Familial dilated cardiomyopathy

Familial dilated cardiomyopathy (familial DCM) is a genetic form of heart muscle disease characterized by dilation (enlargement) of the left ventricle or both ventricles and impaired systolic function (reduced ability of the heart to pump blood effectively), occurring in the absence of coronary artery disease, valvular disease, or other conditions that could explain the degree of myocardial dysfunction. It is defined as familial when dilated cardiomyopathy is diagnosed in two or more closely related family members. The condition primarily affects the cardiovascular system and can lead to progressive heart failure, arrhythmias (abnormal heart rhythms), thromboembolic events (blood clots), and sudden cardiac death. Key symptoms include shortness of breath (dyspnea), fatigue, exercise intolerance, peripheral edema (swelling of the legs and ankles), palpitations, and in some cases syncope (fainting). The disease may remain asymptomatic for years before clinical manifestation, and family members may carry pathogenic variants without showing overt signs of disease. Familial DCM is genetically heterogeneous, with mutations identified in over 40 genes, including those encoding sarcomeric proteins (TTN, MYH7, TNNT2), cytoskeletal proteins (DES, LMNA), and ion channel-related proteins (SCN5A). Mutations in the TTN gene (encoding titin) are the most common cause, accounting for approximately 20-25% of familial cases. LMNA mutations are particularly notable as they are associated with conduction system disease and a higher risk of sudden cardiac death. Treatment follows standard heart failure management guidelines and includes angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor-neprilysin inhibitors (ARNIs), beta-blockers, mineralocorticoid receptor antagonists, and SGLT2 inhibitors. Diuretics are used for symptom relief in patients with fluid overload. Implantable cardioverter-defibrillators (ICDs) may be recommended for patients at high risk of sudden cardiac death, and cardiac resynchronization therapy (CRT) may benefit those with conduction delays. In advanced cases refractory to medical therapy, heart transplantation or mechanical circulatory support devices may be considered. Genetic counseling and cascade screening of at-risk family members with echocardiography and electrocardiography are essential components of management.

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