What are the steps to diagnose hypertrophic cardiomyopathy?

Diagnostic Approach to Hypertrophic Cardiomyopathy

Transthoracic echocardiography (TTE) is the cornerstone diagnostic test and should be performed first in all patients with suspected HCM, combined with a 12-lead ECG. 1, 2

Initial Diagnostic Workup

Primary Imaging and Electrocardiography

• Obtain a transthoracic echocardiogram (TTE) to measure left ventricular wall thickness and assess for dynamic obstruction, myocardial function, and mitral valve abnormalities 1, 2

• Perform a 12-lead ECG as part of the initial evaluation, recognizing that abnormalities are present in 75-95% of HCM patients 1, 2

• Order 24-hour ambulatory (Holter) monitoring in the initial evaluation to detect ventricular tachycardia and identify candidates for ICD therapy 1, 2

Diagnostic Criteria Based on Imaging

For adults: HCM is defined by a left ventricular wall thickness ≥15 mm in one or more LV myocardial segments (measured by echocardiography, cardiac MRI, or CT) that is not explained solely by loading conditions such as hypertension or aortic stenosis 1, 2

For first-degree relatives of patients with confirmed HCM: A wall thickness ≥13 mm is considered diagnostic 1, 2

For children: The diagnosis requires an LV wall thickness more than two standard deviations greater than the predicted mean (z-score >2) 1, 2

Systematic Search for Underlying Etiology

Once unexplained left ventricular hypertrophy is detected, a systematic evaluation is essential to differentiate sarcomeric HCM from phenocopies 1

History and Physical Examination

• Obtain detailed family history including sudden cardiac death, heart failure, and known HCM in relatives 1

• Assess for non-cardiac symptoms that may suggest phenocopies: peripheral neuropathy, renal dysfunction, or hearing loss (suggesting Fabry disease or amyloidosis) 1

• Evaluate for syndromic features such as dysmorphic features, skeletal abnormalities, or developmental delay that may indicate metabolic or syndromic causes 1

Laboratory Testing

The European Society of Cardiology recommends specific laboratory tests to identify phenocopies 1:

• Hemoglobin to exclude anemia that may exacerbate symptoms 1

• Renal function and urinalysis (impaired GFR and proteinuria may indicate amyloidosis, Fabry disease, or mitochondrial disorders) 1

• Liver transaminases and creatine phosphokinase (elevated in metabolic disorders such as Danon disease and mitochondrial disease) 1

• Plasma/leucocyte alpha-galactosidase A in men aged >30 years (low or undetectable levels indicate Fabry disease; note that levels may be normal in affected females, requiring genetic testing) 1

• Serum immunoglobulin free light chain assay, serum and urine electrophoresis if amyloidosis is suspected 1

• Fasting glucose (may be elevated in mitochondrial disorders or low in fatty acid/carnitine disorders) 1

• Brain natriuretic peptide (BNP/NT-proBNP) and troponin T (elevated levels are associated with higher risk of cardiovascular events, heart failure, and death) 1

• Thyroid function tests at diagnosis and every 6 months if treated with amiodarone 1

Genetic Testing Strategy

Genetic testing is reasonable in the index patient to facilitate identification of first-degree family members at risk for developing HCM 1

• Offer genetic counseling and testing to patients who meet diagnostic criteria for HCM, as this enables cascade screening of relatives 1, 2

• Standard multigene panels should evaluate sarcomeric genes (most commonly MYBPC3 and MYH7) as well as genetic conditions that mimic HCM but require different management 3

• Genetic testing identifies causative variants in 30-60% of patients, with higher yield in those with family history of HCM 3

Important Caveats for Genetic Testing

• Genetic testing is NOT indicated in relatives when the index patient does not have a definitive pathogenic mutation 1

• Ongoing clinical screening is NOT indicated in genotype-negative relatives in families with known HCM mutations 1, 2

• The usefulness of genetic testing for sudden cardiac death risk stratification is uncertain 1

Family Screening Protocol

For First-Degree Relatives

Screen all first-degree relatives with both TTE and 12-lead ECG unless the family member is genotype-negative in a family with known definitive mutations 1, 2

Screening Intervals Based on Age

For children and adolescents (age 12-18/21 years):

• Perform TTE and ECG every 12-18 months 1, 2
• Start screening by age 12 years, or earlier if growth spurt, signs of puberty, plans for intense competitive sports, or family history of sudden cardiac death 1, 2

For adults (>18/21 years):

• Perform TTE and ECG at least every 5 years 1, 2

For genotype-positive/phenotype-negative individuals:

• Perform serial ECG, TTE, and clinical assessment every 12-18 months in children/adolescents and approximately every 5 years in adults 1, 2

Advanced Imaging Considerations

• Exercise TTE can be useful in detecting and quantifying dynamic left ventricular outflow tract (LVOT) obstruction in patients without resting obstruction 1, 2

• Cardiac MRI should be considered when echocardiography is inconclusive, to assess for apical HCM, or to evaluate myocardial fibrosis 1

• Transesophageal echocardiography (TEE) is useful if TTE is inconclusive for clinical decision-making, to exclude subaortic membrane, assess mitral valve abnormalities, or plan for septal reduction therapy 1

Common Diagnostic Pitfalls to Avoid

Distinguish HCM from physiological hypertrophy in athletes (athlete's heart typically shows wall thickness <13 mm, normal or enlarged LV cavity, and regression with detraining) 1

Differentiate from hypertensive heart disease by considering the degree of hypertrophy relative to blood pressure elevation and presence of other HCM features (asymmetric septal hypertrophy, systolic anterior motion, family history) 1

Recognize isolated basal septal hypertrophy in elderly patients, which may represent a distinct entity rather than classic HCM 1

Identify late-stage HCM presenting with dilated and/or hypokinetic left ventricle and LV wall thinning (end-stage or "burned-out" phase) 1

Screen for drug-induced LVH from chronic use of anabolic steroids, tacrolimus, or hydroxychloroquine, though these rarely cause wall thickness ≥15 mm 1