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At the heart of general practice since 1960

June 2007: Preventing sudden death in patients with cardiomyopathies

How are cardiomyopathies classified?

What are the key presenting symptoms?

Who is at risk of sudden cardiac death?

How are cardiomyopathies classified?

What are the key presenting symptoms?

Who is at risk of sudden cardiac death?

Cardiomyopathies represent a diverse group of conditions with a common final pathway of cardiac dysfunction. Estimates of the prevalence of nonischaemic cardiomyopathy in the community or hospital setting range from 2 to 15%.1 In many cases a specific aetiology is not identified, and treatment frequently includes management for systolic heart failure.

In an average sized practice of 6,000 patients, GPs should expect 12 cases of hypertrophic cardiomyopathy, three cases of nonischaemic dilated cardiomyopathy and one case of arrhythmogenic right ventricular cardiomyopathy. Identification of these patients can be problematic, and suspicion should be raised in patients with:

• Severe, recurrent and exertional chest pain

• Palpitations associated with dyspnoea, presyncope/syncope

• Exertional presyncope/syncope

• A family history of sudden cardiac death.

GPs should collaborate with coroners in cases of sudden cardiac death to identify inheritable causes and initiate screening of first-degree family members. First-line investigation should involve timely referral to a cardiologist, with a resting 12-lead ECG (abnormal repolarisation and prolonged QT-interval being the most discriminatory features), 24-hour Holter monitoring and a two-dimensional echocardiography.2

Management of cardiomyopathy is multidisciplinary and involves primary prevention of sudden cardiac death and symptom control.

The cornerstones of management are:

• Restriction of competitive sports in those with a confirmed diagnosis.

• Awareness of drugs predisposing to prolonged QT interval

• Optimal heart failure management

• Aggressive treatment of traditional risk factors for ischaemic heart disease.

Cardiomyopathies can present at any age. The most common presenting complaint is symptoms of heart failure, however this only represents the tip of the iceberg. A significant proportion of individuals are asymptomatic until they present as cases of sudden cardiac death, usually caused by ventricular tachycardia or ventricular fibrillation. The annual incidence of sudden cardiac death in the general population in the UK is one per 1,000, and 15% of these deaths are attributable to cardiomyopathies.2

Currently population screening is not advocated in the UK to identify patients before the first arrhythmic episode, making early diagnosis challenging. However, screening is carried out in professional sportsmen and is recommended for competitive athletes.

The traditional classification of cardiomyopathies as dilated, hypertrophic or restrictive has evolved following the identification of several new disease entities, particularly in the field of molecular genetics in cardiology.

A new definition has been proposed by the American Heart Association: ‘Cardiomyopathies are a heterogeneous group of diseases of the myocardium associated with mechanical and/or electrical dysfunction that usually (but not invariably) exhibit inappropriate ventricular hypertrophy or dilatation and are due to a variety of causes that frequently are genetic. Cardiomyopathies either are confined to the heart or are part of generalised systemic disorders, often leading to cardiovascular death or progressive heart failure-related disability.'3

Cardiomyopathies are divided into two major groups based on predominant organ involvement (see figure 1,attached):1

• Primary cardiomyopathies (genetic, mixed and acquired) are solely or predominately confined to heart muscle

• Secondary cardiomyopathies show pathological myocardial involvement as part of a large number and variety of generalised systemic (multi-organ) disorders.

In primary care, the most common cardiomyopathy encountered is hypertrophic cardiomyopathy, followed by nonischaemic dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy.

Hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy is defined by the presence of myocardial hypertrophy in the absence of haemodynamic stress sufficient to cause that degree of hypertrophy. Its prevalence in the UK population is one per 500.4 It is considered to be the most common cause of death during sporting activities, and has an annual cardiovascular mortality of approximately 1%.4 Half of these deaths are caused by sudden cardiac death and the remainder by heart failure or stroke, predominantly in adult and elderly patients.

Most adults with hypertrophic cardiomyopathy have familial forms of the condition that demonstrate an autosomal dominant inheritance pattern with incomplete penetrance.

Mutations in 10 identified genes that encode for components of the cardiac sarcomere are responsible for 50-60% of cases. The most frequently identified mutations involve ß-myosin heavy chain (located on chromosome 14) and cardiac myosin binding protein C (located on chromosome 11). These mutations result in the classic histopathological description of myocyte disarray, in which individual cardiac myocytes vary in size and shape and have abnormal intercellular connections.

Diagnosis

Most patients with hypertrophic cardiomyopathy are asymptomatic and are diagnosed incidentally or when screening the family of sudden cardiac death cases. The most common symptoms are dyspnoea, related predominantly to diastolic dysfunction, and chest pain. Chest pain can be exertional or, more curiously, related to the consumption of large meals and alcohol. A combination of microvascular abnormalities and left ventricular outflow tract (LVOT) obstruction is thought to be involved. A day-to-day variation in the level of activity required to precipitate these symptoms is characteristic.

Diagnosis is by two-dimensional echocardiography demonstrating unexplained maximum left ventricular wall thickness >15mm in any myocardial segment (see figure 3, attached). However, any degree of wall thickness may be compatible with the diagnosis of hypertrophic cardiomyopathy because of the variability of gene expression.

Approximately 25% of patients have dynamic LVOT obstruction caused by contact between the anterior mitral valve leaflet and the interventricular septum. This may produce pressure gradients across the obstruction significant enough to cause syncope. Further investigations are also performed in confirmed cases of hypertrophic cardiomyopathy to identify patients at high risk of sudden cardiac death (see table 1, attached).

Management

The management of hypertrophic cardiomyopathy is complex and can change throughout the natural history of the disease. Strategies are mainly targeted at symptom relief and treatment of complications such as progressive heart failure and arrhythmias. Symptoms caused by progressive heart failure are treated in the conventional manner. However,

ACE inhibitors must be used with caution as they may worsen the LVOT gradient (see table 2, attached). Symptoms associated with significant LVOT obstruction are treated with negatively inotropic agents, including ß-blockers, disopyramide and verapamil.

In patients with LVOT obstruction refractory to pharmacological management, surgery may be considered to de-bulk the interventricular septum. This may be carried out by septal myotomy-myomectomy in open surgery, or by the more recently developed percutaneous transcoronary septal myocardial ablation. In this approach alcohol is injected into septal perforating vessels to produce localised myocardial necrosis.

Atrial fibrillation (AF) is poorly tolerated in patients with hypertrophic cardiomyopathy and may cause severe deterioration in symptoms. If normal sinus rhythm cannot be sustained, control of the ventricular response with ß-blockers and calcium channel blockers is almost as effective. In those with paroxysmal AF, amiodarone is the most effective treatment to maintain sinus rhythm. Patients at high risk of sudden cardiac death, or who have experienced aborted sudden cardiac death or sustained ventricular tachycardia, are candidates for implantable cardioverter defibrillator (ICD) insertion.4

Dilated Cardiomyopathy

Dilated cardiomyopathy is characterised by dilatation and impaired systolic function of one or both ventricles, with normal coronary arteries. Five to eight people per 100,000 develop this disorder each year.5 It can develop at any age and is more common in men and Afro-Caribbean patients.

Dilated cardiomyopathy conveys a 50% risk of mortality within two years of symptom onset. The risk is 4% per year thereafter.6 It is the most common indication for cardiac transplant. Sudden cardiac death resulting from malignant arrhythmias is the most common cause of death in dilated cardiomyopathy.

Around 50% of cases of nonischaemic dilated cardiomyopathy are idiopathic. Data suggest that at least 20% of cases of dilated cardiomyopathy are familial, and multiple patterns of inheritance have been identified. In the autosomal dominant form several genes have been implicated. These include actin, laminin and desmin, which code for cytoskeletal proteins.

Infectious causes of myocarditis, which account for 9% of dilated cardiomyopathy, include viral (such as enteroviruses and HIV), bacterial and parasitic infections, such as Chagas disease. Dilated cardiomyopathy can also result from toxins (for example alcohol or chemotherapeutic agents), pregnancy, infiltrative disorders, nutritional deficiencies, connective tissue diseases and chronic endocrine disorders (such as thyroid dysfunction or phaeochromocytomas).

Mechanism

Damaged myocardium is replaced by fibrous scar tissue, with compensatory hypertrophy of the remainder of the myocardium until this mechanism is exceeded and overt dilated cardiomyopathy and heart failure develop.

Functional mitral and tricuspid regurgitation with atrial and ventricular dilatation predispose the patient to arrhythmias and thromboembolic disease.

There may be a preceding flu-like illness indicating myocarditis before the onset of heart failure, of which exertional dyspnoea is the most common presenting symptom. Tachycardia develops and blood pressure may become low. Peripheral oedema, ascites and pulmonary oedema may develop.

Diagnosis

Diagnosis is aided by a two-dimensional echocardiography revealing dilatation of the cardiac chambers, particularly the left ventricle and/or right ventricle, with reduced wall thickness and poor global contraction (see figure 4, attached).

Cardiac MRI may be used, but if the diagnosis remains in doubt cardiac catheterisation, the gold standard investigation, will provide additional information about the function of the heart and confirm diagnosis. The pressures within each chamber can be measured and a myocardial biopsy can be taken for histological examination.

Management

Management should target the underlying cause in individual cases. However, optimal pharmacological treatment of heart failure is key. Interventricular conduction delay occurs in up to 30% of patients, leading to asynchronous ventricular contraction and worsening mitral regurgitation.

Cardiac resynchronisation therapy with biventricular pacemaker insertion improves quality of life, cardiac function and survival.7 Recent trials also advocate insertion of ICDs for the primary prevention of sudden cardiac death in patients with a left ventricular ejection fraction ? 35%.8

For refractory end-stage heart failure, surgical options include valve annuloplasty, mechanical cardiac assist devices and cardiac transplantation.3

Arrhythmogenic Right Ventricular Cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy is characterised pathologically by fibrofatty replacement of myocytes, with a propensity to cause malignant ventricular arrhythmias. The prevalence is one per 5,000 in the general population and it is responsible for 20% of cases of sudden cardiac death in patients under 30 years, with an annual mortality of 3% in untreated cases in the US.9

Around 50% of cases demonstrate an autosomal dominant mode of inheritance, with variable penetrance and expression. Four genes have been identified on chromosome 8 that are individually responsible: the cardiac ryanodine receptor; desmoplakin; plakophillin-2 and transforming growth factor-ß.

Arrythmogenic right ventricular cardiomyopathy most commonly presents with symptomatic ventricular arrhythmias, originating from the right ventricle and associated with dyspnoea, palpitations and presyncope/syncope. These characteristically occur during exercise, indicating an adrenergic trigger.

Symptoms of heart failure predominate late in the natural history of the disease.

Diagnosis

Definitive diagnosis requires confirmation of characteristic histological findings at biopsy or postmortem, thus clinical diagnosis remains problematic.

In 1994 an expert consensus group proposed criteria for diagnosis.10 These are divided into major and minor criteria and involve structural and functional changes on imaging, ECG changes, identification of ventricular arrhythmias and family history.

More than half of patients with arrhythmogenic right ventricular cardiomyopathy demonstrate repolarisation abnormalities on ECG. T wave inversion in leads V1-V3 in the absence of a complete right bundle branch block is a minor criterion, but is useful in raising suspicion. Delayed right ventricle activation is a major criterion and manifests as epsilon waves (small amplitude potentials that occur at the end of the QRS complex in 30% of cases) and preferential widening of the QRS in V1-V3 compared with V6.

Although echocardiography is the first-line imaging modality, the gold standard for diagnosis is right ventricle angiography identifying severe dilatation and/or functional loss of the right ventricle.

Management

In addition to restriction of activities, current evidence suggests that either sotalol alone, or amiodarone alone or in combination with ß-blockers, are most effective at reducing symptoms of, and suppressing, ventricular arrhythmias.

ICD implantation is advocated in those at high risk of sudden cardiac death, as judged by an aborted cardiac arrest or threatening arrhythmias not suppressed by drug therapy, and as primary prevention in those with extensive disease, family history of sudden cardiac death or unexplained syncope.9

Authors Authors

Dr Anthony Li
MBBS BSc MRCP
senior house officer

Dr Asim Zaidi
MBBS
senior house officer

Professor A. John Camm
BSc MD FRCP
Professor of Clinical Cardiology, St George's Hospital, London

key points Key points

key points

fig 1 Figure 1: Classification of primary cardiomyopathies - American Heart Association (2006)

fig 1

pt 1 Table 1: Summary of cardiomyopathies (part 1)

part 1 of 2

part 2 Table 1: Summary of cardiomyopathies (part 2)

part 2

table 2 Table 2: Summary of heart failure management

table 2

Preventing sudden death in patients with cardiomyopathies Figure 2

Apical four chamber view of a normal heart Figure 2 Figure 4

Apical four chamber view of dilated cardiomyopathy Figure 4 Figure 3

Apical four chamber view

of hypertrophic cardiomyopathy Figure 3

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