Nitroxyl gets to the heart of the matter

Abstract

Heart failure (HF) is a progressively disabling and ultimately fatal disease, which is characterized by a decline in the heart's ability to pump blood efficiently enough to meet the body's metabolic demands. Despite substantial advances in our understanding of the underlying pathophysiology (1) and the therapeutic management of acute and chronic HF (2) in recent years, the outlook of patients with these conditions remains poor. Not only are mortality and morbidity discouragingly high, but also the patients' quality of life remains impaired because of a substantial symptom burden. In the United States alone, HF is responsible for almost 1 million hospital admissions (more than for all forms of cancer combined) and >50,000 deaths each year, with estimated annual costs exceeding $20 billion (3, 4). Despite improved patient information, beneficial changes in lifestyle and better treatment options, HF remains to be a major public health problem in industrialized nations and the leading cause of hospitalization in people older than 65 years. At a time when other cardiovascular diseases are on the decline, HF is rising and likely to further escalate over the coming decades because of an aging population and increased survival from the underlying causes such as coronary heart disease and hypertension. A broad spectrum of different drugs and various guidelines for the treatment of HF exist (5, 6). In the past, HF was mainly viewed as a problem of diminished cardiac output. Maximization of the latter with positive inotropic (contractility enhancing) agents led to therapies that initially improved functional capacity, but increased mortality. Today, the therapeutic focus is on reducing elevated filling pressures that lead to the symptoms of congestion (7). Although most recommendations agree on the major drug classes for the first-line and adjunct therapy of HF, there is considerable controversy about the role of positive inotropic agents (8). Despite a documented negative impact on survival, these agents are still widely used, often combined with vasodilators, to limit severe episodes of HF or as a bridge to transplantation. The rationale for combining vasodilatation with positive inotropic intervention lies in the possibility to “unload” the heart, i.e., to reduce its preload and afterload by venous and arterial dilatation, allowing to stimulate cardiac output without increasing oxygen consumption. Although conceptually ideal compounds, currently used inodilators (compounds with positive inotropic and vasodilatior properties) tend to increase myocardial oxygen demand at higher doses, precipitating ischemia in patients with coronary artery disease. Clearly, there is room for improvement in HF management, in particular with regard to quality of life and survival.