PATHOPHYSIOLOGIC ASPECTS OF END-STAGE HEART-FAILURE

Heart failure is not a distinct disease, but rather a complex clinical syndrome that can result from virtually any form of heart disease. The so-called ''end stages'' of heart failure do not respect etiologic boundaries. Patients are characterized clinically by extreme cardiomegaly, breathlessness, and fluid retention. Despite recent ad vances in the pharmacologic management of congestive heart failure, it remains a highly lethal and disabling disorder. Only through an improved understanding of the basic biology of the early stages of the syndrome can heart failure be prevented or at least forestalled. There is now intense interest in understanding the mechanisms operative in early left ventricular remodeling, which has the potential to culminate in end-stage heart failure. The study of animal models has been particularly useful in this card, as have clinical studies performed in the early stages of acute myocardial infarction. The remodeling process is characterized by myocyte loss and segmental scarring, interstitial fibrosis, myocardial slippage, and myocyte hypertrophy. Although the mechanisms responsible for these topographic changes are as yet unclear, the net result is progressive enlargement of the heart, culminating in severe left ventricular dysfunction. A long-held view that cardiomegaly is a necessary adaptive process that maintains stroke volume in the presence of a falling ejection fraction has been challenged, although undoubtedly the early responses to myocardial injury In the form of myocyte hypertrophy and maintenance of wall stress are useful adaptations. However, as the left ventricle continues to dilate and hypertrophy over time, a form of overadjustment occurs that perhaps is an important contributory factor toward end-stage failure. Current therapeutic strategies designed to modify this process include the use of pharmacologic agents designed to optimize loading conditions and reduce myocyte hypertrophy. Although we are only now beginning to understand the underpinnings of progressive left ventricular remodeling, it is apparent that this is a potentially modifiable process.