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Neurohumoral activation in preclinical heart failure. Remodeling and the potential for intervention
G S Francis1, K M McDonald, J N Cohn
1Department of Medicine, University of Minnesota Medical School, Minneapolis.
Insights
Preclinical heart failure involves neuroendocrine activation and left ventricular dysfunction. Angiotensin converting enzyme inhibitors may block cardiac remodeling, offering a potential therapeutic target for preventing heart failure progression.
Area of Science:
- Cardiology
- Physiology
- Pathology
Background:
- Congestive heart failure (CHF) often follows a preclinical phase with asymptomatic neuroendocrine activation and left ventricular (LV) dysfunction.
- Myocardial damage is linked to sympathetic nervous system activation, LV hypertrophy, and increased LV volume.
- Nondamaged heart tissue shows increased angiotensinogen mRNA and angiotensin converting enzyme activity, suggesting a role for angiotensin II in cellular growth.
Purpose of the Study:
- To investigate the interrelationship between neuroendocrine activation, LV dysfunction, and cardiac remodeling during preclinical heart failure.
- To examine the morphological and functional changes in the heart following acute myocardial damage in a canine model.
- To evaluate the effect of angiotensin converting enzyme (ACE) inhibitors on cardiac remodeling.
Main Methods:
- Utilized a canine model to induce acute myocardial damage.
- Monitored changes in left ventricular mass, volume, and function post-myocardial damage.
- Assessed sympathetic nervous system activation and neuroendocrine markers.
- Administered ACE inhibitors to evaluate their impact on cardiac remodeling.
Main Results:
- Increased left ventricular mass was the initial response to myocardial damage, observed within 1 week.
- Progressive sympathetic nervous system activation, LV dilatation, and modest LV dysfunction followed.
- Cardiac remodeling, including increased LV mass and volume, was significantly reduced by ACE inhibitors.
Conclusions:
- Acute myocardial damage initiates a cascade of events mimicking preclinical heart failure, including LV remodeling and neuroendocrine activation.
- ACE inhibition demonstrates potential in blocking the detrimental remodeling process in the preclinical phase of heart failure.
- Targeting the renin-angiotensin system may be a viable strategy for preventing the progression to overt congestive heart failure.
Abstract:
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.(ABSTRACT TRUNCATED AT 250 WORDS)
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