Activation of cytokines as a mechanism of disease progression in heart failure

The scientific quest for the basic mechanism(s) responsible for the development and progression of congestive heart failure in humans has been practically exhaustive; none the less, the mechanisms responsible for the decompensation of myocardial function after myocardial injury or haemodynamic overloading, or both, have remained elusive. Initially clinicians viewed heart failure as a problem of excessive salt and water retention that was caused by abnormalities of renal blood flow (the cardiorenal model). As clinicians began to perform careful haemodynamic measurements, it also became apparent that heart failure was accompanied by reduced cardiac output and excessive peripheral vasoconstriction. This led to the development of a cardiocirculatory or haemodynamic model for heart failure, in which heart failure was thought to arise from abnormalities of the pumping capacity of the heart. Neither of these models explained the progression of heart failure. Subsequently neurohormones were considered to lead to disease progression through myocyte loss, progressive myocardial fibrosis, as well as salt and water retention. More recently, it has become evident that another class of biologically active molecules, generally referred to as cytokines are also important in heart failure.1-8 The term cytokine is applied to a group of relatively small molecular weight protein molecules (generally 15–30 kDa) that are secreted by cells in response to a variety of different inducing stimuli. Classically, cytokines are thought to be secreted by neighbouring “producer cells” and to act in an autocrine, juxtacrine or paracrine manner to influence the biological behaviour of neighbouring “target cells” (see Mann and Young8 for a brief review). However, when cytokines are overproduced they can “spill over” into the peripheral circulation where they can exert endocrine-like effects. It should be recognised that although cytokines are similar in many respects to polypeptide hormones, cytokines can be produced by a variety of different cell …