Division of Cardiovascular Diseases Strategic Plan

Goals in Cardiovascular Clinical Problems or Disease States

2.4a. Reduce the morbidity and mortality of ischemic and non-ischemic dilated cardiomyopathy

Table of Contents

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Overview

Heart failure is a major public health problem which, in contrast to overall CV disease, is increasing in prevalence and incidence. It constitutes a major cause of morbidity, mortality, and economic burden. Five million Americans are afflicted, and 500,000 new cases are diagnosed each year. Although survival after the onset of heart failure has improved, modern therapies for this disease may slow, but cannot stop, its progression. Heart failure is now the leading cause of hospitalization for people aged 65 years or older. Ventricular remodeling with dilation is a common pathologic pathway, associated with clinical heart failure, in patients who have suffered major myocardial ischemic injury and in those with non-ischemic dilated Cardiomyopathy (DCM). Knowing which variables are associated with normalization or further deterioration of ventricular function is a critical step in determining the prognosis of patients with ischemic and non-ischemic DCM and for identifying patients in the early stages of the disease who may require more complex or aggressive optimal management strategies.

Strategies to Accomplish this Goal May Entail:

Basic Research:

  • Elucidate and identify key molecular, cellular and tissue signaling pathways and systems interactions underlying the pathophysiology of ischemic and non-ischemic DCM.
  • Investigate the role of adverse myocardial remodeling, apoptosis, fibrosis and necrosis.
  • Elucidate key molecular pathways that control CV extracellular membrane remodeling, and intracellular and intercellular and extracellular communications, and functional and structural interactions in ischemic and non-ischemic DCM.
  • Elucidate neurohormonal, hemodynamic and mechanical contributions leading to myocardial dilatation and dysfunction.
  • Investigate the roles of contractile proteins, channel dysfunction, and specific abnormalities in immune function (e.g. anticardiac antibodies, altered immunoglobulin absorption, and abnormal cytokine profiles) as they impact myocardial contractile dysfunction.
  • Investigate the contribution of cellular energy imbalance and mitochondrial dysfunction in the development and maintenance of ischemic and non-ischemic DCM.
  • Use genomic, proteomic, informatic and systems biology approaches to advance our understanding of cardiac muscle disease.
  • Investigate the impact of promising growth factors in the early post-infarction stage and the late reperfusion stage on the extent of cardiomyocyte death, interstitial cell proliferation, remodeling and progression to ischemic cardiomyopathy.
  • Explore the role of age-related changes on cell and organ function.
  • Investigate the expression of vascular factors, messenger RNA, and protein, in the myocardium of patients with ischemic heart failure.
  • Examine the impact on left ventricular remodeling of increasing angiogenesis and/or decreasing apoptosis and fibrosis in ischemic and non-ischemic DCM.
  • Investigate specific critical cellular processes involved in the reversal of structural remodeling in ischemic and non-ischemic DCM to provide a platform for developing new therapeutic targets in managing established heart failure.
  • Elucidate the contribution of myocyte apoptosis regulators and metabolic and energetic signaling pathways involved in the pathogenesis of diabetic cardiomyopathy.
  • Investigate the role of renal failure in myocardial protein expression, apoptosis, and intramyocardial vascular pathology and its relationship to ventricular dysfunction.

Translational Research:

  • Investigate and validate suitable biomarkers and noninvasive imaging techniques for the diagnosis, screening, prevention and treatment of ventricular dilatation and dysfunction leading to DCM in children and adults. Specifically, focus attention on the pathologic effects of underlying metabolic syndrome, diabetes, and chronic renal insufficiency and failure.
  • Investigate the pathways by which familial, infectious, infiltrative, and metabolic etiologies lead to cardiac dilatation and heart failure.
  • Identify animal and human responses to cardiotoxic drugs to elucidate new pathways of cardiac repair and adaptation in adults and children.
  • Study cardiac recovery and recompensation from acute injury or in the setting of afterload reduction or mechanical circulatory support to better understand acute decompensation in adults and children.
  • Investigate neurohormonal influences on ventricular function, focusing on the pathophysiology of stress-induced DCM.
  • Advance regenerative therapy for ischemic and non-ischemic DCM by using cell- and tissue-based therapies.
  • Investigate the balance between protective (i.e., brain natriuretic peptide) and putative (i.e., phosphatidylinositol glycan, class F) neurohormonal factors that impact angiogenesis and the growth of collateral vessels in ischemic tissues.

Clinical Research:

  • Apply the results of both basic and clinical studies to develop a cohesive pathophysiologic concept for DCM in order to develop and improve treatment strategies.
  • Apply insights about genetic alterations to develop specific targeted therapies, maximizing the efficacy and minimizing the adverse effects of therapeutic interventions in children and adults.
  • Define genotype-phenotype relationships and elucidate how point mutations in sarcomeric proteins in inherited DCM could lead to divergent clinical phenotypes.
  • Identify subpopulations of patients most responsive to conventional and future therapeutics through pharmacogenomic and other means.
  • Identify disease-causing mutations and functional effects for patients with inheritable DCM.
  • Define genetic risk factors for DCM and study genetic variations that are indicative of individual differences in therapeutic response in all age groups.
  • Elucidate additional genes responsible for pediatric cardiomyopathies.
  • Identify and apply primary markers of contractile function to identify responders vs. non-responders to specific pharmacologic, regenerative or mechanical interventions.
  • Conduct clinical investigations in patients with diabetic cardiomyopathy to better understand the specific factors involved in its initiation and progression.
  • Conduct clinical investigations in patients with chronic renal insufficiency to better understand the best therapeutic approaches for mitigating or reversing cardiac dysfunction.
  • Identify optimal hemodynamic and volume management strategies in patients with acute and chronic heart failure decompensation.

Contributing Sources:

September 2008

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