Aliskiren on Retinal Vasculature Treatment Study

Overview

Hypertension affects approximately one fourth of the world population and therefore contributes substantially to the worldwide burden of cardiovascular (CV) disease and end-organ damage. Changes in small artery structure characterized by an increased wall-to-lumen ratio (WLR) are characteristic feature of target organ damage in hypertension. Of clinical importance, structural arteries of small subcutaneous arteries have been shown to be of prognostic significance, with adverse prognosis in subjects with higher WLR. However, the assessment of arteriolar structure from biopsies of subcutaneous tissue is invasive and impractical in clinical practice. A new approach focuses on retinal arteriolar structural parameters by using scanning laser Doppler flowmetry (SLDF) with automatic full-field perfusion imaging analyses (9). This approach allows the non-invasive assessment of both the outer diameter (OD) and inner diameter (ID) of retinal arterioles in vivo and, thus, analyses vascular remodeling of retinal arterioles by calculating WLR = (OD - ID) / ID). A crucial role in the efforts of prevention of end-organ damage plays the renin angiotensin system (RAS). The increased mechanical strain on the vasculature at a higher BP can cause injury to the endothelial wall. Activation of the RAS increases BP and stimulates a local inflammatory response to repair the injury. Long-term or repeated response to injury leads to endothelial dysfunction and microvascular damage, and hence end-organ damage. Combining RAS inhibitors may provide greater end-organ protection than use of either class alone. However, ONTARGET has failed to show superiority of the dual RAS blockade (ACE-I and ARB) in patients at high cardiovascular risk. The combination of ARBs and direct renin inhibitors (DRIs) emerged as the only available, valid and innovative option for blocking the RAS at two different sites (sequential blockade). Indeed, AVOID study and ALLAY study demonstrated that the DRI aliskiren has additional and to some extent blood pressure independent effects on albuminuria and left ventricular hypertrophy, both signs of subclinical organ damage in hypertension, respectively. However, no data are available with respect to the effects of ARBs and DRIs on vascular properties in the short and long term To close this gab we focus in this study on vascular structural and functional changes since vascular adaptation to high blood pressure occurs in the early phase of hypertensive disease.

Hypertension affects approximately one fourth of the world population and therefore contributes substantially to the worldwide burden of cardiovascular (CV) disease and end-organ damage (1). Therefore, the goal of antihypertensive therapy is to provide effective long-term lowering of elevated blood pressure (BP) and prevention of hypertensive end-organ-damage and mortality (2). Changes in small artery structure characterized by an increased wall-to-lumen ratio (WLR) are characteristic feature of target organ damage in hypertension. (3; 4). A clinical study examining small arteries obtained from gluteal biopsies of patients with hypertension revealed that an increased WLR of subcutaneous small arteries is one of the first manifestations of target organ damage in hypertension that occur before proteinuria and cardiac hypertrophy (5). Of clinical importance, structural arteries of small subcutaneous arteries have been shown to be of prognostic significance, with adverse prognosis in subjects with higher WLR (6-8). However, the assessment of arteriolar structure from biopsies of subcutaneous tissue is invasive and impractical in clinical practice. A new approach focuses on retinal arteriolar structural parameters by using scanning laser Doppler flowmetry (SLDF) with automatic full-field perfusion imaging analyses (9). This approach allows the non-invasive assessment of both the outer diameter and inner diameter of retinal arterioles in vivo and, thus, analyses vascular remodeling of retinal arterioles by calculating WLR = (outer diameter - inner diameter) / inner diameter) (10). In a previous study, we could demonstrate that treated hypertensive patients with poor BP control have a greater WLR of retinal arterioles than those with good blood pressure control. Interestingly, in this cohort we did not find a significant relation between BP and WLR of retinal arterioles using correlation analyses. We have concluded that this lack of a relation might well be the result of the effects of some antihypertensive drugs to beneficially influence vascular structure (9). Subsequently, we analyzed WLR of retinal arterioles in a cohort of never-treated patients with essential hypertension and normotensive controls. In this cohort, both systolic BP and diastolic BP were significantly related to WLR of retinal arterioles independent of traditional CV risk factors and other confounders, e.g. subclinical inflammation, endothelial dysfunction and dietary salt intake. Moreover, in this cohort, the WLR of retinal arterioles was greater in hypertensive than in normotensive subjects (11). A crucial role in the efforts of prevention of end-organ damage plays the renin angiotensin system (RAS) due its dual role on salt and water homeostasis (blood pressure) and the vascular response to injury. The increased mechanical strain on the vasculature at a higher BP can cause injury to the endothelial wall. Activation of the RAS increases BP and stimulates a local inflammatory response to repair the injury. Long-term or repeated response to injury leads to endothelial dysfunction and microvascular damage (12), and hence end-organ damage. Therefore increasing evidence is not suppressing, that antihypertensive medications which inhibit the RAS may provide incremental end-organ protection. Recently, we have shown that hypertensive patients have an impaired vasodilatory response of retinal arterioles to Flickerlight test - which improves after treatment with Angiotensin Receptor Blockers (ARBs) - and have a reduced nitric oxide (NO) activity in the retinal circulation, that is normalized after treatment with ARBs (13; 14). Likewise, in a previous study analyzing the arterial resistance vessels also in the systemic circulation we found that in contrast to diuretics and placebo, valsartan improved endothelial function and vascular properties (estimated by pulse wave anlalysis) (15; 16). Combining RAS inhibitors may provide greater end-organ protection than use of either class alone. However, the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) has failed to show superiority of the dual RAS blockade (Angiotensin converting enzyme inhibitor and ARB) in patients at high cardiovascular risk (17). The combination of ARBs and direct renin inhibitors (DRIs) emerged as the only available, valid and innovative option for blocking the RAS at two different sites (sequential blockade). Indeed, the Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID) study (18) and the Aliskiren in Left Ventricular Hypertrophy (ALLAY) study (19) demonstrated that the DRI aliskiren has additional and to some extent blood pressure independent effects on albuminuria and left ventricular hypertrophy, both signs of subclinical organ damage in hypertension, respectively (20). However, no data are available with respect to the effects of ARBs and DRIs on vascular properties in the short and long term To close this gab we focus in this study on vascular structural and functional changes since vascular adaptation to high blood pressure occurs in the early phase of hypertensive disease.