Genetic and epigenetic as predictive factors in the response to renal sympathetic denervation in patients with treatment-resistant hypertension

• Grant number: 18/20369-2
• Support Opportunities: Regular Research Grants
• Start date: July 01, 2019
• End date: June 30, 2022
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: Celso Amodeo
• Grantee: Celso Amodeo
• Host Institution: Instituto Dante Pazzanese de Cardiologia (IDPC). Fundação Adib Jatene (FAJ). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
• Associated researchers: Alexandre Antônio Cunha Abizaid ; FLAVIO ANTONIO DE OLIVEIRA BORELLI ; Mario Hiroyuki Hirata

Abstract

Sympathetic hyperactivity is related to severity of systemic arterial hypertension (SAH). Renal SympatheticDenervation (RSD) reduces the local and systemic sympathetic activity. Although there are several predictors ofsuccess, a new method to quantify and to predict the procedure success rate it is still necessary. Iodine-123metaiodobenzylguanidine scintigraphy (I123-MIBG) is an efficient diagnostic method to measure the sympatheticnerve activity degree using a noradrenaline analogue. Early diagnosis of sympathetic hyperactivity may improvethe selection of good responder patients undergoing treatment with RSD. In addition, it has been known that theresponse to both antihypertensive drugs and RSD treatment may be affected by genetic and epigenetic factorsrelated to the pathophysiological pathways that affect the control of blood pressure. The aim of the study is toevaluate the association between RSD response determined by I123-MIBG scintigraphy and the presence ofgenetic and epigenetic factors in patients with Resistant Hypertension (RH). The study will include two hundredand fifty patients diagnosed with RH for at least 1 year. The diagnosis of RH will be performed according to therecommendation of VII guidelines of systemic arterial hypertension from the Brazilian Society of Cardiology, usingvalidated and calibrated equipments. In order to confirm the RH diagnosis, the patients will be admitted to IDPCwards for 7 days. Next, the assessment of central blood pressure, pulse wave velocity and the renal arteriographywill be performed. MIBG-123 scintigraphy will be performed to evaluate the renal and cardiac sympatheticactivity. Whole-body images will be collected 15 minutes and 4 hours after injection at the following time points:before, 30 days and 6 months after RSD procedure. The genetic polymorphisms ADRB1 rs1801252, ADRB1rs1801253, AGT rs699, AGT rs5051, CYP11B2 rs1799998, NOS2 rs2297518 and NOS3 rs41322052 will beanalyzed by quantitative PCR (qPCR) using TaqMan® SNP Genotyping Assay. The expression of miR-584, miR-31,miR-181a, miR-663, miR-483-3p, miR-296, miR-9, miR-126 miR-145, miR-132 and miR-212 will also be analyzedby qPCR using the TaqMan® MicroRNA Assays. DNA methylation analysis of HSD11B2, ACE, NKCC1, ADD1,ADRB1, ±ENaC genes will be performed by pyrosequencing. The expected outcome of this study is to select thoseRH patients who are good responders to RSD treatment and to propose an additional modality of therapy forpatients at high risk of a cardiovascular event, reducing the number of antihypertensive drugs and their sideeffects. (AU)