Lecture 5: Hypertrophic and Restrictive Cardiomyopathy

Presenter: Aaron Miller, Genetic Counselor at Cincinnati Children's Hospital
Objectives:
- Describe clinical diagnosis of HCM
- Discuss genetic testing and counseling approaches for HCM
- Explain cascade screening for family members

Definition: Cardiomyopathy refers to heart muscle disease.
Types: Various types exist; some isolated, some overlapping, others associated with genetic conditions.
Focus on nonsyndromic HCM causes today.

Characteristic: Left Ventricular Hypertrophy (LVH) without other diseases causing it.
LVH Definition: Thickening of the left ventricular wall, particularly affecting the septum.
Measurement:
- Adults: At least 15 mm thick.
- Children: z-score > +2 standard deviations based on age.
Asymmetry: Thickening usually greater in septum than the free wall.
Terms: HCM, HOCM (Hypertrophic Obstructive Cardiomyopathy), and IHSS (Idiopathic Hypertrophic Subaortic Stenosis) often used interchangeably.

Incidence: Affects approximately 1 in 500 adults.
Less common in children; some acquired causes like high blood pressure or athlete's heart exist.
Many individuals asymptomatic, with potential symptoms including:
- Shortness of breath
- Chest pain with exertion
- Fatigue, dizziness, and palpitations.

Diagnostic Tools:
- Cardiac Imaging (Gold Standard): Echocardiogram and MRI for characterizing heart muscle.
- Important to review specific echo report metrics: septal thickness, measurement phases (diastole vs systole).
- Look for late gadolinium enhancement in MRI to assess scar burden and risk for arrhythmias.
Phenocopies: Conditions mimicking HCM should be considered for accurate management:
- Athlete’s heart, hypertension-related LVH, glycogen storage disorders, etc.

HCM linked to sarcomere proteins like myosin-binding protein C3 and beta-myosin heavy chain.
Myocyte Structure: HCM characterized by myocyte disarray; compared with normal, organized cardiomyocytes.
Family History: Gather details on imaging from first-degree relatives; symptoms do not rule out disease.

Recommendations:
- Testing for all with suspected HCM; should be accompanied by genetic counseling.
- Cascade screening for high-risk relatives; infants and young children included.
Genetic Testing Yield: About 35% of cases yield positive results; common mutations involve MYBPC3 and MYH7.
Predictors of Positive Testing:
- Age at diagnosis, male sex, hypertension, positive family history, asymmetric hypertrophy.

First-Line Medications:
- Beta-blockers and calcium channel blockers for symptom relief.
Novel Therapies:
- Mavacamten: Cardiac myosin inhibitor targeting hypercontractility.
Surgical Options:
- Septal myectomy for severe obstruction; septal alcohol ablation as a minimally invasive alternative.
Defibrillator: For individuals at high arrhythmia risk; possible heart transplant for severe cases.

Screening Recommendations: Regular checks for at-risk relatives.
High frequency of screening under specific genetic testing circumstances:
- Positive testing or unknown status before age 20, less frequent post-20.
Non-familial HCM identified by older diagnosis age and lack of family history.

Potential for CRISPR-based and AAV vector therapies in HCM management.
Expanded testing may be warranted in cases of negative panels or complex family histories.
Integrating Polygenic Risk Scores: In future clinical care; current clinical practice primarily focused on monogenic causes.

Genetic testing is vital for LVH evaluation; the yield can vary significantly.
Recommendations emphasize the need for careful genetic counseling and consideration of family screening.
Proper management can lead to normal life expectancy, reassuring patients while facilitating active lifestyles.