EFFECT OF RENIN INHIBITION ON CARDIOVASCULAR AUTONOMIC NERVE FUNCTION IN DIABETE

University Of Delaware, Newark DE

Investigators

Linked publications & trials

Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Diabetic neuropathy, a serious and common complication of diabetes, is a heterogeneous disorder affecting different parts of the nervous system. Most common among the neuropathies are diabetic autonomic neuropathy and distal symmetric polyneuropathy (DPN). DPN causes impaired sensation of the lower extremities predisposing individuals to neuropathic foot ulcers, which may lead to infection and lower extremity amputations. The rate of amputation is 10 times higher for patients with diabetes than those without diabetes. Cardiovascular autonomic neuropathy is the most studied and clinically important form of diabetic autonomic neuropathy. Meta-analyses of published data demonstrated that reduced cardiovascular autonomic function, as measured by heart rate variability, is strongly associated with increased risk of silent myocardial ischemia and mortality. If left controlled, persistent overactivity of the autonomic nervous system will result in irreparable cardiac damage, culminating in hypertension, cardiac muscle dysfunction and ultimate failure. Thus, it is vital to find new therapies to stop the development and progression of nerve dysfunction in order to reduce both morbidity and mortality. Both metabolic and vascular defects have been implicated in the pathogenesis of diabetic neuropathy. Interventions to ameliorate diabetic neuropathy have been evaluated in clinical trials based on theories of pathogenesis. The renin-angiotensin-aldosterone system (RAAS) plays an integral role in the regulation of the cardiovascular system. Inhibition of the RAAS with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) has shown varied results for the treatment of diabetic neuropathy. One explanation could be due to incomplete blockage of the RAAS. Aliskiren, a direct renin inhibitor, is the first in a new class of antihypertensives. Blocking the RAAS at the first point of the pathway may offer an important advantage over other RAAS inhibitors for the treatment of diabetic neuropathy by providing more complete blockage than downstream RAAS inhibitors. It is clear that both the RAAS and autonomic nervous system play integral roles in the development of diabetic neuropathy. The interaction between them, however, has not been studied sufficiently. In the proposed study, we will assess the effect of direct renin inhibition on nerve dysfunction due to diabetes. To accomplish this goal a double-blind, placebo-controlled randomized trial involving two treatment arms (i.e., [1] 30 participants enrolled and randomized to 300 mg of Aliskiren;[2] 30 participants enrolled and randomized to placebo) will be performed. In specific aims I and II, we will test the hypothesis that six weeks of targeted-intervention with Aliskiren will lead to changes in activity of the autonomic nervous system (e.g., enhanced parasympathetic function and improved sympathetic/parasympathetic balance with renin blockage) and improved peripheral nerve function. Cardiovascular autonomic function will be measured via assessment modalities of heart rate variability including a new method which evaluates power spectral analysis in combination with respiratory activity. DPN will be assessed via quantitative sensory threshold testing. Study data will be analyzed by repeated measures analysis of variance with 2 independent treatment groups (Aliskiren vs. placebo), and 2 repeated measures, baseline and 6 weeks post-intervention. The study is sufficiently powered (i.e., 80% power) to estimate a mean difference of 0.10 between baseline and follow-up for a measure of parasympathetic function. Endothelial dysfunction has been demonstrated in individuals with diabetes and hyperglycemia has been implicated as a cause of dysfunction. Hyperglycemia also increases the production of angiotensin II in the vessel wall and stimulates vascular NAPH oxidase, increasing oxidative stress. RAAS inhibition may improve endothelial function by reduction of vascular oxidative stress. Studies utilizing both ACE-inhibitors and ARBs have been shown to improve endothelial function in patients with diabetes. The effect of Aliskiren on endothelial function in individuals with diabetes has not been examined. Thus, specific aim III will assess changes in flow mediated dilation, an established measure of vascular endothelial function. This will be performed in a subset of the study cohort. It is hypothesized that Aliskiren will show a positive trend indicating both enhanced vascular endothelial and nerve function. The ability to assess for a trend will provide mechanistic insights into how changes in nerve function are associated with improved blood flow and feasibility data for the development of future studies