Manipulating Cardiac Contractility in Heart Failure

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Abstract
In the year 1990, cardiovascular disease surpassed infectious diseases as the leading cause of death worldwide, and by the year 2020 it is predicted to be the leading cause of all disability.1,2 In the United States, cardiovascular disease has been estimated to account for 44% of the nation’s mortality and is a leading cause of morbidity.3,4 Heart failure afflicts an estimated 5 million Americans, with ≈400 000 new individuals diagnosed each year at an annual cost of more than $20 billion.4–6 The alarming reality behind these statistics is our current lack of an effective therapy to repair or otherwise reverse severe forms of cardiac dysfunction and pathological remodeling associated with heart failure. Typically, heart failure is the final culmination of protracted disease states precipitated by underlying hypertension, ischemic disease and atherosclerosis, valvular insufficiency, viral myocarditis, or mutations in genes encoding sarcomeric proteins.6 Given these diverse etiologies, it is not surprising that the final phenotypic manifestations of heart failure can also vary considerably, although dilated cardiomyopathy is the most common. This syndrome is characterized by a progressive loss in contractility and ejection fraction, ventricular chamber dilatation, ventricular wall thinning, increased peripheral vascular resistance, and dysregulated fluid homeostasis. The predominant therapeutic strategy used over the past two decades for treating such patients has been based in pharmacological manipulation of cardiac contractility.7–9 Initially, positive inotropic agents were used as a means of enhancing cardiac pump function aimed at alleviating congestive symptomology. However, use of positive inotropes is now indicated only as a means of acutely bridging patients in severe heart failure because these agents actually worsen prognosis in individuals with somewhat more stable heart failure.8 More recently, pharmacological blockade of β-adrenergic receptors has emerged as the favored treatment for individuals in heart failure. β-Adrenergic receptor antagonists initially …