Eric Devaney Lab - Research

Heart Failure

Heart failure has become a major public health burden, affecting between 2% and 6% of the US population. The mortality associated with this condition is substantial; approximately 75% of patients with heart failure under the age of 65 will die within eight years of diagnosis.

Figure 1. Heart Failure Death Rates. From the Center for Disease Control heart failure fact sheet

Heart failure is a complex progressive condition characterized by an inability of the heart to adequately perfuse the tissues. Heart failure generally occurs in the context of cardiovascular disease, such as coronary artery disease or valvular heart disease. From a pathophysiologic standpoint, heart failure occurs when the heart is chronically subjected to one or more of the following conditions: abnormal pressure load (e.g., aortic stenosis, hypertension, or coarctation); volume load (valvular regurgitation, ventricular septal defect); dysrhythmias; or cardiac muscle disease (ischemia or cardiomyopathy). Failure of adequate pump function is associated with a number of secondary physiologic changes including increased heart rate, increased afterload, and remodeling of the ventricular wall. Many of these changes are mediated by the neurohormonal axis, principally the sympathetic nervous system and the renin-angiotensin-aldosterone system. Early therapy of heart failure was directed towards improving left ventricular function by augmenting ventricular contractility with inotropic agents and reducing afterload with vasodilators; surprisingly, this approach was found to be associated with increased mortality. Modern pharmacologic therapy of heart failure involves blocking the neurohormonal axis with agents such as angiotensin converting enzyme (ACE) inhibitors, aldosterone antagonists, and beta-blockers. Surgical therapy of heart failure has also evolved, and implantation of left ventricular assist devices has resulted in improved survival compared to medical therapy in patients with the most advanced forms of heart failure. Despite advances in pharmacologic and surgical treatments for heart failure, the only definitive therapy is cardiac transplantation. Due to limitations in donor organ availability (only about 3000-4000 heart transplants are performed each year worldwide), transplantation is incapable of treating the increasing numbers of patients with medically refractory heart failure. A better understanding of the biology of heart failure is essential, in order that novel therapies, such as gene delivery, can be made available to treat patients with heart failure. .

Figure 2. AdMYH6 gene transfer augments failing human cardiac myocyte contraction. A) Fluorescent image of a single human cardiac myocyte demonstrates successful adenovirus-mediated gene transfer of GFP. B) Biophysical measurements in human failing ventricular cardiac myocytes. C) Summary of data. (From FASEB 24:2, 2010)

Preliminary results suggest that in both isolated animal and human heart failure cells genetic transfer of myosin can improve myocyte contractility. Current research is focused on developing the ideal myosin molecule and delivery system to treat heart failure.

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