Dual renin-angiotensin system blockade and vascular remodeling

Essential hypertension is characterized by increased peripheral vascular resistance to blood flow particularly in younger individuals. Resistance arteries undergo vascular remodeling (reduced vascular lumen with increased media thickness) that may be functional, mechanical, and/or structural [1,2][1,2]. Small decreases in the lumen diameter significantly increase resistance to blood flow. Increased media-to-lumen ratio (M/L) is the most reproducible parameter of vascular remodeling of resistance arteries [1,3][1,3]. Interestingly, an increased M/L ratio of subcutaneous small resistance arteries is a potent predictor of cardiovascular events in patients with increased blood pressure values [4–6][4–6][4–6] and different cardiovascular risk [4,5][4,5]. In hypertensive patients, it is thought that increased M/L ratio could be the earliest alteration that occurs in the vasculature [7] and may precede endothelial dysfunction [7,8][7,8]. The extent of structural alterations in subcutaneous small resistance arteries is particularly pronounced in hypertensive patients with type 2 diabetes mellitus [9] or obesity [10–12][10–12][10–12]. Thus, the association of several cardiovascular risk factors may have a synergistic, deleterious effect on the microcirculation. Furthermore, the remodeled resistance arteries are the sites of origin of most of the wave reflections that travel backward toward the heart, contributing to the stiffness of large arteries and the increased central SBP. Despite the evidence that M/L ratio of small arteries evaluated by micromyography has a strong prognostic significance, its evaluation on a large scale, however, is limited by the local invasiveness of the assessment [13]. Therefore, the development of new, noninvasive approaches for the evaluation of microvascular damage is warranted. A promising approach for the study of microcirculation is the evaluation of the retinal vascular district, as it may be directly viewed with simple and relatively noninvasive approaches, such as the scanning laser Doppler flowmetry [13]. Recent evidence, obtained by micromyographic approaches [14] as well as by scanning laser Doppler flowmetry of retinal arteriolar vessels [15,16][15,16], suggest that presence of structural alterations of small resistance arteries may be associated with the increase in large arteries stiffness. In the study by Jumar et al.[17], arteriolar remodeling was assessed in retinal arterioles noninvasively and in vivo by scanning laser Doppler flowmetry. This is an interesting study that attempts to investigate the role of dual renin–angiotensin system (RAS) blockade obtained with aliskiren on top of angiotensin receptor blockers (ARBs) on resistance arteries remodeling as well as on parameters of vascular stiffness, in hypertensive patients with no other cardiovascular risk factors. The molecular mechanisms involved in the remodeling of resistance arteries are not fully understood. Among the factors that may contribute to the structural alterations within the arterial wall, the variation of myogenic tone (ability of vessels to constrict in response to an increase in intraluminal pressure) may exert a significant contribution [18]. With chronic vasoconstriction, vessels may become embedded in a remodeled extracellular matrix and may not return to their dilated state [1,18][1,18]. Thus, structural narrowing of the lumen may amplify vasoconstriction. Constriction may be a consequence of increased concentration of specific agents at the level of receptors including enhanced angiotensin II signaling, which leads to changes in intracellular calcium, protein kinases, diacylglycerol, and increased reactive oxygen species (ROS) generation [18,19][18,19], as well as cell growth and extracellular matrix deposition. Thus, the activation of the RAS is a key factor in the pathophysiology and development of hypertension, and it is responsible, in part, for the hypertension-related functional and structural alterations in the cardiovascular system [20]. Antihypertensive treatment is able to favor a regression of the structural alterations in subcutaneous small-resistance arteries of essential hypertensive patients [21]. However, despite similar blood pressure-lowering effects, angiotensin-converting enzyme (ACE) inhibitors, ARBs, and calcium channel blockers provide a more effective effect than diuretics and β-blockers in terms of reduction in M/L ratio [21]. Therefore, the reduction of blood pressure values is a necessary and not sufficient condition to improve microvascular alterations, because drugs with similar hemodynamic effects have different effects on small artery morphology [21,22][21,22], particularly in diverse subsets of patients. For instance, hypertensive and diabetic patients present persistent remodeling of small arteries despite effective antihypertensive treatment [23]; thus, it is difficult to obtain a complete regression of small-resistance artery structural alterations in those patients despite the use of combination therapy and consistent blood pressure reductions [19,23–25][19,23–25][19,23–25][19,23–25]. Nevertheless, the addition of an ARB on top of antihypertensive medications resulted in an improvement in resistance artery remodeling in diabetic hypertensive patients [25]. Aliskiren is the newest antihypertensive drug and the first orally active direct renin inhibitor to become available for clinical use. Clinical data have shown that the antihypertensive effectiveness of aliskiren is similar to that of the other major antihypertensive agents. In experimental and clinical studies, the hemodynamic effects of aliskiren and ramipril were similar, and both treatments induced similar pressure control in hypertensive and diabetic patients [26,27][26,27]. Clinical and experimental studies and data from the real world suggest that aliskiren is a very potent antihypertensive agent, particularly when administered in combination with other RAS blockers as well as in low-sodium states [28]. Nevertheless, it is questionable whether dual RAS blockade is effective in terms of safety particularly in high cardiovascular risk patients, such as diabetic patients, taking optimal treatment (including full dose of ACE inhibitors or ARBs) with good blood pressure control before aliskiren treatment [29]. Furthermore, although aliskiren seems to have a similar effect in reducing vascular remodeling of resistance arteries as compared with ACE inhibitors, a more pronounced effect has been observed in peripheral resistance arteries with respect to retinal arterioles in high cardiovascular diabetic patients [27]. The study by Jumar et al.[17] is one of the few studies that investigated the effect of dual RAS blockade in hypertensive patients. The results show that aliskiren given on top of ARBs in patients with primary hypertension and no other cardiovascular risk factors presented no clear effect on vascular parameters. However, when the analyses were restricted to patients with preexisting vascular remodeling, aliskiren improved wall-to-lumen ratio of retinal arterioles as compared with placebo along with an improvement of pulse pressure amplifications, indicative of less stiff arteries in the peripheral circulation. The results of this study further extend to retinal microvasculature the data obtained with RAS blockers in peripheral resistance arteries in high cardiovascular risk patients, and highlight the putative role of dual RAS blockade on vascular remodeling particularly in retinal microcirculation. Nonetheless, aliskiren given on top of valsartan in hypertensive patients reduced blood pressure more than placebo; therefore, it is uncertain whether the more pronounced effect on vascular remodeling and arterial stiffness was because of blood pressure reduction or an independent amplifying effect of dual RAS blockade. In previous studies, ARBs or aliskiren given on top of other antihypertensive medications including RAS blockers or calcium channel blockers improved the remodeling of peripheral resistance arteries independently of blood pressure control [25,27][25,27]. Further evaluation on this issue is warranted, to clarify whether aliskiren may exert blood pressure-independent effects on vascular remodeling in distinct vascular beds particularly when given in combination with ARBs. Moreover, another important issue that remains to be clarified is whether dual RAS blockade with alsikiren and ARBs could be effective and well tolerated in light of the debated evidence of clinical data [28]. ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.