title: Refractory Hypertension: Evidence of Heightened Sympathetic Activity as a Cause of Antihypertensive Treatment Failure.
abstract: Refractory hypertension is an extreme phenotype of treatment failure defined as uncontrolled blood pressure in spite of ≥5 classes of antihypertensive agents, including chlorthalidone and a mineralocorticoid receptor antagonist. A prospective evaluation of possible mechanisms of refractory hypertension has not been done. The goal of this study was to test for evidence of heightened sympathetic tone as indicated by 24-hour urinary normetanephrine levels, clinic and ambulatory heart rate (HR), HR variability, arterial stiffness as indexed by pulse wave velocity, and systemic vascular resistance compared with patients with controlled resistant hypertension. Forty-four consecutive patients, 15 with refractory and 29 with controlled resistant hypertension, were evaluated prospectively. Refractory hypertensive patients were younger (48±13.3 versus 56.5±14.1 years; P=0.038) and more likely women (80.0 versus 51.9%; P=0.047) compared with patients with controlled resistant hypertension. They also had higher urinary normetanephrine levels (464.4±250.2 versus 309.8±147.6 µg per 24 hours; P=0.03), higher clinic HR (77.8±7.7 versus 68.8±7.6 bpm; P=0.001) and 24-hour ambulatory HR (77.8±7.7 versus 68.8±7.6; P=0.0018), higher pulse wave velocity (11.8±2.2 versus 9.4±1.5 m/s; P=0.009), reduced HR variability (4.48 versus 6.11; P=0.03), and higher systemic vascular resistance (3795±1753 versus 2382±349 dyne·s·cm(5)·m(2); P=0.008). These findings are consistent with heightened sympathetic tone being a major contributor to antihypertensive treatment failure and highlight the need for effective sympatholytic therapies in patients with refractory hypertension.
authors.affiliation: From the Vascular Biology and Hypertension Program, Division of Cardiovascular Disease, Department of Medicine (T.D., S.O., D.A.C.), Department of Biostatistics (P.L.), University of Alabama, Birmingham; Department of Medicine, University of South Alabama, Mobile (M.C.A.); and Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston (R.P.). tduden@uab.edu.
authors.forename: Tanja
authors.initials: T
authors.lastname: Dudenbostel
authors.affiliation: From the Vascular Biology and Hypertension Program, Division of Cardiovascular Disease, Department of Medicine (T.D., S.O., D.A.C.), Department of Biostatistics (P.L.), University of Alabama, Birmingham; Department of Medicine, University of South Alabama, Mobile (M.C.A.); and Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston (R.P.).
authors.forename: Maria C
authors.initials: MC
authors.lastname: Acelajado
authors.affiliation: From the Vascular Biology and Hypertension Program, Division of Cardiovascular Disease, Department of Medicine (T.D., S.O., D.A.C.), Department of Biostatistics (P.L.), University of Alabama, Birmingham; Department of Medicine, University of South Alabama, Mobile (M.C.A.); and Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston (R.P.).
authors.forename: Roberto
authors.initials: R
authors.lastname: Pisoni
authors.affiliation: From the Vascular Biology and Hypertension Program, Division of Cardiovascular Disease, Department of Medicine (T.D., S.O., D.A.C.), Department of Biostatistics (P.L.), University of Alabama, Birmingham; Department of Medicine, University of South Alabama, Mobile (M.C.A.); and Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston (R.P.).
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.affiliation: From the Vascular Biology and Hypertension Program, Division of Cardiovascular Disease, Department of Medicine (T.D., S.O., D.A.C.), Department of Biostatistics (P.L.), University of Alabama, Birmingham; Department of Medicine, University of South Alabama, Mobile (M.C.A.); and Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston (R.P.).
authors.forename: Suzanne
authors.initials: S
authors.lastname: Oparil
authors.affiliation: From the Vascular Biology and Hypertension Program, Division of Cardiovascular Disease, Department of Medicine (T.D., S.O., D.A.C.), Department of Biostatistics (P.L.), University of Alabama, Birmingham; Department of Medicine, University of South Alabama, Mobile (M.C.A.); and Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston (R.P.).
authors.forename: David A
authors.initials: DA
authors.lastname: Calhoun
mesh_terms: D000328:Adult; D000368:Aged; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D018660:Blood Pressure Monitoring, Ambulatory; D002307:Cardiography, Impedance; D004359:Drug Therapy, Combination; D005260:Female; D006339:Heart Rate; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000503:physiopathology* / Q000652:urine; D008297:Male; D008875:Middle Aged; D009647:Normetanephrine / Q000652:urine; D011446:Prospective Studies; D063177:Pulse Wave Analysis; D013564:Sympathetic Nervous System / Q000503:physiopathology*; D017211:Treatment Failure; D014655:Vascular Resistance; D059289:Vascular Stiffness
chemical_list: D000959:Antihypertensive Agents; D009647:Normetanephrine
keywords: aldosterone; arterial stiffness; blood pressure monitoring, ambulatory; catecholamines; sympathetic activity