What is the approach to diagnose hypertrophic ventricular disease?

Diagnosis of Hypertrophic Cardiomyopathy

Transthoracic echocardiography (TTE) is the primary diagnostic test for hypertrophic cardiomyopathy, with diagnosis established by left ventricular wall thickness ≥15 mm in any segment (or ≥13 mm in first-degree relatives of confirmed HCM patients) in the absence of another cardiac or systemic disease capable of producing that magnitude of hypertrophy. 1, 2

Initial Clinical Assessment

The diagnostic workup begins with specific elements that raise suspicion for HCM:

• Obtain a detailed 3-generation family pedigree documenting relatives with HCM, unexplained sudden death, heart failure, cardiac transplantation, or pacemaker/ICD implants 2
• Document specific symptoms: dyspnea, chest pain, palpitations, syncope, and lightheadedness, particularly their relationship to exertion 2
• Assess for syndromic features: ataxia, hearing/visual impairment, cognitive abnormalities, or neurodevelopmental issues that suggest phenocopy conditions like Fabry disease, Noonan syndrome, or mitochondrial disorders 1, 2
• Perform provocative maneuvers during physical examination: Valsalva, squat-to-stand, passive leg raising, and walking to elicit left ventricular outflow tract (LVOT) obstruction 2

Mandatory Diagnostic Testing

12-Lead ECG

• Obtain in all patients with suspected HCM as the initial screening test 1, 2
• The ECG is abnormal in 75-95% of HCM patients 1, 3
• Look for patterns suggesting specific diagnoses: Wolff-Parkinson-White syndrome (suggests certain phenocopies), patterns mimicking myocardial infarction (may be present before wall thickening appears on echo), or LVH voltage criteria 1, 2

Transthoracic Echocardiography (TTE)

TTE is the cornerstone imaging modality for diagnosis 1, 2:

• Measure maximum diastolic wall thickness using 2D short-axis views in all LV segments from base to apex, with particular attention to the anterolateral wall and apex where hypertrophy may be missed 2, 4
• Diagnostic threshold: ≥15 mm maximal wall thickness in any LV segment in adults, or ≥13 mm in first-degree relatives of confirmed HCM patients 2
• Assess for LVOT obstruction using continuous wave Doppler at rest and with provocation (Valsalva maneuver in sitting and semi-supine positions, then standing if no gradient is provoked) 1, 2
  • Obstruction defined as gradient ≥30 mmHg
  • Hemodynamically significant obstruction is ≥50 mmHg 1, 4
  • Use peak instantaneous gradient, not mean gradient 1
• Evaluate for systolic anterior motion (SAM) of the mitral valve and mitral-septal contact, which are key diagnostic features 1, 3
• Assess LV diastolic function: 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 2

Exercise Echocardiography

• Perform exercise TTE in symptomatic patients with resting or provoked peak instantaneous LVOT gradient <50 mmHg to detect provocable obstruction 2
• Combine exercise testing with Doppler echocardiography in patients with symptoms during routine physical activities who lack obstruction at rest 1
• Note: Dobutamine provocation is no longer recommended 1

Advanced Imaging

Cardiac MRI (CMR)

• Consider CMR when echocardiographic images are suboptimal or when LV apical hypertrophy or aneurysm is suspected 2, 5
• CMR provides precise measurement of LV and right ventricular volumes and mass, and characterizes myocardial tissue properties that aid in differential diagnosis 5, 6

Transesophageal Echocardiography (TEE)

• Consider TEE 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 2

Genetic Testing

• Perform genetic testing in the index patient to facilitate identification of at-risk first-degree family members 2
• Comprehensive sequence-based analysis of all HCM genes identifies pathogenic mutations in approximately 60-70% of patients with positive family history 1
• Genetic counseling by someone knowledgeable in cardiovascular genetics must accompany testing 2
• Eight genes definitively cause HCM: beta myosin heavy chain, myosin binding protein C, troponin T, troponin I, alpha tropomyosin, actin, regulatory light chain, and essential light chain 1

Family Screening Protocol

All first-degree relatives of HCM patients require clinical screening unless genotype-negative in families with known definitive mutations 1, 2:

• Children (ages 12-18 years): Screen every 12-18 months with TTE and ECG, starting at age 12 or earlier if growth spurt/puberty evident, plans for intense competitive sports, or family history of sudden cardiac death 1, 2
• Adults (≥18 years): Screen at symptom onset or at least every 5 years; more frequent intervals appropriate in families with malignant clinical course or late-onset HCM 1, 2

Critical Differential Diagnoses

Distinguishing HCM from Other Causes of LVH

Common pitfalls occur when maximum wall thickness is 13-15 mm 1:

Hypertensive Heart Disease

• Coexistence of HCM and hypertension is common in older patients 1
• HCM is more likely if: LV thickness ≥25 mm, LVOT obstruction with SAM and mitral-septal contact present, or diagnostic sarcomere mutation identified 1

Athlete's Heart

• Athletic conditioning can produce LV, right ventricular, and left atrial enlargement, ventricular septal thickening 1
• Features favoring athlete's heart: enlarged LV cavity dimension, normal diastolic function, contiguous pattern of hypertrophy, decrease in wall thickness after 3-month deconditioning period 1, 4
• Features favoring HCM: sarcomeric mutations, family history of HCM, unusual location or noncontiguous pattern of hypertrophy 1

Infiltrative/Storage Diseases (Phenocopies)

Specific echocardiographic features suggest alternative diagnoses 2:

• Increased interatrial septum thickness: consider amyloidosis 2
• Increased AV valve thickness: consider amyloidosis or Anderson-Fabry disease 2
• Increased RV free wall thickness: consider amyloidosis, myocarditis, Anderson-Fabry disease, or Noonan syndrome 2
• Ground-glass appearance: consider amyloidosis 2
• Concentric LVH: consider glycogen storage disease, Anderson-Fabry disease, or PRKAG2 mutations 2
• Extreme concentric LVH (≥30 mm): consider Danon disease or Pompe disease 2
• Global LV hypokinesia: consider mitochondrial disease, TTR-related amyloidosis, PRKAG2 mutations, Danon disease, myocarditis, or advanced sarcomeric HCM 2

Monitoring and Follow-up

• Perform serial TTE every 1-2 years in symptomatically stable patients to assess degree of myocardial hypertrophy, dynamic obstruction, and changes in clinical status 1, 3
• Ambulatory ECG monitoring annually or every 2 years in stable patients without ICDs to screen for nonsustained ventricular tachycardia (NSVT), which identifies patients at higher risk of sudden cardiac death 1, 3
• Repeat TTE for any change in clinical status or new cardiovascular event 1