Lecture 10: Familial Coronary Heart Disease

Introduction

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

  • No conflicts of interest to disclose.

Objectives

  • Identify different categories of heart disease.

  • Describe clinical aspects and risk factors for coronary artery disease (CAD).

  • Describe lipoproteins and lipid disorders.

  • Conduct risk assessment for familial hypercholesterolemia (FH).

  • Recognize additional lipid disorders.

Overview of Cardiovascular Disease

  • Leading cause of death across many demographic groups in the U.S.

  • In 2021, one in five deaths were attributed to heart disease, predominantly CAD.

  • CAD affects various age groups; one in 20 adults over 20 years have CAD.

  • Increasing incidences of heart attacks among younger populations.

  • Heart attacks occur approximately every 40 seconds in the U.S.

Types of Cardiovascular Disease

  • Includes ischemic and non-ischemic disease.

  • Atherosclerotic Cardiovascular Disease (ASCVD): Characterized by plaque buildup in arteries (fat, cholesterol, calcium).

    • Types include:

      • CAD

      • Cerebrovascular disease

      • Peripheral artery disease

      • Aortic diseases

Coronary Artery Disease (CAD)

  • Most common heart disease type in the U.S., accounting for one in seven deaths.

  • Ischemia: Insufficient blood flow to tissue; possible damage or death of heart muscle.

  • Heart requires oxygen-rich blood supplied by coronary arteries.

  • Myocardial infarction or heart attack is a significant outcome of ischemic injury.

Symptoms of Heart Attack

  • Primary symptom: Chest pain and discomfort, often described as spreading through the chest and upper abdomen.

  • Other symptoms:

    • Shortness of breath

    • Fatigue

    • Nausea/vomiting

    • Lightheadedness/fainting

Diagnosis and Treatment of Heart Attacks

  • Classification

    • ST Elevation Myocardial Infarction (STEMI): 100% blockage.

    • Non-ST Elevation Myocardial Infarction (Non-STEMI): Partial blockage.

  • Diagnostic Tests

    • Electrocardiogram (ECG) to identify damage and blockage.

    • Angiogram for blockage assessment.

    • Blood tests for tissue damage markers.

  • Treatment Options

    • Stenting: Insertion of a stent to relieve blockage.

    • Coronary Artery Bypass Grafting (CABG): Bypass surgery for damaged arteries.

Causes of Heart Attacks

  • Predominantly caused by dyslipidemia (abnormal lipid levels).

  • Hyperlipidemia: Excess fats in blood, prevalent in developed countries, leads to plaque formation.

  • Risk factors for CAD include:

    • Body composition

    • Hypertension

    • Smoking

    • Older age

    • Male sex

    • Diabetes

Understanding Lipids and Lipoproteins

  • Lipids: Fats including cholesterol and triglycerides, transported by lipoproteins.

  • Lipoproteins include:

    • LDL (Low-Density Lipoprotein): Bad cholesterol, high levels increase risk of heart attack and stroke.

    • HDL (High-Density Lipoprotein): Good cholesterol, protects against heart disease.

  • Triglycerides: Transported by chylomicrons and VLDL.

  • Routine lipid testing (lipid panels) measures total cholesterol, HDL, LDL, and triglycerides.

  • Normal Cholesterol Levels:

    • LDL: <160 (high if >160)

    • Total cholesterol: <240 (high if >240)

    • Triglycerides: <115 (normal)

Genetic Lipid Disorders

Lipoprotein A (Lp(a))

  • One in five people have high Lp(a); independent risk factor for ASCVD.

  • Elevated Lp(a) levels increase cardiovascular disease risk 2-4 fold for individuals with familial hypercholesterolemia.

  • Testing for Lp(a) is biochemical, normal level is <50.

Familial Hypercholesterolemia (FH)

  • A monogenic condition leading to high cholesterol from an early age.

  • Heterozygous FH prevalence: 1 in 250; homozygous FH: 1 in 300,000.

  • Significant elevation in total cholesterol (>300 in heterozygous). Premature coronary artery disease risk elevated 20-fold.

  • Suspect FH in:

    • LDL >160 for individuals under 20

    • LDL >190 for individuals over 20

    • 250 indicates very high suspicion of FH.

  • Cholesterol Screening: Baseline recommended between ages 9-11, earlier for strong family history.

  • Genetic testing for FH recommended to diagnose and optimize treatment.

  • Clinical manifestations include early coronary artery disease and visible cholesterol deposits.

Clinical Models for FH Diagnosis

  • Models Include:

    • Dutch lipid model

    • U.S. MedPed model

    • Simon Broome model

  • Absence of clinical findings does not rule out FH.

Genetic Basis of FH

  • Caused by four main genes: LDLR, PCSK9, APOB, and LDLRAP1.

  • 80% will show pathogenic variants when tested.

  • Genetic testing aids clinical management and treatment decisions.

Treatment of FH

  • Cholesterol lowering medications (statins) are primary treatment.

  • LDL Apheresis: Removes cholesterol from blood, addressed alongside lifestyle factors such as smoking cessation.

  • New therapies (PCSK9 inhibitors) shown to reduce LDL significantly.

  • Genetic testing aids in treatment justification and can enhance insurance coverage.

Other Types of Lipid Disorders

  • Familial Hyperchylomicronemia: Rare, caused by lipoprotein lipase deficiency; characterized by very high triglycerides.

  • Familial Dysbetalipoproteinemia: Common and underdiagnosed with skin manifestations (xanthomas).

  • APOB Mutations can cause both hyperlipidemia (dominant) and hypolipidemia (recessive), affecting fat absorption.

Conclusion

  • There are diverse lipid disorders, with familial hypercholesterolemia being the most common and significant.

  • Awareness of genetic risk factors and the role of genetic counseling is crucial for effective management and treatment.