What is the diagnostic approach for hypertrophic cardiomyopathy (HCM)?

Diagnostic Approach to Hypertrophic Cardiomyopathy

Diagnose HCM using transthoracic echocardiography demonstrating left ventricular wall thickness ≥15 mm in any segment (or ≥13 mm in first-degree relatives of confirmed cases) that cannot be explained by loading conditions, combined with a 12-lead ECG and detailed family history. 1, 2

Initial Mandatory Testing

Transthoracic Echocardiography (Primary Diagnostic Tool)

• TTE is the cornerstone diagnostic test and must be performed in all patients with suspected HCM 1, 2
• Measure maximum diastolic wall thickness using 2D short-axis views in all LV segments from base to apex 3
• Perform imaging at rest and during Valsalva maneuver in sitting and semi-supine positions, then standing if no gradient is provoked 3
• Assess for left ventricular outflow tract obstruction, measuring peak instantaneous gradients 3, 1
• Evaluate LV diastolic function including pulsed Doppler of mitral valve inflow, tissue Doppler velocities at mitral annulus, pulmonary vein flow velocities, pulmonary artery systolic pressure, and left atrial size/volume 3

12-Lead ECG

• Obtain a 12-lead ECG in all patients with suspected HCM, as abnormalities are present in 75-95% of cases 1, 2
• Look for left ventricular hypertrophy patterns, conduction abnormalities, or superior QRS axis 4

24-Hour Holter Monitoring

• Perform ambulatory ECG monitoring in the initial evaluation to detect ventricular tachycardia and identify ICD candidates 2

Diagnostic Criteria

Adults

• Wall thickness ≥15 mm in one or more LV myocardial segments not explained solely by loading conditions 2
• In first-degree relatives of confirmed HCM patients, ≥13 mm is diagnostic 1, 2
• Do not dismiss 13-14 mm wall thickness in the context of positive family history, as this may represent early disease 4

Children

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

Essential Clinical History Components

Family Pedigree

• Obtain a detailed 3-generation family pedigree documenting relatives with HCM, unexplained sudden death, heart failure, cardiac transplantation, or pacemaker/ICD implants 1, 4

Symptom Assessment

• Document dyspnea, chest pain, palpitations, syncope, and lightheadedness, particularly in relation to exertion 1

Physical Examination with Provocative Maneuvers

• Perform Valsalva, squat-to-stand, passive leg raising, and walking to elicit left ventricular outflow tract obstruction 1

Syndromic Features

• Assess for extracardiac manifestations including ataxia, hearing/visual impairment, cognitive abnormalities, and neurodevelopmental issues that suggest phenocopy conditions 1
• Look for angiokeratomas and corneal opacities on slit-lamp examination if Fabry disease is suspected 4

Exercise Testing for Dynamic Obstruction

• In symptomatic patients with resting or provoked peak instantaneous LV outflow tract gradient <50 mm Hg, perform exercise TTE in standing, sitting, or semi-supine position to detect provocable LVOTO and exercise-induced mitral regurgitation 3, 1
• Exercise echocardiography is critical when resting gradients are absent but symptoms suggest dynamic obstruction 1, 4

Advanced Imaging Considerations

Cardiac MRI

• Obtain cardiac MRI when echocardiography is inadequate or when additional information about magnitude and distribution of hypertrophy would impact management 4

Contrast-Enhanced Echocardiography

• Consider TTE with LV cavity opacification using intravenous echocardiographic contrast agents in patients with suboptimal images or suspected LV apical hypertrophy or aneurysm as an alternative to CMR 3

Transesophageal Echocardiography

• Consider TOE when the mechanism of LVOTO is unclear, when assessing mitral valve apparatus before septal reduction procedures, or when severe mitral regurgitation from intrinsic valve abnormalities is suspected 3

Genetic Testing Protocol

• Perform genetic testing in the index patient once HCM is confirmed to facilitate cascade screening of first-degree family members 1, 4
• Ensure counseling by someone knowledgeable in cardiovascular genetics accompanies testing 1
• Genetic testing identifies mutations in 60-80% of cases but is complex and costly 5

Family Screening Algorithm

First-Degree Relatives

• Screen all first-degree relatives with physical examination, ECG, and TTE unless they are genotype-negative in families with known definitive mutations 1, 2, 4

Screening Intervals

• Children: every 12-18 months starting at age 12 years (or earlier if growth spurt or signs of puberty are evident) 1, 2, 4
• Adults: approximately every 5 years if asymptomatic 1, 2, 4
• Genotype-positive individuals without phenotype: every 12-18 months in children/adolescents, every 5 years in adults 2

Discontinuation of Screening

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

Critical Differential Diagnoses to Exclude

Age-Specific Considerations

• In neonates/infants: inherited metabolic disorders and congenital dysmorphic syndromes 1
• In men >65 years: wild-type TTR-related amyloidosis 1

Secondary Causes

• Long-standing systemic hypertension must be documented and distinguished from primary cardiomyopathy 1, 4
• Renal disease 1
• Infiltrative diseases, particularly amyloidosis 1, 4

Physiologic vs. Pathologic Hypertrophy

• Athletic remodeling must be differentiated from pathologic hypertrophy, particularly in competitive athletes 1, 4

Fabry Disease

• Measure alpha-galactosidase A activity in plasma or leukocytes if Fabry disease is suspected (diagnostic in males; females require genetic testing due to normal enzyme activity) 4

Echocardiographic Features Suggesting Specific Etiologies

The following findings should prompt consideration of alternative diagnoses 3:

• Increased interatrial septum thickness: amyloidosis
• Increased AV valve thickness: amyloidosis or Anderson-Fabry disease
• Increased RV free wall thickness: amyloidosis, myocarditis, Anderson-Fabry disease, Noonan syndrome
• Mild to moderate pericardial effusion: amyloidosis or myocarditis
• Ground-glass appearance: amyloidosis
• Concentric LVH: glycogen storage disease, Anderson-Fabry disease, PRKAG2 mutations
• Extreme concentric LVH (wall thickness ≥30 mm): Danon disease or Pompe disease
• Global LV hypokinesia: mitochondrial disease, TTR-related amyloidosis, PRKAG2 mutations, Danon disease, myocarditis, advanced sarcomeric HCM