The renin angiotensin system in the development of cardiovascular disease: role of aliskiren in risk reduction

Abstract

An association has been shown between plasma renin activity (PRA) and the risk of cardiovascular disease. There is also evidence that angiotensin II exerts detrimental effects on progression and instabilization of atherosclerotic plaque. The renin-angiotensin system (RAS) can be inhibited through inhibition of angiotensin I (Ang I) generation from angiotensinogen by direct renin inhibitors, inhibition of angiotensin II (Ang II) generation from angiotensin I by angiotensin-converting enzyme inhibitors and finally by direct inhibition of the action of Ang II receptor level. Aliskiren, the first direct renin inhibitor to reach the market, is a low-molecular-weight, orally active, hydrophilic nonpeptide. Aliskiren blocks Ang I generation, while plasma renin concentration increases because the drugs blocks the negative feed-back exerted by Ang II on renin synthesis. Because of its long pharmacological half-life, aliskiren is suitable for once-daily administration. Its through-to-peak ratio approximates 98% for the 300 mg/day dose. Because of its mechanism of action, aliskiren might offer the additional opportunity to inhibit progression of atherosclerosis at tissue level. Hypertension is an approved indication for this drug, which is also promising for the treatment of heart failure. The efficacy of this drug in reducing major clinical events is being tested in large ongoing clinical trials.

Aliskiren affects fatty-acid uptake and lipid-related genes in rodent and human cardiomyocytes

“…Whether the additional effects of aliskiren that we have While the up-regulation by aliskiren of cholesterol-biosynthetic enzymes that we observed also merits further investigation, it should be noted that we did not find changes in expression levels of any genes known to be abnormally re-expressed in hypertrophied cardiomyocytes (smooth muscle α-actin, atrial natiuretic peptide, or β-myosin heavy chain). In hypertensive patients, moreover, monotherapy with aliskiren appears to have generally beneficial effects, with respect to cholesterol metabolism and stabilising atherosclerotic plaques more completely, than with ACE inhibitors or ARBs [69,70]. We can not at present say whether the up-regulation in the cholesterol biosynthetic pathway observed at the cardiac level is harmful or beneficial, as the number of relevant published studies is currently too small.…”

Finding a place for aliskiren in the wide spectrum of blood pressure lowering agents

“…In this context, some trials are ongoing to evaluate the effects of aliskiren on different clinical outcomes including reduction of CV death and rehospitalization in patients with congestive HF (Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT)), morbidity and mortality in patients with type 2 diabetes and pre-existing CV disease and/or kidney disease (Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Disease Endpoints (ALTITUDE)), morbidity and mortality in patients with chronic HF (Aliskiren Trial to Minimize Outcomes in Patients with Heart Failure (ATMOSPHERE)) and major CV end points in elderly subjects with normal BP (Aliskiren in Prevention of Later Life Outcomes (APOLLO)). 3,4 In the absence of prognostic data, aliskiren should be used as an alternative when other drugs are ineffective or poorly tolerated, or as an effective and well-tolerated add-on therapy to reach BP target.…”

“…However, in contrast to ACE-Is and ARBs, aliskiren inhibits the activity of secreted renin and markedly lowers PRA. 4 Although results from a wide clinical program is still expected to prove the efficacy of aliskiren in reducing major clinical events, 3 its potential clinical benefits have been indirectly tested investigating the effects on BP and intermediate outcome measures.…”

“…However, both classes stimulate renin release via a negative feedback mechanism, ultimately increasing plasma renin concentration and plasma renin activity (PRA). 4 These findings have led to the suggestion that complete control of the RAS might be effective in reducing morbidity and mortality.…”

“…4 Because renin is the only enzyme that promotes this conversion, it has been speculated that DRIs might provide a more effective means of blockade of the RAS than is possible with ACE-Is and/or ARBs (Figure 1). …”