What are the causes of Dilated Cardiomyopathy (DCM)?

Causes of Dilated Cardiomyopathy

Dilated cardiomyopathy results from either genetic mutations (accounting for 30-50% of cases, with 30-40% having identifiable pathogenic variants) or a broad spectrum of acquired conditions including viral myocarditis, cardiotoxic substances, endocrine disorders, peripartum state, sustained tachyarrhythmias, autoimmune diseases, and nutritional deficiencies. 1, 2

Primary (Genetic/Familial) Causes

Genetic mutations are responsible for 30-50% of all DCM cases, with identifiable pathogenic variants found in 30-40% of these patients. 1, 3, 2 These mutations affect:

• Cytoskeletal proteins (structural framework of cardiac myocytes) 1, 2
• Sarcomeric proteins (contractile apparatus components) 1, 2
• Sarcolemmal proteins (cell membrane structures) 1, 2
• Nuclear envelope proteins (including lamin A/C, which carries particularly high arrhythmic risk) 1, 2
• Desmosomal proteins (cell-to-cell adhesion structures) 4

Familial DCM accounts for 30-50% of cases, making three-generation family history assessment mandatory in every patient. 1, 3

Secondary (Acquired) Causes

Infectious/Inflammatory

• Viral myocarditis represents a well-established pathway from acute inflammation to chronic DCM through cell-mediated autoimmune mechanisms triggered by viral infection. 1, 2, 4
• Chagas disease (parasitic infection endemic to Latin America) causes progressive myocardial damage. 1
• Autoimmune disorders including systemic lupus erythematosus, dermatomyositis, rheumatoid arthritis, scleroderma, and polyarteritis nodosa cause immune-mediated myocardial injury. 1, 2

Cardiotoxic Substances

• Alcohol is a common and potentially reversible cause when consumption is stopped early in the disease course. 1, 2, 4
• Chemotherapeutic agents, particularly anthracyclines (doxorubicin, daunorubicin) and other cancer treatments (trastuzumab, tyrosine kinase inhibitors), cause direct myocyte injury with dose-dependent cardiotoxicity. 1, 2, 4
• Cocaine and amphetamines cause direct myocardial toxicity. 4

Endocrine and Metabolic Disorders

• Diabetes mellitus contributes to secondary cardiomyopathy through metabolic derangements, oxidative stress, and microvascular dysfunction. 1, 2
• Thyroid disorders (both hypothyroidism and hyperthyroidism) affect cardiac contractility and loading conditions. 1, 2
• Nutritional deficiencies including thiamine (beriberi), carnitine, and selenium cause reversible DCM when severe. 1, 2

Pregnancy-Related

• Peripartum cardiomyopathy presents during the last month of pregnancy or within 5 months postpartum, with risk factors including multiparity, advanced maternal age, obesity, hypertension, and African ancestry. 1, 2, 4

Arrhythmia-Induced

• Tachycardia-induced cardiomyopathy results from chronic supraventricular or ventricular arrhythmias with sustained rapid rates (typically >100-120 bpm for weeks to months), causing reversible systolic dysfunction if the arrhythmia is controlled. 1, 2, 4

Infiltrative and Systemic Diseases

• Amyloidosis (light chain or transthyretin) causes restrictive physiology but can present with dilated phenotype. 1, 2
• Hemochromatosis (iron overload) causes myocardial iron deposition with progressive dysfunction. 1, 2
• Sarcoidosis causes granulomatous inflammation with patchy myocardial involvement and high arrhythmic risk. 1, 2

Stress-Related

• Stress-induced (Tako-tsubo) cardiomyopathy presents with acute, usually reversible LV dysfunction triggered by emotional or physical stress, mediated by catecholamine excess, typically affecting apical segments. 2

Hemodynamic Overload

• Long-standing uncontrolled hypertension leads to "burned-out" dilated cardiomyopathy after initial concentric hypertrophy, with progressive chamber dilation and declining ejection fraction representing end-stage hypertensive heart disease. 1, 2
• Coronary artery disease with prior myocardial infarction (ischemic cardiomyopathy) causes ventricular dilation and systolic dysfunction, though this is technically excluded from the DCM definition. 1

Critical Clinical Pitfalls

5-15% of patients with apparently acquired DCM harbor pathogenic genetic variants, meaning genetic testing should be performed even when an acquired cause is identified, as dual pathology may exist. 4

The diagnostic workup must always consider both genetic and acquired factors simultaneously, as they are not mutually exclusive and identifying both influences prognosis and family screening requirements. 4, 5

Many patients present with minor structural abnormalities or arrhythmogenic phenotypes before overt heart failure symptoms, including isolated LV dilation (present in 25% of relatives of familial DCM) or early arrhythmias/conduction defects, particularly in lamin A/C mutations and neuromuscular disorders. 1