Dilated cardiomyopathy

• Signs and symptoms of heart failure are often the presenting symptoms of dilated cardiomyopathy (DCM). These include:
  • breathlessness;
  • reduced exercise tolerance; and
  • peripheral oedema.
• However, affected individuals can be asymptomatic, even if their cardiac dysfunction is advanced. Palpitations and pre-syncope or syncope may be the result of atrial or ventricular arrhythmias, or of atrio-ventricular conduction disease.
• Risk of sudden cardiac death due to ventricular arrhythmias is particularly elevated when there is severe systolic impairment. However, some genetic causes of DCM are associated with elevated risk of sudden cardiac death even when systolic function is relatively preserved. Thrombo-embolic disease, most commonly associated with atrial fibrillation, is another important cause of adverse events.
• DCM can co-exist within a multisystem or syndromic condition. For this reason, the assessment of an affected individual and their family should include clarification as to whether there is evidence of extra cardiac features such as skeletal myopathy, deafness, blindness and/or learning difficulties. For more information about the diagnostic criteria for DCM, see Adult with dilated (including arrhythmogenic) cardiomyopathy.
• DCM is characterised by:
  • injury to the left ventricular (LV) myocardium, which leads to systolic impairment and dilation of the left ventricle;
  • right ventricular (RV) involvement;
  • myocardial fibrosis;
  • atrial myopathy;
  • valvular regurgitation;
  • arrhythmias (atrial, ventricular and conduction block); and
  • other pathological features that may accompany the LV disease or develop as a secondary consequence.
• The most frequent causes of morbidity and mortality are:
  • progressive heart failure;
  • sudden arrhythmic death;
  • conduction disease; and
  • thrombo-embolism.
• DCM can affect otherwise healthy individuals, and its prevalence is much higher than previously suspected: over their lifetimes, as many as 1 in 250 people may be affected.
• In adulthood, DCM affects men more than women (3:1). Genetic forms account for between 20%–50% of cases and, importantly, a negative family history does not rule out a genetic cause.
• For the purposes of managing an individual with DCM and their family members, it is important to establish whether a non-genetic cause could be responsible.
• There are many genetic causes of familial DCM, and many of them are also associated with other forms of familial heart muscle disease. For example, different phenotypes are occasionally seen within the same family, despite each member having DCM or hypertrophic cardiomyopathy caused by the same genetic variant. In other cases, phenotypic characteristics could be alternatively classified – for example, a familial DCM with RV involvement versus an arrhythmogenic cardiomyopathy with LV involvement.

• Rare variants in more than 40 genes have been directly linked to DCM, and others remain to be discovered. Autosomal dominant inheritance is the most common form of transmission, but all inheritance patterns (autosomal recessive, X-linked, mitochondrial) have been identified. In some cases, DCM may be associated with a genetic condition with a broader phenotype, such as Duchenne muscular dystrophy.
• Variants in TTN (the gene that encodes for titin) are the most common cause of DCM.
• Genetic variants in cytoskeletal and sarcomeric protein genes are responsible for most familial forms of DCM. Collectively, variants in beta-myosin heavy chain (MYH7) and other components of the sarcomere are also among the more common causes of familial DCM.
• Genetic variants associated with poorer outcomes for DCM patients include those affecting FLNC, DSP and RBM20, among others.
• Some genetic causes of DCM are associated with more aggressive natural histories than others. In these more aggressive forms, cardiac complications (including ventricular arrhythmias, conduction disease, severe systolic impairment and myocardial fibrosis) occur earlier in the natural history of the disease.
  • An important example is the LMNA gene, which encodes lamin A and lamin C: in the cardiac disease caused by LMNA variants, conduction disease (left bundle branch block may be present early in the disease and is regarded as a clinical ‘red flag’) usually predates ventricular dysfunction, and sudden cardiac death due to ventricular arrhythmias can be an early feature.
• There are several other examples in which the presence of a specific genetic variant will have a strong influence on the natural history of DCM, meaning that a genomic diagnosis will, in turn, have profound implications for the affected individual’s treatment.
• • For instance, in the presence of forms of DCM that are caused by some specific genetic variants, an implantable cardiac defibrillator is considered even when there is only mild cardiac impairment.
  • As another example, genetic causes that are associated with conduction disease may indicate the use of a transvenous rather than a subcutaneous implantable cardiac defibrillator.

• Genomic testing should be offered and undertaken in specialist centres, where patients can be adequately informed of the implications of test result outcomes and where there is sufficient clinical expertise to interpret results appropriately.
• In DCM, genomic testing has utility in:
  • the management of affected individuals; and
  • predictive testing of family members.
• Diagnostic genomic testing should therefore be offered to most individuals who fulfil the diagnostic criteria for DCM. Once a genomic diagnosis has been made, the affected individual’s relatives should be offered predictive testing as part of a coordinated cascade approach to family screening.

Clinical management of individuals diagnosed with DCM often requires a multi-disciplinary approach, and should be performed in conjunction with a specialist inherited cardiac conditions service. A comprehensive approach to DCM management will provide the following.

• Confirmation of the diagnosis of familial or genetically determined DCM, including evaluation for alternative causes of LV systolic dysfunction and dilation (such as coronary disease, valve disease, hypertension, myocarditis, tachycardiomyopathy and anthracyclines).  A detailed personal and family history are key components of the assessment; following this, family screening and genomic testing play a central role in confirming a diagnosis of familial DCM.
• Assessment of symptom status, including the identification of the pathophysiological mechanisms most likely responsible for symptoms, and indications for symptomatic therapies. Symptomatic management most often addresses LV systolic impairment obstruction, but symptoms may also be the result of diastolic dysfunction, tachyarrhythmias, conduction disease and other mechanisms.
• Assessment of prognostic risks, including sudden arrhythmic death, thrombo-embolic disease, conduction disease and progressive heart failure. Implantable defibrillators, anticoagulation and heart failure therapies (device, pharmacological and transplant) may be indicated to mitigate risks. As described above, genomic testing plays an important role in prognostic assessment.
• An individualised evaluation that considers implications that DCM and its treatment may have for the patient’s lifestyle (in areas such as competitive and/or endurance sports and recreational drug-taking), life events (for example, pregnancy, anaesthesia and comorbidities) and livelihood (for example, for professional athletes and for licensing regulations in public transportation).
• Addressing implications for family members of an individual with a genetically determined condition. A genomic diagnosis greatly facilitates the accuracy, efficiency and cost-effectiveness of cascade family screening.

For clinicians

• NHS England: National Genomic Test Directory

References:

• McDonagh TA, Metra M, Adamo M and others. ‘2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) with the special contribution of the Heart Failure Association (HFA) of the ESC‘. European Heart Journal 2021: volume 42, issue 36, pages 3,599–3,726. DOI: 10.1093/eurheartj/ehab368

For patients

• British Heart Foundation: Dilated cardiomyopathy
• NHS Health A to Z: Cardiomyopathy