Heart failure is a varied clinical syndrome with a complex pathophysiology that is still being defined.  These features have led to demanding therapeutic regimens that have made optimal management of heart failure a difficult enterprise.  In addition, heart failure is common, and its public heath consequences are ever growing.  An estimated 4.8 million individuals are afflicted with this syndrome in the United States today, and 400,000 to 700,000 new cases are estimated to develop each year.  The prevalence of heart failure increases with age; it approaches 10% of Americans in the ninth decade of life.  Aging of the population and the prolonged survival of patients with a variety of cardiovascular diseases that culminate in ventricular dysfunction ensure that the magnitude of the heart failure problem will substantially worsen in the next decade.

Experts have projected a 2- to 3-fold increase in prevalence.  In addition to being a common condition,  heart failure causes substantial morbidity with total hospitalizations,  directly and indirectly related, exceeding three million per year. 

This condition directly or indirectly contributes to the death of approximately 250,000 individuals a year.  Advanced heart failure remains one of the most disabling and lethal medical conditions.  Readmission shortly after hospital discharge remains disturbingly common,  and most patients continue to experience limiting symptoms and often poor quality of life despite treatment.  The economic burden of the syndrome is staggering, with estimated direct medical expenditures in excess of $20 billion per year.

Definition and Pathophysiology
Heart failure remains the final common pathway for many cardiovascular diseases whose natural history results in symptomatic or asymptomatic left ventricular dysfunction.  Although left ventricular diastolic dysfunction is an important part of the clinical spectrum of heart failure, our review will be restricted to patients with left ventricular systolic dysfunction.  This condition is accompanied by a number of pathophysiological abnormalities,  including structural remodeling and dilation of the left ventricular chamber; reduced myocyte shortening and wall motion; sodium retention and circulatory congestion;  systemic vasoconstriction and vascular remodeling that increases impedance of left ventricular ejection; and neurohormonal activation that contributes to many of the above pathophysiological events.

A number of basic and clinical investigations have highlighted the major importance of the renin-angiotensin-aldosterone system (RAAS) in the generation and progression of heart failure.

The traditional pharmacological means of blocking the activity of the RAAS has been through the inhibition of angiotensin-converting enzyme (ACE), which limits the production of angiotensin II, the major active biological peptide of this system.  ACE inhibitors initially were viewed as “vasodilator”  therapy because of their ability to reverse smooth muscle vasoconstriction in peripheral arterioles and, thus, substantially lower the elevated systemic vascular resistance that contributes to hemodynamic decompensation in heart failure. 

It is now clear, however, that the long-term benefits of ACE inhibitors and other newer therapies are dependent to a large extent on their ability to cause regression of some of the structural abnormalities and not on their hemodynamic effects.  Progression of heart failure is the hallmark of patients with left ventricular dysfunction.  Dysfunction appears to beget additional dysfunction in a downward spiral that culminates in the demise of the patient. 

An improved understanding of the factors that promote progressive cardiac dysfunction focused attention on the ability of various neurohormones to cause progressive remodeling or structural alteration of the heart in the form of dilatation and hypertrophy.  Substantial clinical and basic evidence now links this remodeling process to the development of progressive ventricular dysfunction that is commonly seen in heart failure.

Recognition of cardiac remodeling as a key component of the progressive heart failure syndrome highlights not only the RAAS but also the important role of the kinin system, as well as the excess sympathetic activity that is commonly present in heart failure.  In addition, a number of other hormonal systems appear to contribute to adverse myocardial remodeling.  Endothelin-1 and various cytokines, including tumor necrosis factor (TNF)-α  are often activated in severe heart failure and have recently become new targets for drug development.  Evidence for the involvement of multiple neurohormonal systems supports the concept that the pathophysiology of heart failure is intimately linked to diffuse activation of these systems.  The adverse role of coronary artery disease in the process of cardiac remodeling has received attention as well.  The therapeutic implications of cardiac remodeling are evident in the approach taken in this guideline.