Lecture 6: Dilated Cardiomyopathy and Left Ventricular Non-Compaction

Introduction

  • Presenter: Cara Barnett, Genetic Counselor in Cardiology at Cincinnati Children's

  • Topic: Dilated Cardiomyopathy (DCM) and Left Ventricular Non-Compaction (LVNC)

  • No conflicts of interest to disclose.

Objectives

  • Describe clinical diagnosis of DCM.

  • Understand nuances of LVNC.

  • Identify phenotypic and genotypic features of DCM.

  • Conduct family history risk assessment for DCM.

Dilated Cardiomyopathy (DCM)

  • Definition: DCM refers to an enlarged and thinned heart muscle disease specifically affecting the left ventricle.

  • Characteristics:

    • Left ventricular dilation.

    • Ejection fraction (EF) < 40% indicates systolic dysfunction.

      • ejection fraction means the percentage of blood that is pumped out of the left ventricle with each heartbeat, reflecting the heart's efficiency and overall function.

  • Idiopathic systolic dysfunction, where EF is decreased without ventricular dilation, shares a similar genetic risk with DCM.

Epidemiology of DCM

  • Prevalence:

    • Historically: 36 in 100,000.

    • New data suggests: 118 in 100,000.

  • Gender Ratio: More prevalent in men (3:1).

  • Idiopathic DCM prevalence: 59 in 100,000.

Symptoms of DCM

  • Overt heart failure may be the presenting symptom.

  • Possible undiagnosed conditions include: conduction system disease, sudden cardiac arrest, stroke.

Causes of DCM

  • Primary Causes:

    • Idiopathic, non-ischemic, familial, genetic.

  • Secondary Causes:

    • Ischemia (heart attacks), infectious diseases, prolonged hypertension, certain medications (chemotherapy), alcohol abuse, HIV, infiltrative diseases.

    • Also associated with myocarditis, peripartum cardiomyopathy, and Takotsubo cardiomyopathy, which may have genetic links.

Left Ventricular Non-Compaction (LVNC)

  • Definition: A condition characterized by prominent trabeculation of the left ventricle with unclear consensus status as a true cardiomyopathy.

  • Prevalence: Approximately 1 in 7,000 people.

  • Characteristics:

    • Often identified at younger ages, thought to be a birth defect in some cases.

    • More common in Black ancestry; can be reversible in trained athletes/pregnant women.

  • Monitoring required for isolated LVNC due to risk of developing DCM.

  • Genetic testing not recommended in isolated cases without dysfunction.

Heart Failure Overview

  • Heart failure refers to impaired pumping ability of the heart, leading to decreased blood flow and pressure.

  • Activation of neurohormonal systems to improve survival, increasing salt/water retention, and narrowing blood vessels.

  • Signs and symptoms include:

    • Edema (swelling), particularly in lower extremities.

    • Confusion, shortness of breath, coughing, palpitations, lack of appetite, fatigue.

  • Difficult to diagnose due to overlap with symptoms of other illnesses.

Evaluation Techniques for DCM & LVNC

  • Cardiac Imaging Methods:

    • Chest X-ray: Enlarged heart silhouette.

    • ECG/Holter monitors: Monitor rhythm.

    • Echocardiograms: Gold standard for assessing heart size and function.

    • Cardiac stress tests: Assess heart function under stress.

    • Cardiac MRI: More precise examination of heart function and disease type.

  • Additional Tests:

    • Cardiac catheterizations, CT scans, myocardial biopsies for detailed assessments.

Genetic Implications of DCM

  • Approximately 30-40% of individuals with idiopathic non-syndromic DCM have a family history of DCM or arrhythmias.

  • 40% of DCM results lead to a diagnostic genetic finding.

  • Consideration of family variant testing is crucial.

Genetics of DCM

  • Focus: Dominantly inherited genes implicated in familial DCM.

  • Notable genes:

    • TTN (Titan): Most common gene associated with familial DCM (15-20% of cases).

      • inheritance pattern is typically autosomal dominant

    • Other genes: Lamin A, MYH7, Filamin C, among others.

  • Gene function involves impact on the sarcomere, which is essential for muscle contraction.

Titan Characteristics

  • Largest protein in the body, essential for heart muscle function.

  • Variant interpretation can be challenging due to population variability.

  • Truncating variants in the A band have a strong association with familial DCM.

Clinical Cases and Family Histories

  • Detailed exploration of a clinical case involving a 17-year-old male with acute DCM.

  • Family history assessment highlighted the potential for familial DCM through various relatives.

  • Genetic testing: Found a paternally inherited VUS in ACTC1, implicating familial risk.

Screening Recommendations for Family

  • Genetic testing follows positive findings to stratify risk among relatives.

  • Regular cardiac screenings recommended across family members based on findings of genetic variants.

  • Discussion of screening intervals based on age and existing family histories.

Conclusion

  • DCM is a genetic condition with dominant inheritance patterns.

  • Genetic testing is important for individuals with idiopathic or non-ischemic DCM.

  • LVNC genetic testing is not recommended unless there's concerning family history.

  • Family screening is critical due to ongoing risks involved with genetic conditions.

Resources

  • GeneReviews: Comprehensive review of genetics concerning DCM.

  • DCM Foundation: Patient and family resources regarding DCM diagnoses and genetic testing.

  • ClinGen DCM expert panel: Evaluates gene validity for DCM; crucial for pediatric cases or strong family histories.