BMJ 2000;320:167-170 ( 15 January )
Clinical review
ABC of heart failure
Pathophysiology
G Jackson,
C R Gibbs,
M K Davies,
G Y H Lip.
Heart failure is a multisystem
disorder which is characterised by abnormalities of cardiac, skeletal
muscle, and renal function; stimulation of the sympathetic nervous
system; and a complex pattern of neurohormonal changes.
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Developments
in our understanding of the pathophysiology of heart failure have been
essential for recent therapeutic advances in this area
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Myocardial systolic dysfunction |
The primary abnormality in non-valvar heart failure is an
impairment in left ventricular function, leading to a fall in cardiac output. The fall in cardiac output leads to activation of several neurohormonal compensatory mechanisms aimed at improving the mechanical environment of the heart. Activation of the sympathetic system, for
example, tries to maintain cardiac output with an increase in heart
rate, increased myocardial contractility, and peripheral vasoconstriction (increased catecholamines). Activation of the renin-angiotensin-aldosterone system (RAAS) also results in
vasoconstriction (angiotensin) and an increase in blood volume, with
retention of salt and water (aldosterone). Concentrations of
vasopressin and natriuretic peptides increase. Furthermore, there may
be progressive cardiac dilatation or alterations in cardiac structure
(remodelling), or both.
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Neurohormonal activation |
Chronic heart failure is associated with neurohormonal
activation and alterations in autonomic control. Although these
compensatory neurohormonal mechanisms provide valuable support for the
heart in normal physiological circumstances, they also have a
fundamental role in the development and subsequent progression of
chronic heart failure.
Renin-angiotensin-aldosterone system
Stimulation of the renin-angiotensin-aldosterone system leads
to increased concentrations of renin, plasma angiotensin II, and
aldosterone. Angiotensin II is a potent vasoconstrictor of the renal
(efferent arterioles) and systemic circulation, where it stimulates
release of noradrenaline from sympathetic nerve terminals, inhibits
vagal tone, and promotes the release of aldosterone. This leads to the
retention of sodium and water and the increased excretion of potassium.
In addition, angiotensin II has important effects on cardiac myocytes
and may contribute to the endothelial dysfunction that is observed in
chronic heart failure.
Sympathetic nervous system
The sympathetic nervous system is activated in heart failure,
via low and high pressure baroreceptors, as an early compensatory
mechanism which provides inotropic support and maintains cardiac
output. Chronic sympathetic activation, however, has deleterious
effects, causing a further deterioration in cardiac function.
The earliest increase in sympathetic activity is detected in
the heart, and this seems to precede the increase in sympathetic outflow to skeletal muscle and the kidneys that is present in advanced
heart failure. Sustained sympathetic stimulation activates the
renin-angiotensin-aldosterone system and other neurohormones, leading
to increased venous and arterial tone (and greater
preload and afterload respectively), increased plasma noradrenaline
concentrations, progressive retention of salt and water, and oedema.
Excessive sympathetic activity is also associated with cardiac myocyte
apoptosis, hypertrophy, and focal myocardial necrosis.
In the long term, the ability of the myocardium to respond to
chronic high concentrations of catecholamines is attenuated by a down
regulation in 
receptors, although this may be associated with
baroreceptor dysfunction and a further increase in sympathetic activity. Indeed, abnormalities of baroreceptor function are well documented in chronic heart failure, along with reduced parasympathetic tone, leading to abnormal autonomic modulation of the sinus node. Moreover, a reduction in heart rate variability has consistently been
observed in chronic heart failure, as a result of predominantly sympathetic and reduced vagal modulation of the sinus node, which may
be a prognostic marker in patients with chronic heart
failure.
Natriuretic peptides
There are three natriuretic peptides, of similar structure, and
these exert a wide range of effects on the heart, kidneys, and central
nervous system.
Atrial natriuretic peptide (ANP) is released from the atria in
response to stretch, leading to natriuresis and vasodilatation. In
humans, brain natriuretic peptide (BNP) is also released from the
heart, predominantly from the ventricles, and its actions are similar
to those of atrial natriuretic peptide. C-type natriuretic peptide is
limited to the vascular endothelium and central nervous system and has
only limited effects on natriuresis and
vasodilatation.
The atrial and brain natriuretic peptides increase in response
to volume expansion and pressure overload of the heart and act as
physiological antagonists to the effects of angiotensin II on vascular
tone, aldosterone secretion, and renal-tubule sodium reabsorption. As
the natriuretic peptides are important mediators, with increased
circulating concentrations in patients with heart failure, interest has
developed in both the diagnostic and prognostic potential of these
peptides. Substantial interest has been expressed about the therapeutic
potential of natriuretic peptides, particularly with the development of
agents that inhibit the enzyme that metabolises atrial natriuretic
peptide (neutral endopeptidase), and non-peptide agonists for the A and
B receptors.
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Other hormonal mechanisms in chronic heart failure
- The arachidonic acid cascade leads to
increased concentrations of prostaglandins (prostaglandin
E2 and prostaglandin I2), which protect the
glomerular microcirculation during renal vasoconstriction and maintain
glomerular filtration by dilating afferent glomerular arterioles
- The kallikrein kinin system forms bradykinin,
resulting in both natriuresis and vasodilatation, and stimulates the
production of prostaglandins
- Circulating concentrations of the cytokine tumour
necrosis factor (
 TNF) are increased in cachectic patients with
chronic heart failure. TNF has also been implicated in the
development of endothelial abnormalities in patients with chronic heart
failure
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Antidiuretic hormone (vasopressin)
Antidiuretic hormone concentrations are also increased in
severe chronic heart failure. High concentrations of the hormone are
particularly common in patients receiving diuretic treatment, and this
may contribute to the development of hyponatraemia.
Endothelins
Endothelin is secreted by vascular endothelial cells and is a
potent vasoconstrictor peptide that has pronounced vasoconstrictor
effects on the renal vasculature, promoting the retention of sodium.
Importantly, the plasma concentration of endothelin-1 is of prognostic
significance and is increased in proportion to the symptomatic and
haemodynamic severity of heart failure. Endothelin concentration is
also correlated with indices of severity such as the pulmonary artery
capillary wedge pressure, need for admission to hospital, and death.
In view of the vasoconstrictor properties of endothelin,
interest has developed in endothelin receptor antagonists as
cardioprotective agents which inhibit endothelin mediated vascular and
myocardial remodelling.
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Patterns of neurohormonal activation and
prognosis |
Asymptomatic left ventricular dysfunction
Plasma norepinephrine concentrations increase early in the
development of left ventricular dysfunction, and plasma renin activity
usually increases in patients receiving diuretic treatment.
Norepinephrine concentration in asymptomatic left ventricular
dysfunction is a strong and independent predictor of the development of
symptomatic chronic heart failure and long term mortality. Plasma
concentrations of N-terminal proatrial natriuretic peptide and brain
natriuretic peptide also seem to be good indicators of asymptomatic
left ventricular dysfunction and may be useful in the future as an
objective blood test in these patients.
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After myocardial infarction
- Plasma noradrenaline is of prognostic value
in patients early after myocardial infarction, predicting subsequent
changes in left ventricular volume
- Natriuretic peptides have also been shown to predict
outcome after myocardial infarction, although it is not clear whether
the predictive value is additive to measurements of ventricular
function
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Congestive heart failure
In severe untreated chronic heart failure, concentrations of
renin, angiotensin II, aldosterone, noradrenaline, and atrial
natriuretic peptide are all increased. Plasma concentrations of various
neuroendocrine markers correlate with both the severity of heart
failure and the long term prognosis. For example, raised plasma
concentrations of N-terminal and C-terminal atrial natriuretic peptide
and of brain natriuretic peptide are independent predictors of
mortality in patients with chronic heart failure. Patients with
congestive heart failure and raised plasma noradrenaline concentrations
also have a worse prognosis.
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Contrast left ventriculogram in patient with poor systolic
function (diastolic (left) and systolic (right) views)
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Other non-cardiac abnormalities in chronic heart
failure |
Vasculature
The vascular endothelium has an important role in the
regulation of vascular tone, releasing relaxing and contracting factors
under basal conditions or during exercise. The increased peripheral
resistance in patients with chronic heart failure is related to the
alterations in autonomic control, including heightened sympathetic
tone, activation of the renin-angiotensin-aldosterone system, increased
endothelin concentrations, and impaired release of endothelium derived
relaxing factor (or nitric oxide). There is emerging evidence that
impaired endothelial function in chronic heart failure may be improved
with exercise training and drug treatment, such as angiotensin
converting enzyme inhibitors.
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Two dimensional echocardiogram in patient with hypertrophic
cardiomyopathy showing asymmetrical septal hypertrophy
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Skeletal muscle changes
Considerable peripheral changes occur in the skeletal muscle of
patients with chronic heart failure. These include a reduction in
muscle mass and abnormalities in muscle structure, metabolism, and
function. There is also reduced blood flow to active skeletal muscle,
which is related to vasoconstriction and the loss in muscle mass. All
these abnormalities in skeletal muscles, including respiratory muscles,
contribute to the symptoms of fatigue, lethargy, and exercise
intolerance that occur in chronic heart failure.
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Diastolic dysfunction |
Diastolic dysfunction results from impaired myocardial
relaxation, with increased stiffness in the ventricular wall and
reduced left ventricular compliance, leading to impairment of diastolic ventricular filling. Infiltrations, such as amyloid heart disease, are
the best examples, although coronary artery disease, hypertension (with
left ventricular hypertrophy), and hypertrophic cardiomyopathy are more
common causes.
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Contrast left ventriculogram in patient with hypertrophic
cardiomyopathy (diastolic (left) and systolic (right) views)
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The incidence and contribution of diastolic dysfunction
remains controversial, although it has been estimated that 30-40% of
patients with heart failure have normal ventricular systolic contraction. Indices of diastolic dysfunction can be obtained non-invasively with Doppler echocardiography or invasively with cardiac
catheterisation and measurement of left ventricular pressure changes.
There is no agreement as to the most accurate index of left ventricular
diastolic dysfunction, but the Doppler mitral inflow velocity profile
is probably the most widely used.
Although pure forms exist, in most patients with heart failure
both systolic and diastolic dysfunction can be present. Knowing about
diastolic dysfunction, however, has little effect on management of most
patients with chronic heart failure, as there are still many
uncertainties over its measurement and optimal management strategies.
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Myocardial remodelling, hibernation, and stunning |
After extensive myocardial infarction, cardiac
contractility is frequently impaired and neurohormonal activation leads
to regional eccentric and concentric hypertrophy of the non-infarcted segment, with expansion (regional thinning and dilatation) of the
infarct zone. This is known as remodelling. Particular risk factors for
this development of progressive ventricular dilatation after a
myocardial infarction include a large infarct, anterior infarctions,
occlusion (or non-reperfusion) of the artery related to the infarct,
and hypertension.
Myocardial dysfunction may also occur in response to
"stunning" (postischaemic dysfunction), which describes delayed
recovery of myocardial function despite restoration of coronary blood
flow, in the absence of irreversible damage. This is in contrast to "hibernating" myocardium, which describes persistent myocardial dysfunction at rest, secondary to reduced myocardial perfusion, although cardiac myocytes remain viable and myocardial contraction may
improve with revascularisation.
When stunning or hibernation occurs, viable myocardium retains
responsiveness to inotropic stimulation, which can then be identified
by resting and stress echocardiography, thallium scintigraphy and
positron emission tomography. Revascularisation may improve the overall
left ventricular function with potential beneficial effects on symptoms
and prognosis.
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Key references
- Grossman W. Diastolic dysfunction in
congestive heart failure. N Engl J Med
1991;325:1557-64.
- Love MP, McMurray JJV. Endothelin in heart failure: a
promising therapeutic target. Heart 1997;77:93-4.
- McDonagh TA, Robb SD, Murdoch DR, Morton JJ, Ford I,
Morrison CE, et al. Biochemical detection of left ventricular systolic
dysfunction. Lancet 1998;351:9-13.
- Rahimtoola SH. The hibernating myocardium. Am
Heart J 1989;117:211-21.
- Wilkins MR, Redondo J, Brown LA. The
natriuretic-peptide family. Lancet 1997;349:1307-10.
- Packer M. The neurohormonal hypothesis: a theory to
explain the mechanisms of disease progression in heart failure.
J Am Coll Cardiol
1992;20:248-54.
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Acknowledgments |
The graph showing mortality curves is
adapted from Cohn et al (N Engl J Med 1984;311:819-23);
the diagram of the process of ventricular remodelling is adapted
from McKay et al (Circulation 1986;74:693-702).
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Footnotes |
G Jackson is consultant cardiologist in the department of
cardiology, Guy's and St Thomas's Hospital, London.
The ABC of heart failure is edited by C R Gibbs, M
K Davies, and G Y H Lip. CRG is research fellow and GYHL is
consultant cardiologist and reader in medicine in the university
department of medicine and the department of cardiology, City Hospital,
Birmingham; MKD is consultant cardiologist in the department of
cardiology, Selly Oak Hospital, Birmingham. The series will be
published as a book in the spring.
© BMJ 2000
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