The Cardiomyopathies: Hypertrophic, Dilated, Restrictive, and Right Ventricular

The cardiomyopathies: hypertrophic, dilated, restrictive, and right ventricular.

Topics covered:

  • Essentials
  • Introduction
  • Hypertrophic cardiomyopathy
  • Dilated cardiomyopathy
  • Restrictive cardiomyopathy
  • Arrhythmogenic right ventricular cardiomyopathy
  • Further reading

Essentials

The term cardiomyopathy is used to describe heart muscle disease unexplained by abnormal loading conditions (hypertension, valve disease, etc.), congenital cardiac abnormalities, and ischaemic heart disease. Cardiomyopathies associated with systemic diseases are described in the article about specific heart muscle disorders. This article describes the various forms of ‘idiopathic’ disease, although the discovery of more and more disease-causing mutations makes the term idiopathic increasingly redundant.

Hypertrophic cardiomyopathy

The diagnosis of hypertrophic cardiomyopathy is based upon the demonstration of unexplained myocardial hypertrophy, defined as a wall-thickness measurement exceeding two standard deviations above normal for gender and age. In practice, in an adult of normal size, the presence of a left ventricular myocardial segment of 1.5 cm or greater in thickness is diagnostic. Less stringent criteria should be applied to first-degree relatives of an unequivocally affected individual. Ninety per cent of patients have familial disease, usually with autosomal dominant inheritance. Mutations in genes encoding proteins of the cardiac sarcomere are most common (60% of cases).

Symptomatic presentation may be at any age, with breathlessness on exertion, chest pain, palpitation, syncope, or sudden death. In children and adolescents, the diagnosis is most often made during screening of siblings and offspring of affected family members. In most patients the physical examination is unremarkable, but characteristic features include a rapid upstroke arterial pulse, a forceful left ventricular cardiac impulse with palpable atrial beat, an ejection systolic murmur, and a fourth heart sound.

Investigation and diagnosis—the 12-lead ECG is the most sensitive diagnostic test, with ST-segment depression and T-wave changes being the most common abnormalities, usually associated with voltage changes of left ventricular hypertrophy and/or deep S waves in the anterior chest leads V1 to V3. Echocardiography reveals left ventricular hypertrophy that may be symmetric or asymmetric and localized to the septum or the free wall, but most commonly to both the septum and free wall with relative sparing of the posterior wall.

Management—β-adrenoceptor blockers and calcium antagonists, especially verapamil, are the mainstay of symptomatic pharmacological therapy. Surgery is considered for patients with obstruction (typically resting left ventricular outflow-tract gradient of more than 50 mmHg) and/or mitral valve abnormalities, with the commonest operation being removal of a segment of the upper anterior septum (myotomy/myectomy) via a transaortic approach. Injection of alcohol into the septal artery that supplies the ‘obstructing’ septal muscle has been developed as a percutaneous, nonpharmacological approach to gradient reduction.

Prognosis—annual mortality is 1 to 2%, but the risk of death and other disease-related complications varies between individuals. Prevention of sudden death relies on risk factor stratification to identify a high-risk cohort.

Dilated cardiomyopathy

Dilated cardiomyopathy is defined by dilatation and impaired systolic function of the left ventricle or both ventricles in the absence of coronary artery disease, valvular abnormalities, or pericardial disease. At least 25% of cases are familial, with a large number of disease-causing gene mutations described.

Initial presentation is usually with symptoms of cardiac failure, but other presentations include arrhythmia, systemic embolism, or the incidental finding of an electrocardiographic or radiographic abnormality. Physical examination may reveal cardiac enlargement and signs of congestive heart failure.

Investigation and diagnosis—on echocardiography, the presence of ventricular end-diastolic dimensions greater than two standard deviations above the mean and fractional shortening less than 25% are generally sufficient to make the diagnosis.

Management—symptomatic therapy involves the treatment of heart failure with diuretics, angiotensin converting enzyme (ACE) inhibitors, and β-blockers. Anticoagulation with warfarin is advised in patients in whom an intracardiac thrombus is identified echocardiographically, or those with a history of thromboembolism. Internal cardioverter defibrillators are warranted if sustained or symptomatic arrhythmias are documented during 24-h ECG monitoring or exercise testing. Biventricular or left ventricular pacing can improve symptoms and prognosis in selected patients, and cardiac transplantation may be appropriate for those with progressive deterioration.

Restrictive cardiomyopathy

Restrictive cardiomyopathies are defined by restrictive ventricular physiology in the presence of normal or reduced diastolic volumes of one or both ventricles, normal or reduced systolic volumes, and normal ventricular wall thickness. In the Western world, amyloidosis is the commonest cause; in the tropics, endomyocardial fibrosis.

Presentation is usually insidious: left-sided disease may present with symptoms of pulmonary congestion and/or mitral regurgitation; right-sided disease with raised jugular venous pressure, hepatomegaly, ascites, and tricuspid regurgitation. Echocardiography confirms the diagnosis, typically showing that ventricular dimensions and wall thickness are normal, but the atria are grossly enlarged.

Congestive symptoms from raised right atrial pressure can be improved with diuretics, though too great a reduction in ventricular filling pressure will lead to a reduction in cardiac output. Prognosis of advanced disease is poor.

Arrhythmogenic right ventricular cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy is a heart muscle disease characterized by progressive fibrofatty replacement of right ventricular myocardium, associated with ventricular arrhythmia, heart failure, and sudden cardiac death. It is inherited in at least 50% of cases.

Symptomatic presentation is usually with palpitation and/or syncope from sustained ventricular arrhythmia, but the first presentation of the disease may be with sudden cardiac death. There is no single diagnostic test, and the diagnosis is based on the presence of major and minor criteria encompassing structural, histological, electrocardiographic, arrhythmic, and genetic factors. The most common electrocardiographic abnormality is T-wave inversion in leads V1 to V3 in the absence of right bundle branch block. Typical echocardiographic findings include right ventricular dilatation, regional hypokinesia or dyskinesia, and other abnormalities.

Management—patients with symptomatic, non-life-threatening ventricular arrhythmias are treated empirically with β-blockers, amiodarone, or sotalol. Those with a history of sustained, haemodynamically compromising ventricular arrhythmia should be offered an implantable cardioverter–defibrillator.

Introduction

Heart muscle disease has traditionally been divided into idiopathic (cardiomyopathies) and secondary types (specific heart muscle diseases); the cardiomyopathies are classified further according to specific morphological and physiological characteristics into hypertrophic, dilated, right ventricular, and restrictive forms. This descriptive classification is useful when describing natural history, treatment, and prognosis, but the discovery of disease-causing mutations in all forms of cardiomyopathy means that the term ‘idiopathic heart muscle disease’ is increasingly redundant. For the purposes of this chapter, the term cardiomyopathy will be used to describe heart muscle disease unexplained by abnormal loading conditions (hypertension, valve disease, etc.), congenital cardiac abnormalities, and ischaemic heart disease. Heart muscle disease associated with systemic or extracardiac diseases are described in more detail in this article: Specific heart muscle disorders.

Hypertrophic cardiomyopathy

Definition

Hypertrophic cardiomyopathy (HCM) is defined clinically by the presence of increased myocardial thickness in the absence of loading conditions (hypertension, valve disease, etc.) sufficient to cause the observed degree of hypertrophy. Historically, ventricular thickening caused by systemic diseases such as amyloidosis and glycogen-storage disease has been excluded from the definition in order to separate conditions in which there is myocyte hypertrophy from those in which left ventricular mass and wall thickness are increased by interstitial infiltration or intracellular accumulation of metabolic substrates. In everyday clinical practice, however, it is frequently impossible to differentiate these two entities using noninvasive imaging, and hence metabolic and infiltrative disease should be considered in the differential diagnosis of hypertrophic cardiomyopathy.

Causes

Pedigree analysis reveals familial disease in 40 to 50% of patients, but when cardiovascular evaluation of first-degree relatives using electrocardiography and echocardiography is performed, 90% of patients have familial disease. In most cases, the inheritance is autosomal dominant.

Approximately 60% of patients with familial hypertrophic cardiomyopathy have mutations in genes encoding proteins of the cardiac sarcomere: specifically cardiac β-myosin heavy chain, cardiac myosin-binding protein C, essential and regulatory myosin light chain, α-tropomyosin, cardiac troponin T and I, cardiac actin, titin, and α-myosin. Most mutations involve a single base-pair change in exons encoding highly conserved regions that result in amino acid substitutions. De novo mutations occur, but appear to account for less than 10% of cases.

Variable expression and incomplete penetrance is common, even within families bearing the same gene defect, but some phenotypes do seem to associate with particular mutations. β-Myosin heavy chain mutations that are fully penetrant are associated with worse prognosis (such as Arg403Glu or Arg453Cys), while disease complications are uncommon in patients with mutations that cause mild or no clinical expression (such as Leu908Val). This contrasts with troponin T disease, which although associated with mild hypertrophy and few symptoms can still cause premature sudden death. Mutations in myosin-binding protein C cause 20 to 30% of disease; most are major deletions rather than single base-pair changes. Disease expression can occur later in life, sometimes associated with mild hypertension. Once disease expression occurs (abnormal ECG and/or echocardiogram), patients are at the same risk from symptoms and disease-related complications as patients with disease onset in early life. The expression of disease in patients with troponin I mutations is variable; such mutations may cause restrictive physiology in the absence of severe hypertrophy and may mimic restrictive cardiomyopathy.

Clinical presentation with left ventricular hypertrophy under the age of 3 years is usually caused by metabolic or mitochondrial disorders (Table 1) and is uncommon in autosomal dominant hypertrophic cardiomyopathy.

Table 1 Causes of left ventricular hypertrophy at age 3 years or less
Metabolic* Pompe’s disease (GSD II)
Forbes’ disease (GSD III)
Total lipodystrophy
Hurler’s syndrome
Infant of a diabetic mother
Hypertrophic cardiomyopathy with associated syndromes Noonan’s syndrome
LEOPARD syndrome
Friedreich’s ataxia
Beckwith–Wiedemann syndrome
Mitochondrial myopathy
MELAS
MERFF
NADH–coenzyme Q reductase deficiency
Cytochrome b deficiency
Miscellaneous causes Hypertension
In utero ritodrine HCl exposure
Swyer’s syndrome (46, XY pure gonadal dysgenesis)

* The main metabolic causes of left ventricular hypertrophy.

GSD, glycogen storage disorder; MELAS, myopathy, encephalopathy, lactic acidosis, stroke-like episodes; MERFF, myoclonic epilepsy and ragged red fibres.

Pathology

Hypertrophic cardiomyopathy may involve the left or both ventricles. Hypertrophy in the left ventricle is usually asymmetric, involving the anterior and posterior septum and the free wall to a greater extent than the posterior wall. Right ventricular hypertrophy, which is usually symmetric, is seen in up to 30% of patients; isolated right ventricular hypertrophy (in the absence of pulmonary hypertension or right ventricular outflow obstruction) has not been reported. Many patients have structural abnormalities of the mitral valve, including increased leaflet area and length, and malposition or anomalous insertion of the papillary muscles. A common macroscopic finding is a patch of endocardial thickening just below the aortic valve, which results from contact of the septum with the anterior mitral leaflet in patients with dynamic left ventricular outflow-tract obstruction.

The histological findings in hypertrophic cardiomyopathy are distinctive and provide the basis for the pathological diagnosis. Affected myocardium shows interstitial fibrosis with gross disorganization of the muscle bundles resulting in a characteristic whorled pattern. The cell-to-cell orientation of muscle cells is lost (disarray) and there is disorganization of the myofibrillar architecture within cells. Myocardial cells are broad, short, and often bizarre in shape. Foci of disorganized cells are often interspersed among areas of hypertrophied muscle cells that are otherwise normal in appearance. Such changes are not completely specific: small amounts of myofibre disarray may be seen in congenitally abnormal hearts and in secondary left ventricular hypertrophy; disarray is also present at the junction of the septum with the anterior and posterior walls of the left ventricle in normal subjects. However, the extent of myocyte disarray in normal subjects rarely exceeds 5%, while in hypertrophic cardiomyopathy up to 40% of the myocardium may be involved. As well as contributing to diastolic and systolic dysfunction, the disorganized myocardial architecture provides a substrate for electrical instability.

Pathophysiology

Diastolic dysfunction

Diastolic abnormalities caused by myocardial hypertrophy, myocardial ischaemia, myocyte disarray, and fibrosis are common but variable in severity. Typically, left ventricular end-diastolic pressure and atrial pressures are elevated as a consequence of abnormal left ventricular diastolic filling and reduced compliance. The isovolumic relaxation time is prolonged, left ventricular filling is slow, and the proportion of filling volume that results from atrial systolic contraction (while still preserved) may be increased. Occasionally, there is rapid early filling with restrictive physiology similar to that seen in constrictive pericarditis or endocardial fibrosis (see: Pericardial diseases).

Systolic function and dynamic outflow-tract obstruction

Most patients with hypertrophic cardiomyopathy have rapid and near-complete ventricular emptying resulting in an increase in measured ejection fraction. ‘Endstage’ hypertrophic cardiomyopathy—characterized by severe impairment of contractile performance, restrictive left ventricular physiology, and heart-failure symptoms—can develop at any age including childhood and adolescence, but, in most, the time from onset of symptoms to diagnosis of severe systolic impairment is long (a mean of 14 years).

Approximately 30% of patients have a gradient between the body and outflow tract of the left ventricle at rest; an additional 20 to 25% develop such a gradient following manoeuvres that increase myocardial contractility or that reduce ventricular afterload or venous return. The presence and magnitude of a gradient is determined by left ventricular outflow-tract size and geometry, which are in turn a function of the severity of septal hypertrophy, mitral leaflet morphology, and papillary muscle size and position. The conventionally accepted mechanism of the gradient is that Venturi forces from increased ejection velocity in the narrowed outflow tract draw the anterior and/or posterior mitral leaflets towards the septum. More recent data suggest that the abnormally positioned mitral valve leaflets are ‘driven’ into the septum.

Myocardial ischaemia

Patients with hypertrophic cardiomyopathy have reduced coronary flow reserve and evidence for myocardial ischaemia during rapid atrial pacing and pharmacological stress. Myocardial ischaemia is almost certainly a major cause of exertional symptoms and may be a trigger for ventricular arrhythmia. However, detection of ischaemia in everyday clinical practice is challenging because conventional markers of ischaemia such as ST-segment change and reversible perfusion abnormalities on single photon emission computed tomography (SPECT) imaging correlate poorly with more objective biochemical markers of ischaemia.

Diagnosis

Left ventricular hypertrophy in the absence of moderate to severe hypertension and valve disease occurs in about 1 in 500 adults. The population frequency of unexplained left ventricular hypertrophy in children is unknown, but the annual incidence of left ventricular hypertrophy ranges between 0·3 and 0·5 per 100 000. The diagnosis of hypertrophic cardiomyopathy is based upon the demonstration of unexplained myocardial hypertrophy, defined as a wall-thickness measurement exceeding two standard deviations for gender and age. In practice, in an adult of normal size the presence of a left ventricular myocardial segment of 1.5 cm or greater in thickness is diagnostic. Less stringent criteria should be applied to first-degree relatives of an unequivocally affected individual, where the probability of carrying the disease gene is 1 in 2 (Table 2).

Table 2 Major and minor criteria for the diagnosis of hypertrophic cardiomyopathy in adult members of affected families. Criteria are fulfilled if (1) one major echocardiographic, or (2) two minor echocardiographic, or (3) one minor echocardiographic plus two minor electrocardiographic abnormalities are seen
Major criteria Minor criteria
Echocardiography
Left ventricular wall thickness ≥13 mm in the anterior septum or posterior wall or ≥15 mm in the posterior septum or free wall Left ventricular wall thickness of 12 mm in the anterior septum or posterior wall or of 14 mm in the posterior septum or free wall
Severe SAM (septal–leaflet contact) Moderate SAM (no septal–leaflet contact)
Redundant mitral valve leaflets
Electrocardiography
Left ventricular hypertrophy + repolarization changes (Romhilt and Estes) Complete bundle branch block or (minor) interventricular conduction defect (in LV leads)
T-wave inversion in leads I and aVL (≥3 mm) (with QRS–T-wave axis difference ≥30°), V3–V6 (≥3 mm) or II and III and aVF (≥5 mm) Minor repolarization changes in LV leads
Abnormal Q (>40 ms or >25% R wave) in at least two leads from II, III, aVF (in absence of left anterior hemiblock), V1–V4; or I, aVL, V5–V6. Deep S in V2 (>25 mm)
Clinical
There are no clinical major criteria Unexplained chest pain, dyspnoea, or syncope

LV, left ventricular; SAM, systolic anterior motion of the mitral valve.

Reproduced from Heart, McKenna WJ et al, 77:130–2. 

Problems in diagnosis often arise in patients with moderate to severe hypertension. The determinants of the hypertrophic response in a patient with hypertension are unknown, but are partly influenced by racial origin, with a greater increase in left ventricular mass in African-Caribbean individuals. In general, however, hypertrophic cardiomyopathy should be suspected in any individual with hypertension and a wall thickness in excess of 1.5 cm, particularly if the ECG shows widespread repolarization abnormalities and there is evidence of good blood pressure control.

The physiological changes of athletic training can rarely mimic hypertrophic cardiomyopathy. Athletes who participate in events that combine both isometric and isotonic activities (e.g. rowing and cycling) have the greatest increases in left ventricular wall thickness. Pure strength training is associated with an increase in left ventricular mass and wall thickness relative to the left ventricular cavity size, but is rarely associated with an increase in absolute wall thickness (unless the athlete also uses anabolic steroids). A diagnosis of hypertrophic cardiomyopathy in an elite athlete is likely when left ventricular wall thickness exceeds 1.6 cm in males and 1.4 cm in females and when they are symptomatic or have a family history of hypertrophic cardiomyopathy and premature sudden death. In athletes, the ECG frequently displays voltage criteria for left ventricular hypertrophy, sinus bradycardia, and sinus arrhythmia. Marked repolarization abnormalities are rare in elite athletes and should always raise suspicion of myocardial disease. Echocardiographic features favouring hypertrophic cardiomyopathy include small left ventricular cavity dimensions, left atrial enlargement, left ventricular outflow gradients, and diastolic impairment.

Clinical features

History

Symptomatic presentation may be at any age with breathlessness on exertion, chest pain, palpitation, syncope, or sudden death. Hypertrophic cardiomyopathy is occasionally found at autopsy in a stillborn baby or presents during infancy with cardiac failure, which is usually fatal. In children and adolescents, the diagnosis is most often made during screening of siblings and offspring of affected family members. Paroxysmal symptoms or mild impairment of exercise tolerance are often present, but in the absence of a murmur may not prompt cardiac evaluation.

About 50% of adults present with symptoms; in the remainder the diagnosis is made during family screening or following the detection of an unsuspected abnormality on physical, electrocardiographic, or echocardiographic examination. Dyspnoea is common (>50%) as a consequence of elevated left atrial and pulmonary capillary wedge pressures resulting from impaired left ventricular relaxation and filling, and about 50% complain of chest pain, which is exertional, atypical, or both in similar proportions of patients. Atypical pain may have no obvious precipitant; more commonly it follows exercise- or anxiety-related tachycardia, when it persists for up to several hours after the stress has been removed without enzymatic evidence of myocardial damage. Syncopal episodes occur in 15 to 25%, but in only a few are there findings suggestive of an arrhythmia or evidence of overt conduction disease: in most patients, the mechanism cannot be determined. Patients rarely present with paroxysmal nocturnal dyspnoea, ascites, or peripheral oedema.

Physical examination

In most patients with hypertrophic cardiomyopathy the physical examination is unremarkable. There may be a rapid upstroke arterial pulse reflecting dynamic left ventricular emptying. In about one-third, the jugular venous pulse may demonstrate a prominent ‘a’ wave, reflecting diminished right ventricular compliance secondary to right ventricular hypertrophy. Many patients have a forceful left ventricular cardiac impulse, best appreciated on full-held expiration in the left lateral position, when there may be a palpable atrial beat reflecting forceful atrial systolic contraction that may or may not be associated with significant forward flow of blood.

The first and second heart sounds are usually normal, and—unless the patient is in atrial fibrillation—there is likely to be a loud fourth heart sound, reflecting increased atrial systolic flow into a non-compliant ventricle. However, in those patients (20–30%) who have a resting left ventricular outflow-tract gradient, the most obvious physical sign is an ejection systolic murmur. This murmur starts well after the first heart sound and ends well before the second. It is best heard at the left sternal border, radiating towards the aortic and mitral areas, but not into the neck or the axilla. The intensity varies with changes in ventricular volume; it can be increased by physiological and pharmacological manoeuvres that decrease afterload or venous return (amyl nitrate, standing, Valsalva, etc.), and decreased by manoeuvres that increase afterload and venous return (squatting, phenylephrine, etc.). Occasionally there is an ejection sound at the onset of the systolic murmur.

Most patients with a left ventricular gradient also have mitral regurgitation, which may be difficult to distinguish by auscultation. Doppler examination reveals that mitral regurgitation usually begins just before (30–40 ms) the onset of the gradient and continues for the duration of systole. Radiation of the systolic murmur to the axilla is often the best auscultatory clue to the presence of coexistent mitral regurgitation, which may be moderate to severe, either alone or in association with a left ventricular outflow-tract gradient. A mid-diastolic rumble may sometimes result from increased transmitral flow in patients with severe mitral regurgitation.

Early diastolic murmurs of aortic incompetence may develop following surgical myotomy/myectomy or infective endocarditis involving the aortic valve. Although such murmurs are rare in the absence of such complications, they appear to occur more commonly than would be expected by chance and may reflect traction on the non-coronary cusp of the aortic valve by the septum. An ejection systolic murmur in the pulmonary area, reflecting right ventricular outflow-tract obstruction, is also rare; when present, it is usually associated with severe biventricular hypertrophy in the young or in those with coexistent Noonan’s syndrome and a dysplastic pulmonary valve (see: Congenital heart disease in adults).

Prognosis

Patients with hypertrophic cardiomyopathy experience slow progression of symptoms and gradual deterioration of left ventricular function, and are at risk of sudden cardiac death throughout life. Annual mortality rates are in the range of 1 to 2%, but the risk of death and other disease-related complications varies between individuals and within individuals during the course of the disease.

Severe heart failure symptoms may develop in association with progressive myocardial wall thinning caused by myocardial fibrosis and severe reduction in left ventricular systolic performance and/or diastolic filling. Patients who experience such deterioration occasionally present with a clinical picture resembling restrictive cardiomyopathy, with grossly enlarged atria, signs of right heart failure, and relative preservation of left ventricular systolic performance. The development of systolic failure is associated with a poor prognosis, with rapid progression from onset to death or transplantation, and an overall mortality rate of up to 11% per year.

Atrial dilatation and the development of atrial fibrillation/flutter are important features in the clinical course, leading to a risk of embolic stroke as well as of acute or chronic cardiac deterioration. Early onset of atrial fibrillation was considered to be an ominous development, but is part of the evolution of patients with diastolic dysfunction, and with appropriate management need not represent a major cause of morbidity or mortality.

Left ventricular hypertrophy develops during childhood and adolescence, but is not progressive in adults. The trigger and other determinants of disease expression in late-onset disease are uncertain.

Investigations

Cardiological evaluation of patients with hypertrophic cardiomyopathy is performed to confirm the diagnosis, to guide symptomatic therapy, and to assess the risk of complications, particularly that of sudden death.

Electrocardiography

The 12-lead ECG is the most sensitive diagnostic test, although occasionally normal (c.5%), particularly in the young. Five to ten per cent of patients are in atrial fibrillation at the time of diagnosis. Many have an intraventricular conduction delay and 20% have left-axis deviation, but complete right bundle or left bundle branch block is uncommon (c.5%). The latter may develop following surgery and is occasionally seen in elderly patients. ST-segment depression and T-wave changes are the most common abnormalities and are usually associated with voltage changes of left ventricular hypertrophy and/or deep S waves in the anterior chest leads V1 to V3. Isolated repolarization changes or giant negative T waves are occasionally seen. Voltage criteria for left ventricular hypertrophy are rare in the absence of repolarization changes. About 20% of patients have abnormal Q waves, either inferiorly (II, III, and aVF), or less commonly in leads V1 to V3. P-wave abnormalities of left and/or right atrial overload are common. The distribution of the PR interval is similar to that in the normal population, but occasionally a short PR interval may be associated with a slurred upstroke to the QRS complex, similar to that seen in the Wolff–Parkinson–White syndrome. At electrophysiological study, such changes are not usually associated with evidence of pre-excitation, although patients with hypertrophic cardiomyopathy and accessory pathways have been described. Despite the many electrocardiographic abnormalities, there is no ECG that is typical of hypertrophic cardiomyopathy; a useful rule is to consider the diagnosis whenever the ECG is bizarre, particularly in younger patients.

The incidence of arrhythmias during 48-h ambulatory electrocardiographic monitoring increases with age. Non-sustained ventricular tachycardia is detected in 20 to 25% of adults and, although usually asymptomatic, is associated with an increased risk of sudden death. Supraventricular arrhythmias are also common in adults: these are poorly tolerated if sustained (>30 s)—unless the ventricular response is controlled—and they carry an increased risk of thromboembolism. By contrast, most children and adolescents are in sinus rhythm, and arrhythmias during ambulatory electrocardiographic monitoring are uncommon. The increased incidence of supraventricular arrhythmias with age is not surprising: their development is related to increased left atrial dimensions and increased left ventricular diastolic pressure, both of which increase with age. The aetiology of ventricular arrhythmias is not known, but may relate to myocyte loss and myocardial fibrosis. Documented sustained ventricular tachycardia is uncommon, but is a recognized complication in patients with an apical out-pouching or aneurysm, which may develop as a consequence of midventricular obstruction.

Chest radiography

The chest radiograph may be normal or show evidence of left and/or right atrial or left ventricular enlargement; if left atrial pressure has been chronically elevated, there may be evidence of redistribution of blood flow to upper lung zones. Mitral valve annular calcification is seen, particularly in elderly patients.

Echocardiography

Left ventricular hypertrophy may be symmetric or asymmetric and localized to the septum or the free wall, but most commonly to both the septum and free wall with relative sparing of the posterior wall. Isolated apical hypertrophic cardiomyopathy appears to be common in Japan, but is rare in the West, although about 10% of patients have left ventricular hypertrophy that is maximal in the distal ventricle from the level of the papillary muscles down to the apex. Approximately one-third of patients also have hypertrophy of the right ventricular free wall, the presence and severity of which is strongly related to the severity of left ventricular hypertrophy. Typically, left ventricular end-systolic and end-diastolic dimensions are reduced, and the left atrial dimension is increased. Indices of systolic function such as ejection fraction may be increased, but systolic function is often impaired, which may be best appreciated by measurement of long-axis rather than short-axis function.

Colour Doppler provides a sensitive method of detecting left ventricular outflow-tract turbulence, and when combined with continuous-wave Doppler the peak velocity (Vmax) of left ventricular blood flow can be measured and left ventricular outflow-tract gradients calculated. Doppler gradients (pressure gradient (mmHg) = 4Vmax2) are seen in 20 to 30% of patients and correlate well with those measured invasively. Systolic anterior motion of the mitral valve is usually present when the calculated outflow tract gradient is more than 30 mmHg, and early closure or fluttering of the aortic valve leaflets is often seen in association with such motion. A posteriorly directed mitral regurgitant jet is seen in association with and related to the magnitude of the outflow-tract gradient. An anterior regurgitant jet or mitral regurgitation in the absence of obstruction suggests the coexistence of structural mitral valve abnormalities.

Other imaging techniques

Good-quality echocardiography suffices for diagnostic and therapeutic purposes in most patients with hypertrophic cardiomyopathy, but MRI is useful in selected cases to assess right ventricular, apical, and lateral left ventricular involvement. Gadolinium-enhanced cardiac MRI permits detection of myocardial fibrosis, the extent of which may predict evolution to the burnt-out phase and risk of sudden death.

Cardiac catheterization

Two-dimensional echo/Doppler evaluation has replaced invasive haemodynamic measurements and angiography as the method of assessing left ventricular structure and function in hypertrophic cardiomyopathy. Cardiac catheterization is not necessary for diagnosis and is rarely indicated unless symptoms are refractory and direct measurement of cardiac pressures is potentially informative, particularly in assessing the severity of mitral regurgitation. Coronary arteriography may be necessary to exclude coexistent coronary artery disease in older patients who have significant angina or ST-segment changes during exercise. The left coronary arteries are usually large in calibre. The left anterior descending and septal perforator arteries may demonstrate narrowing during systole in the absence of fixed obstructive lesions, but such changes do not appear to relate to symptoms. Left ventricular angiography is rarely indicated, but recognition of the abnormally shaped ventricle, which typically ejects at least 75% of its contents in association with mild mitral regurgitation, may provide a valuable diagnostic clue when hypertrophic cardiomyopathy was not suspected before catheterization.

Exercise testing

Maximal exercise testing in association with respiratory gas analysis provides useful functional and prognostic information, which can be monitored serially. Oxygen consumption at peak exercise (peak VO2) is usually moderately reduced, even in patients who claim their exercise tolerance is not limited. Continuous measurement of the blood pressure during upright treadmill or bicycle exercise reveals that about one-third of younger patients (<40 years) have an abnormal blood pressure response, with either a drop of more than 10 mmHg from peak recordings or a failure to rise by 20 mmHg or more despite an appropriate increase in cardiac output. Such changes are usually asymptomatic but are associated with an increased risk of sudden death. The mechanism of the hypotensive response during exercise in hypertrophic cardiomyopathy is uncertain, but may relate to myocardial mechanoreceptor activation and altered baroreflex control causing inappropriate drops in systemic vasculature resistance and to a poor cardiac output response. ST-segment depression of 2 mm from baseline is documented in 25% of patients, but appears not to be of prognostic significance.

Electrophysiological studies

Electrophysiological studies may occasionally be necessary in patients with sustained, rapid palpitation to identify associated accessory pathways or aid management of sustained monomorphic ventricular tachycardia. Conventional, programmed ventricular stimulation does not aid the identification of high-risk patients (see below).

Tests for specific causes of hypertrophic cardiomyopathy

A number of clinical features that suggest particular causes of hypertrophic cardiomyopathy are listed in Table 3; the presence of such clues should trigger appropriate biochemical and genetic testing.

Table 3 Clinical features suggesting the aetiology of HCM
Clinical feature Examples
Symptoms
  • Acroparaesthesiae, tinnitus, deafness (Anderson–Fabry disease).
  • Skeletal muscle weakness (desminopathy, mitochondrial cytopathy, etc.)
Physical examination
  • Retinitis pigmentosa (mitochondrial, Danon disease, etc.)
  • Postural hypotension (amyloid)
  • Angiokeratoma (Anderson–Fabry disease)
  • Lentigines (LEOPARD syndrome)
  • Facial morphology (Noonan, Anderson–Fabry disease, etc.)
Electrocardiogram
  • Pre-excitation/premature conduction disease (AMP kinase)
  • Low-voltage/infarct pattern (amyloid)
Echocardiography
  • Concentric/biventricular hypertrophy (infiltrative, metabolic disease, etc.)
  • Valve thickening (Anderson–Fabry disease, amyloid, etc.)
Family history
  • X-linked inheritance (Anderson–Fabry disease, Danon, etc.)
  • Diabetes, epilepsy, and deafness (mitochondrial)
Biochemistry
  • Creatine kinase (Glycogen storage disease, mitochondrial, etc.)
  • Lactate (mitochondrial)
  • Renal dysfunction (Anderson–Fabry disease, mitochondrial, etc.)
  • Paraproteinaemia (amyloid)
Exercise testing Severe premature acidosis (mitochondrial)

Management

Screening and follow-up of asymptomatic patients

It is now possible to offer relatively rapid genetic testing to individuals with unequivocal disease. If a disease-causing mutation is identified, relatives can be offered predictive testing, but this should only be performed after appropriate genetic counselling.

In children and adolescents with a sarcomeric protein-gene mutation, ECG and echocardiographic manifestations of myocardial hypertrophy often develop during or following growth spurts. For this reason, young people should be assessed annually during adolescence. In adults, de novo development of unexplained left ventricular hypertrophy is less common, but does occur, particularly in patients with myosin-binding protein C gene mutations. Asymptomatic normal adults with a family history of hypertrophic cardiomyopathy but no identifiable mutation should be offered rescreening every 5 years, or sooner should they develop symptoms.

Pharmacological

The goal of therapy is to improve symptoms and prevent complications, in particular sudden death. β-Adrenoceptor blockers, particularly propanolol, and calcium antagonists, especially verapamil, are the mainstay of symptomatic pharmacological therapy. Both drugs have several potentially beneficial actions, including a decrease in myocardial oxygen consumption and blunting of the heart rate response during exercise, thereby increasing time for filling. Both agents exert a negative inotropic effect, thereby reducing hyperdynamic systolic function and left ventricular gradients, and they may improve diastolic function, verapamil by improving relaxation and β-blockers by increasing compliance. The side effects of propranolol are rarely serious, but the suppressant effect of verapamil on atrioventricular nodal conduction may cause problems in patients with unsuspected pre-existing conduction disease, and its vasodilatory and negative inotropic effects can result in acute pulmonary oedema and death in very symptomatic patients with severe obstruction and pulmonary hypertension.

Endocarditis is a rare complication of hypertrophic cardiomyopathy, occurring predominantly in patients with left ventricular outflow tract turbulence and/or mitral regurgitation. Antibiotic prophylaxis should be recommended in any patient with an outflow tract gradient or intrinsic valve disease.

Surgical

Surgery is a therapeutic option in patients with obstruction and/or mitral valve abnormalities. The conventional indication for surgery has been a resting left ventricular outflow tract gradient of more than 50 mmHg in patients refractory to medical therapy, and the commonest operation has been to remove a segment of the upper anterior septum (myotomy/myectomy) via a transaortic approach. Transventricular approaches have been used, but these are associated with a higher incidence of late complications, particularly of cardiac failure. Mitral valve repair and papillary muscle remodelling may be required, and mitral valve replacement has also been advocated; excellent results have been achieved, particularly in elderly patients with severe mitral regurgitation. Specialist hypertrophic cardiomyopathy centres report perioperative mortality of 1% or less, with 90% success in abolishing gradients and improving symptoms.

Alcohol septal ablation

Injection of alcohol into the septal artery that supplies the ‘obstructing’ septal muscle has been developed as a percutaneous, nonpharmacological approach to gradient reduction. Most experienced centres have reported symptomatic improvement in 70% of patients. As for surgery and dual-chamber (DDD) pacing (see below), patient selection—in particular, regarding the mechanism of the gradient—and technical considerations are important determinants of outcome. The major complication has been the need for a pacemaker in up to 30%, and concerns remain about long-term left ventricular function and arrhythmia risk. At present, alcohol septal ablation offers a therapeutic option in older patients with suitable anatomy who are refractory to drugs.

Pacing

Alteration of the ventricular activation sequence by pacing the right ventricular apex may result in reduction of gradients and filling pressures and improved symptoms in selected patients. The role of atrioventricular synchronous pacing (DDD pacing) in symptomatic management of obstruction has been evaluated in two randomized multicentre trials, demonstrating symptomatic improvement and gradient reduction (50%), but no change in exercise capacity. However, the placebo effect of the procedure was considerable: 40% reported significant symptomatic improvement with the pacemaker programmed to a standby mode. Nevertheless, pacing offers a therapeutic option in patients with obstruction that is refractory to drug treatment, and in whom surgery is either not acceptable or inappropriate. It appears that elderly patients with localized septal hypertrophy and without significant free wall involvement or mitral regurgitation may do particularly well.

Clinical approach to individual symptoms

Dyspnoea

Dyspnoea most often occurs in patients who also experience chest pain or discomfort. Treatment depends on the predominant mechanism. In patients with dyspnoea who have slow filling that continues throughout diastole, β-blockers and verapamil are appropriate. Conversely, those with rapid, early filling may benefit from a relative tachycardia and do better without negative chronotrophic agents. When dyspnoea is associated with significant obstruction—meaning at least 50% of stroke volume remaining in the left ventricle at the onset of the gradient—β-blockers, disopyramide, and (failing these) myotomy/myectomy or the other nonpharmacological options may be beneficial. Disopyramide should be used in the maximum tolerated dose (anticholinergic side effects may limit higher doses) in conjunction with a conventional β-blocker. Occasionally, dyspnoea is associated with severe mitral regurgitation and responds well to mitral valve replacement.

Chest pain

Exertional chest pain usually responds to therapy with propranolol or verapamil, and when refractory can respond to very high doses of these agents (propranolol at 480 mg daily, verapamil at 720 mg daily). Short-acting nitrates, diuretics, and high-dose verapamil may be useful in selected patients, perhaps by reducing filling pressures and improving coronary flow to subendocardial layers. Atypical chest pain may persist long after the initial stimulus has been removed.

Arrhythmia

Arrhythmias are a common complication of hypertrophic cardiomyopathy. Treatment with anticoagulants and verapamil or β-blockers is appropriate once atrial fibrillation is established, the aims being to control the ventricular response and prevent emboli. Most patients who develop atrial fibrillation during electrocardiographic monitoring are unaware of changes from sinus rhythm to atrial fibrillation as long as the ventricular response is well controlled. However, in a few cases the loss of atrial systolic contribution to filling volume is important, when electrical cardioversion can be facilitated by prior therapy (4–6 weeks) with amiodarone (300 mg daily) if pharmacological cardioversion does not occur first.

Sustained (>30 s) episodes of paroxysmal atrial fibrillation or supraventricular tachycardia can cause haemodynamic collapse and systemic emboli. Low-dose amiodarone (1000–1400 mg weekly) is effective in suppressing such episodes and also provides control of the ventricular response should breakthrough occur. If episodes persist, the threshold for anticoagulation should be low as embolic complications are common, even when atrial dimensions are only moderately increased.

Nonsustained episodes of supraventricular arrhythmia are common, and although often asymptomatic they are a marker (albeit of low positive predictive accuracy) for the subsequent development of established atrial fibrillation. The threshold to introduce amiodarone, with or without anticoagulation, should be low if they occur in the presence of atrial enlargement. Episodes of nonsustained ventricular tachycardia are common but are rarely symptomatic: therapy is warranted only if it can be shown to improve prognosis (see below).

Prevention of sudden death

Sudden death is a consequence of multiple interacting mechanisms. The histological abnormalities—particularly myocyte disarray, small vessel disease, and replacement scarring—contribute to the underlying substrate. Events may be triggered by haemodynamic alterations, myocardial ischaemia, and arrhythmias, including ventricular tachycardia, atrial fibrillation, atrioventricular block, and rapid conduction of a supraventricular arrhythmia via an accessory pathway. Intense physical exertion may also contribute to the above triggers. The interaction of triggers and substrate may be modified by inappropriate peripheral vascular responses and the development of myocardial ischaemia.

Risk stratification

Prevention of sudden death relies on risk factor stratification to identify a high-risk cohort. Several adverse features that can be elicited from the clinical history and noninvasive evaluation have been identified (Bullet list 1). Their relative importance varies with age; for example, the finding of nonsustained ventricular tachycardia on 24-h electrocardiographic monitoring in children and adolescents is uncommon (<5%), but is associated with an eightfold increased risk of sudden death, whereas in adults this arrhythmia is common (20–25%), but in isolation confers only a twofold increased risk.

Bullet list 1 Risk factors for sudden death

  • ◆ Family history of sudden death (≥2 premature (<40 years) sudden deaths)
  • ◆ Unexplained syncope within previous year
  • ◆ Abnormal exercise blood pressure
  • ◆ Nonsustained ventricular tachycardia (≥3 beats at ≥120 beats/min)
  • ◆ Severe left ventricular hypertrophy (>3 cm)
  • ◆ Severe left ventricular outflow tract obstruction (>90 mmHg)
  • ◆ Cardiac arrest (or sustained ventricular tachycardia)

In young people (<25 years) the finding of nonsustained ventricular tachycardia, severe and extensive left ventricular hypertrophy, unexplained syncope (particularly if recurrent or exertional), or a family history where a high proportion of affected individuals experienced premature (<40 years) sudden death warrants prophylactic treatment. Such patients usually also exhibit abnormal blood pressure responses to exercise; indeed, the finding of a normal exercise blood pressure response appears to identify the low-risk younger (<40 years) patient (negative predictive accuracy 97%), allowing appropriate reassurance that is also clinically important. In adults aged 25 to 60 years, the positive predictive accuracy for each of the risk factors is much lower (15–20%): in general, prophylactic treatment is reserved for those with two or more risk factors who will have a predicted risk of sudden death of at least 3% per year.

It is important to consider risk in all patients, even those who are asymptomatic or who have mild echocardiographic features of hypertrophic cardiomyopathy. Although children and adolescents with severe congestive symptoms may be at greater risk, the data reveals that the severity of chest pain, dyspnoea, and exercise limitation are not reliable predictors of the risk of sudden death in adults. In addition, it is recognized that most patients who die suddenly have mild (1.5–2.0 cm) or moderate (2.0–2.5 cm) left ventricular hypertrophy, while some genetic defects (e.g. cardiac troponin T) may cause sudden death in the absence of symptoms or hypertrophy.

The presence of a left ventricular outflow tract gradient is also associated with sudden death. The management of symptomatic patients should be focused on gradient reduction; in asymptomatic patients, severe left ventricular outflow tract obstruction should be considered in the overall risk profile of the patient. Diastolic impairment with abnormal Doppler filling patterns and atrial enlargement is associated with symptomatic limitation and poor prognosis, but not with premature sudden death.

Some investigators have suggested that the induction of sustained ventricular arrhythmias during programmed electrophysiological stimulation is associated with a higher risk of sudden death. However, the predictive accuracy is low, and as most high-risk patients can be identified using noninvasive clinical markers, the inherent risks and inconvenience associated with programmed stimulation dictate that it should not be used routinely to assess risk in hypertrophic cardiomyopathy.

Dilated cardiomyopathy

Definition

Dilated cardiomyopathy is a heart muscle disorder defined by dilatation and impaired systolic function of the left ventricle or both ventricles in the absence of coronary artery disease, valvular abnormalities, or pericardial disease. A number of different cardiac and systemic diseases are associated with left ventricular dilatation and impaired contractility (see Chapter 16.7.3). When no identifiable cause is found, the condition is referred to as idiopathic dilated cardiomyopathy.

Dilated cardiomyopathy has been described in Western, African, and Asian populations, affecting both genders and all ages. In North America and Europe, symptomatic dilated cardiomyopathy has an incidence and prevalence of 20 and 38 per 100 000, respectively, and is the commonest indication for cardiac transplantation.

Causes

Pedigree analysis reveals familial disease in at least 25% of cases; a further 10 to 20% of relatives have mild abnormalities of left ventricular performance that evolve into dilated cardiomyopathy in about one-third. Inheritance is usually autosomal dominant with incomplete penetrance, with a smaller number of families having X-linked transmission. Penetrance is age dependent and has been estimated to be 10% in those aged less than 20 years, 34% in young adults aged 20 to 30 years, 60% in adults aged 30 to 40 years, and 90% in those over 40 years. Guidelines for the diagnosis of familial disease based on the identification of major and minor criteria are shown in Bullet list 2. The diagnosis of familial dilated cardiomyopathy is fulfilled in a first-degree relative of a proband in the presence of one major criterion, or left ventricular dilatation plus one minor criterion, or three minor criteria.

Bullet list 2 Major and minor criteria for the diagnosis of familial dilated cardiomyopathy in adult members of affected families (see text for details)

Major criteria
  • ◆ A reduced ejection fraction of the left ventricle (<45%) and/or fractional shortening (<25%) as assessed by echocardiography, radionuclide scanning, or angiography
  • ◆ An increased left ventricular end-diastolic diameter corresponding to >117% of the predicted value corrected for age and body surface area
Minor criteria
  • ◆ Unexplained supraventricular or ventricular arrhythmia
  • ◆ Ventricular dilatation (>112% of the predicted value)
  • ◆ An intermediate impairment of left ventricular dysfunction
  • ◆ Conduction defects
  • ◆ Segmental wall motion abnormalities in the absence of intraventricular conduction defect or ischaemic heart disease
  • ◆ Unexplained sudden death of a first-degree relative or stroke before 50 years of age

Disease-causing mutations are reported in numerous genes including dystrophin, taffazin (Barth’s syndrome), metavinculin, cardiac actin (autosomal dominant), lamin A/C (associated with premature conduction disease), desmin, myosin-binding protein C, troponin T and C, β-myosin heavy chain, and Z-line associated protein (ZASP). Lamin A/C mutations also cause Emery–Dreifuss and limb-girdle muscular dystrophy and familial partial lipodystrophy; desmin may cause conduction disease with restrictive cardiomyopathy; dystrophin mutations cause childhood (Duchenne) and adult (Becker) forms of muscular dystrophy.

Different patterns of disease expression are recognized. Disease progression appears to be slow (over decades) in most cases, and conduction disturbance is a late complication related to disease severity. However, in some families (<20%), particularly those with mutations in the lamin A/C gene, the early stages are characterized by progressive conduction disease, and left ventricular dilatation and impairment are later manifestations, in the 4th to 6th decade. Families are also recognized in whom dilated cardiomyopathy develops in later decades in individuals who have had sensorineural hearing loss since childhood, or in association with skeletal myopathy (dystrophin gene mutations).

Pathology and pathophysiology

Macroscopic examination of hearts with dilated cardiomyopathy reveals dilated cardiac chambers, mural thrombi, and platelet aggregates with normal extra- and intramural coronary arteries. Myocardial mass is increased, but ventricular wall thickness is normal or reduced. Histology is nonspecific with patchy perimyocyte and interstitial fibrosis, various stages of myocyte death, as well as myocyte hypertrophy and often extensive myofibrillary loss, resulting in a vacuolated appearance of the myocytes. An interstitial T-lymphocyte infiltrate and focal accumulations of macrophages associated with individual myocyte death are common.

The identification of disease-causing mutations in genes encoding various components of the cardiac myocyte cystoskeletal and sarcomeric contractile apparatus shows that the pathogenesis of dilated cardiomyopathy is heterogeneous. Two models have been proposed to explain ventricular remodelling in dilated cardiomyopathy. In the ‘final common pathway’ hypothesis, dilated cardiomyopathy reflects a nonspecific degenerative state, which may result from a variety of stimuli, including genetic mutations, viral infections, toxins, and volume overload. The alternative hypothesis suggests that a number of distinct, independent, pathways can remodel the heart and cause dilated cardiomyopathy—in other words, the different causes of dilated cardiomyopathy share a common histopathology, but their molecular biology is distinct. The final common pathways resulting in dilated cardiomyopathy remain speculative, but may include altered myocyte energetics and calcium handling.

Clinical features

History

Initial presentation is usually with symptoms of cardiac failure (fatigue, breathlessness, decreased exercise tolerance, etc.), but arrhythmia (atrial fibrillation, ventricular tachycardia, atrioventricular block, etc.), systemic embolism, or the incidental finding of an electrocardiographic or radiographic abnormality during routine screening may prompt earlier diagnosis.

Physical examination

Physical examination may be entirely normal or may reveal evidence of myocardial dysfunction with cardiac enlargement and signs of congestive heart failure. Systolic blood pressure is usually low, with a narrow pulse pressure and a low-volume arterial pulse. Pulsus alternans may be present in patients with severe left ventricular failure, and the jugular veins may be distended, with a prominent V wave reflecting tricuspid regurgitation. In such patients, the liver is often engorged and pulsatile, and there is usually peripheral oedema and ascites. The precordium often reveals a diffuse and dyskinetic left (and occasionally right) ventricular impulse. The apex is usually displaced laterally, reflecting ventricular dilatation. The second heart sound is usually normally split, but paradoxical splitting may be present when there is left bundle branch block, which occurs is about 15% of patients. With severe disease and the development of pulmonary hypertension, the pulmonary component of the second heart sound may be accentuated. Characteristically, a presystolic gallop or fourth heart sound is present before the development of overt cardiac failure. However, once cardiac decompensation has occurred, ventricular gallop or third heart sound is often present. When there is significant ventricular dilatation, systolic murmurs are common, reflecting mitral and (less commonly) tricuspid regurgitation.

The development of unexplained cardiac failure within the last month of pregnancy or 5 months postpartum is termed peripartum cardiomyopathy. There is usually uncertainty whether the cardiac failure is acute (e.g. potentially myocarditic) or chronic and exacerbated by the haemodynamic stress of pregnancy and labour (e.g. dilated cardiomyopathy). When the heart failure is acute and there is persistence of left ventricular chamber dilatation or impaired systolic performance, the diagnosis of peripartum cardiomyopathy can legitimately be made. The mechanism and true natural history is uncertain, though it is probable that the adverse prognostic effect of subsequent pregnancies is less important than the literature would suggest, particularly in those with only mild residual abnormalities of left ventricular structure and function. For further discussion of cardiac disease in pregnancy, see: Heart disease in pregnancy.

Prognosis

The prognosis of dilated cardiomyopathy is uncertain because the diagnosis is usually not made until clinical features, which are late manifestations of the disease, become obvious. Follow-up of asymptomatic first-degree relatives suggests that disease progression is insidious over decades. An upper respiratory tract infection or a salt or fluid load often precipitates clinical presentation. Symptoms develop when filling pressures rise or when stroke volume diminishes sufficiently to cause salt and water retention and oedema. Once clinical symptoms of impaired ventricular performance are apparent, prognosis is poor and related to the degree of left ventricular dilatation and impaired contractile performance. Data in adults and children in the 1970s and 1980s demonstrated 50% mortality from progressive heart failure or its complications in the 2 years following referral diagnosis. Survival has been substantially improved since then by early recognition of mild disease, and by modern management with angiotensin converting enzyme (ACE) inhibitors, β-blockade, aggressive treatment of arrhythmias, and cardiac transplantation. Estimated annual mortality is now 4%, predominantly from sudden death, even in those who improve or stabilize.

Arrhythmia

Atrial arrhythmias, particularly atrial fibrillation, are common and associated with the severity of symptoms, left ventricular dysfunction, and poor prognosis, but atrial fibrillation is not an independent predictor of disease progression or sudden death. Occasionally, however, persistent atrial tachycardia or atrial fibrillation may cause gradual deterioration in left ventricular function, resembling dilated cardiomyopathy (‘tachycardiomyopathy’): systolic function usually returns to normal with control of the arrhythmia.

Ventricular arrhythmias are also common and like supraventricular arrhythmias are markers of disease severity. Nonsustained ventricular tachycardia during ECG monitoring is seen in about 20% of asymptomatic or mildly symptomatic patients and in up to 70% of those who are severely symptomatic. The prognostic significance of this arrhythmia is controversial: its presence early in the course of disease, when left ventricular function is relatively preserved, is probably an independent marker of sudden death risk, whereas in general markers of haemodynamic severity (such as ejection fraction, left ventricular end-diastolic dimension, or filling pressures) are more predictive of disease-related mortality and sudden death. Sudden-death risk in patients with severe disease (New York Heart Association, NYHA class III or IV) increases approximately threefold when syncope is present.

Investigation

Electrocardiography

The electrocardiographic features of dilated cardiomyopathy are nonspecific and highly variable. Sinus tachycardia is common (particularly in children and infants); nonspecific ST-segment and T-wave changes may be seen, most commonly in the inferior and lateral leads; and pathological Q waves may be present in the septal leads in patients with extensive left ventricular fibrosis. Atrial enlargement is common, and in advanced disease may be associated with bundle branch block. All degrees of atrioventricular block may also be seen and should raise the possibility of mutations in the lamin A/C gene if associated with relatively mild impairment of left ventricular function, or when present in a young patient.

Chest radiography

The chest radiograph is usually abnormal in patients with dilated cardiomyopathy, except in a rare subset of patients with acute viral myocarditis associated with left ventricular systolic impairment and preserved cavity dimensions. An increased cardiothoracic ratio (>0.5) is typically seen, reflecting left ventricular and left atrial dilatation. Increased pulmonary vascular markings and pleural effusions may be present in patients with elevated left ventricular filling pressures.

Echocardiography

Echocardiography is used to identify the presence of left ventricular cavity dilatation and systolic impairment, which are the typical features of the condition. In general, the presence of ventricular end-diastolic dimensions more than two standard deviations above body surface area-corrected mean values and fractional shortening less than 25% are sufficient to make the diagnosis. Two-dimensional echocardiography is also used to determine whether intracavitary thrombus is present in the ventricles.

Colour flow Doppler may be used to determine the presence and quantify the severity of functional mitral (and/or tricuspid) regurgitation. Pulsed wave and continuous wave Doppler can be used to estimate pulmonary artery pressures. Patients with dilated cardiomyopathy usually have abnormalities of diastolic left ventricular function in addition to systolic impairment: these can be assessed using mitral inflow, pulmonary vein, and tissue Doppler parameters.

Cardiac biomarkers

The serum creatine kinase should be measured in all patients with dilated cardiomyopathy because this simple test may provide an important clue to the aetiology of the condition (e.g. muscular dystrophy, lamin A/C defect, etc.). Other cardiac biomarkers, e.g. troponin I and troponin T, may also be elevated in dilated cardiomyopathy, particularly in association with an inflammatory cause. Plasma natriuretic peptide levels are elevated in chronic heart failure and predict mortality.

Many of the systemic diseases that are associated with heart muscle disorders have typical clinical, immunological, and biochemical features (see: Specific heart muscle disorders), and in the absence of clinical clues to suggest a systemic disease an exhaustive ‘routine screen’ is probably not cost effective. There are, however, several potential reversible secondary causes of heart muscle disorder that may simulate dilated cardiomyopathy, and basic screening tests should include serum phosphorus (hypophosphataemia), serum calcium (hypocalcaemia), serum creatinine and urea (uraemia), thyroid function tests (hypothyroidism), and serum iron/ferritin (haemochromatosis).

Exercise testing

Symptom-limited exercise testing (treadmill or bicycle) combined with respiratory gas analysis is a useful technique to assess functional limitation in patients with dilated cardiomyopathy and provides a means of objectively evaluating disease progression. The detection of respiratory markers of severe lacticacidaemia during metabolic exercise testing may suggest a mitochondrial or other metabolic cause for dilated cardiomyopathy. Assessment of exercise capacity is essential in the assessment of patients prior to cardiac transplantation.

Cardiac catheterization

Cardiac catheterization is performed to exclude coronary artery disease as a cause of impaired systolic function. Haemodynamic assessment of left ventricular end-diastolic and pulmonary artery pressures is performed as part of cardiac-transplant work-up. Endomyocardial biopsy may be diagnostic for myocarditis and for some metabolic or mitochondrial disorders, but the diagnostic yield is low.

Cardiac MRI

Cardiac MRI may be a useful alternative imaging technique in patients with poor echocardiographic windows. In addition, the detection of fibrosis with gadolinium contrast enhancement may provide additional prognostic and diagnostic information.

Electrophysiological testing

Programmed electrical stimulation is of limited clinical value in the identification of high-risk patients. Polymorphic ventricular tachycardia is inducible in up to 30% of cases, but this is a nonspecific finding. Approximately 10% of patients have inducible sustained monomorphic ventricular tachycardia; about one-third of these die suddenly, but most (75%) who die in this way do not have inducible ventricular tachycardia during programmed stimulation. In some patients (as many as 40% in one series), ventricular tachycardia arises as the consequence of bundle branch re-entry. This tachycardia is typically rapid (mean cycle length 280 ms) and uses a macro re-entrant circuit that involves the His–Purkinje system, usually with right bundle branch anterograde conduction and left bundle branch retrograde conduction. Differentiation from myocardial ventricular tachycardia is confirmed by the presence of a His or right bundle branch potential preceding each QRS: diagnosis is important since catheter ablation of either the left or right bundle branch usually is curative.

Management

Management in dilated cardiomyopathy aims to improve symptoms, to attenuate disease progression, and prevent arrhythmia, stroke, and sudden death.

Pharmacological treatment

Symptomatic therapy is the treatment of heart failure with reliance on diuretics, ACE inhibitors, and β-blockers (see: Heart failure).

Diuretics

Loop and/or thiazide diuretics should be used in all patients with fluid retention to achieve a euvolaemic state, but they should never be used as monotherapy as they exacerbate neurohormonal activation, thereby worsening disease progression. The aldosterone antagonist, spironolactone, reduces the overall risk of death by 30% in adults with severe heart failure (NYHA class IV and ejection fraction <35%): side effects include hyperkalaemia (infrequent in the presence of normal renal function) and painful gynaecomastia.

ACE inhibitors and angiotensin receptor blockers

Activation of the renin–angiotensin–aldosterone system is central to the pathophysiology of heart failure, regardless of the underlying aetiology, and ACE inhibitors should be considered in all patients with dilated cardiomyopathy. Many clinical trials have shown that ACE inhibitors improve symptoms, reduce hospitalizations, and reduce cardiovascular mortality in adults with symptomatic heart failure, and reduce the rate of disease progression in asymptomatic patients. ACE inhibitors are usually well tolerated, the most common side effects being cough and symptomatic hypotension.

The angiotensin receptor blockers (ARBs) have similar haemodynamic effects to ACE inhibitors. Clinical trials in adults with heart failure have shown similar haemodynamic effects, efficacy, and safety to ACE inhibitors, such that ARBs are currently recommended in adults who are intolerant of ACE inhibitors. Combination treatment with ACE inhibitors and ARBs may be more beneficial at preventing ventricular remodelling than either drug alone, but with little additional benefit on overall survival.

β-Blockers

Excess sympathetic activity contributes to heart failure and numerous multicentre placebo-controlled trials—using carvedilol, metoprolol, and bisoprolol—have shown substantial reductions in mortality (both sudden death and death from progressive heart failure) in adults with NYHA class II and III heart-failure symptoms. β-Blockers are usually well tolerated, but side effects include bradycardia, hypotension, and fluid retention, and they are generally contraindicated in asthma. β-Blockers should be started at low doses and slowly up-titrated; they should not be started in patients with decompensated heart failure.

Digoxin

Digoxin improves symptoms in patients with heart failure, but no survival benefit has been demonstrated in large study cohorts. High serum digoxin levels may be associated with increased mortality in some patients. Digoxin should be used only in patients who remain symptomatic in spite of treatment with diuretics, ACE inhibitors, and β-blockers, or to control heart rate in patients with permanent atrial fibrillation.

Anticoagulation

The prevalence of intramural thrombi and systemic thromboembolism ranges between 3 and 50%, with an incidence between 1.5 and 3.5% per year. Anticoagulation with warfarin is, therefore, advised in patients in whom an intracardiac thrombus is identified echocardiographically, or those with a history of thromboembolism. There are no trial data to guide prophylactic anticoagulation in dilated cardiomyopathy, but patients with severe ventricular dilatation and moderate to severe systolic impairment may also benefit from warfarin therapy.

Treatment of arrhythmia in dilated cardiomyopathy

If sustained or symptomatic arrhythmias are documented during 24-h ECG monitoring or exercise testing, conventional treatment is warranted (see: Cardiac arrhythmias). Many commonly prescribed antiarrhythmic agents should be avoided or used with caution because of their negative inotropic and proarrhythmic effects. Data on amiodarone are contradictory, but the recent Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) showed that amiodarone had no beneficial effect on survival when compared with implantable cardioverter–defibrillators. It can, however, be used safely to prevent or treat atrial arrhythmias.

Nonpharmacological treatment

Permanent pacing can correct two important intracardiac conduction abnormalities. First, a small subset of patients who have marked PR interval prolongation (>220 ms), usually secondary to atrioventricular nodal disease, experience deleterious effects on left ventricular haemodynamics with reduction in diastolic ventricular filling time and the development of end-diastolic tricuspid and mitral regurgitation. Correction of PR interval prolongation with short atrioventricular delay dual-chamber pacing may increase stroke volume and blood pressure, thus decreasing mitral regurgitation with dramatic clinical improvement. Second, patients with marked intraventricular conduction delay (left bundle branch block >150 ms) have dyssynchronous contraction of the left ventricular free wall and interventricular septum (which may decrease ejection fraction) and late activation of the anterolateral papillary muscle (which may increase functional mitral regurgitation). Biventricular or left ventricular pacing with specialized leads via the coronary sinus can correct both problems and has been shown to improve symptoms and prognosis in randomized trials. In addition, the resultant increase in blood pressure and pacemaker maintenance of the desired minimum heart rate permits use of higher doses of β-blockade and ACE inhibition with potential secondary benefit.

Surgical removal of nonviable (Dor procedure) and/or viable myocardium (Batista procedure) to improve haemodynamics by reducing left ventricular volume has been advocated, but these and other surgical volume-reduction procedures (partial left ventriculotomy) probably have no role in dilated cardiomyopathy. Mitral valve repair may occasionally be helpful.

Cardiac transplantation may be appropriate in patients with progressive deterioration. In addition, improvements in left ventricular assist devices and artificial heart technology provide alternatives that are now reasonably seen as viable future treatment options. These issues are discussed here: Cardiac transplantation and mechanical circulatory support.

Restrictive cardiomyopathy

Definition

Restrictive left ventricular physiology is characterized by a pattern of ventricular filling in which increased stiffness of the myocardium causes ventricular pressure to rise precipitously with only small increases in volume. The definition of restrictive cardiomyopathy has been confusing because this pattern can occur with a wide range of different pathologies. For the purposes of this chapter, restrictive cardiomyopathies are defined by restrictive ventricular physiology in the presence of normal or reduced diastolic volumes of one or both ventricles, normal or reduced systolic volumes, and normal ventricular wall thickness. Historically, systolic function was said to be preserved in restrictive cardiomyopathy, but it is rare for contractility to be truly normal.

Causes

Restrictive cardiomyopathy is the least common of the cardiomyopathies. Many causes have been identified, including infiltrative and storage disorders, and endomyocardial disease. In the Western world, amyloidosis is the commonest cause in adults, with some familial cases caused by mutations in the transthyretin gene. In the tropics, endomyocardial fibrosis is the commonest cause in adults, and probably also in children.

Rare reports of familial restrictive cardiomyopathy associated with autosomal dominant skeletal myopathy, autosomal recessive musculoskeletal abnormalities, and Noonan’s syndrome have been described in children. Mutations in the gene encoding desmin (an intermediate filament protein) cause restrictive cardiomyopathy associated with skeletal myopathy and, in some cases, abnormalities of the cardiac conduction system. Mutations in the gene encoding cardiac troponin I (a cardiac sarcomeric contractile protein) are reported in 50% of apparently idiopathic restrictive cardiomyopathy in adults. In infants, mutations in other sarcomeric protein genes (troponin I and actin) are reported.

Pathology

Restrictive cardiomyopathy is best regarded as a heterogeneous group of conditions with different aetiologies rather than single disease entity. Macroscopically, restrictive cardiomyopathy is characterized by marked biatrial dilatation in the presence of normal heart weight, a small ventricular cavity, and no left ventricular hypertrophy. The histological features of idiopathic restrictive cardiomyopathy are usually nonspecific, with patchy interstitial fibrosis that may range in extent from very mild to severe. There may also be fibrosis of the sinoatrial and atrioventricular nodes. Myocyte disarray is not uncommon in patients with pure restrictive cardiomyopathy, even in the absence of macroscopic ventricular hypertrophy.

In endomyocardial fibrosis the cardiac pathology is distinctive, with endocardial fibrosis and overlying thrombosis involving the inflow tracts and the apices, but sparing the outflow tracts of one or both ventricles. Necrotic, thrombotic, and fibrotic stages have been defined in patients with endomyocardial fibrosis and hypereosinophilia. In the necrotic stage, there is an acute inflammatory reaction characterized by eosinophilic abscesses in the myocardium, with associated necrosis and arteritis. The endocardium is often thickened and mural thrombi may develop. The thrombotic stage is characterized by endocardial thrombus formation that may be severe, with massive intracavitary thrombosis causing restriction to ventricular filling and a low-output state with high filling pressures. There is a risk of systemic emboli. During the necrotic and thrombotic stages the disease may mimic a hyperacute rheumatic carditis (see: Acute rheumatic fever). If the patient survives, healing by fibrosis with hyaline fibrous tissue occurs. There is no further evidence of inflammation and the impact of the disease is caused by the effect of the dense fibrous tissue on ventricular filling volume and atrioventricular valve function.

Clinical features and investigation

Disease onset is usually insidious. Left-sided disease may present with symptoms of pulmonary congestion and/or mitral regurgitation; right-sided disease with raised jugular venous pressure, hepatomegaly, ascites, and tricuspid regurgitation. Radiographic and electrocardiographic appearances are nonspecific, showing evidence of raised left and/or right atrial pressure and cardiomegaly with left ventricular hypertrophy. Pulmonary infiltrates, nonspecific repolarization changes, and fascicular blocks may be seen.

Two-dimensional echocardiography confirms the diagnosis, allowing visualization of the structural abnormalities involving the endocardium and atrioventricular valves as well as demonstration of the abnormal physiology with restriction to filling. There may be intracavitary thrombus with apical cavity obliteration, or bright echoes from the endocardium of the right or left ventricle with tethering of the chordae and reduced excursion of the posterior mitral valve leaflet. Typically, ventricular dimensions and wall thickness are normal, whereas the atria are grossly enlarged. Left ventricular filling terminates early and is followed by a plateau phase coincident with the third heart sound.

The principal haemodynamic consequence of endomyocardial scarring is a restriction to normal filling. Early diastolic pressures are normal, but there is a rapid mid-diastolic rise (square root sign), which plateaus and is not associated with impairment of systolic performance. A similar functional haemodynamic abnormality is seen in pericardial constriction (see Chapter 16.8), but in the latter condition end-diastolic pressures are usually closely similar within the two ventricles, whereas in endomyocardial fibrosis there is usually inequality of the end-diastolic pressures. Mitral and tricuspid regurgitation may be severe and both ventricles appear abnormal in shape on angiography due to obliteration of the apices. This may be particularly marked in the right ventricle in which the infundibulum is hypertrophied and hypocontractile. In addition, the fibrotic process results in smoothing of the internal architecture of the ventricle with loss of the normal trabeculae. The presence of intracavitary thrombi in the left ventricle may give rise to the erroneous diagnosis of a cardiac tumour.

The structural and physiological abnormalities that can be demonstrated with two-dimensional echocardiography or during cardiac catheterization result from the thrombotic and fibrotic stages of the disease. Diagnosis may be difficult during the early acute phase, when the appearances of the left and right ventricle are far less abnormal, and may require confirmation by endomyocardial biopsy. In later stages, however, the diagnosis should be readily apparent and the risk of biopsy is excessive.

Management

There is no good medical treatment for advanced disease and the prognosis is poor, with 35 to 50% 2-year mortality. Congestive symptoms from raised right atrial pressure can be improved with diuretics, though too great a reduction in ventricular filling pressure will lead to a reduction in cardiac output. Arrhythmias are common, but their prognostic significance is uncertain and they should not be treated unless they are sustained or associated with symptoms. Antiarrhythmic drugs that significantly slow the heart rate may be deleterious because of the small stroke volume. Digoxin may be helpful to control the ventricular response in atrial fibrillation, but cannot be expected to improve congestive symptoms as systolic function is usually well preserved. Anticoagulants may help to prevent venous thrombosis and systemic emboli; both warfarin and antiplatelet drugs are advised.

Surgery with either mitral and/or tricuspid valve replacement, with or without decortication of the endocardium, has been carried out in some patients with endomyocardial fibrosis. Good long-term results have been obtained, but there is significant perioperative mortality (15–20%).

Arrhythmogenic right ventricular cardiomyopathy

Definition

Arrhythmogenic right ventricular cardiomyopathy (ARVC, which replaces the term ‘arrhythmogenic right ventricular dysplasia’ initially used to describe the condition) is a heart muscle disease characterized by progressive fibro-fatty replacement of right ventricular myocardium, initially with regional and later with global right and left ventricular involvement, associated with ventricular arrhythmia, heart failure, and sudden cardiac death, with as many as 20% of such deaths in young individuals and athletes attributable to the condition. Arrhythmogenic right ventricular cardiomyopathy occurs worldwide, in all ethnic groups. The prevalence is unknown, but is conservatively estimated to be between 1 in 1000 and 1 in 5000.

Causes

Systematic family studies have shown that arrhythmogenic right ventricular cardiomyopathy is inherited in at least 50% of cases. The mode of transmission is usually autosomal dominant with variable penetrance, but rare autosomal recessive forms have provided the first insights into the genetic basis of the condition. Two autosomal recessive syndromes characterized by arrhythmogenic right ventricular cardiomyopathy, woolly hair, and palmoplantar keratoderma (Naxos disease (OMIM 601214) and Carvajal–Huerta syndrome (OMIM 605676)) are caused by mutations in the genes encoding plakoglobin and desmoplakin, respectively. These proteins are important components of the desmosome, with key roles in cell-to-cell adhesion and transduction of mechanical stress. Analysis of these and similar proteins in families with the more common autosomal dominant form of disease have revealed mutations in desmoplakin, plakophilin, desmoglein, and desmocollin. Nondesmosomal gene mutations reported in some families with arrhythmogenic right ventricular cardiomyopathy include the ryanodine-2 receptor (more typically associated with catecholaminergic polymorphic ventricular tachycardia) and transforming growth factor β.

Pathology and pathophysiology

Segmental disease is usual in arrhythmogenic right ventricular cardiomyopathy, with involvement of the diaphragmatic, apical, and infundibular regions of the right ventricular free wall (the ‘triangle of dysplasia’). Evolution to more diffuse right ventricular involvement and left ventricular abnormalities with heart failure are more common than the earlier literature suggested. Macroscopic examination of the heart may show diffuse thinning of the right ventricular wall, with aneurysms present in up to 50% of cases. The fibro-fatty replacement of the myocardium may be focal or widespread, usually involves the subepicardial layer of the right ventricular free wall and, when severe, may appear transmural. Histologically, arrhythmogenic right ventricular cardiomyopathy is characterized by replacement myocardial fibrosis with thinning and discrete bulges of the right ventricular free wall, often in association with lymphocytic infiltrates surrounding degenerating or necrotic myocytes. Animal and in vitro studies support the hypothesis that mutations in plakoglobin or analogous genes involved in cell adhesion may cause myocytes under mechanical stress to detach and die, with subsequent fibro-fatty replacement. Other aetiopathogenic factors have been postulated, including enteroviral and adenoviral infection.

Suggested arrhythmic mechanisms include re-entry circuits arising from fibro-fatty myocardial replacement and heterogeneous conduction resulting from destabilization of cell-adhesion complexes and gap junctions.

Clinical features

Symptomatic presentation is usually with palpitation and/or syncope from sustained ventricular arrhythmia, but the first presentation of the disease—especially in young people—may be with sudden cardiac death in an individual who was previously entirely asymptomatic. Occasionally, the victim will have experienced syncope in the months preceding their death (particularly during exercise). Other symptoms are presyncope and chest pain, and features of right and later biventricular failure may be present, including dyspnoea on exertion, as the disease progresses. ‘Hot phases’ are recognized, during which previously stable patients may suffer repeated episodes of ventricular arrhythmia and be prone to sudden death.

Investigation

There is no single diagnostic test for arrhythmogenic right ventricular cardiomyopathy, and the diagnosis is based on the presence of major and minor criteria encompassing structural, histological, electrocardiographic, arrhythmic, and genetic factors, proposed by the Study Group on Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy of the Working Group Myocardial and Pericardial Disease of the European Society of Cardiology and of the Scientific Council on Cardiomyopathies of the International Society and Federation of Cardiology (Table 4). The diagnosis of arrhythmogenic right ventricular cardiomyopathy is fulfilled in the presence of two major criteria, or one major plus two minor criteria, or four minor criteria from different categories. However, these criteria are currently being revised in the light of new family data showing that at least 30% of patients have left ventricular involvement in the form of regional or global left ventricular dysfunction, and many have subclinical left ventricular fibrosis (evident on magnetic resonance) affecting particularly the posterolateral segments.

Table 4 Criteria for the diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC). Criteria are fulfilled if two major criteria, or one major plus two minor criteria, or four minor criteria are seen
Major Minor
Family history
Familial disease confirmed at autopsy or surgery
  • Family history of premature sudden death (<35 years) caused by ARVC
  • Family history (clinical diagnosis based on present criteria)
ECG depolarization/conduction abnormalities
Epsilon waves or localized prolongation (>110 ms) of the QRS complex in the right precordial leads (V1–V3) Late potentials seen on signal- averaged ECG
Repolarization abnormalities
  Inverted T waves in right precordial leads (V2 and V3) in individuals aged >12 years and in the absence of right bundle branch block
Tissue characterization of walls
Fibrofatty replacement of myocardium on endomyocardial biopsy  
Global and/or regional dysfunction and structural alterationsa
Severe dilatation and reduction of right ventricular ejection fraction with no (or only mild) left ventricular impairment Mild global right ventricular dilatation and/or ejection fraction reduction with normal left ventricle
Localized right ventricular areas with aneurysms (akinetic or dyskinetic diastolic bulging) Mild segmental dilatation of the right ventricle
Severe segmental dilatation of the right ventricle Regional right ventricular hypokinesia
Arrhythmias Left bundle branch block type or ventricular tachycardia (sustained or nonsustained) documented on ECG, Holter monitoring, or during exercise testing
Frequent ventricular extrasystoles (>1000/24 h) on Holter monitoring

a Detected by echocardiography, angiography, MRI, or radionuclide scintigraphy.

Reproduced from Br Heart J, McKenna WJ et al, 71:215–18

Family studies have shown that first-degree relatives of affected individuals may have minor cardiac abnormalities, which—although not fulfilling the above diagnostic criteria—are likely to represent disease expression in the context of an autosomal dominant disease. Modified diagnostic criteria for the diagnosis of arrhythmogenic right ventricular cardiomyopathy in family members of affected individuals have been proposed.

Electrocardiography

The most common electrocardiographic abnormality is T-wave inversion in leads V1 to V3 in the absence of right bundle branch block (but note that this is a normal finding in children and therefore cannot be used as a diagnostic criterion). Other electrocardiographic features include QRS dispersion (localized prolongation of the QRS complex in the right ventricular leads, with a difference in QRS duration of at least 40 ms between right and left precordial leads), right intraventricular conduction delay (progressing to right bundle branch block in some patients) and the presence of an epsilon wave (a terminal notch in the QRS complex), typically seen in lead V1. Ventricular tachycardia is of left bundle branch block morphology suggesting a right ventricular origin.

The signal-averaged ECG is used to detect late potentials and predicts susceptibility to ventricular arrhythmia in different cardiac diseases. Up to 80% of patients with arrhythmogenic right ventricular cardiomyopathy have late potentials on the signal-averaged electrocardiogram, which may correlate with the risk of ventricular arrhythmia and disease progression.

Exercise testing

The role of exercise testing in arrhythmogenic right ventricular cardiomyopathy is primarily to detect ventricular arrhythmias induced by physical activity. Ventricular ectopy and nonsustained ventricular tachycardia of right ventricular origin have been described in young patients. Cardiopulmonary exercise testing may be useful as an objective measure of functional capacity in patients with advanced disease.

Echocardiography

Echocardiography is used to confirm the diagnosis and to exclude congenital heart disease, which may present as a differential diagnosis for arrhythmogenic right ventricular cardiomyopathy. Typical echocardiographic findings include right ventricular dilatation, regional hypokinesia or dyskinesia, free wall aneurysms, increased echogenicity of the moderator band, and right ventricular apical hypertrabeculation. Left ventricular involvement with posterior wall hypokinesia or ventricular dilatation may be seen in up to 30% of cases. In patients in whom the right ventricle is difficult to visualize adequately using standard two-dimensional echocardiography, injection of echocardiographic contrast may provide improved definition of the right ventricular endocardial border and allow the identification of subtle wall-motion abnormalities or diastolic bulging.

Cardiac magnetic resonance imaging

Assessment of the right ventricle using echocardiography is challenging, even in experienced hands. Cardiovascular MRI has the advantage that it is a three-dimensional technique with no limitations imposed by acoustic windows. When performed with a dedicated protocol by experienced operators, in both children and adults, the technique has a high sensitivity for detecting right ventricular abnormalities in individuals who fulfil conventional diagnostic criteria, and may help to confirm individuals with early disease who fulfil the modified familial criteria. Reproducibility and accuracy are still, however, strongly operator dependent. Late enhancement with gadolinium has been shown to correlate with fibro-fatty changes in arrhythmogenic right ventricular cardiomyopathy.

Endomyocardial biopsy

Although a histological diagnosis of arrhythmogenic right ventricular cardiomyopathy may be definitive, the sensitivity of endomyocardial biopsies is low because of (1) the segmental nature of the disease, (2) the amount of tissue usually obtained is insufficient to differentiate fibro-fatty replacement from islands of adipose tissue that are not infrequently seen between myocytes in the right ventricle of normal subjects, and (3) the fact that samples are usually taken from the septum, a region that is less frequently involved. The complication rate—which includes cardiac perforation and tamponade because of thinning of the right ventricular wall—is also relatively high, hence endomyocardial biopsies are no longer considered part of the routine diagnostic work-up for the condition.

Management

Treatment in arrhythmogenic right ventricular cardiomyopathy is individualized according to the presence of symptoms, arrhythmia, and perceived risk of sudden death. Patients with symptomatic, non-life-threatening ventricular arrhythmias are treated empirically with β-adrenoreceptor blockers, amiodarone, or sotalol. β-Blockers are particularly effective at treating symptoms related to exercise-induced arrhythmia, and sotalol suppresses ventricular arrhythmia in most patients. Those with a history of sustained, haemodynamically compromising ventricular arrhythmia should be offered an implantable cardioverter–defibrillator (ICD). Studies in such patients have shown a high rate of appropriate device discharges, ranging from 15 to 22% per year. More problematic is the prevention of sudden death in patients without such a history. A number of markers of increased risk have been proposed, including unexplained syncope, symptomatic ventricular tachycardia, family history of sudden death, young age, left ventricular involvement, and diffuse right ventricular dilatation. However, population-based survival studies are needed to evaluate the significance of these and other factors (such as asymptomatic nonsustained ventricular tachycardia).

Patients with severe right ventricular or biventricular involvement should be treated according to current heart-failure treatment guidelines, including the use of diuretics, ACE inhibitors, and anticoagulation. Patients with advanced disease are candidates for cardiac transplantation (see: Cardiac transplantation and mechanical circulatory support).

Further reading

 
 
Hypertrophic cardiomyopathy
 
Davies MJ, McKenna WJ (1995). Hypertrophic cardiomyopathy: pathology and pathogenesis. Histopathology, 26, 493–500. 
 
Elliott P, McKenna WJ (2004). Hypertrophic cardiomyopathy. Lancet, 363, 1881–91.
 
Maron BJ (2002). Hypertrophic cardiomyopathy. A systematic review. JAMA, 287, 1308–20.
 
Maron BJ, et al. (2003). American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents; European Society of Cardiology Committee for Practice Guidelines. American College of Cardiology/European Society of Cardiology Clinical Expert Consensus Document on Hypertrophic Cardiomyopathy. A report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines. Eur Heart J, 24, 1965–91.
 
Richard P, et al. (2003). Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation, 107, 2227–32.
 
Seidman JG, Seidman C (2001). The genetic basis for cardiomyopathy: from mutation identification to mechanistic paradigms. Cell, 104, 557–67.
 
Watkins H (2003). Genetic clues to disease pathways in hypertrophic and dilated cardiomyopathies. Circulation, 107, 1344–46.
 
Wigle ED, et al. (1985). Hypertrophic cardiomyopathy. The importance of the site and the extent of hypertrophy. A review. Progr Cardiovasc Dis, 28, 1–83. 
 
Dilated cardiomyopathy 
 
Burkett EL, Hershberger RE (2005). Clinical and genetic issues in familial dilated cardiomyopathy. J Am Coll Cardiol, 45, 969–81.
 
Dec GM, Fuster V (1994). Idiopathic dilated cardiomyopathy. N Engl J Med, 331, 1564–75.
 
Mestroni L, et al. (1999). Guidelines for the study of familial dilated cardiomyopathies. Collaborative Research Group of the European Human and Capital Mobility Project on Familial Dilated Cardiomyopathy. Eur Heart J, 20, 93–102.
 
Shaw T, Elliott P, McKenna WJ (2002). Dilated cardiomyopathy: a genetically heterogeneous disease. Lancet, 360, 654–5.
 
Arrhythmogenic right ventricular dysplasia
 
Corrado D, Thiene G (2006). Arrhythmogenic right ventricular cardiomyopathy/dysplasia: clinical impact of molecular genetic studies. Circulation, 113, 1634–7.
 
Hulot JS, et al. (2004). Natural history and risk stratification of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circulation, 110, 1879–84.
 
McKenna WJ, et al. (1994). Diagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Br Heart J, 71, 215–18.
 
Sen-Chowdhry S, et al. (2004). Arrhythmogenic right ventricular cardiomyopathy: clinical presentation, diagnosis, and management. Am J Med, 117, 685–95.