Prevention of remodeling in congestive heart failure due to myocardial infarction by blockade of the renin–angiotensin system

Abstract

Ventricular remodeling subsequent to myocardial infarction (MI) is a complex process and is considered to be a major determinant of the clinical course of congestive heart failure (CHF). Emerging evidence suggests that activation of the renin-angiotensin system (RAS) plays an important role in post-MI ventricular remodeling; however, it is becoming clear that this is one of several neurohumoral systems that are activated in CHF. Blockade of RAS by angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor antagonists attenuates the ventricular dysfunction, but the effects of individual drugs in reducing the morbidity and mortality in CHF patients are variable. Furthermore, there is a difference of opinion as to the time of initiation of therapy with RAS blockers after the onset of MI. Since blockade of RAS partially improves cardiac function, it is suggested that a combination therapy involving RAS blockers (angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor antagonists) and agents that affect other neurohumoral systems may prove useful for improved treatment of CHF. Although activation of RAS has been shown to promote oxidative stress in experimental studies, the use of antioxidant therapy in CHF patients is controversial. Recent experimental studies have shown that ventricular remodeling in CHF is associated with remodeling of subcellular organelles such as sarcolemma, sarcoplasmic reticulum, myofibrils and extracellular matrix in terms of their molecular structure and composition. Since attenuation of remodeling in one and/or more subcellular organelles by different agents may prevent the progression of CHF, it is a challenge to develop specific drugs affecting molecular mechanisms associated with subcellular remodeling for the improved therapy of CHF.

Subcellular Remodeling as a Viable Target for the Treatment of Congestive Heart Failure

“…Supporting this view are our observations indicating beneficial effects of RAS blockade at the whole heart, cellular, membrane, protein expression, and gene expression levels in a rat model of CHF due to MI (244)(245)(246)(247)(248)(249). Such molecular and subcellular effects on myofibril, sarcolemma, and sarcoplasmic reticulum remodeling may be complementary to the action of these drugs on changes in gene expression for extracellular matrix and ventricular remodeling in the failing heart.…”

Role of Subcellular Remodeling in Cardiac Dysfunction due to Congestive Heart Failure

“…However, the mechanisms of such subcellular remodeling are understood poorly. Since both SNS and RAS are activated in CHF [2,7,10,77] , it is likely that elevated levels of circulating levels of norepinephrine and angiotensin II (Ang II) may produce subcellular remodeling in the failing hearts. Notwithstanding the fact that the SNS offers a means of supporting cardiac contractile function, it has been documented that the failing human heart becomes less sensitive to stimulation of the SNS [78][79][80][81][82] .…”

“…Furthermore, Lai et al [84] have documented that norepinephrine infusion in dog hearts produced a decrease in the mRNA and protein levels of SERCA, which paralleled those hearts of pacing-induced CHF, with no change in the RyR, calsequestrin and PLB mRNA levels. It should be mentioned that RAS is also a critical entity in the regulation of cardiovascular function, as it plays a major role in the impairment of endothelial cell function, improvement of growth, progression of apoptosis, and the development of oxidative stress [77] . It has been shown by Ju et al [85] that Ang II increased levels of mRNA for the sarcolemmal Na + -Ca 2+ exchange, the SR ryanodine Ca 2+ receptor, and the SR SERCA protein in cardiomyocytes.…”

“…Certain therapies include angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers [77] . In a long-term study focusing on the effects of the ACEI captopril on left ventricular remodeling of the myocardial infarcted canine model, Jugdutt et al [87] revealed attenuation of early infarct expansion, the absence of late wall thinning, a reduction in diastolic bulging, and eradication of aneurysms, as well as a general restitution in overall cardiac systolic function.…”

Insulin inhibits myocardial ischemia-induced apoptosis and alleviates chronic adverse changes in post-ischemic cardiac structure and function

“…However, the compensatory effects of cardiac hypertrophy and dilation processes are limited and, under chronic conditions, cardiac remodeling eventually becomes maladaptive because structural changes to the geometry of the ventricles directly influence the ability of the heart to pump blood effectively. There is a growing body of evidence indicating that the remodeling might contribute to the progression and extent of cardiac dysfunction during HF [8]. On the other hand, recent studies have demonstrated the role of insulin in the regulation of cardiac growth measured by heart size and cardiomyocyte size [9].…”