Causes of Dilated Cardiomyopathy
Dilated cardiomyopathy results from genetic mutations in approximately 30-50% of cases (higher in children), with the remaining cases caused by acquired factors including alcohol, viral myocarditis, cardiotoxic drugs, arrhythmias, metabolic disorders, and autoimmune diseases. 1, 2
Genetic and Familial Causes
Genetic mutations are the single most important cause category, accounting for up to 50% of all dilated cardiomyopathy cases. 1, 2
- Autosomal dominant inheritance is the most common pattern, typically presenting in the third decade with progressive disease 1
- Genes affecting cytoskeletal-sarcomere connections are most frequently implicated, disrupting the mechanical link between contractile apparatus and cellular structure 1
- TTN (titin gene) mutations represent the most common single genetic cause identified to date 3
- LMNA gene mutations (encoding nuclear lamins) cause particularly aggressive disease with high arrhythmia risk and early need for device therapy 1
X-Linked Dilated Cardiomyopathy
- Dystrophin gene mutations cause X-linked cardiomyopathy presenting in males during teen years to early 20s with rapid progression to heart failure or sudden death 1, 2
- Elevated serum creatine kinase distinguishes these patients from other forms 1
- Female carriers develop milder disease in the fifth decade with slower progression 1
- Tafazzin gene mutations cause Barth syndrome, presenting in male infants with neutropenia, 3-methylglutaconic aciduria, and cardiolipin deficiency 1
Clinical Implications of Genetic Testing
- Family screening reveals disease in 30% of first-degree relatives when echocardiography is performed, even in "sporadic" cases 1, 2
- Genetic testing identifies a causative mutation in 30-40% of patients when comprehensive panels are used 1
- Reduced penetrance is common, meaning some individuals inherit the mutation but never develop clinical disease 1
Acquired Causes
Toxic and Substance-Related
Alcohol-induced cardiomyopathy is particularly common in men aged 30-55 years with heavy drinking history 2
- Patients frequently underreport alcohol consumption, requiring careful questioning about current and past use 2
- Genetic susceptibility likely plays a role in determining who develops cardiomyopathy from alcohol 2
- Cocaine and methamphetamine can cause dilated cardiomyopathy through direct cardiotoxic effects 2
- Chemotherapeutic agents (anthracyclines, trastuzumab) are well-established causes 4, 5
Infectious and Inflammatory
Viral myocarditis accounts for up to 75% of myocardial infarction with non-obstructive coronary arteries (MINOCA) presentations and may evolve into dilated cardiomyopathy 2
- Enteroviruses (especially Coxsackie B), adenoviruses, and parvovirus B19 are the most common viral pathogens in North America and Western Europe 6
- Recent viral syndrome preceding heart failure symptoms suggests myocarditis, though serum antibody titers have low diagnostic yield 2
- HIV-associated cardiomyopathy occurs in approximately 8% of asymptomatic HIV-positive individuals 2
- HIV screening should be performed in younger patients with unexplained dilated cardiomyopathy, particularly those with risk factors 2
- Chagas disease (Trypanosoma cruzi) causes progressive myocardial damage through parasite persistence and autoimmune responses, with 50% mortality within 4 years of heart failure onset 7
Arrhythmia-Induced Cardiomyopathy
PVC burden ≥24% is independently associated with cardiomyopathy, though the minimum threshold appears to be 10% 1, 7
- Sustained ventricular rate ≥130 bpm during atrial fibrillation can itself induce dilated cardiomyopathy 2
- Radiofrequency ablation normalizes ejection fraction in 82% of patients with PVC-induced cardiomyopathy within 6 months 1, 7
- Right ventricular outflow tract is the most common PVC origin (52% of cases) 1
- Clues that PVCs are causative include high burden (>10-15%), epicardial origin, and improvement with suppression or ablation 2
- Tachycardia-induced cardiomyopathy was found in 6.8% of a referral heart failure population 1
Metabolic and Endocrine
Both hyperthyroidism and hypothyroidism can cause or contribute to heart failure 2, 7
- Measure thyroid-stimulating hormone in all patients with newly diagnosed dilated cardiomyopathy 2, 7
- Hemochromatosis screening with fasting transferrin saturation is recommended, as mutated alleles are common in Northern European descent 2, 7
Autoimmune and Rheumatologic
Systemic lupus erythematosus increases heart failure hospitalization risk 1-3 times, with highest risk in women <45 years 7
- Three main mechanisms in SLE: atherosclerosis (2-10 fold increased MI risk), myocarditis/inflammation, and drug-induced impairments 7
- Rheumatoid arthritis and other connective tissue disorders can cause dilated cardiomyopathy 2
- Sarcoidosis should be considered, particularly when cardiac MRI shows characteristic patterns 2
Peripartum and Stress-Related
Peripartum cardiomyopathy presents during the last month of pregnancy or within 5 months postpartum 7
- Risk factors include multiparity, advanced maternal age, obesity, and hypertension 7
- Stress-induced (Takotsubo) cardiomyopathy presents with acute, usually reversible LV dysfunction triggered by emotional or physical stress, mediated by catecholamine excess 7
Neuromuscular Disorders
Myotonic dystrophy type 1 causes dilated cardiomyopathy in approximately 80% of patients, with cardiac manifestations being a leading cause of death 7
- DM1 results from CTG trinucleotide repeat expansion in the DMPK gene, with longer repeats correlating with earlier onset and more severe disease 7
- Cardiac involvement is particularly high-risk in younger patients aged 2-30 years, manifesting primarily as progressive conduction defects and tachyarrhythmias 7
Critical Diagnostic Pitfalls
Approximately half of patients with heart failure and reduced ejection fraction have normal or near-normal coronary arteries, underscoring the prevalence of non-ischemic mechanisms 2
- Non-ischemic cardiomyopathy can produce perfusion deficits and regional wall-motion abnormalities that mimic ischemic heart disease on non-invasive testing 2
- A 3-generation family history is essential when assessing cardiomyopathy causes, as genetic mutations account for 30-50% of cases 7
- Cardiac MRI should be considered at least once in every dilated cardiomyopathy patient for tissue characterization (fibrosis, edema, infiltration) to suggest underlying cause 2, 7
- Routine endomyocardial biopsy is not recommended for initial work-up because histology typically shows nonspecific findings that do not guide management 2
- Biopsy may be reserved for cases where a specific, treatable condition is strongly suspected based on other clinical data (e.g., infiltrative disease, sarcoidosis) 2
Heterogeneity and Evolution
Some diseases do not have uniformly static expression but evolve from one category to another during their natural clinical course 1