What are the causes of non-ischemic cardiomyopathy?

Causes of Non-Ischemic Cardiomyopathy

Overview

Non-ischemic cardiomyopathy encompasses a diverse spectrum of myocardial disorders affecting patients without obstructive coronary artery disease, with approximately 50% of heart failure patients with reduced ejection fraction having normal or near-normal coronary arteries. 1 Most cases are idiopathic (no identifiable cause), but systematic evaluation can identify specific etiologies in many patients. 1

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Major Etiological Categories

Genetic and Familial Causes

• Genetic mutations account for 30-50% of dilated cardiomyopathy cases, with even higher rates in younger patients. 2
• Up to 30% of "idiopathic" cases demonstrate familial clustering when first-degree relatives undergo echocardiographic screening, making a 3-generation family history essential. 3, 2
• Common genetic mutations involve cytoskeletal proteins, sarcomere proteins, and nuclear envelope proteins. 2
• X-linked dilated cardiomyopathy (dystrophin gene mutations) typically presents in males during teen years to early 20s with elevated creatine kinase levels. 2

Toxic and Substance-Related Causes

• Alcohol-induced cardiomyopathy is particularly common in men aged 30-55 years with heavy drinking history and probable genetic susceptibility. 3, 2
• Chemotherapeutic agents including anthracyclines, tyrosine kinase inhibitors, trastuzumab, and interferons can cause cardiomyopathy. 3
• Recreational drugs such as cocaine and methamphetamine lead to cardiomyopathy. 1, 3, 2
• Patients often underreport alcohol consumption, requiring careful questioning about current and past use. 2

Infectious and Inflammatory Causes

• Viral myocarditis accounts for up to 75% of patients presenting with myocardial infarction with non-obstructive coronary arteries (MINOCA) and is the most common infectious cause. 3, 2, 4
• Bacterial, fungal, or tuberculosis infections can cause cardiomyopathy. 3
• Chagas disease (Trypanosoma cruzi) is endemic in Central and South America. 3
• HIV-associated cardiomyopathy occurs in approximately 8% of asymptomatic HIV-positive individuals, warranting HIV screening in selected patients with unexplained dilated cardiomyopathy, particularly younger patients with risk factors. 3, 2
• Recent viral syndrome preceding heart failure symptoms suggests myocarditis, though serum antibody titers have low yield and uncertain therapeutic implications. 2

Metabolic and Endocrine Causes

• Thyroid disorders (both hyperthyroidism and hypothyroidism) can cause or contribute to heart failure, requiring thyroid-stimulating hormone measurement in all patients. 1, 3, 2
• Diabetes mellitus and obesity are associated with increased cardiomyopathy risk. 1, 3
• Hemochromatosis should be screened with fasting transferrin saturation, as mutated alleles are common in Northern European descent. 1, 3, 2
• Acromegaly and pheochromocytoma can cause cardiomyopathy. 3
• Other metabolic storage diseases can lead to cardiomyopathy. 3

Autoimmune and Inflammatory Disorders

• Systemic lupus erythematosus, rheumatoid arthritis, and other connective tissue disorders can cause dilated cardiomyopathy. 2
• Sarcoidosis can cause cardiomyopathy, though characteristic changes are often missed on histological evaluation. 1, 2

Arrhythmia-Induced Cardiomyopathy

• Tachycardia-induced cardiomyopathy from frequent premature ventricular contractions (PVCs) or sustained tachyarrhythmias. 2
• Key diagnostic clues include: high PVC burden (>10-15% of total beats), epicardial origin (particularly right ventricular outflow tract), and improvement in ejection fraction with PVC suppression or ablation. 2

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Specific Clinical Entities

Peripartum Cardiomyopathy

• Occurs in late pregnancy or within 5 months postpartum, with an incidence of 1 in 2,500-4,000 births in the United States. 3

Stress-Induced (Takotsubo) Cardiomyopathy

• Characterized by transient left ventricular systolic dysfunction, often triggered by emotional or physical stressors. 3
• Incidental coronary artery disease can be found in 10% of patients, complicating diagnosis. 3

Left Ventricular Non-Compaction

• Characterized by prominent trabeculations due to persistent embryonic sinusoids, leading to left ventricular failure, thromboembolism, and arrhythmias. 3

Muscular Dystrophies

• Can produce dilated cardiomyopathy presenting with heart failure, arrhythmias, or sudden death. 3

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Diagnostic Approach Considerations

Imaging

• Echocardiography typically shows dilated ventricle and global systolic dysfunction (not segmental as in ischemic disease). 3, 2
• Cardiac MRI should be considered at least once in every dilated cardiomyopathy patient for tissue characterization (fibrosis, edema, infiltration) and to suggest underlying cause. 2

Endomyocardial Biopsy

• Not indicated in routine evaluation of cardiomyopathy, as most patients show nonspecific changes (hypertrophy, cell loss, fibrosis). 1
• Risk of serious complication is less than 1% in experienced centers. 1
• May be helpful when specific diagnoses are already suspected: hemochromatosis, endocardial fibroelastosis, Loeffler's syndrome, giant-cell myocarditis (which progresses rapidly to death and may require mechanical support or immediate transplantation), or to assess continued anthracycline therapy risk. 1, 3

Coronary Evaluation

• Coronary angiography appears reasonable in young patients to exclude congenital coronary anomalies. 1
• Only coronary arteriography can reliably demonstrate or exclude obstructed coronary vessels, as perfusion deficits and segmental wall-motion abnormalities suggestive of coronary disease are commonly present in nonischemic cardiomyopathy on noninvasive imaging. 1

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Critical Clinical Pitfalls

• Perfusion deficits and segmental wall-motion abnormalities can occur in nonischemic cardiomyopathy, mimicking ischemic disease on noninvasive testing. 1
• Patients frequently underreport alcohol consumption, requiring persistent questioning. 2
• Familial cases may be missed without systematic screening of first-degree relatives. 3, 2
• "Hot phases" of cardiomyopathy with acute presentations (chest pain, troponin rise, myocardial edema) indicate high risk for adverse remodeling and require prompt recognition. 5