Educational

Dilated Cardiomyopathy

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by

Saim Khalid
in

Introduction

Dilated cardiomyopathy (DCM) is one of the most common forms of cardiomyopathy, characterized by dilatation of the left ventricle (and often right ventricle) with impaired systolic function. It leads to heart failure, arrhythmias, thromboembolism, and sudden cardiac death, contributing significantly to cardiovascular morbidity and mortality worldwide.

While DCM can be secondary to environmental or acquired insults such as viral myocarditis, toxins (e.g., alcohol, chemotherapy), metabolic disturbances, or autoimmune conditions, a substantial proportion of cases are genetic in origin. In fact, modern molecular genetics has revealed that up to 40–50% of idiopathic DCM cases are familial, caused by mutations in more than 60 genes that encode proteins essential for myocardial structure, force transmission, ion regulation, and nuclear integrity.

Understanding the genetic landscape of DCM is essential not only for diagnosis and prognosis but also for guiding precision therapies, cascade family screening, and personalized management.

This article explores the molecular genetics of DCM, focusing on pathogenic mutations, their biological roles, and how they shape the pathogenesis of the disease.

Section 1: Overview of Dilated Cardiomyopathy

1.1 Clinical Features

  • Ventricular dilation (particularly left ventricle).
  • Depressed ejection fraction (LVEF <40%).
  • Symptoms: fatigue, dyspnea, orthopnea, palpitations, syncope.
  • Complications: heart failure, atrial and ventricular arrhythmias, stroke from thromboembolism, sudden cardiac death.

1.2 Epidemiology

  • Prevalence: ~1 in 250 individuals worldwide.
  • Accounts for 30–40% of heart failure cases.
  • A leading indication for heart transplantation.

1.3 Etiological Spectrum

  • Genetic (~40–50%).
  • Non-genetic: infectious myocarditis, alcohol, anthracyclines, peripartum cardiomyopathy, endocrine and metabolic disorders, autoimmune disease.
  • Often a gene–environment interaction (e.g., alcohol abuse in a genetically predisposed individual).

Section 2: Genetic Basis of DCM

2.1 Familial DCM

  • Defined when two or more closely related family members are affected.
  • Inherited typically as autosomal dominant, but autosomal recessive, X-linked, and mitochondrial inheritance are also observed.

2.2 Mutational Spectrum

  • Over 60 implicated genes.
  • Categories:
    1. Sarcomere proteins.
    2. Cytoskeletal and Z-disk proteins.
    3. Nuclear envelope proteins.
    4. Ion channel and calcium-handling proteins.
    5. Mitochondrial proteins.

2.3 Penetrance and Expressivity

  • Variable penetrance: not all mutation carriers develop disease.
  • Phenotypic variability: different individuals in the same family may have different disease severity.
  • Suggests strong influence of modifier genes and environmental triggers.

Section 3: Major Genetic Mutations in DCM

3.1 Sarcomere Protein Genes

  1. TTN (Titin) Mutations
    • Largest human gene; encodes titin, a protein spanning half the sarcomere.
    • TTN truncating variants (TTNtv) are the most common cause of familial DCM, accounting for 20–25% of cases.
    • Pathogenesis: impaired sarcomere assembly, defective elasticity, and abnormal mechanosensing.
    • Clinical features: variable penetrance; associated with arrhythmias and progressive heart failure.
  2. MYH7 (β-Myosin Heavy Chain)
    • Encodes a key motor protein in sarcomeres.
    • Mutations impair force generation and cross-bridge cycling.
    • Mutations can cause both DCM and hypertrophic cardiomyopathy (HCM) depending on variant.
  3. TNNT2 (Troponin T)
    • Mutations reduce calcium sensitivity, impair contractility.
    • Often associated with severe arrhythmia risk.
  4. ACTC1 (Cardiac Actin)
    • Rare cause of DCM.
    • Alters actin–myosin interactions.

3.2 Cytoskeletal and Z-Disk Genes

  1. DES (Desmin)
    • Encodes desmin, an intermediate filament linking Z-disks to sarcolemma.
    • Mutations cause desmin-related myopathy with skeletal muscle involvement.
    • Clinical features: conduction defects and arrhythmias.
  2. DMD (Dystrophin)
    • X-linked gene encoding dystrophin.
    • Mutations cause Duchenne and Becker muscular dystrophies, often with DCM.
    • Female carriers may develop isolated cardiomyopathy.
  3. LDB3 (ZASP)
    • Z-disk–associated protein.
    • Mutations disrupt sarcomere stability.

3.3 Nuclear Envelope Genes

  1. LMNA (Lamin A/C)
    • Encodes nuclear lamins that maintain nuclear structure and regulate gene expression.
    • LMNA mutations are among the most penetrant causes of DCM (~5–10% of cases).
    • Clinical features: high risk of conduction block, atrial and ventricular arrhythmias, sudden cardiac death.
    • LMNA cardiomyopathy is considered malignant, often requiring early implantable cardioverter-defibrillator (ICD).
  2. EMD (Emerin)
    • X-linked; encodes emerin, a nuclear envelope protein.
    • Mutations cause Emery–Dreifuss muscular dystrophy with DCM.

3.4 Ion Channel and Calcium-Handling Genes

  1. SCN5A (Sodium Channel, Nav1.5)
    • Encodes cardiac sodium channel.
    • Mutations linked to DCM, Brugada syndrome, long QT syndrome.
    • Pathogenesis: conduction slowing, arrhythmias, contractile dysfunction.
  2. PLN (Phospholamban)
    • Regulates sarcoplasmic reticulum Ca²⁺ handling.
    • Mutations cause defective calcium reuptake, leading to contractile failure.
    • Specific founder mutation in the Netherlands (PLN R14del).
  3. RYR2 (Ryanodine Receptor)
    • Mutations usually cause catecholaminergic polymorphic ventricular tachycardia (CPVT), but some overlap with DCM.

3.5 Mitochondrial Genes

  • Mutations in mitochondrial DNA and nuclear-encoded mitochondrial proteins can lead to energy deficiency syndromes with DCM as a feature.
  • Example: TAZ (tafazzin) mutations cause Barth syndrome (X-linked, associated with skeletal myopathy, neutropenia, and severe DCM).

Section 4: Pathogenetic Mechanisms

Genetic mutations lead to DCM via several converging mechanisms:

  1. Impaired Force Generation (sarcomere mutations such as TTN, MYH7, TNNT2).
  2. Defective Force Transmission (cytoskeletal proteins like DES, DMD).
  3. Nuclear Dysfunction and Signaling Abnormalities (LMNA mutations disrupting mechano-signaling).
  4. Electrophysiological Abnormalities (SCN5A, PLN mutations altering conduction and calcium handling).
  5. Mitochondrial Energy Deficiency (TAZ and mitochondrial DNA mutations).

The common downstream pathway:

  • Progressive ventricular dilation, reduced contractility, fibrosis, arrhythmias, and eventual heart failure.

Section 5: Genotype–Phenotype Correlations

5.1 TTN Mutations

  • High prevalence in idiopathic DCM.
  • Environmental modifiers (alcohol, pregnancy, chemotherapy) unmask disease.

5.2 LMNA Mutations

  • Early conduction defects and malignant arrhythmias.
  • ICD recommended even before severe LV dysfunction.

5.3 SCN5A Mutations

  • High arrhythmic burden.
  • Overlap with channelopathies.

5.4 PLN Mutations

  • Severe progression, high risk of sudden cardiac death.

5.5 Mitochondrial Mutations

  • Multisystem involvement helps distinguish from isolated idiopathic DCM.

Section 6: Genetic Testing and Counseling

6.1 Genetic Testing

  • Next-generation sequencing (NGS) panels covering >50 DCM genes.
  • Whole exome and genome sequencing for unsolved cases.
  • Helps in risk stratification and family cascade screening.

6.2 Challenges

  • Variants of uncertain significance (VUS): complicate interpretation.
  • Incomplete penetrance means carriers may remain asymptomatic.

6.3 Genetic Counseling

  • Informs families of inheritance risks.
  • Guides reproductive choices.
  • Critical for cascade screening of at-risk relatives.

Section 7: Clinical Implications of Genetic Findings

7.1 Risk Stratification

  • LMNA, PLN, and SCN5A mutations → higher arrhythmia risk → earlier ICD implantation.
  • TTN mutations → often milder but susceptible to environmental triggers.

7.2 Tailored Management

  • Avoidance of specific triggers (alcohol, anthracyclines).
  • Gene-specific therapies in pipeline (e.g., antisense therapy for LMNA).

7.3 Cascade Screening

  • Enables early diagnosis and intervention in relatives.
  • Reduces sudden cardiac death risk.

Section 8: Precision Medicine and Future Directions

8.1 Gene Therapy

  • Viral vector–based delivery of normal gene copies (e.g., DMD, LMNA).
  • CRISPR/Cas9 gene editing under investigation.

8.2 Molecular Chaperones and RNA Therapies

  • Correct misfolded proteins or restore splicing.

8.3 Stem Cell Therapy and Tissue Engineering

  • iPSC-derived cardiomyocytes used to model DCM in vitro.
  • Potential for personalized drug screening.

8.4 Pharmacogenomics

  • Genotype may guide drug choice (e.g., sodium channel blockers in SCN5A mutations).

Section 9: Epidemiology of Genetic DCM

  • Familial/genetic DCM accounts for 20–50% of idiopathic cases.
  • TTN mutations most frequent in Western cohorts.
  • LMNA mutations frequent in European populations.
  • PLN founder mutation (R14del) highly prevalent in the Netherlands.
  • DMD-related cardiomyopathy common in males with muscular dystrophy worldwide.

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