What causes cardiomegaly (enlarged heart)?

Causes of Cardiomegaly (Enlarged Heart)

Cardiomegaly is primarily caused by genetic mutations in sarcomere protein genes, hypertension, coronary artery disease, and various metabolic and systemic disorders that lead to left ventricular hypertrophy or chamber dilation. 1

Primary Causes of Cardiomegaly

Genetic/Inherited Causes

• Hypertrophic Cardiomyopathy (HCM)
  • Most commonly caused by mutations in sarcomere protein genes 1
  • MYH7 (myosin heavy chain 7) and MYBPC3 (myosin-binding protein C) account for 70% of gene-positive cases 1
  • Other genes include TNNI3, TNNT2, TPM1, MYL2, MYL3, and ACTC1 1

Acquired Causes

Cardiovascular Conditions

• Hypertension - chronic pressure overload leading to left ventricular hypertrophy 1
• Coronary Artery Disease - can lead to ischemic cardiomyopathy 1, 2
• Valvular Heart Disease - pressure or volume overload from stenotic or regurgitant valves 1
• Myocarditis - inflammation can cause transient ventricular hypertrophy 1

Metabolic and Systemic Disorders

• Endocrine Disorders:

  • Acromegaly - excess growth hormone causes concentric biventricular hypertrophy 1, 3, 4
  • Pheochromocytoma - catecholamine excess leads to LVH 1
  • Diabetes - can cause transient ventricular hypertrophy in infants of diabetic mothers 1

• Storage Diseases:

  • Glycogen Storage Diseases - Pompe, Danon 1
  • Lysosomal Storage Diseases - Anderson-Fabry 1
  • Amyloidosis - familial ATTR, wild type TTR (senile), AL amyloidosis 1

• Other Systemic Disorders:

  • Mitochondrial Diseases - MELAS, MERFF 1
  • Neuromuscular Diseases - Friedreich's ataxia 1
  • Malformation Syndromes - Noonan, LEOPARD, Costello, CFC 1

Drug-Induced Cardiomegaly

• Anabolic steroids - chronic use can cause LVH 1
• Tacrolimus - immunosuppressant that can cause LVH 1
• Hydroxychloroquine - antimalarial that can cause LVH 1
• Corticosteroids - long-term use can contribute to LVH 1

Pathophysiological Mechanisms

Pressure Overload

• Increased afterload (hypertension, aortic stenosis) leads to concentric hypertrophy 1
• Myocytes increase in width rather than length, resulting in thickened walls without chamber dilation 1

Volume Overload

• Increased preload (valvular regurgitation) leads to eccentric hypertrophy 1
• Myocytes increase in length, resulting in chamber dilation 1

Metabolic Dysfunction

• In diabetic cardiomyopathy, impaired glucose utilization leads to increased fatty acid oxidation 1
• Lipid accumulation in cardiomyocytes causes lipotoxicity and contractile dysfunction 1

Diastolic Dysfunction

• Common in cardiomegaly, especially in HCM 1
• Results from impaired ventricular relaxation and increased chamber stiffness 1
• Contributes to symptoms of dyspnea and exercise intolerance 1

Risk Factors

• Obesity - strongly associated with cardiomegaly and sudden cardiac death 2
• Age - risk increases with advancing age 3
• Disease duration - longer duration of conditions like acromegaly increases risk 3, 5
• Race/ethnicity - possible differences in prevalence, though may reflect healthcare disparities 1, 2

Diagnostic Criteria

Adults

• LV wall thickness ≥15 mm in one or more myocardial segments on imaging (echocardiography, CMR, or CT) 1
• Lesser degrees (13-14 mm) can be diagnostic in family members of HCM patients or with positive genetic testing 1

Children

• LV wall thickness more than two standard deviations greater than predicted mean (z-score >2) 1

Common Pitfalls in Diagnosis

1. Failure to distinguish physiologic from pathologic hypertrophy:

   • Athletic heart vs. HCM 1
   • Hypertensive heart disease vs. HCM 1

2. Overlooking late-phase disease presentation:

   • Dilated and/or hypokinetic left ventricle with wall thinning 1

3. Isolated basal septal hypertrophy in elderly people - may be a normal variant 1

4. Misdiagnosing transient conditions:

   • Myocarditis can mimic HCM but is usually transient 1

5. Not recognizing cardiomegaly as an arrhythmogenic substrate:

   • Cardiomegaly is a common finding in sudden cardiac death cases 2

Understanding the diverse causes of cardiomegaly is essential for proper diagnosis and management. The condition requires thorough evaluation to identify the underlying etiology, as treatment approaches vary significantly depending on the cause.