The classical causes of heart failure
Introduction
Heart failure (HF) is the complex clinical syndrome that may result from a broad spectrum of structural or functional cardiac and noncardiac diseases (see Table 4.1), often causing the classical triad of symptoms: breathlessness, fatigue, and fluid retention. It is not a single disease entity, but rather a process that may potentially complicate most forms of cardiac pathology, particularly in their final stages.
Table 4.1 Causes of heart failure and the common modes of presentation
Cause | Examples of presentations |
|---|---|
CHD | Myocardial infarction Chronic ischaemia Arrhythmias |
Hypertension | Heart failure with preserved systolic function ‘Burnt out’ hypertensive cardiomyopathy Malignant hypertension/acute pulmonary oedema |
Valve disease | Primary valvular disease e.g. endocarditis Secondary valvular disease e.g. functional regurgitation Congenital valvular disease |
Arrhythmias | Incessant atrial arrhythmias Ventricular arrhythmias |
Dilated cardiomyopathy | Idiopathic Inherited (familial) Peripartum Toxins: alcohol, cocaine, iron, copper |
Congenital heart disease | Corrected transposition of great arteries Repaired tetralogy of Fallot Ebstein’s anomaly |
Infective | Viral myocarditis Chagas’ disease HIV Lyme disease |
Iatrogenic | Anthracyclines Abstruzimab |
Infiltrative | Amyloid Sarcoid Neoplastic |
Storage disorders | Haemochromatosis Fabry’s disease Glycogen storage diseases |
Endomyocardial disease | Radiotherapy Endomyocardial fibrosis Carcinoid |
Pericardial disease | Calcification Infiltrative |
Metabolic | Endocrine disease Nutritional disease (thiamine deficiency, selenium deficiency) Autoimmune disease |
Neuromuscular disease | Friedreich’s ataxia Muscular dystrophy |
High-output | Anaemia Thyrotoxicosis A-V fistulae Paget’s disease |
The aetiology of HF can be described in many ways. First, it can be categorized into a disorder of the myocardium, endocardium, pericardium, or great vessels. Myocardial disorders are the most common cause, and these are subdivided into those with reduced and those with normal left ventricular ejection fraction (LVEF). Reduced systolic function HF can also be classed as ischaemic or nonischaemic HF, the latter term only applied when an ischaemic cause has been excluded. Nonischaemic causes of left ventricular systolic dysfunction (LVSD) include hypertension, valvular heart disease, arrhythmias, alcohol, dilated cardiomyopathy, and peripartum cardiomyopathy.
The ‘classical causes’ are the common cardiovascular conditions that result in HF. These exhibit geographical variation and depend on the population being studied. In Western countries, coronary heart disease (CHD) and hypertension are the commonest causes of HF.1 However, valvular heart disease (particularly degenerative), arrhythmias, and alcohol are also frequently implicated. In Africans and African Americans, hypertension is an important precursor of HF,2 and HF secondary to Chagas’ disease is well recognized in South America.3 In developing countries, HF more commonly develops as a result of rheumatic valvular heart disease and nutritional deficiencies.4
The prevalence of ‘classical causes’ of HF in the largest contemporary clinical trials and registries is shown in Table 4.2.5–20 Whilst clinical trials often contain highly selective cohorts of patients, with reduced systolic function only, the large registries consistently demonstrate similar prevalences of the common aetiologies. Thus, the prevalence of the common causes of heart failure in real-life heart failure populations can be extrapolated from these studies, with coronary heart disease being the major cause in approximately two-thirds of patients. However, this has not always been the case. The original Framingham Heart Study, one of the earliest cardiovascular epidemiological studies, recorded hypertension as the most common cause of HF.21 During the subsequent decades of follow-up, the proportion of cases of HF attributable to hypertension and valvular heart disease decreased, and those secondary to coronary artery disease rose (Fig. 4.1). The changing aetiology of HF in recent decades is multifactorial. Improvements in survival post myocardial infarction22 and wider availability of techniques for diagnosing coronary artery disease are plausible reasons for the increasing prevalence of HF secondary to CHD. The declining role of hypertension as the primary cause of HF may be explained by advances in antihypertensive therapy preventing longer-term complications.23
Table 4.2 Aetiology of heart failure in contemporary randomized clinical trials and major registries
Study | RCT/REG | Size | Agea | Male (%) | Ischaemic (%) | Nonischaemic (%) | HT (%) | IDCM (%) | Valveb (%) | Other (%) | Unknown (%) |
|---|---|---|---|---|---|---|---|---|---|---|---|
SOLVD5 | RCT | 2569 | 61 | 80 | 71 | – | – | 18 | – | – | – |
DIG6 | RCT | 6800 | 64 | 78 | 70 | 30 | 9 | 15 | – | 6 | – |
MERIT-HF7 | RCT | 3991 | 64 | 78 | 66 | 34 | – | – | – | – | – |
CIBIS-II8 | RCT | 2647 | 61 | 81 | 50 | – | – | 12 | – | – | 38 |
ATLAS9 | RCT | 3192 | 64 | 79 | 64 | 35 | 20 | 28 | – | 6 | – |
RALES10 | RCT | 1663 | 65 | 73 | 54 | 46 | – | – | – | – | – |
Val-HeFT11 | RCT | 5010 | 62 | 80 | 57 | – | 7 | 31 | – | 5 | – |
COPERNICUS12 | RCT | 2289 | 63 | 80 | 67 | – | – | – | – | – | – |
COMET13 | RCT | 3029 | 62 | 80 | 53 | – | 18 | – | – | – | – |
COMPANION14 | RCT | 1520 | 67 | 68 | 56 | 44 | – | – | – | – | – |
CARE-HF15 | RCT | 813 | 67 | 73 | 38 | – | – | – | – | – | 62 |
GISSI-HF16 | RCT | 4574 | 68 | 77 | 40 | – | 18 | 34 | – | 3 | 5 |
SOLVD17 | REG | 6273 | 62 | 74 | 69 | 31 | 7 | 13 | – | 11 | – |
SPICE18 | REG | 9580 | 66 | 74 | 63 | – | 4 | 17 | 5 | – | 6 |
ADHERE19 | REG | 105 388 | 72 | 48 | 57 | – | – | – | – | – | – |
OPTIMIZE-HF20 | REG | 48 612 | 73 | 48 | 46 | – | 23 | – | – | – | – |
HT, hypertension; IDCM, idiopathic dilated cardiomyopathy; RCT, randomized clinical trial; REG, registry.
a Mean age in years.
b Valvular heart failure.
From McMurray JJ, Stewart S. Epidemiology, aetiology, and prognosis of heart failure. Heart 2000;83:596–602.
At present, genetic and mitochondrial abnormalities are thought to be less frequent causes of HF, although increasingly it is apparent that many forms of ‘idiopathic’ dilated cardiomyopathy have a familial link. HF may also result from less common aetiologies, such as metabolic conditions, infiltrative processes, infective conditions, and iatrogenic causes. These rarer causes will be addressed in subsequent chapters of this section. The rest of this chapter will focus on the ‘classical’ causes of HF in Western countries.
The importance of establishing an aetiology
The appropriate management of the HF patients relies on establishing its aetiology, particularly with regard to the selection of investigations and the most suitable treatment strategies. Many of the robust evidence-based therapies available for the treatment of HF are derived from cohorts of patients with specific causes of HF. Determining the cause of HF, and identifying potential secondary contributing factors, is also important for targeting ways to avoid future episodes of acute decompensation. Examples of this include addressing risk factors for myocardial infarction and enrolling patients with alcoholic cardiomyopathy in rehabilitation programmes to attempt to alleviate their addiction. Identifying the genetic abnormality in familial conditions is also important, as it may give prognostic information as well as having an impact on the lives of other members of an individual patient’s family. Finally, establishing the cause of HF can be curative. An example of this is radiofrequency ablation (RFA) for tachycardiomyopathy.
Challenge of attributing aetiology
Although establishing the aetiology of HF is important, it is often challenging for the clinician. Several causes of HF frequently coexist and determining the primary aetiology can be difficult: one cause may obviously dominate, but commonly a patient may have multiple contributing causes. An example of this is the hypertensive diabetic patient with confirmed coronary artery disease on angiography who consumes excess alcohol. Secondary causes may contribute to the progression of HF and may be the primary reason for episodes of acute decompensation, although not the original primary cause of HF.
Coronary artery disease can be challenging to attribute as the primary cause of HF. Although coronary angiography may reveal the presence of atherosclerotic disease, this does not confirm an ischaemic cause for any cardiac dysfunction. Conversely, a myocardial infarction may result from plaque rupture in the context of otherwise unobstructed coronary arteries. Cardiac magnetic resonance imaging (CMR) can help to clarify the underlying diagnosis by characterizing the myocardium, with late gadolinium-enhanced images useful in identifying areas of previous myocardial infarction. In the absence of a definite clinical myocardial infarction, or evidence of such from coronary angiography/CMR, coronary artery disease can only be suspected as a possible cause of HF.
A further challenge in accurately ascribing the primary aetiology of HF may be when the condition is no longer present. Patients with HF secondary to long-standing hypertension may have normal or low blood pressure at the time of their HF presentation. A subset of patients with hypertrophic cardiomyopathy develop progressive left ventricular dilation with systolic dysfunction and thinning of the previously hypertrophied myocardium. This condition is often referred to as ‘burnt out’ hypertrophic cardiomyopathy and patients presenting at this stage of the disease may be incorrectly diagnosed as having primary dilated cardiomyopathy.
Coronary heart disease
Coronary artery disease is the commonest cause of HF in the Western world (Table 4.2). It may present in several different ways; acute myocardial infarction, chronic ischaemia, arrhythmia, and asymptomatic (occult) disease.
Acute physiological responses
An acute myocardial infarction initiates acute physiological mechanisms–the same processes that are used to enhance cardiac output in normal circumstances.24 Activation of the sympathetic nervous system causes an increase in heart rate and cardiac output. Activation of systemic neurohumoral pathways leads to increases in circulating volume, enhancing venous return, and the effective maintenance of preload. Ultimately, these pathways act to preserve cardiac output via the Frank–Starling mechanism. Other physiological changes following myocardial infarction include systemic vasoconstriction, which maintains blood pressure at the expense of increasing the workload of the heart by increasing afterload. Often the outcome of the adaptive responses is the maintenance of normal cardiac output at rest but reduced reserve for any further demands in cardiac output. The consequence clinically is a reduction in exercise capacity and symptoms of HF on exertion for some patients. However, initially, many patients remain asymptomatic in response to these compensatory adjustments.24
Chronic remodelling and progressive cardiac injury
After myocardial infarction, cardiac structure changes occur in parallel with, and are linked to, physiological changes in activated neurohormonal systems. Activation of the sympathetic nervous system and renin–angiotensin–aldosterone system (RAAS) lead to the release of cytokines and growth factors that stimulate structural alterations at the cellular and extracellular level. The alterations include cardiac myocyte hypertrophy and extracellular matrix changes which lead to regional alterations in ventricular wall and chamber sizes in order to preserve cardiac output.25
Although initially protective, compensatory mechanisms that maintain cardiac output may ultimately be deleterious. Chronic activation of compensatory neurohormonal processes can lead to the development of HF in the absence of any further ischaemic injury.26
Chronic catecholamine secretion promotes myocyte hypertrophy and interstitial fibrosis.27 It also interferes with inter- and intracellular signalling pathways by inducing down-regulation of adrenoreceptors and causing hyperphosphorylation of intracellular proteins. The consequence is hindrance of the ability of the adrenergic compensatory mechanisms to maintain cardiac output during future times of acute haemodynamic stress. Sympathetic nervous system activation also leads to further myocardial dysfunction by inducing the transcription of fetal genes and inducing cardiac myocyte death by promoting apoptosis and necrosis (see Chapter 12).
Chronic activation of the renin–angiotensin–aldosterone system occurs in response to a variety of triggers including renal hypoperfusion, myocardial production of angiotensin and aldosterone in response to increased wall stress, and sympathetic nervous system activation stimulating renal renin release28. Although activation of the RAAS maintains blood pressure and enhances preload by stimulating vasoconstriction and renal sodium retention, harmful consequences arise from the effects of angiotensin and aldosterone on cardiac myocytes. These effects include enhancing myocardial fibrosis by promoting collagen deposition, cardiac myocyte hypertrophy, and cellular apoptosis and necrosis.
Ultimately, chronic activation of the compensatory response damages cardiac structure and function.24 Structural changes lead to ventricular dilatation, and the heart remodels to a more globular shape (Fig. 4.2), thereby altering atrioventricular valvular function, resulting in functional regurgitation and an increase in ventricular preload. A vicious cycle ensues. Furthermore, increases in cardiac load which increase myocardial oxygen requirements may precipitate subendocardial ischaemia, exacerbating further reductions in cardiac contractility.
Acute complications post myocardial infarction
Acute myocardial infarction may cause acute HF. Particular complications include acute mitral valve incompetence secondary to papillary muscle rupture, hibernation and stunning of the left ventricle, ventricular septal rupture, ventricular free wall rupture, right ventricular infarct syndrome, and cardiogenic shock.
Cardiogenic shock usually results from severe cardiac dysfunction, although the acute mechanical complications of myocardial infarction may contribute. It is defined as evidence of end-organ hypoperfusion and characterized by reduced blood pressure (systolic 〈90 mmHg) with raised ventricular filling pressure (pulmonary capillary wedge pressure 〉18 mmHg) and low cardiac output.29
Acute HF due to stunning or hibernation may completely return to normal when appropriately treated.30 Stunning may occur following a prolonged ischaemic episode and can persist in the short term even after restoration of normal coronary blood flow. The amount and duration of stunning depends on the severity and duration of the preceding ischaemic event. Hibernation describes the state when cardiomyocytes fail to contract normally but remain structurally intact despite a significant reduction in coronary blood flow. Improving blood flow and oxygenation allows hibernating myocytes to return to normal function.
Hypertensive heart disease
Hypertension affects around one-quarter of the population of the Western world. It is an important cause of chronic HF in Western societies,1,4 and remains the most common cause in developing countries.31 It is particularly prevalent in Africans and African Americans.2,32 Hypertension is proportionately more common in patients with HF and normal LVEF.33
Hypertension leads to an increase in afterload which consequently leads to concentric left ventricular hypertrophy (Fig. 4.3). This compensatory mechanism preserves contractile function by recruiting additional sarcomere units of the muscle fibres to share the additional ventricular wall tension generated by the increased afterload, enabling higher forces and greater pressures to be generated.34 The more hypertrophied the ventricular wall, the less tension experienced by each individual muscle fibre and consequently systolic function is not initially compromised. However, with progressive hypertrophy the compliance of the left ventricle reduces, producing a ‘stiff’ ventricle. This interferes with ventricular filling, leading to a reduction in end-diastolic volumes and increase in left ventricular end-diastolic pressure (LVEDP). Rises in LVEDP lead to increased left atrial and pulmonary venous pressures. A consequence may be atrial arrhythmias and reduced exercise tolerance.
As left ventricular hypertrophy progresses, sarcomeres are added in parallel to established sarcomeres, leading to ventricular dilatation and systolic dysfunction. The progression from left ventricular hypertrophy to HF is complex, involving multiple pathophysiological processes including altered cellular signalling processes, myocyte apoptosis and increased collagen deposition.35 As progressive pump failure develops, blood pressure may normalize, known as ‘burnt out’ hypertensive HF.
Malignant hypertension is an important cause of acute HF.36 Malignant hypertension is the sudden development of severe high blood pressure with diastolic measurements often in excess of 130 mmHg. Characteristics of this condition include fundal changes (retinal haemorrhages, exudates, and papilloedema), central nervous system involvement (headache, confusion, seizures, and coma) and renal impairment (oliguria and uraemia). Malignant hypertension may present as ‘flash pulmonary oedema’ with very rapid onset of symptoms and signs. Flash pulmonary oedema is often seen in patients with normal LVEF. Malignant hypertension affects almost 1% of all people with essential hypertension36 and is more common in younger adults (particularly those with secondary hypertension) and African American men.35,36 Although any cause of secondary hypertension may be a precursor to malignant hypertension, recurrent episodes of flash pulmonary oedema in the presence of significant hypertension is a classic presentation of renal artery stenosis. Other causes include phaeochromocytoma and Conn’s syndrome.36
Valvular heart disease
Valvular dysfunction can be a cause (primary) or effect (secondary) of HF, with acquired valvular heart disease accounting for the majority of cases. There is a geographical variation in valvular pathology; for example, rheumatic valvular heart disease is a common cause of HF in the developing world.4
Primary valvular pathology causing heart failure
Aortic valve disease
Aortic stenosis and regurgitation are common causes of valvular disease. Both can have long latent asymptomatic stages but progression in severity will ultimately lead to HF if left untreated.
Aortic stenosis is the most common valvular heart disease in developed countries and a frequent cause of HF internationally.38 The three main causes are congenital, rheumatic, and degenerative. Degenerative aortic stenosis is more common in Western societies and tends to present in elderly populations (Fig. 4.4), and as a result, the prevalence of this valvular pathology is increasing as the average life expectancy increases.38 A chronic inflammatory process involving deposition of lipids in the valve leaflets is followed by calcification of the valve annulus and subsequently the valve leaflets, limiting the circulatory flow across the aortic valve.39,40 Rheumatic aortic valve disease is more common in developing countries38 and leads to stenosis by causing inflammatory mediated fusion of the commissures and a reduction in the valve orifice area. Aortic stenosis causes HF by obstructing left ventricular outflow, resulting in an increased afterload, lower stroke volume, and reduced ejection fraction, with advanced disease suspected by the presence of symptoms. The severity of aortic stenosis is best assessed by calculating valve orifice area and using dobutamine stress echocardiography.41
Aortic regurgitation may be acute or chronic. Acute severe aortic regurgitation (e.g. secondary to infective endocarditis, aortic dissection, or trauma) is potentially life threatening by causing extremely elevated left ventricular filling pressures, severe pulmonary oedema, and inadequate cardiac output.42 Chronic aortic regurgitation shares the same three main causes as aortic stenosis–congenital, rheumatic, and degenerative. Other less common causes include infective endocarditis, connective tissue or inflammatory diseases, antiphospholipid syndrome, anorectic drugs, and trauma.43 Untreated, chronic aortic regurgitation slowly progresses from volume overload and left ventricular hypertrophy to left ventricular dilatation, then contractile dysfunction.43 Patients are often asymptomatic in the early stages of this disease and may remain so after the left ventricle has begun to dilate. LVSD is potentially reversible if valve repair/replacement is undertaken soon after the onset of contractile dysfunction.
Mitral valve disease
Mitral regurgitation may be caused by primary (e.g. rheumatic heart disease, infective endocarditis, mitral valve prolapse, and connective tissue disease) or secondary valve disease.44 Most patients with mitral regurgitation have a slow, insidious progression of their valve disease. Many are asymptomatic in the early stage, although the presentation may be more acute in cases of infective endocarditis. Progression to severe mitral regurgitation usually results in the development of symptoms of left-sided HF and pathophysiological consequences of left ventricular remodelling, left ventricular dysfunction, and pulmonary hypertension.44 Sudden symptomatic deterioration is often seen with the subsequent development of atrial fibrillation secondary to left atrial dilatation.
Mitral stenosis is a primary valve disease, most commonly caused by rheumatic fever and persistent inflammatory valve disease in developing countries, and by degenerative disease with calcification of the annulus in developed countries.45 As with mitral regurgitation, the early stages of this valve disease may be asymptomatic. As the severity of the stenosis progresses, a series of pathological changes ensues ultimately leading to a rise in left atrial pressure with dilatation of the atrium and consequently development of pulmonary hypertension,45 leading to symptoms of exertional breathlessness. Left ventricular systolic function is usually preserved in severe mitral stenosis.
Tricuspid valve disease
Tricuspid stenosis is a more prevalent valvular pathology in developing countries, as the vast majority of cases are caused by rheumatic heart disease,46 and usually coexists with mitral stenosis. The main causes of solitary tricuspid stenosis are congenital heart disease and carcinoid syndrome.46,47 Tricuspid stenosis may be detected by the auscultation of a diastolic murmur, loudest in inspiration. Clinical signs of HF are those of right HF.
Tricuspid regurgitation is most commonly functional. However, primary tricuspid regurgitation may be caused by infective endocarditis (particularly in intravenous drug users), or rheumatic valve disease, as well as carcinoid syndrome.48 Symptoms and signs of tricuspid regurgitation are those of right-sided HF with a classic pansystolic murmur accentuated by inspiration.
Pulmonary valve disease
Pulmonary stenosis is exclusively a form of congenital heart disease. Most cases of pulmonary regurgitation also occur in patients with congenital heart disease, the causes of which are outlined below. Acquired cases of pulmonary regurgitation are rare and include infective endocarditis or carcinoid syndrome.
Secondary valvular dysfunction causing heart failure
Valvular dysfunction may be the consequence of many other causes of HF. Any cause of left ventricular dilation can result in regurgitation of the aortic, mitral, and tricuspid valves, known as functional regurgitation: the valve dysfunction is related to abnormal ventricular shape and function. Functional mitral regurgitation is common in ischaemic cardiomyopathy, where dilatation of the valve annulus prevents coaptation of the valve leaflets49 (Fig. 4.5). Secondary mitral valve dysfunction can also result from failure of the valve apparatus following acute myocardial infarction if there is rupture or stretching of the chordae or papillary muscle,49 often presenting with the sudden onset of pulmonary oedema. Functional tricuspid regurgitation may be caused by several pathologies including; right ventricular dysfunction, left-sided valvular disease causing pulmonary hypertension, left ventricular dysfunction, or chronic pulmonary disease.48
Adult congenital valvular heart disease
A detailed account of congenital heart disease as a cause of HF is given in Chapter 7. A brief summary of congenital valve disease follows.
Pulmonary valve disease is usually congenital and detected early in childhood. Pulmonary stenosis may occur as an isolated congenital abnormality or as a feature of Noonan’s syndrome or tetralogy of Fallot.50 The symptomatic presentation is usually breathlessness with chronic progression to right HF.
Clinically significant pulmonary regurgitation occurs almost exclusively in patients with congenital heart disease. It may be a long-term complication of the repair of tetralogy of Fallot51 and occur secondary to transannular patching, commissurotomy of the pulmonary valve, or failure of a pulmonary conduit. Progression in the severity of pulmonary regurgitation leads to right ventricular dilatation and subsequent right ventricular systolic dysfunction, reduced exercise tolerance and ventricular arrhythmias.51 Sudden death may be a sequela of this condition.
Congenital tricuspid valve disease most commonly occurs as part of Ebstein’s anomaly,52 a condition characterized by apical displacement of the septal and posterior valve leaflets, leading to atrialization of a portion of the right ventricle. The structural deformity of the valve leads to tricuspid regurgitation and, although often detected in childhood, Ebstein’s anomaly may present in adulthood with symptoms of fatigue, exercise intolerance, palpitations, and dyspnoea. Signs include cyanosis, a tricuspid regurgitant murmur, and right-sided HF. Arrhythmias are common, with supraventricular tachycardias occurring in approximately one-third. Ventricular arrhythmias are due to the presence of accessory pathways and sudden death may occur.
Arrhythmias
Arrhythmias are common in patients with HF, and may be either a cause or a consequence of it. Defining the cause and effect relationship can be difficult, particularly when tachycardia and cardiomyopathy present at the same time. HF predisposes to arrhythmias due to structural and electrical remodelling (see Chapter 36).
Sustained tachycardias may lead to HF (a tachycardiomyopathy, or tachycardia-related cardiomyopathy). Tachycardiomyopathy is systolic or diastolic (or both) dysfunction that usually results in ventricular dilatation and HF, and is caused by an uncontrolled ventricular rate.53 Tachyarrhythmias may lead to a reduction in LVEF, an increase in end-diastolic and end-systolic volumes, and an increase in end-diastolic and pulmonary artery pressures. The degree of LVSD does not necessarily correlate with the duration or rate of the tachycardia.54 Making the diagnosis is crucial, as treatment can be potentially curative (Fig. 4.6).55–57
From Walker NL, Cobbe SM, Birnie DH. Tachycardiomyopathy: a diagnosis not to be missed. Heart 2004;90:e7.
The most common causes of tachycardiomyopathy are incessant atrial arrhythmias. The cardiomyopathy and tachycardia often present simultaneously. Potential causes include atrial tachycardias, reentrant tachycardias, and atrial fibrillation (AF).58
Atrial fibrillation is common in HF, with each condition predisposing to the other.59 Some 10–50% of patients with LVSD have AF,60 although AF is also common in patients with HF and normal LVEF.61 Haemodynamic disturbances associated with AF include the loss of atrial contraction (and subsequent contribution to ventricular filling), an irregular and often uncontrolled ventricular rhythm, and activation of the deleterious neurohumoral systems. These all contribute to a reduction in cardiac output.62
Ventricular tachyarrhythmias are also common in chronic HF (see Chapter 36). Although more commonly a consequence of HF, ventricular tachycardia can potentially cause a tachycardiomyopathy if there are frequent paroxysms or the tachycardia is incessant.63 The likely focus of ventricular tachycardia that is stable enough to cause a tachycardiomyopathy is the right ventricular outflow tract.64 This form of ventricular tachycardia is recognized by the pattern of left bundle branch block with an inferior axis. Recognition is extremely important as it can be potentially cured by RFA.64
Alcohol
Alcohol excess is one of the commonest causes of a dilated cardiomyopathy and accounts for at least one-third of all cases.65 There are no pathognomonic signs or specific tests for diagnosing alcoholic cardiomyopathy. It is impossible to differentiate it pathologically from other causes of dilated cardiomyopathy, and nonspecific pathological findings include interstitial fibrosis, myocytolysis, small-vessel coronary artery disease, and myocyte hypertrophy.65 The diagnosis depends on a history of excessive alcohol consumption and the absence of other causes of cardiomyopathy. Two distinct phases and modes of clinical presentation of alcoholic heart disease are recognized: asymptomatic and symptomatic. The latter may be further divided into acute and chronic stages. Consumption of more than 90 g of alcohol per day for at least 5 years increases the risk of asymptomatic alcoholic cardiomyopathy.64,65 The asymptomatic phase is often associated with diastolic dysfunction, whereas continual consumption of excess alcohol increases the risk of developing symptomatic HF which is frequently associated with LVSD (Fig. 4.7).65 Importantly, in contrast with many other causes of cardiomyopathy, disease progression can be terminated or even reversed by complete abstinence from alcohol. However, the prognosis for patients with alcoholic cardiomyopathy who continue to consume excess alcohol is poor.67
Alcohol and its metabolites have direct toxic effects on cardiac myocytes, including disruption of: calcium transport and binding, mitochondrial respiration, lipid metabolism, myocardial protein synthesis, and cellular signal transduction68 as well as apoptosis64. Alcohol excess may have other indirect toxic effects on the myocardium such as those derived from nutritional deficiencies (e.g. vitamin B1 deficiency). Myocardial impairment due to cobalt sulphate (used as an additive) no longer occurs as this substance is no longer used in beer manufacturing.
Symptomatic alcoholic cardiomyopathy may present with any of the symptoms or signs of dilated cardiomyopathy of any aetiology, either as acute pulmonary oedema or more commonly with chronic HF. AF is a frequent finding in alcoholic cardiomyopathy (more so than other arrhythmias), and a paroxysm of AF is a common initial presenting sign. Stigmata of chronic liver disease may also be evident.
Approximately one-third of all alcoholics have evidence of LVSD. However, not all alcoholics develop a dilated cardiomyopathy and the reason for this is likely to be multifactorial. There is a genetic predisposition to alcohol cardiomyopathy. The DD genotype of the angiotensin converting enzyme (ACE) gene polymorphism increases the risk of developing cardiomyopathy by 16 times in those who consume excess alcohol.69
Peripartum cardiomyopathy
Peripartum cardiomyopathy (PPCM) is a rare but devastating complication of pregnancy, associated with heart failure, malignant arrhythmias, thromboembolism, and death. Until recently it was defined as heart failure due to LV systolic dysfunction occurring between the last month of pregnancy and five months postpartum in women with no pre-existing heart disease.70 However, a recent position statement by the working group on PPCM of the Heart Failure Association of the European Society of Cardiology proposed a more simplified definition with time constraints removed: ‘Peripartum cardiomyopathy is an idiopathic cardiomyopathy presenting with HF secondary to left ventricular (LV) systolic dysfunction towards the end of pregnancy or in the months following delivery, where no other cause of HF is found. It is a diagnosis of exclusion. The LV may not be dilated but the ejection fraction (EF) is nearly always reduced below 45%’.71
Relatively little is known about the incidence and prevalence of PPCM, and the pathogenesis is also poorly understood. Multiple causes have been proposed, including myocarditis, auto-immune disease, oxidative stress, and the uncovering of existing cardiac disease by the haemodynamic stresses of pregnancy. Although definitive evidence for a disease-specific culprit is lacking, there is considerable interest in the putative role of the shorter 16-kDa form of prolactin in the progression of PPCM.72
Presentation and diagnosis
The clinical presentation of PPCM is very variable, from exertional dyspnoea and peripheral oedema to cardiogenic shock. Cases that present in the prepartum period are typically delayed because symptoms of worsening dyspnoea and ankle oedema are frequently attributed to the pregnant state itself. Common complications of PPCM include malignant arrhythmias and mural thrombus formation, as well as both systemic and pulmonary thromboembolism.
The diagnosis of PPCM is currently one of exclusion70–71 that requires both the clinical confirmation of symptoms and signs of heart failure and objective evidence of LV systolic dysfunction. The electrocardiogram may be normal or display non-specific ST or T wave abnormalities and the chest radiograph may display cardiomegaly with varying degrees of pulmonary venous congestion. However, in some younger patients clinical and radiographic evidence of congestion may be absent whilst the pulmonary wedge pressure is high.
Prognosis and predictors of outcome
Studies of varying sizes and populations have reported mortality rates ranging from 0-30%,73–76 and full recovery in 23-66% in patients on contemporary therapy.74–77 Predictors of an adverse prognosis include increasing maternal age,73 higher parity,78 later onset of symptoms following delivery,78 non-caucasian,73, 79 and a delay in diagnosis.79 Various echocardiographic parameters have been associated with poorer outcome including reduced LVEF,76, 79 increased LVEDD,73, 78, 80 reduced fractional shortening,80 and presence of LV thrombus.73 More recently, NT-proBNP,77 Fas/APO-1,75 and troponin T (cTnT)81 have been shown to predict patients whose LV function subsequently fails to improve.
There are few data describing the outcome for subsequent pregnancies in PPCM, but there is a higher reported incidence of HF in those with previous PPCM compared to mothers with no previous history of PPCM. Varying incidences of recurrence of LV dysfunction and heart failure as well as mortality have been reported.81–83Therefore women with PPCM who previously presented with LV ejection fraction of 〈25%, or in whom LV function has not recovered completely, should be advised against future pregnancy.71
Treatment
The management of PPCM should reflect the clinical presentation. Patients should be managed in a specialist heart failure unit with multidisciplinary input from a team that includes a cardiologist, cardiac anaesthetist, obstetrician, and neonatologist. Emergency delivery of the baby should be an early aim when PPCM is diagnosed prenatally.71 Where possible, patients should be established on standard disease-modifying therapy, but advanced treatments including intra-aortic balloon pump, ventricular assist devices (as bridge to recovery, or bridge to transplantation) and transplantation are occasionally necessary.71
In Murine models of enhanced oxidative stress, the increased expression and activity of cathepsin-D led to an increase in the 16kDa fragment of prolactin. This possesses vasoconstrictor, anti-angiogenic, and pro-inflammatory apoptotic properties, and resulted in a dilated cardiomyopathy. However, mice treated with the prolactin antagonsist bromocriptine did not develop cardiomyopathy. Following this finding and the subsequent publication of numerous case reports of recovery of LV function following bromocriptine therapy,84,85 a small single-centre pilot-study has recently been published.86 PPCM patients randomised to receive bromocriptine had a higher incidence of recovery of LV function (p=0.012), a lower mortality, and a significant reduction in the composite end point of poor outcome (death, New York Heart Association functional class III/IV, or left ventricular ejection fraction 〈35% at 6 months) compared with the group on standard therapy (10% vs 80%; p=0.006). The size of this study prevents robust and definitive conclusions about the benefits of bromocriptine therapy in PPCM, but larger studies are on-going.
Summary
HF is the common endpoint of a wide range of cardiovascular and noncardiovascular conditions. The list of potential causes continues to expand as our knowledge of the pathophysiology of HF increases. In Western societies, CHD and hypertension remain the commonest causes of HF. The prevalence of HF secondary to CHD has increased in recent years, due in part to improved survival following acute myocardial infarction. In addition to coronary disease and hypertension, valvular heart disease, arrhythmias and alcohol are other common causes of HF in developed countries. Peripartum cardiomyopathy should also be considered in women developing symptoms and signs of heart failure towards the end of pregnancy, or in the months following delivery.
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