Clinical presentation

The first presentation of IDC may be with systemic embolism or sudden death, but patients more typically present with signs and symptoms of pulmonary congestion and/or low cardiac output, often on a background of exertional symptoms and fatigue for many months or years before their diagnosis. Intercurrent illness or the development of arrhythmia, in particular atrial fibrillation, may precipitate acute decompensation in such individuals. Increasingly, IDC is diagnosed incidentally in asymptomatic individuals during routine medical screening or family evaluation of patients with established diagnosis.

A careful family history facilitates diagnosis of inherited causes of IDC by characterising the family phenotype, and also defines the scope of family screening.1 At least 25% of patients have evidence for familial disease with predominantly autosomal dominant inheritance. Clinically, familial disease is defined by the presence of two or more affected individuals in a single family and should also be suspected in all patients with IDC and a family history of premature cardiac death or conduction system disease. A further 20% of relatives have isolated left ventricular enlargement that can progress to IDC in a minority of cases. Dilated cardiomyopathy can occur in a number of X linked diseases such as Becker's and Duchenne's muscular dystrophies and X linked IDC. It may also occur in patients with mitochondrial DNA mutations and inherited metabolic disorders. Thus when taking a family history, specific attention should be given to a history of muscular dystrophy, features of mitochondrial disease (for example, familial diabetes, deafness, epilepsy, maternal inheritance), and signs and symptoms of other inherited metabolic diseases. Inborn errors of metabolism usually present in infancy and childhood, but some may present in adulthood, in particular haemochromatosis. Nutritional deficiencies and endocrine abnormalities may produce heart failure, and a complete drug history is essential, both in relation to the administration of cardiotoxic drugs such as anthracyclines and with respect to the use of illegal substances. Cocaine abuse, in particular, can produce a chronic IDC picture as well as an acute cardiomyopathy. Exposure to HIV and other infectious agents such as hepatitis C may be relevant in some patients.

Electrocardiography

The ECG in patients with IDC may be remarkably normal, but abnormalities ranging from isolated T wave changes to septal Q waves in patients with extensive left ventricular fibrosis, prolongation of atrioventricular (AV) conduction, and bundle branch block may be observed. Sinus tachycardia and supraventricular arrhythmias are common, in particular atrial fibrillation. Approximately 20–30% of patients have non-sustained ventricular tachycardia and a small number present with sustained ventricular tachycardia.

Echocardiography

An echocardiogram is essential for the diagnosis of IDC (fig 1). In patients with poor echo windows other imaging modalities such as radionuclide scans and magnetic resonance may be useful. Recently suggested echocardiographic criteria for IDC are shown in the adjacent box. When making the diagnosis of IDC it is important to take into account sex and body size. The most widely applied criteria in family studies are based on the Henry formulae, with a left ventricular cavity dimension of > 112% of predicted normal values used to define left ventricular enlargement and a shortening fraction of < 25% defining abnormal systolic function. These criteria have some limitations, in particular the use of only short axis dimensions and a relatively low specificity in young patients, but they are practical and reproducible. Recent European guidelines have suggested that when screening family members a more conservative cut off of > 117% of predicted values (2 SD plus 5%) should be used in order to increase specificity.1

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Figure 1

Parasternal long axis (A) and apical four chamber (B) cross sectional (two dimensional) echocardiograms in a 23 year old patient with IDC.

Exercise testing

Symptom limited upright exercise testing is of considerable value when assessing functional limitation in patients with IDC, particularly when combined with respiratory gas analysis. Metabolic exercise testing provides an objective measure of exercise capacity, facilitates assessment of disease progression, helps assess prognosis, and is useful in selecting patients for cardiac transplantation. Metabolic exercise testing may also provide diagnostic information in patients with left ventricular impairment caused by primary metabolic abnormalities such as mitochondrial disease, by detecting severe acidaemia.

Viral serology

In children and adults with acute myocarditis, viral culture and serology may be useful in establishing a diagnosis of viral myocarditis by demonstrating rising titres of neutralising antibodies, or virus specific IgM class antibodies to enteroviruses indicative of recent infection. In adults with IDC the relation between viral infection and disease is more uncertain. Many studies purporting to demonstrate a positive association between viral infection and IDC are very small, and have failed to control for cross contamination with laboratory controls.2 The source of disease and control populations is also important as the most commonly implicated enterovirus, coxsackie B, is ubiquitous in most communities and causes small subclinical epidemics. At present, the detection of viral antibodies in patients with stable chronic IDC has little impact on management, but viral studies may become more important in the future if current trials suggest a role for immunosuppressive/modulatory treatments in IDC.

Endomyocardial biopsy

Although endomyocardial biopsy can be used to diagnose a wide range of myocardial diseases, most are rare causes of IDC and can often be diagnosed by other means. Even the detection of an inflammatory cardiomyopathy is of limited use, given the uncertainties and inconsistencies surrounding its diagnosis using conventional light microscope criteria. Endomyocardial biopsy may be of use in selected patients—for example, those with suspected cardiac haemochromatosis and other infiltrative or malignant diseases—but in general it should be confined to carefully conducted clinical trials. A number of immunohistological studies have already demonstrated increased numbers of T cells and increased expression of endothelial and interstitial MHC (major histocompatibility complex) antigens and cell adhesion molecules in IDC hearts, consistent with previous observations of immune activity in IDC (fig 2).3 As our understanding of the clinical significance of immunohistochemical markers improves, it is likely that endomyocardial biopsy will become more important in guiding immunomodulatory treatment.

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Figure 2

Myocardial section from a patient with IDC stained for the intercellular adhesion molecule 1 (ICAM-1) (green) and factor VIII (red). Dual staining in yellow indicates the presence of endothelial ICAM activity, indicative of chronic low grade inflammation. Reproduced with permission from Professor Michael Davies.    

Angiotensin converting enzyme inhibitors

Activation of the renin–angiotensin–aldosterone system (RAAS) is central to the pathophysiology of heart failure of whatever underlying aetiology. For this reason, angiotensin converting enzyme (ACE) inhibitors are the mainstays of treatment in patients with IDC, irrespective of the severity of heart failure.4 ACE inhibitors improve dyspnoea and exercise tolerance, reduce hospitalisation rates, and reduce cardiovascular mortality. They also prevent or slow disease progression in asymptomatic patients. A substantial proportion of patients who are given ACE inhibitors fail to reach the target doses reported in randomised studies. Recent evidence from the ATLAS study5 suggests that maximum recommended doses of lisinopril (32.5–35 mg) are as well tolerated as low doses (2.5–5 mg), and are associated with a 12% greater reduction in the combined risk of death or hospitalisation. Although the comparative benefit of intermediate doses is still uncertain, it seems prudent to try to achieve recommended target doses in most patients.

Significant side effects are uncommon during ACE inhibitor treatment, the most frequent being hypotension, cough, and deterioration of renal function. Mild impairment of renal function (creatinine up to 265 μmol/l) in the absence of renal artery stenosis is not, however, an absolute contraindication for ACE inhibition. Similarly, a resting systolic pressure of 80–90 mm Hg during treatment is acceptable in the absence of postural symptoms. When side effects are problematic, the first step is to consider reducing the dose of other medications. In particular, diuretic doses can often be reduced in patients who no longer have congestive symptoms. When ACE inhibitors have to be discontinued, hydralazine–nitrate combination can be useful in treating congestive symptoms.

Angiotensin II receptor antagonists

Angiotensin II (AII) receptor antagonists have recently attracted much interest and controversy with regard to their place in the heart failure therapeutic armoury. AII receptor antagonists have haemodynamic effects broadly similar to those of ACE inhibitors, but may be slightly better tolerated and at least theoretically overcome the “escape” of angiotensin system blockade observed in some patients on ACE inhibitors. However, unlike ACE inhibitors, AII receptor antagonists do not inhibit bradykinin metabolism and thus lack a potentially beneficial vasodilatory effect. The ELITE-1 study6suggested that losartan may have a greater effect on mortality than captopril in elderly patients with mild to moderate heart failure. Preliminary data from the follow up to this study have failed to demonstrate a superior effect of losartan over captopril, but the study was not powered to detect equivalence between the two drugs. The recent RESOLVD study7 has suggested that combination treatment with an ACE inhibitor and an AII antagonist may be more beneficial in reducing neurohumoral activation and in preventing ventricular remodelling than either drug alone. A number of trials (VALHEFT, CHARM) are currently addressing these and other issues regarding AII receptor treatment.

β Blockers

In spite of ACE inhibitor treatment, mortality continues to be high in patients with heart failure. This is perhaps not surprising given that ACE inhibitors act on only one aspect of the neurohumoral cascade (RAAS) that contributes to progressive left ventricular dysfunction. It has been recognised for some time that excess sympathetic activity contributes to the clinical syndrome of heart failure, but it was only recently that use of β blockers in heart failure patients gained widespread acceptance. Three recent multicentre placebo controlled studies, the US carvedilol studies,8CIBIS II (bisoprolol),9 and MERIT-HF (metoprolol),10 have demonstrated substantial reductions in sudden death and death from progressive heart failure in patients with predominantly New York Heart Association (NYHA) class II and III symptoms treated with β blockers. In CIBIS II and MERIT-HF, but not the US carvedilol study, subgroup analysis suggested a greater effect in patients with ischaemic heart failure compared to “non-ischaemic” heart failure. Nevertheless, when taken together with earlier studies, these data suggest that it is advisable to consider β blockers in IDC patients with mild to moderate symptoms in spite of maximal treatment with ACE inhibitors. Patients should not be started on β blockers if they have signs or symptoms of decompensated heart failure, and initial doses should be low (carvedilol 3.125 mg twice daily, bisoprolol 1.25 mg once daily, metoprolol SR 12.5 mg once daily). Doses should be increased gradually every 2–4 weeks, monitoring closely for hypotension, bradycardia or worsening heart failure until the target dose is achieved or side effects occur.

Spironolactone

High plasma concentrations of aldosterone are frequent in patients with moderate to severe heart failure and contribute to sodium retention, potassium loss, sympathetic activation, myocardial fibrosis, and baroreceptor dysfunction. ACE inhibition usually results in only a transient decrease in aldosterone concentrations, probably because a major source of aldosterone is reduced hepatic clearance rather than angiotensin dependent adrenal secretion. The recent RALES study11 has shown that the addition of 25 mg of spironolactone to conventional treatment in patients with an ejection fraction < 35% and a history of NYHA class IV heart failure is associated with a 30% reduction in the overall risk of death. Hospitalisation rates for cardiac causes and functional status also improved, and serious hyperkalaemia was infrequent in patients with a serum creatinine < 221 μmol/l. The drug should be considered in all patients presenting with moderate to severe heart failure symptoms.

Natriuretic peptides

Atrial natriuretic peptide (ANP) is released from atrial myocytes in response to stretch, and induces diuresis, naturesis, vasodilatation, and suppression of the renin–angiotensin system. Circulating concentrations of ANP are increased in congestive cardiac failure and correlate with NYHA functional class and prognosis. Both ANP and brain natriuretic peptide are potent vasodilators and diuretics, but clinical trials have shown that tolerance frequently develops during intravenous ANP administration. This problem may be overcome by the development of drugs that inhibit neutral endopeptidase, the enzyme responsible for breakdown of natriuretic peptides.

Cytokine antagonists

Tumour necrosis factor α (TNFα) or cachectin is a proinflammatory cytokine released from activated macrophages, T cells, and failing myocardium. It circulates at high concentrations in patients with congestive cardiac failure and in experimental models causes pulmonary oedema, cardiomyopathy, cachexia, and reduced peripheral blood flow. Raised plasma concentrations of TNFα and other proinflammatory cytokines such as interleukin 6 have been interpreted as epiphenomena of heart failure, but it is increasingly thought that cytokines may promote heart failure progression. The experience with TNFα antagonists in heart failure is limited, but there are intriguing data on pentoxyfilline, a xanthine derivative that suppresses TNFα production,12 and etanercept, a soluble P75 tumour necrosis factor receptor that binds irreversibly with TNFα.13 Etanercept is currently being evaluated in two large multicentre studies (RENAISSANCE and RECOVER).

Endothelins are another family of locally acting peptides with profound vasoconstrictor effects found in high plasma concentrations in patients with heart failure. Experimental data using the endothelin antagonist bosentan have shown favourable haemodynamic effects in heart failure patients, although the drug is associated with dose related hepatic dysfunction, prompting the investigation of more selective endothelin antagonists.

Anticoagulants

Although the annual risk of thromboembolism in patients with IDC is relatively low, many patients are young and are exposed to an appreciable cumulative risk of systemic embolisation. At present there are no trial data to guide anticoagulant treatment in IDC, but warfarin is advised in patients with a history of thromboembolism or evidence of intracardiac thrombus. Patients with more than moderate ventricular dilatation and moderate to severe systolic dysfunction should also be advised to take warfarin.

Partial left ventriculectomy (“Batista” procedure)

Partial left ventriculectomy is based on the hypothesis that as wall tension is related to left ventricular diameter (Laplace's law), reducing the left ventricular size by excision of a portion of its circumference should reduce wall stress and improve ventricular haemodynamics. In the best centres results from this intervention were initially remarkably good given the nature of the procedure. It is clear, however, that even with careful patient selection many patients survive only with the benefit of left ventricular assist devices and subsequent transplantation.17 Late sudden death is also described in a proportion of survivors. The difficulties associated with patient selection and subsequent postoperative care suggest that, at best, this form of treatment will be confined to a very small number of experienced centres.

Left ventricular assist devices

Left ventricular assist devices (LVADs) have recently received approval from the US Food and Drug Administration for use in patients with end stage heart failure as a bridge to cardiac transplantation. Experience in patients with IDC suggests that LVAD treatment can result in an apparent improvement in left ventricular function that may persist when the device is removed. However, there are as yet no reliable markers that distinguish the minority of patients that sustain useful recovery from the majority that deteriorate following explantation of the device. Technical advances in LVAD design now raise the possibility of using these devices as an alternative to transplantation in patients who are not transplant candidates. This mode of treatment is currently being evaluated in the REMATCH study,18 which if positive will have substantial clinical and resource implications for centres managing advanced heart failure.

Multisite ventricular pacing

Many patients with advanced IDC have abnormal left ventricular activation that in turn results in prolonged and incoordinate ventricular relaxation. In some patients ventricular conduction delay is also associated with prolongation of atrioventricular conduction, resulting in a loss of atrioventricular synchrony and a predisposition to prolonged functional mitral regurgitation. Dual chamber pacing has been advocated as a method for restoring AV synchrony and improving left ventricular coordination in patients with severe congestive heart failure. Although initially favourable haemodynamic results using conventional right ventricular pacing were not confirmed by later studies, there has been a more consistent response in studies that have used biventricular pacing, the outcome depending critically on the native QRS duration and the paced AV delay.19 Patients should be considered for biventricular pacing if they have QRS duration greater than 150 ms, PR interval prolongation, and symptoms refractory to conventional medical treatment.