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Pathologic hypertrophy with fibrosis: the structural basis for myocardial failure
K T Weber1, C G Brilla, S E Campbell
1Department of Internal Medicine, University of Missouri-Columbia.
Insights
Left ventricular hypertrophy (LVH) causes cardiovascular events due to structural changes, not just increased mass. Myocardial fibrosis, driven by hormones like aldosterone, disrupts heart function and can be reversed, suggesting potential for heart failure treatment.
Area of Science:
- Cardiovascular Medicine
- Pathology
- Pharmacology
Background:
- Left ventricular hypertrophy (LVH) is a major risk factor for cardiovascular events.
- LVH-related adverse outcomes stem from structural disruption, specifically myocardial fibrosis, rather than increased heart muscle mass alone.
- This fibrosis impairs the electrical and mechanical functions of the hypertrophied heart.
Purpose of the Study:
- To investigate the mechanisms behind fibrillar collagen accumulation in the heart.
- To determine the role of the renin-angiotensin-aldosterone system in myocardial fibrosis.
- To explore the potential for reversing cardiac fibrosis and improving heart function.
Main Methods:
- In vivo studies in animals examining myocardial fibrosis in relation to mineralocorticoid excess and hemodynamic workload.
- In vitro studies using cultured cardiac fibroblasts to assess the effects of hormones on collagen synthesis.
- Pharmacological interventions including aldosterone receptor antagonists and angiotensin-converting enzyme (ACE) inhibitors.
Main Results:
- Myocardial fibrosis is linked to chronic mineralocorticoid excess, independent of workload, and can occur in various forms of hypertrophy.
- Aldosterone receptor antagonists and ACE inhibitors effectively prevented or reversed myocardial fibrosis in animal models.
- In vitro, aldosterone and angiotensin II were found to stimulate fibroblast collagen synthesis.
Conclusions:
- Myocardial fibrosis, driven by hormones of the renin-angiotensin-aldosterone system, is a key structural basis for pathological hypertrophy and cardiovascular events.
- Pharmacological interventions targeting this system show promise for cardioreparation and treating heart failure.
- Reversing cardiac fibrosis may offer a new therapeutic strategy for heart failure management.
Abstract:
The major risk factor associated with the appearance of adverse cardiovascular events and outcome attributable to cardiovascular disease is left ventricular hypertrophy (LVH). Why this should be so resides not in the increase in myocardial mass per se, but in the disruption of myocardial structure. An abnormal accumulation of fibrillar collagen within the adventitia of intramyocardial coronary arteries and neighboring interstitial spaces represents such a distortion in structure. Furthermore, this fibrosis disrupts the electrical and mechanical behavior of the hypertrophied myocardium. Mechanisms responsible for fibrillar collagen accumulation have been examined in intact animals and cultured cardiac fibroblasts. In vivo studies indicate that myocardial fibrosis is associated with the presence of chronic mineralocorticoid excess, relative to sodium intake and excretion, not hemodynamic workload. Accordingly, fibrosis can appear in both the hypertensive, hypertrophied and nonhypertensive, nonhypertrophied ventricles. In both primary and secondary hyperaldosteronism it was possible to prevent myocardial fibrosis with an aldosterone receptor antagonist, while in unilateral renal ischemia angiotensin converting enzyme (ACE) inhibition was similarly cardioprotective. A regression in fibrous tissue and normalization of diastolic stiffness has also been possible using ACE inhibition, bringing forward the concept of cardioreparation and the notion that heart failure due to fibrosis may be reversible. In vitro studies indicate that effector hormones of the renin-angiotensin-aldosterone system stimulate fibroblast collagen synthesis. Aldosterone, in pathophysiologic concentrations, and angiotensin II, in much larger concentrations, each enhance collagen synthesis without altering the mitogenic potential of these cells. Thus, elevations in circulating aldosterone and angiotensin II, relative to sodium intake, have the potential to not only alter sodium homeostasis and vascular tonicity, but also the structure of cardiovascular tissue. Thus, myocardial fibrosis represents a structural basis for pathologic hypertrophy and ultimately accounts for the appearance of adverse cardiovascular events and outcomes.