In-Depth Notes on HCM and its Treatment

Learning Outcomes

  • Understand diagnostic tools for Hypertrophic Cardiomyopathy (HCM)
  • Evaluate the importance of genetic testing in HCM
  • Analyze available treatments for HCM

HCM Diagnosis

  • Clinical heterogeneity is prevalent in HCM:

    • Patients may be asymptomatic.
    • Common symptoms include:
    • Dyspnoea
    • Atrial arrhythmias
    • Heart failure
    • Ventricular arrhythmias
    • Sudden cardiac death

  • Diagnostic Tools:

    • Medical History
    • Physical Examination
    • Family History
    • Electrocardiogram (ECG)
    • Echocardiogram
    • Cardiac MRI
    • Genetic Testing

  • Important considerations for HCM diagnosis:

    • Maximum LV thickness of ≥ 15 mm at any site in the chamber is consistent with HCM.
    • An LV thickness of 13-14 mm can be diagnostic, especially with a family history of HCM.

HCM Genetic Testing

  • Purpose:

    • Helps patients understand their prognosis.
    • Identifies family members at risk for HCM.

  • Commercial genetic testing companies include:

    • Correlagen
    • GeneDX
    • PGxHealth
    • Transgenomic-Familion

  • Next-Generation Sequencing (NGS):

    • Facilitates molecular diagnosis of HCM.
    • Ideal for genetically heterogeneous disorders.

Types of Genetic Sequencing

  • Targeted Gene Panels:
    • Sequence specific regions of genes associated with clinical phenotypes.
  • Whole Exome Sequencing (WES):
    • Targets all known protein-coding genes (~85% of known disease-related variants).
  • Whole Genome Sequencing (WGS):
    • Sequences the entire genome, coding and non-coding regions.
  • RNA-Seq:
    • Used to identify novel RNA variants.
  • Epigenetics:
    • Involves genome-wide DNA methylation analysis.

Comparison of Sanger Sequencing and NGS

  • Sanger Sequencing:
    • Requires DNA denaturation, amplification, and gel electrophoresis to read sequences.
  • Next-Generation Sequencing (NGS):
    • Involves fragmenting genomic DNA, adding adapters, and performing cluster amplification for sequencing.
    • Allows for massive parallel sequencing of millions of fragments simultaneously, yielding high throughput.

HCM Treatment

  • Therapeutic Goals:

    • Improve symptoms, function, and quality of life.

  • Pharmacological Strategies include:

    • LATE SODIUM ION CHANNEL INHIBITORS (e.g., Ranolazine)
    • ANGIO-TENSIN II RECEPTOR BLOCKERS (e.g., Losartan, Valsartan)

  • Mechanisms of Action:

    • Cardiac function modulation via targeting various cellular pathways.

  • Non-Pharmacological Treatments include:

    • Septal reduction therapies such as:
    • Alcohol septal ablation
    • Transcatheter myotomy
    • Septal myectomy

  • Gene Therapy Potential:

    • Aims to prevent disease development in HCM through methods like gene replacement, silencing, and signaling pathway modulation.

Future Directions

  • Addressing challenges related to translating HCM gene therapies into clinical applications.

Extra Reading

  • Challenges of Translating HCM Gene Therapy to Clinical Applications