NEUROHUMORAL ACTIVATION IN PRECLINICAL HEART-FAILURE - REMODELING ANDTHE POTENTIAL FOR INTERVENTION

Congestive heart failure is often preceded by a latent or preclinical phase in which patients are relatively asymptomatic. During this perio d, there is neuroendocrine activation, left ventricular dysfunction, a nd remodeling of the heart. The extent to which these activities are i nterrelated is unclear, but it appears from experimental studies that myocardial damage is associated with chronic sympathetic nervous syste m activation, left ventricular hypertrophy, and a subsequent increase in left ventricular volume. The nondamaged myocardial tissue demonstra tes enhanced messenger RNA for angiotensinogen and angiotensin convert ing enzyme activity. Angiotensin II along with other trophic signals m ay prime the cell for ''growth.'' Alteration of left ventricular funct ion may produce unusual loading conditions on the myocardium. Stretch of membrane-bound ion channels may impart mechanical signals that may be transduced and expressed as cellular hypertrophy. Interstitial coll agenase may be activated, leading to disruption of the collagen-suppor ting network. Elongated cells (eccentric hypertrophy), cell slippage, and cell dropout may contribute to the dilatative process. The end pro duct is cardiac dilatation, inefficient left ventricular performance, and congestive heart failure. We have observed that an increase in lef t ventricular mass is the initial morphological response to acute myoc ardial damage in a canine model. This occurs at 1 week and is followed by progressive activation of the sympathetic nervous system, left ven tricular dilatation, and modest left ventricular dysfunction, a condit ion that mimics preclinical heart failure in patients. The remodeling process in the canine model, including the increase in mass and volume , may be blocked by angiotensin converting enzyme inhibitor. These obs ervations suggest that neuroendocrine activation may be associated wit h the early hypertrophic response to myocardial injury, particularly s ince nonspecific vasodilators such as hydralazine fail to prevent remo deling in the rat myocardial infarction model. Understanding the mecha nisms of myocardial cell hypertrophy has remained an elusive goal, but unraveling certain aspects of the process into a coherent scheme is w ithin reach. It is possible that myocardial hypertrophy and remodeling are adaptive responses to injury that ultimately become counterproduc tive. If this hypothesis gains support, it would provide a more clear rationale for early or even prophylactic treatment strategies.