Congestive heart failure (CHF) is responsible for more than half a million deaths annually in the U.S., carries a 1-year mortality rate of more than 50% in patients with advanced forms of the condition, and is responsible for nearly $27 billion annually in healthcare costs (Binanay et al., 2005). Fortunately, substantive advances in CHF pharmacotherapy have altered clinical practice by shifting the paradigm of its management from exclusively symptom palliation to modification of disease progression and, in some cases, an expectation of prolonged survival.
In the past, drug therapies targeted the endpoints of this syndrome: volume overload (congestion) and myocardial dysfunction (pump failure). As a consequence, diuretics and cardiac glycosides dominated the medical management of CHF for more than 40 years. These drugs remain effective for symptom relief and in stabilizing patients with hemodynamic decompensation but do not improve long-term survival. The contemporary focus of CHF as a disorder of circulatory hemodynamics, pathologic cardiac remodeling, and increased arrhythmogenic instability has translated into the development of novel pharmacotherapies that reduce CHF-associated morbidity and mortality rates. Before discussing the clinical pharmacology of CHF in specific, it is useful to establish a pathophysiologic framework through which its treatment is approached.
Defining Congestive Heart Failure. The onset and progression of clinically evident CHF from left ventricular (LV) systolic dysfunction follows a pathophysiologic sequence in response to an initial insult to myocardial dysfunction. A reduction in forward cardiac output leads to expanded activation of the sympathetic nervous system and the renin–angiotensin–aldosterone axis that, together, maintain perfusion of vital organs by increasing LV preload, stimulating myocardial contractility, and increasing arterial tone. Acutely, these mechanisms sustain cardiac output by allowing the heart to operate at elevated end-diastolic volumes, while peripheral vasoconstriction promotes regional redistribution of the cardiac output to the central nervous system, coronary, and renal vascular beds.
Unfortunately, however, these compensatory mechanisms over time propagate disease progression. Intravascular volume expansion increases diastolic and systolic wall stress that disrupts myocardial energetics and causes pathologic LV hypertrophy. By increasing LV afterload, peripheral arterial vasoconstriction also adversely affects diastolic ventricular wall stress, thereby increasing myocardial O2 demand. Finally, neurohumoral effectors such as norepinephrine (NE) and angiotensin II (AngII) are associated with myocyte apoptosis, abnormal myocyte gene expression, and pathologic changes in the extracellular matrix that increase LV stiffness (Villarreal, 2005).
In clinical practice, the term CHF describes a final common pathway for the expression of myocardial dysfunction. While some emphasize the clinical distinction between systolic versus diastolic heart failure, many patients demonstrate dysfunction in both contractile performance and ventricular relaxation/filling. Indeed, these physiologic processes are interrelated; for example, the rate and duration of LV diastolic filling are directly influenced by impairment in systolic contractile performance. Despite inherent difficulties in creating a singular description to encompass the diverse pathophysiologic mechanisms that result in CHF (e.g., myocardial infarction (MI), viral myocarditis), the following definitions are useful ...