Steven is a 37-year-old builder. Though active in his job he has noticed that over the last year he has found himself increasingly tired at the end of the day. His ability to carry heavy weights appeared to have declined substantially and occasionally he had chest pain whilst exerting himself. He sought the advice of his GP. Physical examination was largely normal apart from a high resting heart rate of 98 bpm and a loud ejection systolic murmur heard at the left sternal edge and at the apex but radiating to the neck. Steven’s GP also elicited a history of unexpected death at a young age in his father’s family. Two of Steven’s paternal uncles had died suddenly at less than 30 years of age. The GP was concerned that there may be a familial cardiomyopathy of the obstructive type and referred him for urgent cardiology investigations. This history raises some fundamental questions:

1. Which aspects of this history might be consistent with a diagnosis of heart failure?

2. Which valves are likely to be associated with the systolic murmur and is it an indication of stenosis or regurgitation (or both)?

3. What investigations would you expect the cardiologist to carry out initially?

Answers to these questions can be found in the text of this chapter and in Chapter 3.

Interesting facts

Reduced performance of the heart muscle in systole is the most common form of heart failure but impaired diastolic function is also a common scenario.

Systolic vs diastolic failure

Impaired systolic function is the commonest cause of heart failure. However in 30–40% of all patients diastolic dysfunction is a major contributor and sometimes the primary cause of congestive cardiac failure.

In general the causes of heart failure can be attributed to one or more of the following:

• decreased myocyte contractility

• inappropriate workload due to pressure overload (e.g. hypertension causing increased afterload) or volume overload (increased preload)

• restricted filling of the ventricles (e.g. valve stenosis)

• myocyte loss.

These changes may represent either myocyte-related failure as in ischaemic heart disease or problems such as valve disease in a heart which may have normal myocyte function.

Heart failure may result from functional changes affecting either systole or diastole or both. Table 6.1 summarizes some of the key differences between systolic and diastolic heart failure. Examples of these different forms of cardiac failure are:

Table 6.1

Some characteristic differences between systolic and diastolic heart failure

	Systolic heart failure	Diastolic heart failure
Systolic BP	Low normal; hypertension	Low normal; hypertension
End-diastolic volume	↑↑	Normal or ↓
End-systolic volume	↑↑	↓
Stroke volume	Normal or ↓	Normal or ↓
Ejection fraction	↓↓	Normal
Myocardial hypertrophy	Eccentric	Concentric
LV wall thickness	↓	↑↑
Extracellular matrix	↓	↑↑

It is widely thought that cardiac myocytes cannot proliferate, only change size and shape. Some recent reports however suggest limited myocyte division is possible after myocardial infarction. In eccentric hypertrophy extra sarcomeres (see Fig. 2.1) are added in series and so myocyte length increases leading to a dilated heart. In concentric hypertrophy extra sarcomeres are added in parallel and so myocyte diameter increases.

• Mainly systolic dysfunction:

ischaemic heart disease

dilated cardiomyopathy

decreased myocyte contractility.

• Mainly diastolic dysfunction:

impaired relaxation due to fibrosis (e.g. amyloidosis)

mitral or tricuspid valve stenosis

constrictive pericarditis.

• Mixed systolic/diastolic dysfunction:

hypertension

aortic valve stenosis

cardiac hypertrophy.

Primary left heart failure is more common than primary right heart failure and systolic failure is more common than diastolic failure. Left-sided failure is the commonest cause of right heart failure.

In order to understand the fundamental mechanisms involved we need to consider a range of topics which can be grouped under the following subheadings:

• haemodynamic events

• metabolic events

• neurohormonal aspects.

Haemodynamic events

Haemodynamic events in systolic heart failure

If the degree of functional impairment of the heart is relatively small then at rest the ventricle may be able to maintain a normal stroke volume and hence a normal cardiac output. This is achieved by an increase in filling pressure of the ventricle and hence an increase in end-diastolic volume. This increase in ‘preload’ causes the impaired ventricular function to move up a Starling curve (see Chapter 4) to reach a normal stroke volume (Fig. 6.1). There is however a limitation on the ability to increase stroke volume above the resting levels. This manifests itself as part of the exercise limitation experienced by heart failure patients. The increase in preload to restore resting stroke volume for a damaged heart to normal levels is referred to as ‘compensation’.

Fig. 6.1 Compensatory mechanisms in a failing ventricle. A compensatory increase in filling pressure allows a failing ventricle to achieve a normal resting stroke volume. The scope for increasing stroke volume in response to increased workload in exercise is limited. This diagram does not have numerical values on the horizontal axis and so could refer to either the right or left ventricle.

The extent to which compensation can occur is limited by the shape of the cardiac function curve. If end-diastolic volume increases too much then a plateau is reached when further increases in end-diastolic volume do not produce a corresponding increase in the force of contraction of the ventricle. If the cardiac output is still inadequate when this plateau region is reached then end-diastolic volume may continue to increase and this will eventually cause the force of contraction to decrease. This is the region of ‘decompensation’ on the Starling curve and may rapidly lead to death (Fig. 6.2).

Fig. 6.2 Decompensated cardiac failure. In compensated cardiac failure the resting stroke volume and therefore resting cardiac output can reach normal levels by virtue of an increase in filling pressure (preload) for the ventricle (see Fig. 6.1). In decompensated failure increases in preload fail to achieve a satisfactory cardiac output and further increases may lead to a decline in stroke volume.

The commonest form of heart failure is left ventricle systolic failure. It has an annual mortality rate of 15–30% depending on disease severity. In pure left heart failure, the healthy right ventricle will continue to pump blood into the lungs until left ventricular preload is increased enough to restore ventricular balance, i.e. the same output from the two sides of the heart. This ventricular balance will be achieved at the price of raised left atrial, pulmonary capillary and pulmonary artery pressures. The raised pulmonary capillary pressure may result in pulmonary oedema (see Chapter 11) and this will cause the lungs to become ‘stiff’. There will be an increased resistance to inflation of the lungs (a decreased compliance) and this will produce a sensation of breathlessness (dyspnoea). The pulmonary oedema may also upset the balance between the distribution of lung ventilation and pulmonary blood flow causing a ‘ventilation-perfusion mismatch’ which will result in arterial hypoxaemia. This in turn will further reduce the delivery of oxygen to the heart and potentially exacerbate heart failure, producing a vicious circle of events.

The commonest cause of right heart failure is left heart failure. The right ventricle fails because of the increased afterload (increased pulmonary circuit blood pressure) produced by the left-sided failure. Right heart failure may also follow from a raised pulmonary vascular resistance (hypoxic vasoconstriction) such as may occur during decreased oxygenation of the blood in lung disease or in response to low oxygen pressures at altitude (see Chapter 9). The condition of right heart failure resulting from increased pulmonary vascular resistance or some other aspect of lung dysfunction leading to pulmonary artery hypertension is known as cor pulmonale.

In right heart failure ventricular output may be maintained by an increased preload (right atrial pressure; RAP). Clinically it is possible to assess RAP by monitoring jugular venous pressure (Box 6.1). An increase in right atrial pressure will lead to an increase in pressure back through the vena cava and peripheral veins and capillaries and will result in peripheral oedema (see Chapter 11). This is manifested by ankle oedema (if the subject is standing or seated) or sacral oedema (if they are supine). There may also be enlargement of the liver which becomes palpable below the lower ribs. However it should be remembered that the most common cause of ankle swelling in the elderly is not right heart failure but immobility or vascular disease.

Box 6.1 Jugular venous pressure

Right-sided heart failure is accompanied by a compensatory increase in filling pressure. This increased preload on the ventricle leads to improved stroke volume (Fig. 6.1). In a normal heart pressure in the right atrium is typically in the range −1 to +8 mm Hg (mean 4). The pressure in any venous vessel above the level of the heart must be less than in the right atrium. Pressure in the jugular vein in the neck is therefore likely to be negative (less than atmospheric pressure) and so the vein is normally collapsed and in an upright posture is not visible as a bulge on the neck. However, if right atrial pressure rises then the jugular will be inflated further up the neck. This principle is used to estimate right atrial pressure.

The subject is positioned sitting but supported leaning back at an angle of 45 degrees to the horizontal plane (Fig. 6.3). The anatomical reference point for measuring how far up the neck the jugular vein is inflated is the sternal angle (angle of Louis). An approximation of actual right atrial pressure (in pressure units of cm blood/water) could be obtained by adding 5 cm to the height of jugular vein inflation above the sternal angle (note: 1.36 cm water ≡ 1 mm Hg pressure because the density of mercury relative to water is 13.6).

Fig. 6.3 Jugular venous pulse. Measurement of the height of the jugular venous pressure.

The mechanisms associated with compensatory increases in filling pressure of the ventricles are largely attributable to a combination of the sympathetic nervous system and the renin-angiotensin system. These events are discussed later in this chapter under the heading ‘Neurohormonal aspects of heart failure’. The result of these compensatory changes is that, despite an intrinsic decline in some aspects of myocardial function, patients may remain asymptomatic or minimally symptomatic for years. A decline in exercise tolerance is often attributed to normal ageing rather than to developing heart failure. However at some point they are likely to develop symptoms with an associated increase in morbidity and mortality.

Haemodynamic events in diastolic heart failure

The characteristics of diastolic heart failure are delayed relaxation of the ventricle and impaired filling of the left ventricle often linked to increased stiffness of the ventricular wall. Mitral and/or tricuspid valve stenosis will also lead to diastolic dysfunction by providing an increased resistance to atrial emptying. If left-sided heart failure is purely associated with diastole then the ejection fraction (EF) of the ventricle (stroke volume expressed as a percentage of end-diastolic volume) will be normal or only slightly reduced at 40–50%. There will be an increase in left atrial pressure and pulmonary congestion secondary to raised pulmonary capillary pressure. Diastolic failure is typically seen in patients with cardiac hypertrophy (often as a result of hypertension) or restrictive problems such as the fibrotic changes which occur in amyloidosis or in pericarditis. These problems may be exacerbated by any tachycardia, as when the heart rate increases the time available for diastole is shortened more than the time available for systole (see Chapter 5).

Diastolic heart failure has a relatively high prevalence in elderly patients. Although the prognosis in terms of mortality for diastolic heart failure (annual rate about 8%) is much better than for systolic heart failure (annual rate about 19%), it is still associated with substantial morbidity.

Metabolic events in heart failure

In Chapter 5 the regulation of coronary blood flow is described. Impaired blood supply will lead to reduced ATP generation and impaired ventricular muscle performance. In Chapter 2 the roles of ATP in systole and diastole are described. Each cycle of cross-bridge formation requires the binding of a Ca⁺⁺ ion to troponin C and the hydrolysis of an ATP molecule in order to achieve cardiac myocyte contraction during systole. ATP is also essential for myocyte relaxation during diastole as Ca⁺⁺ must be actively pumped back into the sarcoplasmic reticulum stores. Changes in intracellular [Ca⁺⁺] are the major factor determining the contractility of cardiac muscle (see Chapter 4).

Dysfunction of the mechanisms regulating cardiac contractility (Fig. 6.4) are important in the initiation and progression of some forms of heart failure. The defects are thought to be associated with altered sarcoplasmic reticulum uptake, storage and release of Ca⁺⁺. In experimental animal studies of heart failure it has been shown that maintaining contractility can prevent the development of cardiac failure. This is however a complex and still developing area. Clinical trials have shown that improving contractility by the use of positive inotrope agents (see p. 68) which increase intracellular [cAMP] have tended to increase mortality. Cardiac glycosides are drugs which increase intracellular [Ca⁺⁺] and hence contractility by a different mechanism compared to sympathomimetic drugs (Fig. 6.5). They are only relatively weak inotropes and neither increase nor decrease mortality among patients with congestive heart failure but do provide symptomatic relief. Further aspects of the actions of these drugs are discussed below and in Chapter 2.

Fig. 6.4 Myocardial contractility and stroke volume. Effect of changes in myocardial contractility on stroke volume. The middle curve represents an initial starting position with a resting stroke volume achieved with an appropriate initial filling pressure (atrial pressure) or, in other words, end-diastolic volume. A disease-associated fall in contractility means that at a given filling pressure, stroke volume is reduced. Correspondingly, in response to the use of a positive inotrope drug which increases contractility, stroke volume at that initial end-diastolic volume or atrial pressure is increased.

Fig. 6.5 Renin-angiotensin system. Role of the renin-angiotensin system in producing a compensatory increase in preload in response to cardiac failure. The site of action of two groups of drugs, angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) which are used to suppress excessive actions of the renin system are also shown.

Different ways of altering cardiac myocyte contractility using drugs which do not involve increased cAMP formation are being evaluated. In this context the Na⁺/Ca⁺⁺ exchange mechanism in the sarcolemma is of considerable interest (see Fig. 2.3).

In relation to drug therapy, low doses of β-adrenoceptor antagonists, which in the short term have negative inotropic actions and were therefore previously thought to be contraindicated, seem to have beneficial effects in relation to reversal of cardiac remodelling (see p. 67), increase in contractility and in improving patient survival. Some aspects of the mechanisms behind these beneficial effects of beta-blockers are still a matter for conjecture.

A further component of the metabolic changes in heart failure is the role played by H⁺ ions. As described in Chapter 4, H⁺ ions are the strongest naturally occurring negative inotrope and the actions involved include decreased binding of Ca⁺⁺ to troponin C. Underventilation of the lung and the consequent increases in the Pco₂ of body fluids leads to respiratory acidosis (see Chapter 1). Oxidative metabolism also generates forms of acid which have to be excreted via the kidneys. Overproduction of such acids, as in diabetic ketoacidosis, or a failure of excretory mechanisms as in renal failure, will lead to metabolic acidosis. Either form of acidosis, but particularly respiratory acidosis (as CO₂ can quickly diffuse into the myocyte), is likely to impair myocyte contraction and make heart failure worse.

Interesting facts

In earlier times heart failure was often referred to as ‘the dropsy’. This word is thought to be a corruption of the term hydropsy meaning a generalized swelling of the body due to accumulation of excess water.

Neurohormonal aspects of Heart Failure

Activation of the sympathetic nervous system is a central component of the physiological response to heart failure and the mechanisms involved, the baroreceptor reflex, are described in Chapter 10. Sympathetic activation may be manifested as an increased heart rate, which is not necessarily helpful for a patient with a poorly functioning ventricle. Other characteristics of increased sympathetic drive include:

• Increased contraction of venous smooth muscle will contribute to increased right ventricle preload and therefore to compensation in moderate heart failure (Fig. 6.1).

• Vasoconstriction, particularly in the skin, splanchnic circulation and skeletal muscle, will help to sustain arterial blood pressure (the driving force for tissue perfusion) and divert available cardiac output to the most critical organs (heart and brain).

• Increased contractility of cardiac myocytes by a β-adrenoceptor mediated increase in intracellular [Ca⁺⁺].

• Increased renin secretion from the juxtaglomerular cells in the kidney (see below).

It is sometimes suggested that overstimulation of pathways activated by β-adrenoceptor agonists including both the effects of neurotransmitters released by sympathetic nerves to the heart and circulating catecholamines released by the adrenal medulla may become counterproductive in heart failure. The increased mortality associated with prolonged use of β-adrenoceptor agonists as inotrope drugs is referred to above.

Figure 6.1 shows that the compensation response for cardiac failure is an increase in preload (increased end-diastolic volume or atrial pressure) on the heart. This is largely achieved by an expansion of the extracellular fluid volume, including blood volume, driven by activation of the renin-angiotensin system. Increased renin secretion occurs in response to decreased blood pressure or to any situation in which blood volume is inadequate to support the necessary preload for an appropriate cardiac output. The components of the renin-angiotensin system are summarized in Figure 6.6 and are further discussed in Chapters 9 and 14. The mechanisms regulating renin secretion from the juxtaglomerular (JG) cells in the kidney may be summarized as:

• Direct innervation of JG cells by sympathetic nerves which act through a β-adrenoceptor mechanism. Renin secretion will therefore be increased as part of the baroreceptor reflex (see Chapter 10).

• JG cells are intrinsically sensitive to stretch. A fall in renal afferent arteriole pressure will lead to increased renin secretion. This mechanism is independent of the sympathetic nervous system.

• A putative Na⁺ and/or Cl⁻ load detector located at the macula densa, a group of specialized tubular cells where the ascending limb of the loop of Henle becomes the distal tubule as it passes the JG cells. It is still unclear exactly how or if this mechanism functions to control renin secretion.

• Circulating angiotensin II (Ang II) concentration exerts a negative feedback control on renin secretion via an AT₁ receptor on the JG cells.

Case 6.1 Heart failure: 2

Investigations on Steven’s symptoms

During his cardiology appointment Steven received an ECG and an echocardiographic investigation. The ECG showed extremely large left-sided voltages. There was also evidence of abnormal repolarization with ST segment elevation and T wave inversion particularly in leads V₄–V₆.

The echocardiogram demonstrated left ventricular hypertrophy dominated by thickening of the septum which reached a maximum of 22 mm.There was outflow obstruction with a left ventricular outflow velocity of 2.8 m/s implying a high pressure gradient of 35 mm Hg across the valve. The obstruction was below the aortic valve which itself appeared normal. The left ventricle was hyperdynamic with an ejection fraction of 85% but the left ventricular cavity was almost obliterated in systole and remained small even in diastole.

An exercise test was performed during which Steven managed 8 minutes 10 seconds of a standard protocol and became very breathless. He experienced some chest pain towards the latter stage of the test and the ECG at this time showed 3 mm of ST depression in leads V₅ and V₆.

The diagnosis for Steven was hypertrophic obstructive cardiomyopathy. This form of outflow obstruction imposes an afterload on the left ventricle and is therefore a form of pressure overload.

Steven was commenced on beta-blockers. He was advised to give up his job as a builder and adopt a more sedentary lifestyle particularly avoiding ‘explosive’ activities. His clinical history gives rise to the following questions:

1. Why, when Steven’s cardiac function remains so good, does he get breathless with exercise?

2. Why was Steven’s myocardium thickened?

3. What was the origin of the changes on his ECG?

4. Why were beta-blockers prescribed?

5. Why was Steven advised to adopt a more sedentary lifestyle?

6. Is this history consistent with systolic, diastolic or mixed (systolic and diastolic) heart failure?

Answers to these questions can be found in this chapter and in Chapters 3, 4 and 7.

Increased Ang II concentration increases sodium and water retention via stimulation of the synthesis of aldosterone in the zona glomerulosa of the adrenal cortex and also via direct effects of Ang II on sodium transport mechanisms in the nephron. Ang II will also increase antidiuretic hormone (ADH) secretion which further contributes to fluid retention. If the expansion of blood volume fails to generate an adequate arterial blood pressure which would eventually suppress renin secretion, this will lead to excessive expansion of the extracellular fluid compartment. This may lead to further deterioration of cardiac performance and to decompensated failure (Fig. 6.2). This scenario provides part of the rationale for the use of diuretics and blockers of the renin system (angiotensin-converting enzyme inhibitors and Ang II receptor blockers) in the management of heart failure (see p. 68). Overproduction of Ang II also contributes to the series of fibrotic changes in the heart known as remodelling. This seems to start as an adaptive response to changes in cardiac function but as failure progresses remodelling becomes counterproductive.

The potent vasoconstrictor peptide endothelin-1 (ET-1) (see Chapter 9) has also been implicated in the pathogenesis of congestive heart failure. Initially in an adaptive context ET-1 is thought to have a positive role promoting inotropic actions on the myocyte and increasing myocyte protein synthesis. Overexpression of ET-1 leads to myocardial fibrosis and myocyte necrosis in addition to local vasospasm, all of which promote the progression of failure. Endothelin production may be potentiated by the increased concentrations of Ang II which frequently occur in heart failure (see p. 66).

The two types of endothelin receptors are designated ET_A and ET_B (see Chapter 9), and drugs which block these receptors are given trivial names ending in -sentan. Drugs such as the non-selective ET_A/ET_B receptor blocker bosentan are undergoing clinical trials to evaluate their efficacy in the management of heart failure. It is not yet clear whether mixed ET_A/ET_B blockers or selective ET_A receptor blockers will be the more valuable approach.

Heart failure is also associated with the release of cytokines, particularly tumour necrosis factor alpha (TNFα) and members of the interleukin (IL) family. These cytokines appear to be particularly involved in mechanisms leading to cardiac myocyte hypertrophy.

Interesting facts

In 7th century England, blood-letting (venesection) was widely practiced because of the belief that too much blood was a cause of illness. This practice has continued in one form or other, including the use of leeches, through to the present day. Some current pharmacological therapy for heart failure is targeted at reducing blood volume.

Drug therapy for heart failure

A detailed discussion of management strategies for heart failure is outside the scope of this book, but the following generalizations can be made about the classes of drugs used.

Sympathomimetic inotropes

This group includes drugs such as isoprenaline/isoproterenol (a non-selective β₁/β₂ agonist), dobutamine (a selective β₁ agonist) and dopamine (a non-selective β-adrenoceptor agonist which is also a dopamine D₁/D₂ receptor agonist). These drugs are given intravenously to acutely ill hospitalized patients in order to provide a short-term increase in cardiac contractility. β-adrenoceptor activation leads to an increase in myocyte [cAMP] and hence an increase in intracellular [Ca⁺⁺] (see Chapter 2). Activation of D₁ receptors by dopamine also leads to vasodilatation within the kidney and activation of presynaptic D₂ receptors leads to peripheral vasodilatation by inhibition of noradrenaline (norepinephrine) release from sympathetic nerve endings. Dopamine-induced hypotension but with increased renal blood flow and increased cardiac contractility is often a useful combination in the management of heart failure. Dobutamine has positive inotropic actions but, compared to isoprenaline, a reduced effect increasing heart rate.

Adverse effects on patient mortality of drugs which increase intracellular [cAMP] have been referred to on page 65. In prolonged use of β-adrenoceptor agonists, downregulation of receptor number will also limit their therapeutic response.

The apparently counter-intuitive use of low dose beta-blockers in heart failure is described on page 65.

Phosphodiesterase inhibitors

Phosphodiesterase III, an enzyme in cardiac and smooth muscle which promotes the breakdown of cAMP, can be blocked with the drugs milrinone and enoximone. The increased myocyte [cAMP] increases [Ca⁺⁺] and hence provides useful short-term increases in myocardial contractility. Unwanted side effects include increased heart rate and arrhythmias. Unlike β-agonists, phosphodiesterase inhibitors do not cause downregulation of β-receptor number. However, as with other drugs which increase intracellular [cAMP], long-term use is associated with increased patient mortality.

Digitalis glycosides

The most widely used drug in this category is digoxin which acts as an inhibitor of the Na⁺/K⁺-ATPase in cardiac muscle (see Fig. 4.7). The consequent increase in intracellular [Na⁺] results in reduced Na⁺/Ca⁺⁺ exchange across the plasma membrane and so Ca⁺⁺ is retained within the cell. The increase in intracellular [Ca⁺⁺] provides an increase in myocardial contractility.

Although a relatively mild inotrope, digoxin can be used for an extended period provided the potential unwanted effects are kept under review. The digitalis glycosides have a narrow therapeutic window between doses which are too low to be effective and doses which are high enough to cause significant side effects. Toxicity may result from excessive increases in intracellular [Ca⁺⁺] which may cause various arrhythmias. There may also be increased vagal activity causing an excessive atrioventricular (AV) node block (see Chapter 2). Anorexia, nausea and vomiting are quite common side effects as are neurological disturbances including fatigue, vertigo and visual disturbances. Digitalis toxicity will be worse if it is accompanied by hypokalaemia and thus care must be taken when combining digitalis treatment with diuretics. Renal failure, hypoxaemia and hypothyroidism will also increase the risk of toxicity.

Interesting facts

In 1785, William Withering, a physician in Birmingham, described the treatment of heart failure with digoxin in his book ‘An account of the foxglove’.