
40 consultation rates per 1000 population
20 9.9
for heart failure, angina and hypertension
0
45–64 65–74 75–84 85+ 45–64 65–74 75–84 85+ 45–64 65–74 75–84 85+ in men. Reprinted with permission [26].
TETC23 12/2/05 9:43 Page 689

Heart Failure: Epidemiology, Pathophysiology and Diagnosis 689

100

90

80

70

SF-36 score (%)

60
Figure 23.4 Quality of life in patients
50
with congestive heart failure compared to
other chronic illnesses and the normal 40
population. The eight scales of the SF-36
short-form health survey instrument are 30
CHF (n=205)
physical functioning (PF), role limitations Depression (n=502)
due to physical limitations (RP), bodily 20 Dialysis (n=120)
pain (BP), general health perceptions Hepatitis C (n=70)
10 Normal population (n=906)
(GH), vitality (VT), social functioning
(SF), role limitations caused by emotional 0
problems (RE), and mental health (MH). PF RP BP GH VT SF RE MH
Reprinted with permission [175]. SF-36 scales

Women Breast Men MI

MI Bladder
1.0 Bowel 1.0 Prostate
Cumulative probability of survival

Cumulative probability of survival

0.9 Ovarian 0.9 Bowel

Heart failure Heart failure
0.8 Lung 0.8 Lung
0.7 0.7
0.6 0.6
0.5 0.5
0.4 0.4
0.3 0.3
0.2 0.2
0.1 0.1
0.0 0.0
0 6 12 18 24 30 36 42 48 54 60 0 6 12 18 24 30 36 42 48 54 60
Months of follow-up Months of follow-up

Figure 23.5 Five-year survival following a first admission to any Scottish hospital in 1991 for heart failure, myocardial infarction,
and the four most common sites of cancer specific to men and women. Reprinted with permission [30].

and asymptomatic individuals and no conclusions can ischaemic, metabolic, endocrine, immune, inflammatory,
yet be drawn about the epidemiology of asymptomatic infective, endocrine, genetic and neoplastic processes,
diastolic dysfunction [31–39,41]. by failure of the heart to develop properly and even by
pregnancy. The potential causes of heart failure are,
therefore, legion, vary geographically and have changed
over time. Rheumatic valvular disease remains a com-
mon cause in many developing countries whereas this
Aetiology: causes of heart failure diagnosis is now uncommon in developed countries; in
the latter, degenerative valvular disease in the elderly is
now more common [42–45]. Valve disease may lead to
As already mentioned, any structural, mechanical or volume and pressure overload of the heart, as described
electrical abnormality of the heart can cause it to fail in more detail below. Endocardial disease is very rare in
(Table 23.2). Similarly, heart failure can be caused by Europe but much less so in parts of Africa, where it can
TETC23 12/2/05 9:43 Page 690

690 Chapter 23

A Leicestershire, England B Scotland

1.0

0.9

Adjusted hazard ratio (95% CI)

Males

0.8 1.1 Females

Hazard ratio

1.0
0.7
0.9
0.6 0.8
0.7
0.5 P<0.0001
0.6
0.4 0.5
1993/4 1995/6 1997/8 1999/0 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995
1994/5 1996/7 1998/9 2000/1
Year Year of admission

C Framingham, USA D Sweden

1.0 45
30 days
1960–1969 40
One year
Probability of survival

0.8 1970–1079 35
1980–1089
1990–1999 Percentage 30
0.6
25
20
0.4
15
0.2 10
5
0.0 0
0 2 4 6 8 10 1988 1990 1992 1994 1996 1998 2000
1989 1991 1993 1995 1997 1999
Year Year of admission

Figure 23.6 Evidence of improving survival from heart failure in the general population. (A) Hazard ratio and 95% confidence
intervals for all-cause mortality in patients having a first admission for heart failure, according to year of admission (adjusted for
age, gender, comorbidity, and social deprivation). Hazard ratio for first year of study (1993/1994) set at 1. (B) Odds ratios and 95%
confidence intervals for all-cause mortality (≥ 30 days after a first heart failure admission), according to year of admission (adjusted
for age, gender, comorbidity, and social deprivation). Odds ratio for first year of period of study (1986) set at 1. (C) Standardized
30-day and 1-year case fatality rates (%) for women with a first admission to hospital for heart failure. (D) Age-adjusted survival after
the onset of heart failure in men. Values were adjusted for age (< 55, 55 to 64, 65 to 74, 75 to 84, and ≥ 85 years). Estimates are shown
for men who were 65 to 74 years of age. Similar trends were observed in women. Reprinted with permission [174].

cause what is referred to as a restrictive cardiomyopathy, improves systolic function, is also a question of great cur-
as described further below [42–45]. rent interest, addressed by ongoing studies of coronary
In the developed world, ventricular dysfunction is ‘revascularization’ [46].
the commonest underlying problem and is caused, In Europe, North America and Australasia, hyper-
mainly, by myocardial infarction (leading to systolic tension was once the principal cause of heart failure
ventricular dysfunction, i.e. failure of normal contrac- whereas now that position is filled by coronary heart dis-
tion and emptying of the heart), hypertension (causing ease (or more exactly, myocardial infarction); this is also
systolic dysfunction, diastolic dysfunction, i.e. failure increasingly the case in many developing countries [47].
of normal relaxation and filling of the heart or both) While myocardial infarction is a much more important
or, often, both infarction and hypertension. Whether individual risk factor than hypertension, the population-
persisting systolic dysfunction is caused by coronary attributable risk due to hypertension is probably still
artery disease in the absence of infarction is uncertain. more important [48]. Both causal factors also interact to
The converse, i.e. whether treatment of ischaemia and a augment the risk of heart failure. By the time heart failure
state known as ‘hibernation’ (where chronic poor perfu- presents, prior hypertension may no longer be present.
sion results in non-contracting but viable myocardium) Both of these factors probably result in underestimation
TETC23 12/2/05 9:43 Page 691

Heart Failure: Epidemiology, Pathophysiology and Diagnosis 691

1.0 Table 23.2 Aetiology of heart failure

There is no agreed or satisfactory classification for the causes
of heart failure with much overlap between potential
0.8 categories, e.g. dilated cardiomyopathy may be variously
regarded as idiopathic, genetic, caused by a remote virus
infection or the result of current or previous excessive
alcohol consumption.
Proportion alive

0.6
Myocardial disease
l coronary artery disease

l hypertension

l immune/inflammatory
0.4
viral myocarditis
Chagas’ disease
l metabolic/infiltrative
No HF-PSF thiamine deficiency
0.2 HF-PSF haemochromatosis
HF borderline SF
amyloidosis
HF reduced SF
sarcoidosis
l endocrine
0.0
0 2 4 6 thyrotoxicosis
l toxic
Survival time (years) alcohol
cytotoxics
Figure 23.7 Unadjusted Kaplan–Meier survival curves for
negatively inotropic drugs (e.g. calcium-channel
participants with heart failure (HF) based on left ventricular blockers)
function from The Cardiovascular Health Study. Preserved l idiopathic

systolic function (PSF), Systolic function (SF). Reprinted with cardiomyopathy (dilated, hypertrophic, restrictive,
permission [35]. peri-partum)
Valvular disease
l mitral stenosis/regurgitation
of the role of hypertension in causing heart failure.
l aortic stenosis/regurgitation
Hypertension is a more common aetiology in women l pulmonary stenosis/regurgitation

than men. l tricuspid stenosis/regurgitation

‘Idiopathic’ dilated cardiomyopathy remains the Pericardial disease

only other cause of systolic dysfunction commonly l effusion

encountered, perhaps accounting for 15–20% of cases of l constriction

heart failure with reduced systolic function. These cases Endocardial/endomyocardial disease
probably have multiple causes and an increasing num- l Loeffler endocarditis

l endomyocardial fibrosis
ber of genetic causes are being identified [49]. Prior viral
infection and current or previous excessive alcohol con- Congenital heart disease
sumption may also cause a dilated cardiomyopathy, as can l e.g. atrial or ventricular septal defect

exposure to other toxins, including chemotherapeutic Genetic

agents used in cancer treatment. These must always be l e.g. familial dilated cardiomyopathy

considered when a patient presents with an unexplained Arrhythmias (brady- or tachy-)

dilated cardiomyopathy. If angiography is not carried l atrial

out to exclude coronary disease, it may also be wrongly l ventricular

concluded that the patient has an ‘idiopathic’ dilated Conduction disorders

cardiomyopathy. Chagas’ disease caused by the protozoan l sinus node dysfunction

l second-degree atrioventricular block

parasite Trypanosoma cruzi can also cause systolic dysfunc-
l third-degree atrioventricular block
tion. Though rarely encountered in Europe it is a relat-
ively common cause of heart failure in South America and High output states
l anaemia
is now recognized in Central and North America [42–45].
l sepsis
The contribution of diabetes to systolic and diastolic l thyrotoxicosis

dysfunction is not well understood, as is the relationship l Paget’s disease

l arteriovenous fistula
between atrial fibrillation and both types of heart fail-
ure [50,51]. Diabetics have a higher prevalence of heart Volume overload
failure. Diabetes accelerates the development of coronary l renal failure

l iatrogenic
atherosclerosis and is often associated with hypertension
TETC23 12/2/05 9:43 Page 692
692 Chapter 23
[50,52]. Whether it directly causes a specific cardiomyo-
pathy is, however, uncertain [50]. Diabetes also increases
the risk of developing heart failure in patients with other
causes, e.g. acute myocardial infarction. It is believed
that diabetes promotes the development of myocardial
fibrosis and diastolic dysfunction [53]. Diabetes is also
associated with more autonomic dysfunction and worse
renal, pulmonary and endothelial function, as well as
worse functional status and a worse prognosis. Conversely,
heart failure increases the risk of developing diabetes
[54].
Atrial fibrillation can cause heart failure directly as
a consequence of the loss of the atrial contribution to
cardiac output and reduced diastolic filling as a result of
tachycardia [51]. Patients with underlying structural or
functional cardiac disease are more likely to develop
failure as a consequence of these effects with the onset of
atrial fibrillation. There is, however, a growing belief that
atrial fibrillation can cause a dilated cardiomyopathy the
exact mechanism of which is uncertain, though persist-
ent tachycardia may play a role (i.e. atrial fibrillation may
cause a ‘rate-related cardiomyopathy’) [55,56]. Heart fail-
ure also increases the risk of developing atrial fibrillation
and this risk increases with the severity of heart failure.
Consequently, when a patient presents with left ventri-
cular dilatation systolic dysfunction and atrial fibrilla-
tion it can be difficult to determine which came first.
Comorbidity
It is important to appreciate that heart failure does not
occur in isolation. It is caused by an underlying cardiac
defect in, usually, elderly individuals frequently treated
for other medical problems with multiple medications.
Consequently, the patient with heart failure often has
comorbidity related to the underlying cardiac problem or
its cause (e.g. angina, hypertension, diabetes, smoking-
related lung disease) and age (e.g. osteoarthritis), as well
as a consequence of heart failure (e.g. arrhythmias) and
its treatment (e.g. gout from diuretics) [57]. Some
common comorbidities have multiple causes (e.g. renal
dysfunction – see below), whereas others are not fully
explained (e.g. anaemia, depression, disorders of breath-
ing and cachexia) [57– 61]. The existence of multiple
comorbidities creates the potential for drug intolerance
[e.g. angiotensin-converting enzyme (ACE) inhibitor and
renal dysfunction], drug interactions [e.g. non-steroidal
anti-inflammatory drugs (NSAIDs) and ACE inhibitors]
and makes the management of heart failure very com-
plex [57,62–65]. This is especially true of renal dysfunc-
tion, the importance of which is increasingly recognized
by a growing use of the term ‘cardiorenal syndrome’
[66,67] to describe concurrent heart and renal failure.
Cardiorenal syndrome
This syndrome arises from multiple interactions between
the age-related decline in glomerular filtration, the effects
of treatment for heart failure (diuretics, ACE inhibitors,
angiotensin receptor blockers and aldosterone antagon-
ists) and other conditions (e.g. NSAIDs for arthritis), co-
morbidity (e.g. hypertension, diabetes, atherosclerosis),
reduced renal blood flow and the actions on the kidneys
of the array of neurohumoral pathways activated in heart
failure [66,67]. The prevalence of severe renal dysfunc-
tion in heart failure is often underestimated because
serum creatinine concentration may not be greatly
elevated because of the reduction in skeletal muscle
mass in advanced heart failure. Renal dysfunction may
contribute to the high prevalence of anaemia in patients
with heart failure.
Anaemia
Anaemia is another important comorbidity and can be
both the cause and, it seems, consequence of heart failure
[68–71]. Anaemia is common (especially in more severe
heart failure) and is associated with worse symptoms,
increased risk of hospital admission and reduced survival.
The causes are unknown but may include renal dysfunc-
tion, poor nutrition, inflammation (see below), blood
loss related to medication and reduced production of
(or response to) erythropoietin.
Catabolic/anabolic imbalance and cachexia
Patients with heart failure often exhibit some degree of
muscle wasting which is restricted to the lower limbs
(disuse atrophy) [72,73]. This loss of tissue may become
more extensive in some patients, usually when their
heart failure is more advanced, and may affect all body
compartments (muscle, fat and bone tissue). This general
wasting is referred to as cardiac cachexia. The underlying
metabolic causes are complex and differ from patient
to patient. Three important contributors are, probably,
dietary deficiency (exacerbated by anorexia) and loss of
nutrients through the urinary or digestive tracts (malab-
sorption) and metabolic dysfunction (including an imbal-
ance of anabolic and catabolic factors and inflammation).
The development of cachexia is an ominous sign.
It is important to appreciate that it is comorbidity,
along with the key pathophysiological processes in heart
TETC23 12/2/05 9:43 Page 693

Heart Failure: Epidemiology, Pathophysiology and Diagnosis 693

failure, i.e. left ventricular remodelling and activation of A

systemic pathways (and age), that are the principal deter-
minants of prognosis.

Pathophysiology

We have only limited knowledge of the pathophysiology

of heart failure, and that of left ventricular systolic dys-
function is best understood. Much of our understanding
comes from studies of myocardial infarction (Fig. 23.8)
[74–77]. Following an initial injury to the myocytes and B
cytoskeleton, heart failure may develop immediately, in
the short term (over days or weeks), over a longer time
period (months to years), or not at all. The factors leading
to the development of heart failure acutely after myo-
cardial infarction (e.g. size of infarction), the important
pathophysiological mechanisms operating (e.g. cardiac
remodelling) and the time-course of this complication
of infarction are fairly well established. On the other
hand, the natural history of asymptomatic left ventricu-
lar systolic dysfunction is less well understood, as are
the pathophysiological mechanisms causing progression
from the asymptomatic to the symptomatic state. Once
symptomatic heart failure has developed we believe
that the pathophysiology is again better understood, at
least in patients with systolic dysfunction. One thing is
certain: the syndrome is characterized by progressive
worsening of the patient’s symptoms, of cardiac function
and of the function of other tissues (e.g. skeletal muscle) Figure 23.8 Gross pathological appearance of (A) an
and organs (e.g. the kidneys). anteroseptal myocardial infarction, with wall thinning and
The progression of left ventricular systolic dysfunction endocardial fibrosis, in a patient with a background of left
(and the heart failure syndrome), because of ‘remodelling’ ventricular hypertrophy due to hypertension, and (B) a heart
in idiopathic dilated cardiomyopathy characterized by four
of the left (and right) ventricle (as a result of the loss
chamber enlargement.
of myocytes and maladaptive changes in the surviving
myocytes and extracellular matrix), probably occurs in
two main ways [76–79]. One is because of intercurrent result in electrical as well as mechanical dysfunction of
cardiac events (e.g. myocardial infarction) and the other the heart.
is as a consequence of the local processes (e.g. the auto- It is important to remember that atrial function (see
crine pathway and molecular adaptations, including, above), synchronized contraction of the left ventricle
perhaps, apoptosis) and systemic processes (e.g. neuro- and normal interaction between the right and left ven-
humoral pathways) that are activated as a result of tricles are also important in preserving stroke volume
reduced systolic function (Fig. 23.9) [80–82]. These [83]. Loss of these key mechanical interactions are often
systemic processes, which are discussed in detail below, secondary to disturbances of conduction arising as a
also have detrimental effects on the functioning of the consequence of cardiac fibrosis.
lungs, blood vessels, kidneys, muscles and probably
other organs (e.g. the liver) and contribute to a patho-
Dilated and ischaemic cardiomyopathy
physiological vicious cycle (Fig. 23.10). The molecular,
structural and functional changes in the heart and these Myocyte necrosis whether caused by infarction or by
systemic processes, coupled with electrolyte imbalances, other injury has a common consequence. Whether
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694 Chapter 23

Myocyte loss Excess load Mutation

Mechanical
sensors

Cell grafting Apoptosis Signal

Growth
transducers

Angiogenesis Transcription
factors

Mitochondrial Calcium Sarcomere,

metabolism cycling cytoskeleton

Impaired cardiac pump function

Secondary neurohumoral responses

Figure 23.9 A partial wiring diagram of biological circuits for heart failure. Impaired pump function after myocyte death
from myocardial infarction or abnormal loading conditions such as found in hypertension (white) activate a biomechanical
stress-dependent signalling cascade (purple). The responsible targets of altered signal transduction cascades in heart failure
include transcription factors, coactivators and co-repressors for cardiac gene expression (green) as well as the effector mechanisms
like calcium cycling, metabolism, growth and apoptosis (yellow) that culminate in ventricular dysfunction (orange) and
secondary neurohumoral responses (grey) such as adrenergic drive and intramyocardial growth factors. Inherited mutations for
cardiomyopathy (blue) affect proteins at many of these points and are thought to engage a similar cascade of events to elicit the
full myopathic phenotype. Cell-based therapies (red), although often envisioned working chiefly or wholly by replacing dead
myocytes, probably improve ventricular performance through a combination of mechanisms, including angiogenesis, paracrine
signals for myocyte protection, and conceivably augmenting host self-repair. Reprinted with permission [176].

diffuse or focal, myocyte loss leads to replacement fibrosis,
hypertrophy of the remaining myocytes and dilatation
of the affected cardiac chamber [84–89]. How these
molecular and cellular changes affect the left ventricle
macroscopically (by causing remodelling) is discussed
in more detail below [76]. The resulting anatomical
and pathophysiological picture is, however, identified by
clinicians as a dilated cardiomyopathy (Fig. 23.8; see also
Chapter 16). Patients with a dilated poorly contracting
left ventricle as a result of prior myocardial infarction
are sometimes referred to as having an ‘ischaemic car-
diomyopathy’. Poor contraction and emptying of the
ventricle are usually referred to as systolic dysfunction.
Systolic vs. diastolic dysfunction
Systolic and diastolic dysfunction are terms used to
describe whether the principal abnormality of the myo-
cardium is an inability of the ventricle to contract and
expel blood or to relax and fill normally, respectively
(though in reality these two abnormalities frequently
coexist). Systolic dysfunction is the result of reduced
shortening of sarcomeres, which is a consequence of a
global or regional reduction of contractility or greatly
increased impedance to left ventricular ejection. An
increase in preload can provide short-term compensa-
tion (via the Frank–Starling mechanism – see below) for
a reduction in contractility or increases in impedance.
However, long-term compensation usually involves myo-
cardial hypertrophy, which is the result of laying down
new sarcomeres that increase the width (concentric) or
the length (eccentric) of myocytes [76,90]. Remodelling
also contributes to reduced sarcomere shortening. All
these factors causing reduced fibre shortening also lead
to a decrease in the left ventricular ejection fraction
(LVEF). Hence, end-systolic volume increases.
TETC23 12/2/05 9:43 Page 695
Heart Failure: Epidemiology, Pathophysiology and Diagnosis
Injury to myocytes and
extracellular matrix
Neurohumoral
imbalance, increased Apoptosis,
cytokine expression, altered gene
Ventricular
immune and expression,
remodelling
inflammatory energy starvation,
changes, altered oxidative stress
fibrinolysis
Electrical Ventilatory
Vascular Muscle
Renal Haematological
and other effects
Syndrome of heart failure
Figure 23.10 Pathophysiology of heart failure as a result
of left-ventricular systolic dysfunction. Damage to the
myocytes and extracellular matrix leads to changes in the
size, shape, and function of the left ventricle and heart more
generally (‘remodelling’). These changes, in turn, lead to
electrical instability, systemic processes resulting in many
effects on other organs and tissues, and further damage to
the heart. These vicious cycles, along with intercurrent
events, such as myocardial infarction, are believed to cause
progressive worsening of the heart-failure syndrome over time.
Adapted from McMurray JJ and Pfeffer MA [173].
Rapid filling during systole is assisted by active, energy-
dependent, relaxation of the ventricle [85,91]. Primary
myocardial diseases may affect this process. Ventricular
relaxation also depends on myocardial mass, collagen
content and extrinsic forces (e.g. the pericardium) [91].
The hallmark of diastolic dysfunction is elevation in left
ventricular end-diastolic pressure or left arterial pressure
in the absence of systolic dysfunction [92–97].
Restrictive cardiomyopathy and pericardial
constriction
Infiltrative processes in the myocardium or pericardium
may cause a restrictive cardiomyopathy [98]. The prin-
cipal consequence of these processes is impaired ven-
tricular filling with normal or decreased diastolic volume
of either or both ventricles, akin to the diastolic dysfunc-
tion described above. Systolic function is typically main-
tained during the early stages of the disease and wall
thickness is normal or increased. The main problem is
that increased stiffness of the myocardium causes pres-
sure within the ventricle to rise precipitously with only
small increases in volume. Restrictive cardiomyopathy
695
may affect either or both ventricles. Elevated jugular
venous pressure, peripheral oedema and ascites are often
prominent features (see below).
Valve disease: pressure and volume overload
Arterial hypertension and aortic stenosis cause a sus-
tained increase in systolic wall stress during left ven-
tricular ejection leading to concentric hypertrophy of
the left ventricle because of myocyte hypertrophy and
extracellular matrix overgrowth [99].
Conversely, mitral and aortic regurgitation result in
an increased volume load on the ventricle. The resultant
ventricular remodelling is characterized by dilatation,
representing, at least in part, lengthening of the cardiac
myocytes [100,101].
Other terms sometimes used when describing
heart failure
Right and left heart failure
These terms are not useful and are reminiscent of the
now discarded terminology of ‘backwards and forwards
heart failure’. The term right heart failure is often used
to describe patients in whom there are prominent signs
of ‘congestion’, e.g. a raised jugular venous pressure
(Fig. 23.11), hepatomegaly and peripheral oedema
(Fig. 23.11), on the basis that these findings reflect right
ventricular failure; in fact all of these signs are also found
in patients with predominantly left ventricular involve-
ment. The description pulmonary heart disease is used to
depict patients who do have isolated right heart failure as
a result of primary lung disease and has generally replaced
the term ‘cor pulmonale’.
High- and low-output heart failure
A more useful pathophysiological classification is to
distinguish between high- and low-output heart fail-
ure, although the former is uncommonly encountered
in Western clinical practice. Cardiac index is normally
2.2–3.5 l/min/m2. Low-output cardiac failure implies
that cardiac output fails to rise adequately during exer-
cise or that it is inadequate even at rest. This prototypical
form of heart failure is seen in cases of heart failure as
a result of left ventricular systolic dysfunction. High-
output cardiac failure, on the other hand, implies that
although the pumping action of the heart is intact other
factors make it difficult for the heart to deliver oxygen
commensurate with the needs of the metabolizing
tissues, either because of increased tissue demand (e.g.
as a result of anaemia, hyperthyroidism or pregnancy)
or reduced oxygen carrying content of the blood (e.g.
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696 Chapter 23

A B

Figure 23.11 (A) A raised jugular venous pressure ( JVP) reflects an elevation in right atrial pressure as occurs in heart failure.
However this can also be seen in pericardial disease, tricuspid stenosis, superior vena cava obstruction, reduced compliance
of the right ventricle, and hypervolaemia. (B) Pitting pedal oedema as seen in a patient with heart failure. This can also be
seen in hypoalbuminaemia, nephrotic syndrome, chronic venous insufficiency and myxoedema.

anaemia). This type of heart failure can also be caused by
arteriovenous shunting.
Cardiac responses to ventricular injury
and reduced stroke volume
Frank–Starling mechanism
The Frank–Starling law describes an intrinsic mechanism
that helps maintain stroke volume when the heart is
acutely injured and may also play a compensatory role
in chronic heart failure, though this is less certain [103].
Together with neurohumoral activation (an extrinsic
mechanism), the Frank–Starling law is an adaptive phen-
omenon that comes into play within minutes of cardiac
injury. The resultant acute fall in the volume of blood
ejected by the ventricle (the stroke volume) leads to a rise
in left ventricular end-diastolic volume (and pressure).
Through the Frank–Starling mechanism this rise in
preload increases the force of contraction, thereby help-
ing restore stroke volume. The mechanism whereby
increased stretch of the myocyte causes increased force of
contraction is also referred to as the law of heterometric
autoregualtion. In the chronic setting, sodium retention,
water retention and venoconstriction may represent con-
tinuing attempts by the body to use the Frank–Starling
mechanism by increasing left ventricular filling pressure
and preload.
These adaptations may, however, lead to abnormally
high pulmonary capillary and artery pressures, probably
contributing to the shortness of breath experienced by
patients with heart failure. Furthermore arterial constric-
TETC23 12/2/05 9:43 Page 697
Heart Failure: Epidemiology, Pathophysiology and Diagnosis
Figure 23.12 Colour-flow Doppler study
of a patient with mitral regurgitation as
a result of left ventricular dilatation seen
in the apical four-chamber view.
tion and stiffening (as a result of sodium and water reten-
tion in the vascular wall) increase afterload and will
eventually cause the injured left ventricle to fail further
because it is especially sensitive to increases in afterload
(law of homeometric regulation).
Ventricular remodelling
The heart attempts to compensate for increased preload
(e.g. because of increased extracellular fluid volume and
venous return) and afterload (e.g. because of systemic
arterial constriction) in several ways. One is the develop-
ment of ventricular hypertrophy in an attempt to main-
tain systolic wall stress within normal limits [76,90,103].
Pressure overload tends to lead to concentric hyper-
trophy, whereas volume overload tends to lead to ventri-
cular dilatation [76,85,90,103]. Both entities are distinct
at the molecular level. Pressure overload is associated with
parallel replication of myofibrils and thickening of indi-
vidual myocytes. Volume overload, on the other hand,
leads to replication of sarcomeres in series and elonga-
tion of myocytes. The two types of haemodynamic over-
load are presumed to activate distinct signalling pathways.
Compensated remodelling results in relatively little
change in ventricular dimensions, shape, function and
wall thickness. However, these compensatory adaptations
only seem to be capable of maintaining pump function
over a limited period of time and a ventricle subjected to
an elevated load for a prolonged period will ultimately
fail [76]. Ventricular dilatation may lead to stretching of
the mitral valve ring and cause valvular incompetence
697
(Fig. 23.12). This may further increase the load on the
failing ventricle; this is an example of another ‘vicious
cycle’ that develops and which may drive progression of
heart failure.
An initial stress-induced increase in sarcomere
length yields an optimal overlap between myofilaments
[85,86,90,103,104]. Severe haemodynamic overload
eventually yields depression of myocardial contractility
[85,86,90,103,104]. In patients with mild disease, this
depression is manifested by reduced velocity of shorten-
ing of the myocardium or by a reduction in the rate of
force development during isometric contraction. More
severe stages are accompanied by a decline in isometric
force development and shortening as well. Ejection frac-
tion and cardiac output during exercise decline [105].
Our understanding of the molecular mechanisms
behind these changes is still limited and can only be
touched upon briefly (Fig. 23.9). They comprise myocyte
loss by necrosis and apoptosis, alterations in excitation–
contraction coupling, and alterations in composition of
the extracellular matrix [76,84,87–89]. Myocyte loss as
a result of necrosis is a well-understood process which
is localized after myocardial infarction but more diffuse
in patients with dilated cardiomyopathy or myocarditis.
Apoptosis, or programmed cell death, on the other hand,
results from the induction of a genetic programme
that leads to degradation of nuclear DNA (Fig. 23.9)
[79,87,88]. Several recent reports have described apop-
totic cells in the failing myocardium. It may be relevant
that several substances, such as angiotensin II, reactive
oxygen species, nitric oxide (NO), and pro-inflammatory
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698 Chapter 23

cytokines may induce apoptosis experimentally in car-
diac myocytes. However, the precise frequency of occur-
rence and role of apoptosis in the failing myocardium
remains unclear. Changes in the extracellular matrix are
usually manifested by an increase in collagen content
though both degradation and synthesis (and the activ-
ity of the enzymes controlling these processes) may be
increased [78,79,89,90]. While this change in collagen
content may contribute to impaired systolic contraction
it may be even more important in reducing ventricular
compliance and impaired ventricular filling.
Systemic responses
a number of other self-sustaining pathophysiological
vicious cycles may develop.
The predominant effects of the neurohumoral sys-
tems activated in heart failure are to cause vasocon-
striction, sodium and water retention and abnormal cell
growth. Two exceptions are the natriuretic peptides [107]
(secreted mainly by the failing heart, Fig. 23.13) and
adrenomedullin (secreted mainly from blood vessels)
[108].
The neurohumoral pathways activated in heart failure
are thought to be particularly important because they
appear to explain how many of the successful pharmaco-
logical treatments for heart failure work (and offer the
potential for more such therapeutic interventions).

Neurohumoral responses
The human body responds to the haemodynamic
changes in patients with heart failure in a highly com-
plex way. Many neurohumoral systems appear to be
involved to varying degrees and at different stages. It
has been suggested that these are initially activated in a
manner appropriate to haemorrhage or some other crisis
threatening vital organ perfusion [80,82,105,106]. Their
sustained activation in heart failure, however, is not
only inappropriate but probably detrimental (Fig. 23.10).
Moreover, at some stage during the progression of heart
failure, haemodynamic abnormalities may cease to be
the main trigger of neurohumoral activation. Instead,
Sympathetic nervous system It has long been recognized
that an increased activity of the sympathetic nervous
system and parasympathetic withdrawal are prototyp-
ical characteristics of heart failure [109,110]. Elevated
levels of plasma noradrenaline are a common finding in
patients with heart failure. Increased sympathetic nerve
traffic and enhanced spill-over of noradrenaline from
the synaptic cleft account for this. Raised plasma nor-
adrenaline concentrations predict higher mortality rates
[111]. Heart failure is also characterized by reductions
in myocardial noradrenaline stores and in myocardial
beta-receptor density. These again reflect generalized
adrenergic activation.

Central nervous system

Sympathetic outflow CNP (NPR-A, NPR-B)
Neuroendocrine function
AVP
Clearance by
Corticotropin NPR-C
NEP
Salt appetite

Water intake Figure 23.13 Physiological effects of the

natriuretic peptides in heart failure.
Increased secretion of the natriuretic
Blood Plasma Venous return ANP
peptides reduces blood pressure and plasma
pressure volume BNP
volume through coordinated actions
–
in the brain, adrenal gland, kidney,
and vasculature. Urodilatin (URO);
neutral endopeptidase (NEP); C-type
Adrenal natriuretic peptide (CNP); natriuretic
aldosterone peptide receptors A, B and C (NPR-A,
NPR-B, and NPR-C respectively); arginine
vasopressin (AVP); atrial and brain
Peripheral vasculature Kidney URO natriuretic peptides (ANP and BNP);
Vasodilatation GFR
glomerular filtration rate (GFR); urinary
Permeability haematocrit UNaV
(NPR-A, NPR-B) UV sodium excretion (UNaV); urinary volume
Renin (UV); blood pressure (BP). Reprinted with
(NPR-A) permission [177].
TETC23 12/2/05 9:43 Page 699
Heart Failure: Epidemiology, Pathophysiology and Diagnosis
It is believed that enhanced sympathetic activity
initially increases myocardial contractility and heart rate
(leading to an increase in cardiac output). Sympathetic
activation also promotes renin release, sodium retention
and vasoconstriction thereby increasing preload and
activating the Frank–Starling mechanism (see above).
These responses are capable of maintaining ventricular
performance and cardiac output for a limited period of
time. In part this may be because the increase in afterload
caused by arterial constriction (to which the failing ven-
tricle is particularly sensitive) leads to a further fall in
stroke volume (see above). Sympathetic overdrive prob-
ably alters myocardial metabolism and catecholamines
may also even be directly toxic to cardiomyocytes. Excess-
ive adrenergic activity (and reduced vagal activity) also
increases the electrical instability of the heart. As well
as having complex and changing effects on myocardial
contractility and structure, activation of the sympathetic
nervous system leads to redistribution of regional blood
flow and even to changes in the structure of the vascula-
ture [110].
The precise cause of sympathetic activation in heart
failure is unknown. Reduced stimulation of stretch-
activated baroreceptors in the carotid arteries and the
aorta from decreased arterial pressure and stroke volume
may contribute (in an analogous way to haemorrhage).
Another factor suggested is structural and functional
abnormalities of afferent receptors. Other neurohumoral
systems may also activate the sympathetic nervous sys-
tem and augment its actions, i.e. many neurohumoral
systems act in concert, synergistically reinforcing each
other.
Renin–angiotensin– aldosterone system Increased activity
of the renin–angiotensin–aldosterone system (RAAS)
also produces deleterious effects on the cardiovascular
system (and other organs and tissues) and contributes to
the poor prognosis in heart failure [80,82,112]. The
plasma components of this system are usually increased
in patients with heart failure and a low serum sodium
concentration is a marker for particularly excessive activa-
tion of the RAAS [113]. The increase in renin release is
mediated by decreased stretch of the glomerular afferent
arteriole and reduced delivery of chloride to the macula
densa. Although the sympathetic nervous system also
stimulates renin release, the two systems are independ-
ently regulated. One puzzle about heart failure is why
the sodium and volume overload that characterizes the
syndrome does not suppress renin release, as would
normally occur.
The increased secretion of renin leads to an augmented
production of angiotensin II, which, it is believed, has
mostly deleterious effects in heart failure (although its
699
efferent glomerular arteriolar action may help maintain
glomerular filtration). The deleterious effects of angio-
tensin II are mediated via the angiotensin type I receptor.
Angiotensin II not only induces vasoconstriction, but
also salt and water retention directly and via aldosterone
[114]. Moreover, it mediates myocardial cell hypertrophy
and fibrosis and these effects may contribute to the
progressive loss of myocardial function in heart failure.
Plasma aldosterone levels are also increased in heart
failure, and release of this hormone is influenced by
angiotensin and other stimuli such as potassium and
corticotropin. Aldosterone is now recognized as an inde-
pendent and harmful component of the RAAS [115]. It
causes sodium and water retention, potassium wastage
and may contribute to myocardial and vascular fibrosis,
autonomic dysfunction and other abnormalities in heart
failure.
Vasopressin Vasopressin (also known as antidiuretic
hormone) is a neurohypophysial peptide involved in
the regulation of free water reabsorption, body fluid
osmolality, blood volume, blood pressure, cell contrac-
tion, cell proliferation and adrenocorticotropin secretion
[116,117]. Vasopressin binds to three different specific G
protein-coupled receptors. These are currently classified
as V1-vascular, V2-renal, and V3-pituitary subtypes. All
subtypes have distinct pharmacological profiles and
intracellular second messengers. As well as reducing
renal water excretion, vasopressin is one of the most
powerful vasoconstricting substances known. It also
stimulates blood platelet aggregation, coagulation factor
release and cellular proliferation. This profile of action
is clearly unattractive in heart failure.
Elevated circulating levels of vasopressin are often,
but not invariably, found in patients with chronic heart
failure. It appears that vasopressin release from the
posterior pituitary in heart failure is largely non-osmotic,
although, normally, increased serum osmolality is the
major physiological stimulus for its secretion.
Natriuretic peptides A-type (atrial) natriuretic peptide
(ANP) and B-type (brain) natriuretic peptide (BNP) are
released in response to atrial and ventricular wall stretch
and, as their names suggest, serve to maintain sodium
homeostasis by enhancing renal sodium and water excre-
tion (Fig. 23.13) [118,119]. These peptides also have
haemodynamic effects, dilating arteries and, especially,
veins. They also suppress the RAAS and, possibly, the
sympathetic nervous system. There is some evidence
that natriuretic peptides inhibit arginine vasopressin
and endothelin-1 release and the biological actions of
these peptides. Consequently, the natriuretic peptides
are thought to play an important protective role in heart
TETC23 12/2/05 9:43 Page 700
700 Chapter 23
failure, countering the actions of the other vasoconstrict-
ing and anti-natriuretic neurohumoral systems which
are activated in heart failure.
Circulating levels of both ANP and BNP are greatly
increased in heart failure. This is the consequence of an
increased synthesis and release of these hormones. In
humans, BNP is mostly secreted from the ventricles in
both healthy individuals and patients with heart failure.
ANP secretion, on the other hand, is mainly from the
atria in healthy individuals but from both the atria and
the ventricles in patients with heart failure. Therefore, it
appears that BNP is the only natriuretic peptide that is
specific to the ventricles. Pro-BNP, the precursor of BNP,
is stored in granules in myocytes. Pro-BNP is activated
by a protease to form its biologically active form, BNP,
and N-terminal (NT)-proBNP.
BNP levels vary according to sex and age in healthy
subjects [120]. Female patients display higher plasma
concentrations than male patients with heart failure.
Advancing age and declining renal function are asso-
ciated with increases in BNP levels (Fig. 23.14).
C-type natriuretic peptide (CNP), which was origin-
ally believed to be of endothelial origin, may also be
produced by the failing heart. A D-type (Dendroaspis)
natriuretic peptide has also been described recently
though its origins and actions in humans are not yet
well defined [121].
As well as having important physiological effects, the
various A-type and B-type natriuretic peptides and related
fragments can be used to aid the diagnosis of heart failure
and to provide prognostic information (see below).
The endothelium, nitric oxide and endothelin-1 The prin-
cipal product of the endothelium, NO, plays a central
role in vascular homeostasis. Endothelial dysfunction,
which is characterized by reduced production and action
of NO, occurs as a result of ageing, as well as in a number
of chronic conditions related to heart failure, such as
hypercholesterolaemia, atherosclerosis, as well as in heart
140
120 Males
Females
NT-proBNP (pg/ml)
100
80
60
40
20
0 <30 30–39 40–49 50–59
Age (years)
failure itself [122]. Endothelium-dependent dilatation
of coronary and peripheral resistance vessels is blunted
in patients with heart failure. This probably contributes
to the impaired reactive hyperaemia in various vascular
beds, an impairment in tissue perfusion and, perhaps,
reduced muscular function [123]. There has even been
speculation that NO might be a key regulator of lung
function and that exercise-induced dyspnoea may be
related to impaired pulmonary vasodilatation resulting
from reduced NO production compared to healthy sub-
jects. Endothelial dysfunction in heart failure may be
partly the result of increased oxidative stress (see below).
Although lack of NO is associated with the develop-
ment of endothelial dysfunction, its overproduction by
the inducible isoform of NO synthase (iNOS) may also
be detrimental [124]. Increased iNOS activity is thought
to lead to increased free radical formation and to depres-
sion of myocardial activity. Increased iNOS expression
may result from the actions of inflammatory cytokines
(see below).
The endothelins are another important product of the
endothelium and endothelin-1 is one of the most power-
ful vasoconstrictor peptides known [125]. It is also a
mitogen and generally shares the potentially detrimental
properties of angiotensin II and vasopressin in heart fail-
ure. Plasma concentrations of endothelin-1 are increased
in heart failure, probably because of increased secre-
tion, both by blood vessels and the failing myocardium.
The importance of this is, however, uncertain because
specific antagonists have not improved outcome in heart
failure.
Oxidative stress, xanthine oxidase and uric acid Oxygen free
radicals have a number of potentially detrimental actions
in heart failure [126,127]. They inactivate NO, depress
myocardial contractility and may induce apoptosis [128].
One source of the superoxide anion radical is NADPH
oxidase which is activated by angio-tensisn II and aldos-
terone [129]. Xanthine oxidase may be another source of
Figure 23.14 NT-proBNP concentrations
in normal subjects, according to age and
sex. The concentrations are in medians,
60–69 ≥70 the bars represent the 95th centile values.
Reprinted with permission [178].
TETC23 12/2/05 9:43 Page 701
Heart Failure: Epidemiology, Pathophysiology and Diagnosis
increased free oxygen radical load in heart failure and is
normally involved in the last step of purine breakdown
which yields uric acid. Hyperuricaemia is a consistent
finding in patients with heart failure, may reflect impair-
ment of oxidative metabolism and is a predictor of worse
outcome [130]. Oxidative stress may be part of the gener-
alized inflammatory state that characterizes at least some
patients with heart failure.
Inflammatory responses Inflammation may also be a
factor contributing to the progression of heart failure
although its role has not been ‘confirmed’ in the same
way as neurohumoral activation, i.e. by the demonstra-
tion of improved outcomes with blocking agents [131].
Several cytokines have been studied in detail. Different
cell types secrete cytokines for the purpose of altering
either their own function (autocrine) or that of adjacent
cells (paracrine). Some cytokines also act as circulating
hormones (i.e. have an endocrine action). Tumour
necrosis factor-α (TNF-α), interleukin-1 and interleukin-
6 are thought to be the most important pro-inflammatory
cytokines that may be implicated in heart failure pro-
gression. Among those, TNF-α has been studied in the
greatest detail. It exerts its effects via TNF-α receptors
(TNFR), which are expressed by almost all nucleated
cells. The origin of cytokine activation in heart failure
remains unclear. Pro-inflammatory cytokines may be
secreted by mononuclear cells, hypoxic peripheral tissue
or even by the myocardium itself. Catecholamines may
augment myocardial cytokine production, one of several
possible links between neurohumoral activity and inflam-
mation. It has also been hypothesized that increased
bowel wall oedema may lead to translocation of bacterial
endotoxin or lipopolysaccharide from the gut which
may cause pro-inflammatory cytokine production from
blood monocytes and possibly other tissues [132].
Plasma TNF-α and TNFR concentrations are increased
in some patients with heart failure, especially in those
whose disease is severe, and they are independent pre-
dictors of poor prognosis. Although TNF-α has several
potentially untoward effects that could contribute to the
progression of heart failure, studies of TNF antagonists to
date have not shown benefit in this syndrome.
Diagnosis: symptoms, signs and
investigations
It is symptoms and signs that usually alert the patient
(and physician) to the presence of a cardiac disorder.
701
However, neither the symptoms nor signs commonly
recognized as suggesting the presence of heart failure are
specific for this syndrome. Therefore confirmation of
heart failure requires objective tests to confirm that the
patient’s symptoms and the physical findings are the
result of abnormal cardiac function and not of another
cause (see below) [133].
Symptoms
Fatigue is a key symptom reported by patients with heart
failure. Its origins are not clearly understood but probably
include low cardiac output and skeletal muscle abnormal-
ities (see Pathophysiology). Fatigue is very non-specific
and is found in the population at large, as well as in many
non-cardiovascular disorders.
Dyspnoea or breathlessness is another cardinal
symptom of heart failure. Dyspnoea is usually first man-
ifested on exertion and the level of exertion which causes
breathlessness is useful in gauging heart failure severity
and monitoring the patient’s progress. Though it is more
specific than fatigue, dyspnoea is still caused by many
other disorders such as pulmonary disease, obesity and
anaemia which are common in the elderly population
and may coexist with heart failure. Even ageing is asso-
ciated with dyspnoea on exercise. The origin of dyspnoea
in heart failure is also probably multifactorial. It may be
related to elevated pulmonary pressures, abnormalities
in pulmonary compliance, respiratory dysfunction, accen-
tuated respiratory drive, increased airway resistance and
even low haemoglobin [134]. It is notable that there is a
poor correlation between dyspnoea and left ventricular
function at rest [135].
Orthopnoea is defined as dyspnoea which occurs in
the recumbent position and is usually relieved by sitting
upright or by the addition of pillows. In extreme cases,
the patient is unable to lie down and may spend the
night in the sitting position. Orthopnoea results from
the return of venous blood which has pooled in the lower
extremities while the patient is ambulatory. The failing
heart may be unable to cope with return of this blood
from the legs on adoption of the recumbent position and
pulmonary oedema may occur.
Paroxysmal noctural dyspnoea (PND) is characterized
by acute episodes of suffocation usually occurring while
recumbent at night. It has the same pathogenesis as
orthopnoea. PND may manifest as cough or wheezing,
possibly because increased pressure in the bronchial
arteries (and resultant increase in their diameter), along
with interstitial pulmonary oedema, leads to increased
airways resistance. Sometimes these patients are described
as having ‘cardiac asthma’, which must be differentiated
from primary asthma and pulmonary causes of wheezing.
TETC23 12/2/05 9:43 Page 702
702 Chapter 23
Both orthopnoea and PND are relatively specific for
heart failure but are usually only encountered in untreated
or advanced heart failure and are uncommon in most
patients with mild to moderate heart failure taking
diuretics [136]. Treated patients developing either symp-
tom should be advised to report this to their physician/
nurse as soon as possible. PND requires urgent treatment.
Cerebral symptoms such as confusion, disorientation,
sleep or mood disturbances may be observed in advanced
heart failure, particularly in the presence of hypona-
traemia. These symptoms can be the first manifestation of
heart failure in elderly patients. Sometimes sleep distur-
bances can be associated with ventilatory abnormalities
(obstructive sleep apnoea and Cheyne–Stokes respira-
tion) which occur in advanced heart failure and may be
reported by the patient’s spouse or partner [137,138].
Nausea and abdominal discomfort may occur when
there is marked congestion of the liver and gastrointest-
inal tract. Congestion of the liver and stretching of its
capsule may cause pain in the right upper quadrant of
the abdomen.
Oliguria is usually present in advanced heart failure as
the result of reduced renal perfusion and avid sodium
and water retention.
Functional classification
The New York Heart Association (NYHA) functional classi-
fication is the most commonly used means of describing
the degree to which a patient is restricted in ordinary
activities by the typical symptoms of heart failure [139].
Although it is subjective and has a large interobserver
variation, the NYHA classification is used world-wide
and has been employed as an entry criterion in almost all
important clinical trials in heart failure.
l Class I: no limitation—ordinary physical activity does
not cause undue fatigue, dyspnoea or palpitations.
l Class II: slight limitation of physical activity—patient
is comfortable at rest but ordinary activity results in
fatigue, palpitations, or dyspnoea. These patients are
sometimes described as having mild heart failure
(nomenclature referring to their symptoms and not
cardiac function or prognosis).
l Class III: marked limitation of physical activity—
patient comfortable at rest but less than ordinary
activity results in symptoms. These patients are
sometimes described as having moderate heart
failure.
l Class IV: inability to carry out any physical activity
without discomfort—symptoms of heart failure are
present even at rest with increased discomfort with
any physical activity. These patients are sometimes
described as having severe heart failure.
At the individual patient level it is useful to measure
functional limitation (and monitor progress) by way
of the distance the patient can walk on the level, the
number of steps that can be climbed and ordinary activ-
ities that can (or cannot) be carried out, e.g. washing,
bed-making, vacuum-cleaning, sweeping, shopping, etc.
Because there is a poor correlation between symptoms
and cardiac dysfunction, it must be emphasized that mild
symptoms do not imply minor cardiac dysfunction or
a good prognosis. Patients with very different ejection
fractions can experience quite similar degrees of func-
tional limitation and treatment with a diuretic may lead
to a marked improvement in symptoms without having
any effect on cardiac function [140].
The Killip classification may be used to assess the
severity of heart failure in the acute context, e.g. in
myocardial infarction [141].
Quality of life
‘Quality of life’ assessments have been used to assess the
impact of heart failure on patient well-being in a more
complete way than just measuring specific symptoms
or functional limitations. Various dimensions of quality
of life including those reflecting physical, social, sexual
and professional activities can be measured, along with
indices of mood, emotions and mental health. Various
questionnaires or visual scales have been proposed but
none has been universally accepted. One of the most
widely used is the Minnesota Living with Heart Failure
questionnaire which includes a list of 21 questions, each
answered on a scale of 0 to −5 [142]. These measures are
more often used in clinical trials than in clinical practice.
Signs
Clinical examination, including observation of the patient
and palpation and auscultation of the heart, is essential
in the assessment of an individual with suspected heart
failure. Percussion of the heart is seldom performed
although it can provide an accurate assessment of cardiac
size; percussion of the lung fields is valuable [136].
General examination
Patients with advanced heart failure are sometimes severely
dyspnoeic even when speaking and have peripheral
oedema (see below), cachexia or cyanosis. Conversely,
the general appearance of a patient presenting with mild
to moderate heart failure is often normal.
Systolic blood pressure is usually reduced in heart fail-
ure because of left ventricular systolic dysfunction,
TETC23 12/2/05 9:43 Page 703
Heart Failure: Epidemiology, Pathophysiology and Diagnosis
especially if severe or treated. Sometimes blood pressure
may be elevated, especially if hypertension is the cause of
heart failure and particularly if systolic function is pre-
served. Blood pressure can be markedly increased during
an episode of acute pulmonary oedema. It is important
to distinguish between low blood pressure (hypotension)
which may be unimportant per se and hypoperfusion
of the vital organs, i.e. where there are symptoms such
as dizziness or confusion, renal dysfunction or myocar-
dial ischaemia, which is always important and requires
treatment.
Sinus tachycardia is a non-specific sign which is caused
by increased sympathetic activity and can be absent in
the presence of conduction disturbances (or if the patient
is taking β-adrenergic blocker therapy). Some patients
may also have tachycardia because of atrial fibrillation
(or another supraventricular arrhythmia) or, rarely, ven-
tricular tachycardia.
Peripheral vasoconstriction with coldness, cyanosis
and pallor of extremities is also caused by increased
sympathetic activity.
Peripheral oedema is a key manifestation of heart failure
but is non-specific and usually absent in patients already
treated with diuretics (Fig. 23.11). It is related to extra-
cellular volume expansion, is accompanied (and even
preceded) by weight gain and is progressive. It is usually
bilateral and symmetrical, painless, pitting and occurs
first in the lower extremities in ambulatory patients,
namely the feet and the ankles. In bedridden patients,
oedema may instead be found over the sacrum and scro-
tum. Even oedema to mid-calf may reflect an increase of
two or more litres in extracellular fluid volume. Long-
standing leg oedema may be associated with indurated
and pigmented skin. If untreated, oedema may become
generalized (anasarca), with the development of hepatic
congestion, ascites and hydrothorax (pleural effusions—
see below). At this stage there is usually clear jugular
venous distension (Fig. 23.11—see below). Generalized
oedema is often accompanied by resistance to oral diuretic
treatment. Patients should be warned to be observant
for progressive increases in weight, accompanied by ankle
swelling and, especially, increasing dyspnoea. Daily weight
monitoring is important to identify sodium and water
retention episodes and initiate early therapy. A prompt
(and often temporary) increase in diuretic therapy may
resolve worsening congestion in this situation.
Hepatomegaly is an important but uncommon sign in
patients with heart failure. The liver is usually tender
except in long-standing heart failure and can pulsate
703
during systole in the presence of tricuspid regurgitation.
Firm and continuous compression of the right upper
abdominal quadrant for 30 seconds to 1 minute may
exhibit hepato-jugular reflux, i.e. an increase in jugular
distension that is sustained during and after compression
(see Jugular venous distension, below). Examination
should be made on a patient lying comfortably with their
head resting on a pillow.
Cardiac signs
Jugular venous distension, detected by inspection of the
internal jugular veins, may identify an elevated right
atrial pressure and by inference (and in the absence of
tricuspid and pulmonary valve disease) left atrial pres-
sure (Fig. 23.11). However, estimates of jugular venous
pressure by physical examination correlate poorly with
invasive measurement of right atrial pressure and inter-
observer reproducibility is low among non-specialists
[143–145]. Giant ‘V waves’ indicate the presence of tri-
cuspid incompetence.
A third heart sound is usually only heard when there is
left ventricular dilatation and systolic dysfunction, but
interobserver agreement on this sign is low. A third heart
sound is more common in severe heart failure and is
associated with poor prognosis [146].
A systolic murmur as because of mitral or tricuspid regur-
gitation can be present, even in the absence of primary
valve disease, when the left or right ventricle is markedly
enlarged, leading to a dilatation of the mitral or the tri-
cuspid annulus. In the latter case, the tricuspid murmur
is selectively increased in loudness following inspiration
(Carvallo’s sign). The degree of mitral regurgitation can
be dynamic and increase on exertion.
Lung examination
Pulmonary crackles (crepitations or rales) result from the
transudation of fluid from the intravascular space into
the alveoli. The presence of crackles at the lung bases
is suggestive of pulmonary congestion but the positive
predictive value of this sign is low and the interobserver
variability is high [143]. Moreover, the origin of crackles
can be difficult to assess in smokers who may also have
chronic pulmonary disease (or in patients at risk of
pulmonary disease for some other reason). In acute pul-
monary oedema, bubbling crackles may be accompanied
by expectoration of frothy sputum which is blood stained.
Patients with long-standing heart failure may become
resistant to developing pulmonary oedema and only do
so at very high left atrial pressures. Pleural effusions can
TETC23 12/2/05 9:43 Page 704

704 Chapter 23

I aVR V1 V4

II aVL V2 V5

III aVF V3 V6

Figure 23.15 Twelve-lead ECG depicting

an established transmural inferior
II
myocardial infarction—there are Q-waves
and T-wave inversion seen in leads II, III,
and aVF.

I aVR V1 V4

II aVL V2 V5

III aVF V3 V6

II
Figure 23.16 Twelve-lead
electrocardiogram depicting left
bundle branch block (LBBB).

also be detected in patients with heart failure; they are
normally bilateral and usually associated with marked
dyspnoea and generalized congestion.
Overall, the presence of several of the aforementioned
symptoms and signs, particularly in the context of a
history of previous cardiac disease, is suggestive of heart
failure, if not its precise cause. The declining skill of
physicians in clinical examination, the lack of sensitiv-
ity and specificity of most signs (and the large inter-
observer variability in their detection) and the subjective
nature of clinical assessment highlight the need for
objective assessment of cardiac function. This objective
assessment is also essential for diagnosis of the cause
of heart failure and, therefore, treatment tailored to
aetiology.
Simple investigations
pean Society of Cardiology (ESC) Guidelines [133]. The
ECG provides diagnostic and prognostic information and
helps in choosing treatment. ECG changes are frequent
in heart failure and a normal ECG virtually excludes left
ventricular systolic dysfunction [147]. Various abnor-
malities may be present, such as abnormal Q waves
(Fig. 23.15), left bundle branch block (Fig. 23.16) and
other conduction disturbances, left atrial or left ventri-
cular hypertrophy (Fig. 23.17), atrial or ventricular arrhy-
thmias may suggest a specific aetiology or precipitating
factor. Some abnormalities provide prognostic informa-
tion and help in choosing treatment, e.g. bundle branch
block is predictive of a worse prognosis in patients
with left ventricular systolic dysfunction and may also
identify patients who benefit from a specific treatment
(cardiac resynchronization therapy). The same is true of
atrial fibrillation where there may be an indication for
warfarin.

Electrocardiogram
A resting 12-lead ECG is one of the most useful investi-
gations in a patient with suspected heart failure and is
recommended as a first-line diagnostic test in the Euro-
Chest X-ray
The chest X-ray (or radiograph) is also recommended as
a first-line investigation. It may identify a non-cardiac
TETC23 12/2/05 9:43 Page 705

Heart Failure: Epidemiology, Pathophysiology and Diagnosis 705

I aVR V1 V4

II aVL V2 V5

III aVF V3 V6

Rhythm strip: II
25 mm/s: 1 cm/mV
Figure 23.17 Twelve-lead
electrocardiogram depicting left
ventricular hypertrophy.

A B

Figure 23.18 Posteroanterior chest X-rays of (A) a patient

with left ventricular systolic dysfunction showing marked
cardiomegaly; (B) a patient in acute pulmonary oedema.
There is evidence of ‘bat’s wings pulmonary oedema’, upper
lobe venous diversion, as well as fluid in the horizontal fissure.

cause for the patient’s symptoms. It also provides informa-
tion on the size and shape of the cardiac silhouette
and the state of the pulmonary vasculature [148]. This
information is, however, of limited value [149]. The
absence of cardiomegaly (Fig. 23.18) does not exclude
valve disease or left ventricular systolic dysfunction
(heart size is more often normal in patients with left
ventricular diastolic dysfunction and in acute compared
to chronic heart failure). Even if cardiomegaly is present
(Fig. 23.18), the chest X-ray does not identify the cause
TETC23 12/2/05 9:43 Page 706
706 Chapter 23
of cardiac enlargement. The relationship between cen-
tral haemodynamic and pulmonary vascular radiological
abnormalities is also variable and some patients with
long-standing severe heart failure may not show pulmon-
ary venous congestion or oedema (Fig. 23.18) despite a
very high pulmonary capillary pressure [150].
Haematology and biochemistry
Several laboratory investigations are recommended in
the ESC guidelines as part of the routine diagnostic
evaluation of patients with suspected heart failure: com-
plete blood count, electrolytes, glucose, urea, creatinine,
hepatic enzymes and urinalysis. Myocardial biomarkers
such as troponin T or I are important during an acute
episode to rule out myocardial infarction. Other tests
including serum uric acid, C-reactive protein and thyroid
stimulating hormone are optional. It is important to
repeat some of these tests during follow-up and after the
initiation of certain treatments (or dose changes), e.g.
urea, creatinine and potassium.
Electrolyte disturbances are uncommon in untreated
mild to moderate heart failure.
Hyponatraemia is sometimes found in severe heart failure
and its cause is complex and probably multifactorial.
Impaired free water excretion, sodium restriction and
diuretic therapy (especially thiazide diuretic treatment or
excessive use of loop diuretics) are thought to be import-
ant. Hyponatraemia may identify patients with a par-
ticularly activated RAAS [113].
Potassium concentration is usually normal but may be
reduced by the use of kaliuretic agents such as loop
diuretics, or increased in patients with end-stage heart
failure with markedly reduced glomerular filtration rate,
particularly in the presence of concomitant renal disease,
treatment with an inhibitor of the RAAS (e.g. some com-
bination of an ACE inhibitor, angiotensin II receptor
blocker or spironolactone) [151]. Nephrotoxic drugs
such as NSAIDs may also precipitate hyperkalaemia.
Elevation of creatinine and urea is common in treated
heart failure, especially if severe. A significant reduction
in glomerular filtration rate may be present despite a
normal urea and creatinine, especially in patients with
reduced muscle mass. Several causes are recognized:
(1) primary renal disease particularly renal artery stenosis,
(2) reduced glomerular filtration rate in advanced heart
failure, (3) excessive treatment with diuretics alone or
in combination with inhibitors of the RAAS (e.g. some
combination of an ACE inhibitor, angiotensin II receptor
blocker or spironolactone), and (4) ageing.
Impaired renal function and worsening renal func-
tion are associated with a poor outcome in chronic heart
failure though, paradoxically, drugs which improve prog-
nosis, particularly inhibitors of the RAAS, may cause
some deterioration in renal function (although this is
usually mild).
Elevation of liver enzymes, including aspartate amino-
transferase (AST) and alanine aminotransferase (ALT)
and of serum bilirubin, is often observed in heart failure.
These changes may be caused by reduced hepatic blood
flow as much as by liver congestion [152].
Anaemia may be the cause or consequence of heart
failure. It is common, especially in advanced heart
failure, and is associated with a worse prognosis.
Urinalysis is important for the detection of proteinuria or
glycosuria, indications of underlying renal disease and
diabetes mellitus, respectively.
Thyroid function tests are indicated if either hyper- or
hypothyroidism is suspected.
Natriuretic peptides
The use of plasma natriuretic peptides as a tool for
the diagnosis of heart failure has developed in recent
years, particularly in primary care and emergency units
(Fig. 23.19) [153]. Both BNP and N-terminal pro-BNP are
available as commercial assays. In clinical practice, both
Non-CHF Non-systolic CHF Systolic CHF
1000
500
BNP (pg/ml)
200
100
50
20
10
Male Female Male Female Male Female
Figure 23.19 Box plots showing median levels of B-type
natriuretic peptide (BNP) measured in men and women over
70 years of age with dyspnoea not caused by heart failure, and
those with an adjudicated final diagnosis of heart failure,
subdivided into those with systolic and those with non-systolic
congestive heart failure. Reprinted with permission [156].
TETC23 12/2/05 9:43 Page 707
Heart Failure: Epidemiology, Pathophysiology and Diagnosis
are used as ‘rule out’ tests, i.e. a normal concentration of
either peptide in an untreated patient means that it is
very unlikely that heart failure is present [154]. Con-
versely, an elevated concentration identifies a patient
who merits comprehensive cardiac examination includ-
ing echocardiography. Natriuretic peptides may, there-
fore, offer a cost-effective means of ensuring the efficient
use of echocardiography. One important caveat is that
prior treatment may reduce natriuretic peptide concen-
trations to within the normal range.
Age and female gender both influence the plasma
concentration of natriuretic peptides and must be con-
sidered when defining ‘normal’ cut-off values which are
also assay-specific (Fig. 23.14) [155]. Plasma levels are also
increased in other conditions including renal dysfunc-
tion, pulmonary embolism, left ventricular hypertrophy,
acute ischaemia and hypertension. Because these various
cardiac and non-cardiac disorders lead to a moderate
increase in plasma concentrations of natriuretic peptides,
a ‘grey zone’ exists and is the reason why natriuretic
peptides are used as a ‘rule out’ (rather than a ‘rule in’) test.
In heart failure with preserved ejection fraction, plasma
levels of BNP, although higher than in patients without
heart failure, are significantly lower than in patients with
left ventricular systolic dysfunction (Fig. 23.19) [156].
In a general population, the ability of plasma nat-
riuretic peptides to detect left ventricular hypertrophy
appears limited [157]. Patients with relaxation abnorm-
alities and mild symptoms or who are asymptomatic may
have normal levels of natriuretic peptides. Thus low
levels cannot be used to rule out diagnosis of diastolic
dysfunction [158]. Among patients with heart failure
Figure 23.20 Measurement of ejection
fraction using Simpson’s biplane method.
Only the apical four-chamber view at
end-diastole is shown here. This young
man has a dilated cardiomyopathy, with
a left ventricular end-diastolic diameter
of 9.7 cm.
707
and preserved ejection fraction, those with definite
diastolic dysfunction seem to have higher natriuretic
peptide concentrations [159].
Doppler echocardiography
Transthoracic Doppler echocardiography (or ultrasound)
is recognized by the ESC guidelines as the most import-
ant investigation for the patient with suspected heart
failure. Echocardiography is a widely available, rapid,
non-invasive and safe technique which provides extens-
ive information on chamber dimensions, wall thickness
and measures of systolic and diastolic function.
Determination of the LVEF is a key measure of left
ventricular systolic function. Systolic function is usually
considered to be reduced when the LVEF is < 0.40 and
‘preserved’ if > 0.50. This clearly leaves a ‘grey area’ in the
range 0.40–0.50. Furthermore, LVEF is a crude method
for the evaluation of systolic function and is dependent
not only on the intrinsic inotropic state of the myo-
cardium, but also on the loading conditions of the heart.
The most widely recommended approach to the
accurate measurement of LVEF is the modified Simp-
son’s method, using apical biplane summation of discs
(Fig. 23.20) [160]. It is, however, dependent on reliable
endocardial detection. Other methods are less accurate,
particularly in the presence of regional hypokinesia or
akinesia. Other measures are, however, used including
fractional shortening, sphericity index and left ventricu-
lar wall motion index.
Identification of diastolic dysfunction is even more dif-
ficult and requires evidence of abnormal left ventricular
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708 Chapter 23

Figure 23.21 Patterns of left ventricular

diastolic filling as shown by standard
Normal Mild diastolic Moderate diastolic Severe diastolic Doppler echocardiography. The abnormal
diastolic dysfunction dysfunction dysfunction
function (impaired relaxation) (pseudonormal) (restrictive)
relaxation pattern (mild diastolic
dysfunction) is brought on by abnormally
Transmitral flow velocity

2.0 2.0 2.0 2.0 slow left ventricular relaxation, a reduced

E
E A E velocity of early filling (E wave), an
increase in the velocity associated with
(m/s)

A A atrial contraction (A wave), and a ratio of

E A E to A that is lower than normal. In more
advanced heart disease, when left atrial
pressure has risen, the E-wave velocity
0 0 0 0
and E : A ratio is similar to that in normal
Left ventricular
subjects (the pseudonormal pattern). In
relaxation Normal Normal Impaired Impaired
Left ventricular advanced disease, abnormalities in left
compliance Normal Normal to ventricular compliance may supervene
(called the restrictive pattern because it
Atrial pressure Normal Normal to was originally described in patients with
restrictive cardiomyopathy). Reprinted
with permission [165].

relaxation or diastolic distensibility or diastolic stiffness,

all of which are difficult to assess in daily practice [161–
165].
The presence of morphological changes such as left HFPEF:
atrial dilatation or left ventricular hypertrophy, together AF
Diastolic Asymptomatic
with measures of left ventricular diastolic filling (includ- valve disease
HF DD
ischaemia
ing transmitral and pulmonary venous flow velocities
other?
with pulsed Doppler echocardiography or mitral annulus
velocities with tissue Doppler imaging), frequently help
demonstrate diastolic dysfunction.
Three abnormal left ventricular filling patterns have
been described (Fig. 23.21) [166]:
Figure 23.22 The overlapping syndromes of heart failure
l Impaired relaxation with a reduction in peak
with preserved election fraction (HFPEF) and heart failure
transmitral E-wave velocity, coupled with an increase due to diastolic dysfunction (DD). Atrial fibrillation (AF);
in A-wave velocity, resulting in a decrease in the E : A heart failure (HF).
ratio to < 1.
l A restrictive filling pattern, with a short isovolumetric Valve function can also be assessed by Doppler echo-
relaxation time, an increased E velocity and increased cardiography, e.g. semi-quantitative evaluation of mitral
E : A ratio, considered the hallmark of severe diastolic regurgitation is possible (Fig. 23.12), as is calculation of
dysfunction. pulmonary artery systolic pressure (based on the velocity
l Pseudonormal filling pattern, when atrial pressure of tricuspid regurgitation).
rises in more advanced heart failure, the E-wave Doppler echocardiography may also be repeated
velocity and E : A ratio may be similar to those in during the follow-up of patients receiving treatment, to
normal subjects. assess changes in cardiac structure and function.
These patterns are however influenced by intrinsic Despite the value of Doppler echocardiography, sur-
cardiac properties, loading conditions and are age depen- veys in Europe commonly show that cardiac function
dent. However, they also have some prognostic import- is only evaluated in approximately 50% of such patients
ance: the restrictive pattern in particular, with a short [167]. The recent development of portable echocardiog-
transmitral E-deceleration time and increased E : A flow raphy machines, together with the potential of remote
velocity ratio, is associated with poor outcome. It is analysis of echocardiograms, may help improve this
important to appreciate that the terms heart failure with situation.
preserved ejection fraction and heart failure as a result of Other new ultrasound techniques, such as three-
diastolic dysfunction (‘diastolic heart failure’) describe dimensional echocardiography, are still being evaluated
overlapping but not identical syndromes (Fig. 23.22). clinically.
TETC23 12/2/05 9:43 Page 709

Heart Failure: Epidemiology, Pathophysiology and Diagnosis 709

A
Stress echocardiography
Dobutamine (or exercise) stress echocardiography may
be used to detect ischaemia as a cause of cardiac dysfunc-
tion and to assess myocardial viability in the presence of
marked hypokinesia or akinesia. It may be useful in identi-
fying myocardial stunning and hibernating myocardium.

Other imaging techniques

Radionuclide angiography
This technique provides information on left and right
ventricular volumes and ejection fraction but is not widely
available. It does not provide information on valve func- B
tion but is generally more accurate than echocardiog-
raphy for measuring right ventricular function. The
reproducibility of this technique is also better than that
of echocardiography.

Cardiac magnetic resonance

Cardiac magnetic resonance (CMR) allows compre-
hensive and reproducible analysis of cardiac anatomy
and function, including cardiac volumes and mass, global
and regional function and wall thickening [168]. When
combined with contrast agents such as gadolinium, CMR
also provides information on myocardial perfusion at
rest (Fig. 23.23) or following pharmacological interven-
C
tion. CMR is now the gold standard for the assessment of
mass volumes and wall motion but it is expensive and is
not as widely available as echocardiography.

Other functional tests

Exercise testing
Treadmill or bicycle testing can be used to determine
the maximum level of exercise which can be achieved.
Recommendations on testing have been published by
the ESC [169]. Small increments in workload are recom-
mended. As well as exercise duration, gas exchange is
often measured. Peak oxygen uptake (Vo2) and the
anaerobic threshold are useful indicators of the patient’s
capacity to exercise. There is a poor correlation between
exercise capacity and ejection fraction. Peak Vo2 has Figure 23.23 (A) Short-axis contrast-enhanced CMR
been used also for prognostication and selection of demonstrating extensive inferior myocardial infarction
indicated by late gadolinium enhancement. There is also a
patients for heart transplantation (see below). A peak Vo2
smaller anterior infarct. (B) Non-contrast still end-diastolic
> 14 ml/kg/min is associated with a relatively good prog-
cine image showing marked wall thinning in the inferior wall
nosis unlikely to be improved by heart transplantation. corresponding with the area of infarction. There is marked
Patients with a Vo2 max of less than 14 ml/kg/min have ventricular dilatation and systolic dysfunction. (C) Vertical
been shown to have a better survival if transplanted long-axis view of the same patient demonstrating both a large
than if treated medically. This latter threshold is part of inferior infarct and a much smaller apical anterior infarct.
the criteria used for listing patients for heart transplanta- (Courtesy of Dr Patrick Mark, Western Infirmary, Glasgow.)
TETC23 12/2/05 9:43 Page 710

710 Chapter 23

tion. It should be noted that the survival studies on (e.g. palpitations and syncope) and in monitoring vent-
which this threshold is based were carried out before the ricular rate control in patients with atrial fibrillation.
advent of modern treatments for heart failure such as Asymptomatic ventricular premature beats and non-
beta-blockers and cardiac resynchronization therapy. sustained ventricular tachycardia are frequent in heart
failure but do not appear to be predictive of sudden death
or of selecting treatment to reduce sudden death.
Pulmonary function testing
Pulmonary function testing is indicated in patients in
An approach to the diagnosis of a patient
whom the origin of dyspnoea is unclear, to determine
with suspected heart failure
whether it is of cardiac or pulmonary origin or both.
Heart failure itself is associated with abnormalities of The following describes a stepwise approach to the diagno-
pulmonary function. These include reductions in vital sis of the patient with suspected heart failure (Table 23.3).
capacity, pulmonary diffusion at rest (and on exercise)
and pulmonary compliance. Conversely, airway resist-
Table 23.3 Stepwise approach to the diagnosis of heart failure
ance is usually increased.
Step 1: Diagnosis
Signs and symptoms of heart failure
Invasive investigations History of cardiac disease
First-line tests: ECG, X-ray, BNP or NT-proBNP
Pulmonary arterial catheterization is usually only used
Documentation of cardiac dysfunction: Doppler
in acute or emergency situations, especially in patients echocardiography
not responding to appropriate medical therapy. This Nuclear angiography/Nuclear magnetic resonance
procedure allows close monitoring of haemodynamic
Step 2: Clinical profile
changes following medical intervention. It is also indi-
Clinical presentation: acute de novo/decompensated/chronic
cated in patients with valvular heart disease who are
heart failure
candidates for valve replacement or repair and in the Left/right side heart failure
assessment of patients for transplantation. Comorbidities
Coronary angiography is indicated in patients with Age and severity
heart failure and angina or evidence of myocardial
Step 3: Aetiology
ischaemia, if revascularization is being considered. How-
Consider other diagnostic tests (coronary angiography,
ever, the role of revascularization in the treatment of central haemodynamics, etc.)
heart failure, including in patients with hibernating
myocardium, remains to be determined [170]. Step 4: Precipitating factors
Anaemia
Coronary angiography may also be indicated in acute
Infection (pulmonary infection)
heart failure with shock that is not responding to initial
Tachycardia (atrial fibrillation)
therapy. Bradycardia
Many also believe that coronary angiography is indic- Pulmonary embolism
ated as a diagnostic test in patients with heart failure or Hypertensive crisis
left ventricular systolic dysfunction of unknown origin. Acute myocardial ischaemia
Endomyocardial biopsy of the left or the right vent- Poor compliance (diet and/or drugs)
ricle is only indicated when a specific myocarditis or a Thyroid disorders
specific myocardial disease is suspected and during the Medications (NSAIDs, cyclooxygenase-2 inhibitors [coxibs],
follow-up of patients after cardiac transplantation to glitazones, class I antiarrhythmics, corticosteroids,
detect graft rejection. tricyclic antidepressants)
Overall, the indication for invasive procedures in heart Step 5: Prognostic evaluation
failure has declined. They are not necessary to establish Clinical factors
the presence of heart failure but may be helpful on an Biological factors
individual basis to determine the aetiology and for the Neurohumoral factors and cytokines
monitoring of patients in acute or difficult situations. Electrical variables
Imaging variables
Exercise testing
Ambulatory ECG monitoring Central hemodynamic indices
Genetic factors
Ambulatory monitoring is valuable in the assessment
of patients with symptoms suggestive of an arrhythmia Step 6: Treatment and follow-up
TETC23 12/2/05 9:43 Page 711

Heart Failure: Epidemiology, Pathophysiology and Diagnosis 711

Suspected LV dysfunction Suspected heart failure

because of signs because of symptoms and signs

Assess presence of cardiac disease by ECG, X-ray Normal heart failure

or natriuretic peptides (where available) or LV dysfunction unlikely

Tests abnormal

Imaging by echocardiography (nuclear Normal heart failure

angiography or MRI where available) or LV dysfunction unlikely

Test abnormal

Figure 23.24 Algorithm for the

diagnosis of heart failure: task force
for the diagnosis and treatment of
chronic heart failure of the European
Society of Cardiology. Reprinted with
permission [133].
Assess aetiology, degree, precipitating
factors and type of cardiac dysfunction Additional diagnostic tests
where appropriate
(e.g. coronary angiography)
Choose therapy

with preserved systolic function may be different

Step 1: Establish the presence of heart failure
This requires the presence of signs and symptoms sug-
gestive of heart failure at rest or on exercise and also
objective evidence of a cardiac abnormality, preferably
by Doppler echocardiography. Doppler echocardiography
may not be necessary in previously untreated patients
with a normal plasma natriuretic peptide concentration
and those patients should be investigated for another
cause of their symptoms or signs. Other essential first-
line diagnostic tests should be performed, including an
ECG, chest X-ray and blood tests. Pulmonary function
and exercise testing may help when the diagnosis remains
doubtful. The guidelines of the ESC usefully illustrate
how these investigations are combined in the patient
presenting with suspected heart failure (Fig. 23.24).
Step 2: Evaluation of the patient’s clinical status
This step includes:
l The assessment of clinical profile: patients may
present with acute new-onset heart failure, e.g.
after acute myocardial infarction, acute or subacute
decompensation of chronic heart failure or acute
or subacute onset of heart failure in a patient with
previously asymptomatic cardiac dysfunction. The
clinical presentation may be in primary care or to
hospital. The patient may have breathlessness, fatigue
or both with few clinical signs. Alternatively, the
patient may have these symptoms and peripheral
oedema or may present as an emergency with frank
pulmonary oedema. The clinical profile of patients
from that of patients with systolic dysfunction: on
average, the former patients are older and are more
likely to be women. They are also more likely to have
hypertension but are less likely to have a third heart
sound (Fig. 23.25) [171]. It is important to assess the
severity of symptoms, with the Killip and NYHA
classifications being the most widely used in the
acute and chronic setting, respectively. In acute new-
onset heart failure, the patient may be hypotensive
if there has been a haemodynamic catastrophe,
e.g. rupture of a mitral valve papillary muscle or
interventricular septum (Fig. 23.26).
l In advanced heart failure, another system of
classification may be useful. This is based on
the presence/absence of signs of congestion and
adequate/inadequate perfusion. Four categories
have been proposed: dry–warm, wet–warm,
dry–cold and wet–cold [172]. Wet patients with
or without hypoperfusion are at higher risk
than dry patients.
l It is also important to identify comorbid factors such
as stroke, chronic pulmonary obstructive disease,
asthma, diabetes mellitus and renal failure, which
can complicate patient management and modify
outcome. The proportion of patients presenting with
multiple comorbidities increases with age. In the
Euro Heart Failure Survey, 9% had had a previous
stroke, 10% a previous transient ischaemic attack,
27% were reported to have diabetes mellitus,
12% had dementia, 17% a renal dysfunction and
32% a pulmonary disease [167].
TETC23 12/2/05 9:43 Page 712

712 Chapter 23

35
Alternative
Added
30 Preserved

25
Percentage

20

15 Figure 23.25 Signs, symptoms and

radiographic findings in patients with
10 reduced and preserved left ventricular
ejection fraction in the CHARM studies
5
(CHARM-alternative, -added, and
-preserved). Paroxysmal nocturnal
0 dyspnoea (PND); third heart sound (S3).
Oedema Orthopnoea PND Rest S3 Crackles JVP Cardiomegaly
dyspnoea >6 cm Reprinted with permission [179].

Figure 23.26 Colour flow Doppler of

mitral regurgitation and a ventricular
septal rupture post-myocardial infarction
in the parasternal long-axis view.

dysfunction (such as valvular heart disease, reversible

Step 3: Identify underlying aetiology
Ischaemic heart disease and hypertension are the com-
monest causes of heart failure in Western countries and
their contribution to heart failure is also rapidly expand-
ing in the developing countries. In the Euro Heart Failure
Survey, ischaemic heart disease was the commonest cause
of heart failure, 40% of patients having myocardial infarc-
tion and 51% a history of angina; 53% of the patients
also had hypertension [167]. The extent of investiga-
tion to identify the underlying cardiac disease should be
decided on an individual basis taking into considera-
tion the patient profile (age, severity of heart failure and
comorbidities) and the potential reversibility of cardiac
ischaemia).
Step 4: Identify precipitating factors
It is also important to identify precipitating factors:
decompensation of heart failure is frequently associated
with comorbid factors which: (1) increase body metabolic
requirements such as fever, infection or hyperthyroid-
ism, (2) decrease cardiac output such as rapid tachycardia
or marked bradycardia, (3) reduce the oxygen transport
capacity (anaemia) or oxygen exchange (pulmonary
infection), (4) induce a sudden haemodynamic overload
(pulmonary embolism or hypertension crisis) or water
TETC23 12/2/05 9:43 Page 713

Heart Failure: Epidemiology, Pathophysiology and Diagnosis 713

and sodium overload (excessive sodium intake, poor Table 23.4 Prognostic factors
compliance with diet and heart failure medications) or
Clinical factors
(5) ischaemic episodes (Table 23.3).
Age, ethnicity, NYHA class
Among arrhythmias, a new episode of atrial fibrilla-
Signs of congestion, jugular vein pressure, third heart sound,
tion can be particularly harmful because it combines both low systolic blood pressure
an increase in ventricular rate (with a risk of myocardial Diabetes mellitus, renal dysfunction, depression
ischaemia and reduced time for diastolic filling) and loss Ischaemic aetiology
of atrial contraction.
Biochemical factors
Serum sodium
Step 5: Prognostic evaluation Serum creatinine/creatinine clearance
Haemoglobin
Prognostic assessment in heart failure remains difficult.
Neurohormones and cytokines
Indeed the number of clinical, aetiological, comorbid,
Plasma renin activity
biological, haemodynamic, structural, functional, elec-
Angiotensin II
trical and neurohumoral variables independently asso- Aldosterone
ciated with poor outcome is high and suggests that Noradrenaline
there is no simple method to assess the risk of death Endothelin-1
or re-hospitalization in patients with this syndrome Adrenomedullin
(Table 23.4). Most studies have been performed in popu- B type natriuretic peptide/N-terminal pro-BNP
lations of patients with systolic dysfunction and little Tumour necrosis factor-α
is known about prognostic evaluation in patients with Vasopressin
preserved systolic function. Electrical variables
The assessment of prognosis has also been conducted QRS width
differently in acute and in chronic heart failure: in acute Left ventricular hypertrophy
heart failure, in-hospital and short-term (3–6 months) Atrial fibrillation
mortality or readmission have usually been evaluated Complex ventricular arrhythmia
whereas in chronic heart failure, long-term (> 1 year) Heart rate variability
prognosis and re-hospitalization rates have normally Imaging variables
been considered. Left ventricular internal dimensions and fractional
Furthermore, factors which predispose to overall shortening
mortality or pump failure mortality do not necessarily Cardiothoracic ration X-ray (normal < 0.55)
apply to sudden death. Wall motion index (various*)
An additional problem is that extrapolation of risk Ejection fraction (normal > 0.40)
Restrictive filling pattern/short deceleration time (various*)
assessment based on a small series of selected patients
Right ventricular function (various*)
exposed to conventional therapy (including low rate
of prescription of ACE inhibitors and beta-blockers) to Exercise test/haemodynamic variables (rest/exercise)
the overall current heart failure population is difficult. Vo2 max/peak (normal > 20 ml/kg/min† )
The changing background therapy of heart failure also 6-minute walk distance (normal > 600 m† )
Cardiac index (normal > 2.5 l/min/m2)
makes it difficult to provide simple prognostic algorithms.
Left ventricular end-diastolic pressure/pulmonary artery
For instance, beta-blockers have more influence on the
wedge pressure (normal < 12 mmHg)
remodelling process than exercise capacity, so that the
relative role of these two independent predictors of *Various measures/classifications can be used and no single
mortality may be different in patients treated with a beta- threshold for normal/abnormal can be given; †functional
capacity varies greatly according to prior fitness, age and sex;
blocker and those not so treated.
values given are a guideline for older (> 65 years) adults.
The temporal role of the various prognostic factors
can be variable: the time course of the activation of the
neurohumoral systems after myocardial injury is dif- The multivariable analyses reported so far usually
ferent. Therefore, the relative weight of elevated plasma include only a limited number of parameters and these
levels of neurohumoral factors may be different in the may lose their predictive power in more comprehensive
short term compared to the longer term. Moreover, little analyses.
is known about the relation between the change in plasma Finally, some factors can provide prognostic informa-
concentrations of biochemical markers as a result of tion in advanced heart failure but not in mild to moder-
treatment and long-term prognosis. ate heart failure: severely reduced functional capacity,
TETC23 12/2/05 9:43 Page 714
714 Chapter 23
measured by Vo2, is a recognized index for the selection
of patients who might benefit from heart transplantation
whereas elevated, non-reversible, pulmonary resistance
is an index of poor outcome after heart transplantation
or implantation of a ventricular assist device.
Step 6: Treatment and management
Full diagnosis is a prerequisite for optimal treatment [133].
Often, however, a diuretic may be required before a full
diagnostic work-up is completed. The further treatment
Personal perspective
Though we have learnt much about heart failure there is
a lot we still do not know. The epidemiology of heart
failure outside Europe and North America has not been
studied to any great extent. We know much less about
the natural history of heart failure with preserved
ejection fraction than that with reduced ejection
fraction. Similarly, we know very little about the
pathophysiology of the former compared to the latter.
Understanding of the entity of heart failure with
preserved ejection fraction is greatly hampered by
the lack of simple, agreed and universally applicable
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