Cardiovascular risk reduction by reversing endothelial dysfunction: ARBs, ACE inhibitors, or both? Expectations from the ONTARGET Trial Programme

Abstract

Endothelial dysfunction is the initial pathophysiological step in a progression of vascular damage that leads to overt cardiovascular and chronic kidney disease. Angiotensin II, the primary agent of the renin-angiotensin system (RAS), has a central role in endothelial dysfunction. Therefore, RAS blockade with an angiotensin receptor blocker (ARB) and/or angiotensin-converting enzyme (ACE) inhibitor provides a rational approach to reverse endothelial dysfunction, reduce microalbuminuria, and, thus, improves cardiovascular and renal prognosis. ARBs and ACE inhibitors act at different points in the RAS pathway and recent evidence suggests that there are differences regarding their effects on endothelial dysfunction. In addition to blood pressure lowering, studies have shown that ARBs reduce target-organ damage, including improvements in endothelial dysfunction, arterial stiffness, the progression of renal dysfunction in patients with type 2 diabetes, proteinuria, and left ventricular hypertrophy. The ONgoing Telmisartan Alone in combination with Ramipril Global Endpoint Trial (ONTARGET) Programme is expected to provide the ultimate evidence of whether improved endothelial function translates into reduced cardiovascular and renal events in high-risk patients, and to assess possible differential outcomes with telmisartan, the ACE inhibitor ramipril, or a combination of both (dual RAS blockade). Completion of ONTARGET is expected in 2008.

Figure 1

The cardiovascular–renal continuum.

Figure 2

Blockade of the RAS pathway with ACE inhibitors and ARBs.

Figure 3

Schematic representation of the multiple effects of increased tissue production of angiotensin II. Reprinted from Schmieder RE, 2005. Mechanisms for the clinical benefits of Angiotensin II receptor blockers. Am J Hypertens, 18:720–30. Copyright © 2005, with permission from American Journal of Hypertension, Ltd. Abbreviations: ET-1, endothelin-1; MCP-1, monocyte chemoattractant protein-I; MMP, matrix metalloproteinase; NF-_kB, nuclear factor-_kB; NO, nitric oxide; PAI-1, plasminogen activator type 1;VCAM, vascular cell adhesion molecule;ACE, angiotensin-converting enzyme.

Figure 4

Improved endothelial function with telmisartan compared with ramipril in the TRENDY study. From Schmieder et al. 2005. Effects of telmisartan versus ramipril on endothelium function of the renal vasculature in type 2 diabetes. J Hypertens, 23:S147.