Neurohumoral activation in preclinical heart failure: Remodeling and the potential for intervention

Congestive heart failure is often preceded by a latent or preclinical phase in which patients are relatively asymptomatic. During this period, there is neuroendocrine activation, left ventricular dysfunction, and remodeling of the heart. The extent to which these activities are interrelated is unclear, but it appears from experimental studies that myocardial damage is associated with chronic sympathetic nervous system activation, left ventricular hypertrophy, and a subsequent increase in left ventricular volume. The nondamaged myocardial tissue demonstrates enhanced messenger RNA for angiotensinogen and angiotensin converting enzyme activity. Angiotensin II along with other trophic signals may prime the cell for "growth." Alteration of left ventricular function 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 collagenase may be activated, leading to disruption of the collagen-supporting network. Elongated cells (eccentric hypertrophy), cell slippage, and cell dropout may contribute to the dilatative process. The end product is cardiac dilatation, inefficient left ventricular performance, and congestive heart failure. We have observed that an increase in left ventricular mass is the initial morphological response to acute myocardial damage in a canine model. This occurs at 1 week and is followed by progressive activation of the sympathetic nervous system, left ventricular dilatation, and modest left ventricular dysfunction, a condition 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 observations suggest that neuroendocrine activation may be associated with the early hypertrophic response to myocardial injury, particularly since nonspecific vasodilators such as hydralazine fail to prevent remodeling in the rat myocardial infarction model. Understanding the mechanisms of myocardial cell hypertrophy has remained an elusive goal, but unraveling certain aspects of the process into a coherent scheme is within reach. It is possible that myocardial hypertrophy and remodeling are adaptive responses to injury that ultimately become counterproductive. If this hypothesis gains support, it would provide a more clear rationale for early or even prophylactic treatment strategies.