Division of Cardiovascular Diseases Strategic Plan

Goals in Cardiovascular Clinical Problems or Disease States

2.4c. Establish strategies to prevent or reverse the phenotypic expression of genetically identifiable myocardial and rhythm disorders

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In an era of rapidly expanding knowledge of the genetic bases of diseases, prevention of the adverse consequences of diseases with identified genetic determinants should be achievable through early identification and intervention. Examples of genetically identifiable myocardial and rhythm disorders include hypertrophic cardiomyopathy (HCM) and long QT syndrome (LQTS). 

The global prevalence of HCM is estimated at 0.2 percent, but may be higher, since patients may be asymptomatic.  Even asymptomatic patients suffer a significant, case fatality rate (reported in some series as 6 per 10,000).   Improved risk stratification is needed to identify the high-risk asymptomatic individual to prevent the consequences of heart failure symptoms and sudden death. 

The frequency of inherited cases of LQTS may be as high as 1 in about 6000 newborns.  Also, its prevalence may be underestimated since the only symptom may be sudden and unexplained death in children and young adults.  Mutations (e.g., loss of function in K+ channels and gain of function in Na+ channels) may lead to early afterdepolarizations and other forms of triggered electrical activity that result in polymorphic ventricular arrhythmias  associated with syncope, sudden cardiac arrest, or sudden death. 

The value of this goal reaches far beyond improving the outcome in any one specific genotype or disease state.  Rather, it represents the “low-hanging-fruit” of advancement towards personalized medicine.  It is anticipated that success within an overarching program designed to influence outcomes in any one of these disease entities will open the door to numerous other advances in therapeutics across the spectrum of CV diseases.

Strategies to Accomplish this Goal May Entail:

Basic Research:

  • Investigate the cellular and molecular pathways through which the genetic defect drives myocardial pathology, heterogeneous phenotypes, and delayed onset of disease.
  • Evaluate tissue engineering and gene- and cell-based therapeutic approaches for biologic strategies to treat rhythm disorders.
  • Describe how different phenotypes derived from known genetic defects are affected by genetic and environmental modifiers (including those from the microenvironment).

Translational Research:

  • Examine the effects of potential interventions to prevent or reverse phenotypic expression in transgenic models.
  • Use novel genetic strategies (such as genome-wide association studies, candidate gene and genome mapping) to identify gene variants in patients at increased risk for myocardial and rhythm disorders and predict their response to therapy.
  • Develop better phenotypic classifications and better understanding of phenotype-genotype associations of familial myocardial and rhythm disorders to enhance genetic counseling and treatment decisions.
  • Investigate the genetic basis of cardiomyopathic and rhythm disorders, based on both low- and high-prevalence genetic abnormalities.
  • Understand the association between genotype and phenotypic expression, including the role of environmental factors that influence clinical disease.

Clinical Research:

  • Examine the therapeutic or preventive effects on credible surrogate and relevant clinical outcomes, including the potential of genotype to influence treatment effect.
  • Conduct clinical trials with interventions that change the phenotypic expression of genetically determined diseases (e.g., genetically identify HCM early, and assess whether treatment would diminish phenotypic expression of hypertrophy and/or arrhythmias).

Contributing Sources:

September 2008

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