Summary
For more than a decade, the inhibition of the renin-angiotensin system in heart failure has been regarded as pure vasodilator therapy. Consequently, the role of the renin-angiotensin system has been seen as contributing to hemodynamic overload by vascoconstriction and volume retention. Meanwhile, clinical experience was indicated that important additional aspects of ACE-inhibition in heart failure are attenuation of the enhanced neuroendocrine activity and reversal or prevention of inappropriate trophic reactions of the overloaded myocardium. In overloaded hearts there is enhanced intracardiac formation of angiotensin due to enhanced expression of angiotensinogen and ACE, and due to accumulation of circulating, nephrogenic active renin. In human hearts, a mast-cell-derived chymase, which is not blocked by ACE-inhibition, contributes to intracardiac angiotensin formation. The enhanced intracardiac angiotensin-II formation in overloaded hearts is involved in coronary constriction, impairment of diastolic relaxation, myocyte enlargement and interstitial fibrosis, which aggravate the diastolic impairment. The major problem in overloaded, hypertrophied cardiocytes is the dedifferentiation with instabilization of Ca++-homeostasis due to an altered program of gene expression. Dedifferentiated cardiocytes have a reduced expression of sarcoplasmic reticulum Ca++-ATPase and an enhanced expression of the sarcolemmal Na+/Ca++-exchanger, resulting in an attenuation of active diastole (Ca++-reaccumulation into the sarcoplasmic reticulum), a depressed force-frequency relation, and an enhanced susceptibility for fatal arrhythmias. Furthermore, an enhanced local renin-angiotensin system in distensible coronary and systemic arteries seems to contribute to a reduced releasability of endothelium-derived relaxing factor, probably by reducing bradykinin availability. This modulation of endothelial function appears to contribute to the localization and progression of atheroma development in presence of risks factors for atherosclerosis.
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Holtz, J. (1993). Pathophysiology of heart failure and the renin-angiotensin-system. In: Grobecker, H., Heusch, G., Strauer, B.E. (eds) Angiotensin and the Heart. Steinkopff. https://doi.org/10.1007/978-3-642-72497-8_13
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