Cardiac remodelling and RAS inhibition

Abstract

Risk factors such as hypertension and diabetes are known to augment the activity and tissue expression of angiotensin II (Ang II), the major effector peptide of the renin–angiotensin system (RAS). Overstimulation of the RAS has been implicated in a chain of events that contribute to the pathogenesis of cardiovascular (CV) disease, including the development of cardiac remodelling. This chain of events has been termed the CV continuum. The concept of CV disease existing as a continuum was first proposed in 1991 and it is believed that intervention at any point within the continuum can modify disease progression. Treatment with antihypertensive agents may result in regression of left ventricular hypertrophy, with different drug classes exhibiting different degrees of efficacy. The greatest decrease in left ventricular mass is observed following treatment with angiotensin converting enzyme inhibitors (ACE-Is), which inhibit Ang II formation. Although ACE-Is and angiotensin receptor blockers (ARBs) provide significant benefits in terms of CV events and stroke, mortality remains high. This is partly due to a failure to completely suppress the RAS, and, as our knowledge has increased, an escape phenomenon has been proposed whereby the human sequence of the 12 amino acid substrate angiotensin-(1-12) is converted to Ang II by the mast cell protease, chymase. Angiotensin-(1-12) is abundant in a wide range of organs and has been shown to increase blood pressure in animal models, an effect abolished by the presence of ACE-Is or ARBs. This review explores the CV continuum, in addition to examining the influence of the RAS. We also consider novel pathways within the RAS and how new therapeutic approaches that target this are required to further reduce Ang II formation, and so provide patients with additional benefits from a more complete blockade of the RAS.

Alteration in the expression of the renin-angiotensin system in the myocardium of mice conceived by in vitro fertilization†

“…An abnormal expression of COL1 and COL3 in the embryonic period may affect the heart's structural development [25]. Sustained changes in the expression of COL1 and COL3 in adulthood would further increase the risk of cardiovascular diseases, such as hypertension, arrhythmia, and cardiac hypertrophy, and enhance the process of cardiovascular fibrosis and remodeling [26]. The effects of ART on genome-wide changes in DNA methylation levels have been confirmed by several studies [64][65][66].…”

“…During the embryonic period, abnormal expression of COL1 and COL3 can affect the normal development of the cardiovascular structures [24,25]. In adulthood, overstimulation of the RAS can contribute to the pathogenesis of a number of cardiovascular diseases, affecting the normal function of cardiovascular tissue cells and increasing the risk of hypertension, heart arrhythmias, and cardiac hypertrophy [26]. Connective tissue growth factor (CTGF) promotes fibrosis therefore playing a further key role in AT1-mediated intracellular signal transmission that results in myocardial remodeling and vascular fibrosis [27].…”

Renin angiotensin aldosterone inhibition in the treatment of cardiovascular disease

“…This conclusion is reminiscent of the report made by the Blood Pressure Lowering Treatment Trialists’ Collaboration group who reported no evidence for differences among drug classes for major cardiovascular events [101]. While many arguments may be posited as to the reasons for this disconnect, we have proposed that incomplete blockade of Ang II pathological actions is due to the failure of RAAS inhibitors to access intracellular proteins accounting for canonical and non-canonical mechanisms of Ang II formation [19–21, 39]. …”

“…In our minds, such lackluster and/or nonexistent efficacy improvements beyond ACE inhibitors underscores the role of the RAAS in the etiopathogenesis of cardiovascular disease. The small effect of ARBs is suggestive of intracellular sites of Ang II activity that would be largely unopposed [19, 20, 173–175]. That ARBs induce compensatory pathways that increase circulating Ang II as well as increased expression of downstream metabolites like Ang-(1-7) [13, 59] underscore the complexity of understanding the mechanisms that limit their efficacy.…”

Passiflora quadrangularis L. PREVENTS EXPERIMENTAL HYPERTENSION AND VASCULAR REMODELLING IN RATS EXPOSED TO NITRIC OXIDE DEFICIT

“…At the same time, the increase in the thickness of small muscular resistance arteries, arterioles, and the microvasculature resulting from the remodelling of vessels in hypertension implies not only a maintained resistance due to excessive vasoconstriction, but a progressive lesion in the function of targets organs such as the brain, heart, kidney and retina. Therefore, antihypertensive agents that are able not only to reduce high blood levels but to ameliorate the progression of cardiovascular remodelling could represent an advantage in reducing the complication of hypertension (12).…”