PATHWAY PHARMACOGENETICS AND ANGIOTENSIN RECEPTOR BLOCKER RESPONSES

University Of Florida, Gainesville FL

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Through both angiotensin II-blocking and non-angiotensin II-mediated properties, angiotensin receptor blockers (ARBs) favorably affect glucose and lipid metabolism, adipocytokines and cardiac structure and function. to the extent that ARBs exhibit multiple beneficial effects that improve cardiovascular (CV) risk profiles, these agents represent a potentially important treatment modality for diverse patient populations. However, as with most drug classes, patients display tremendous variability in response to ARBs. Recent evidence suggests that ARBs increase plasma concentrations of the anti-atherosclerotic adipocytokines adiponectin. This effect is important given adiponectin's central role in protecting against insulin resistance, dyslipidemia, atherosclerosis, myocardial hypertrophy, and ischemic injury. In fact, adiponectin is an upstream effector of several molecular pathways that mediate myriad inflammatory and metabolic bioprocesses. As such, ADIPOQ, the gene that encodes adiponectin, is a strong candidate mediator of response to ARBs, and genetic variability in ADIPOQ could plausibly alter drug responses. Herein, we propose a fixed-sequence, run-in phase clinical study of the ARB telmisartan with in-depth metabolic phenotype and genotype characterization in post-myocardial infarction patients with features of the metabolic syndrome. We propose a comprehensive evaluation of ADIPOQ in order to determine which genetic subgroup(s) of patients might derive the greatest benefit from telmisartan with respect to molecular and myo-dimensional endpoints important in CV disease progression.