Is hypertrophic cardiomyopathy (HCM) a diagnosis of exclusion?

Hypertrophic Cardiomyopathy is NOT a Diagnosis of Exclusion

Hypertrophic cardiomyopathy (HCM) is a specific clinical entity characterized by unexplained left ventricular hypertrophy that requires positive diagnostic criteria rather than being a diagnosis of exclusion. 1, 2

Diagnostic Criteria for HCM

The diagnosis of HCM is based on the following specific criteria:

• Adults: LV wall thickness ≥15 mm in one or more myocardial segments measured by any imaging technique (echocardiography, CMR, or CT) 1, 2
• Borderline cases: Wall thickness of 13-14 mm may be diagnostic when present in:
  • Family members of HCM patients
  • Patients with positive genetic testing 2
• Children: LV wall thickness more than two standard deviations greater than the predicted mean (z-score >2) 1
• First-degree relatives: LV wall thickness ≥13 mm in one or more LV myocardial segments 1

Systematic Diagnostic Approach

HCM diagnosis requires a positive identification of unexplained LV hypertrophy plus systematic exclusion of secondary causes that could produce similar hypertrophy:

1. Imaging confirmation of increased LV wall thickness
2. Exclusion of secondary causes capable of producing the observed magnitude of hypertrophy:
   • Systemic hypertension
   • Aortic stenosis
   • Athletic training ("athlete's heart")
   • Other cardiac or systemic diseases 1, 2
3. Evaluation for phenocopies that can mimic HCM:
   • Metabolic disorders (Fabry disease)
   • Storage diseases
   • Mitochondrial diseases
   • Infiltrative diseases (amyloidosis)
   • RASopathies
   • Other genetic syndromes 2

Diagnostic Workup

The European Society of Cardiology recommends specific laboratory tests to exclude phenocopies:

• Hemoglobin
• Renal function tests
• Liver transaminases
• Creatine phosphokinase
• Alpha-galactosidase A
• Immunoglobulin free light chain assay
• Fasting glucose
• Brain natriuretic peptide and troponin T
• Thyroid function tests 2

Common Diagnostic Challenges

• Athlete's heart vs. HCM: Distinguished by LV cavity dimension (if enlarged, favoring athlete's heart), diastolic function, pattern of LV hypertrophy, and response to deconditioning 1, 2
• Hypertensive heart disease vs. HCM: Consider HCM when LV thickness is ≥25 mm or when LVOT obstruction with systolic anterior motion and mitral-septal contact is present 1
• Focal hypertrophy: About one-third of HCM patients have segmental wall thickening involving only a small portion of the left ventricle 1
• Phenotype-negative/genotype-positive individuals: Family members with disease-causing sarcomere mutations but without evidence of LV hypertrophy 1

Role of Genetic Testing

• Genetic testing is recommended in patients fulfilling diagnostic criteria for HCM to enable cascade genetic screening of relatives 1
• Approximately 60% of HCM cases have identifiable genetic mutations, most commonly in genes encoding sarcomeric proteins (MYH7 and MYBPC3 account for ~50% of cases) 3
• Genetic testing helps distinguish sarcomeric HCM from phenocopies that require different management approaches 2

HCM is a specific clinical entity with positive diagnostic criteria that requires systematic evaluation to confirm the diagnosis and exclude secondary causes and phenocopies. This approach makes it a positive diagnosis rather than a diagnosis of exclusion.