THE ROLE OF CYTOKINES IN THE FAILING HUMAN HEART

Despite repeated attemptsto develop a unifying hypothesis that explains the clinical syndrome of heart failure, no single conceptual paradigm has withstood the test of time. Although clinicians viewed heart failure initially as a problem of excessive salt and water retention that was caused by abnormalities of renal blood flow (the cardiorenal model 55 ), as physicians began to perform careful hemodynamic measurements, it also became apparent that heart failure was associated with a reduced cardiac output and excessive peripheral vasoconstriction. This latter realization led to the development of the cardiocirculatory or hemodynamic model for heart failure, 55 wherein heart failure was thought to arise largely as a result of abnormalities of the pumping capacity of the heart. Although both the cardiorenal and the cardiocirculatory models for heart failure explained the excessive salt and water retention that heart failure patients experience, neither of these models explained the relentless disease progression that occurs in this syndrome. The important insight that heart failure was also a progressive disorder and not simply a disorder of excessive salt and water retention led to the so-called neurohormonal model for heart failure, in which the elaboration of neurohormones was considered to lead not only to salt and water retention, but also to disease progression through progressive left ventricular remodeling and left ventricular dysfunction. 54 More recently, it has also become evident that another class of biologically active molecules, generically referred to as cytokines, are also overexpressed in heart failure. Over the past several years, there has been an increasing appreciation that overexpression of proinflammatory cytokines may play an important role in the pathogenesis of heart failure. This article reviews clinical and experimental material that suggests that proinflammatory (or stress-activated ) cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6), may represent another class of biologically active molecules that are responsible for the development and progression of heart failure.