Local Passive Heat for the Treatment of Hypertension in Autonomic Failure
Luis E Okamoto, Jorge E Celedonio, Emily C Smith, Alfredo Gamboa, Cyndya A Shibao, André Diedrich, Sachin Y Paranjape, Bonnie K Black, James A S Muldowney 3rd, Amanda C Peltier, Ralf Habermann, Craig G Crandall, Italo Biaggioni, Luis E Okamoto, Jorge E Celedonio, Emily C Smith, Alfredo Gamboa, Cyndya A Shibao, André Diedrich, Sachin Y Paranjape, Bonnie K Black, James A S Muldowney 3rd, Amanda C Peltier, Ralf Habermann, Craig G Crandall, Italo Biaggioni
Abstract
Background Supine hypertension affects a majority of patients with autonomic failure; it is associated with end-organ damage and can worsen daytime orthostatic hypotension by inducing pressure diuresis and volume loss during the night. Because sympathetic activation prevents blood pressure (BP) from falling in healthy subjects exposed to heat, we hypothesized that passive heat had a BP-lowering effect in patients with autonomic failure and could be used to treat their supine hypertension. Methods and Results In Protocol 1 (n=22), the acute effects of local heat (40-42°C applied with a heating pad placed over the abdomen for 2 hours) versus sham control were assessed in a randomized crossover fashion. Heat acutely decreased systolic BP by -19±4 mm Hg (versus 3±4 with sham, P<0.001) owing to decreases in stroke volume (-18±5% versus -4±4%, P=0.013 ) and cardiac output (-15±5% versus -2±4%, P=0.013). In Protocol 2 (proof-of-concept overnight study; n=12), we compared the effects of local heat (38°C applied with a water-perfused heating pad placed under the torso from 10 pm to 6 am) versus placebo pill. Heat decreased nighttime systolic BP (maximal change -28±6 versus -2±6 mm Hg, P<0.001). BP returned to baseline by 8 am. The nocturnal systolic BP decrease correlated with a decrease in urinary volume (r=0.57, P=0.072) and an improvement in the morning upright systolic BP (r=-0.76, P=0.007). Conclusions Local heat therapy effectively lowered overnight BP in patients with autonomic failure and supine hypertension and offers a novel approach to treat this condition. Future studies are needed to assess the long-term safety and efficacy in improving nighttime fluid loss and daytime orthostatic hypotension. Registration URL: https://www.clinicaltrials.gov; Unique identifiers: NCT02417415 and NCT03042988.
Keywords: autonomic failure; heat; orthostatic hypotension; supine hypertension; thermoregulation.
Conflict of interest statement
Biaggioni received 2 donated units of the Norm‐O‐Temp system and Gelli‐roll pads from Cincinnati Sub‐Zero for the conduct of the overnight studies. The remaining authors have no disclosures to report.
Figures
References
- Kaufmann H. Consensus statement on the definition of orthostatic hypotension, pure autonomic failure and multiple system atrophy. Clin Auton Res. 1996;6:125–126. DOI: 10.1007/BF02291236.
- Gibbons CH, Schmidt P, Biaggioni I, Frazier‐Mills C, Freeman R, Isaacson S, Karabin B, Kuritzky L, Lew M, Low P, et al. The recommendations of a consensus panel for the screening, diagnosis, and treatment of neurogenic orthostatic hypotension and associated supine hypertension. J Neurol. 2017;264:1567–1582. DOI: 10.1007/s00415-016-8375-x.
- Garland EM, Gamboa A, Okamoto L, Raj SR, Black BK, Davis TL, Biaggioni I, Robertson D. Renal impairment of pure autonomic failure. Hypertension. 2009;54:1057–1061. DOI: 10.1161/HYPERTENSIONAHA.109.136853.
- Vagaonescu TD, Saadia D, Tuhrim S, Phillips RA, Kaufmann H. Hypertensive cardiovascular damage in patients with primary autonomic failure. Lancet. 2000;355:725–726. DOI: 10.1016/S0140-6736(99)05320-9.
- Jordan J, Shannon JR, Pohar B, Paranjape SY, Robertson D, Robertson RM, Biaggioni I. Contrasting effects of vasodilators on blood pressure and sodium balance in the hypertension of autonomic failure. J Am Soc Nephrol. 1999;10:35–42.
- Espay AJ, LeWitt PA, Hauser RA, Merola A, Masellis M, Lang AE. Neurogenic orthostatic hypotension and supine hypertension in Parkinson’s disease and related synucleinopathies: prioritisation of treatment targets. Lancet Neurol. 2016;15:954–966. DOI: 10.1016/S1474-4422(16)30079-5.
- Arnold AC, Okamoto LE, Gamboa A, Shibao C, Raj SR, Robertson D, Biaggioni I. Angiotensin II, independent of plasma renin activity, contributes to the hypertension of autonomic failure. Hypertension. 2013;61:701–706. DOI: 10.1161/HYPERTENSIONAHA.111.00377.
- Arnold AC, Okamoto LE, Gamboa A, Black BK, Raj SR, Elijovich F, Robertson D, Shibao CA, Biaggioni I. Mineralocorticoid receptor activation contributes to the supine hypertension of autonomic failure. Hypertension. 2016;67:424–429. DOI: 10.1161/HYPERTENSIONAHA.115.06617.
- Gamboa A, Shibao C, Diedrich A, Paranjape SY, Farley G, Christman B, Raj SR, Robertson D, Biaggioni I. Excessive nitric oxide function and blood pressure regulation in patients with autonomic failure. Hypertension. 2008;51:1531–1536. DOI: 10.1161/HYPERTENSIONAHA.107.105171.
- Okamoto LE, Gamboa A, Shibao CA, Arnold AC, Choi L, Black BK, Raj SR, Robertson D, Biaggioni I. Nebivolol, but not metoprolol, lowers blood pressure in nitric oxide‐sensitive human hypertension. Hypertension. 2014;64:1241–1247. DOI: 10.1161/HYPERTENSIONAHA.114.04116.
- Shibao C, Gamboa A, Abraham R, Raj SR, Diedrich A, Black B, Robertson D, Biaggioni I. Clonidine for the treatment of supine hypertension and pressure natriuresis in autonomic failure. Hypertension. 2006;47:522–526. DOI: 10.1161/01.HYP.0000199982.71858.11.
- Rowell LB. Reflex control of the cutaneous vasculature. J Invest Dermatol. 1977;69:154–166. DOI: 10.1111/1523-1747.ep12497938.
- Rowell LB, Brengelmann GL, Detry JM, Wyss C. Venomotor responses to local and remote thermal stimuli to skin in exercising man. J Appl Physiol. 1971;30:72–77. DOI: 10.1152/jappl.1971.30.1.72.
- Crandall CG, Wilson TE, Marving J, Vogelsang TW, Kjaer A, Hesse B, Secher NH. Effects of passive heating on central blood volume and ventricular dimensions in humans. J Physiol. 2008;586:293–301. DOI: 10.1113/jphysiol.2007.143057.
- Crandall CG, Wilson TE. Human cardiovascular responses to passive heat stress. Compr Physiol. 2015;5:17–43. DOI: 10.1002/cphy.c140015.
- Pathak A, Lapeyre‐Mestre M, Montastruc J‐L, Senard J‐M. Heat‐related morbidity in patients with orthostatic hypotension and primary autonomic failure. Mov Disord. 2005;20:1213–1219. DOI: 10.1002/mds.20571.
- Gilman S, Wenning GK, Low PA, Brooks DJ, Mathias CJ, Trojanowski JQ, Wood NW, Colosimo C, Durr A, Fowler CJ, et al. Second consensus statement on the diagnosis of multiple system atrophy. Neurology. 2008;71:670–676. DOI: 10.1212/01.wnl.0000324625.00404.15.
- Postuma RB, Berg D, Stern M, Poewe W, Olanow CW, Oertel W, Obeso J, Marek K, Litvan I, Lang AE, et al. MDS clinical diagnostic criteria for Parkinson’s disease. Mov Disord. 2015;30:1591–1601. DOI: 10.1002/mds.26424.
- Shannon J, Jordan J, Costa F, Robertson RM, Biaggioni I. The hypertension of autonomic failure and its treatment. Hypertension. 1997;30:1062–1067. DOI: 10.1161/01.HYP.30.5.1062.
- Mosqueda‐Garcia R. Evaluation of autonomic failure. In: Disorders of the Autonomic Nervous System. Luxembourg, Europe: Harwood Academic Publishers GmbH; 1995:25–59.
- Goldstein DS, Eisenhofer G, Stull R, Folio CJ, Keiser HR, Kopin IJ. Plasma dihydroxyphenylglycol and the intraneuronal disposition of norepinephrine in humans. J Clin Invest. 1988;81:213–220. DOI: 10.1172/JCI113298.
- Omboni S, Smit AA, van Lieshout JJ, Settels JJ, Langewouters GJ, Wieling W. Mechanisms underlying the impairment in orthostatic tolerance after nocturnal recumbency in patients with autonomic failure. Clin Sci (Lond). 2001;101:609–618. DOI: 10.1042/cs1010609.
- Domitrovich JW, Cuddy JS, Ruby BC. Core‐temperature sensor ingestion timing and measurement variability. J Athl Train. 2010;45:594–600. DOI: 10.4085/1062-6050-45.6.594.
- Thomas SH. Impedance cardiography using the Sramek‐Bernstein method: accuracy and variability at rest and during exercise. Br J Clin Pharmacol. 1992;34:467–476.
- Chaseling GK, Crandall CG, Gagnon D. Skin blood flow measurements during heat stress: technical and analytical considerations. Am J Physiol Regul Integr Comp Physiol. 2020;318:R57–R69. DOI: 10.1152/ajpregu.00177.2019.
- Jordan J, Shannon JR, Grogan E, Biaggioni I, Robertson D. A potent pressor response elicited by drinking water. Lancet. 1999;353:723. DOI: 10.1016/S0140-6736(99)99015-3.
- . 2020. 510(K) premarket notification. [online] Available at: . Accessed May 11, 2020.
- Kamijo Y, Lee K, Mack GW. Active cutaneous vasodilation in resting humans during mild heat stress. J Appl Physiol (1985). 2005;98:829–837. DOI: 10.1152/japplphysiol.00235.2004.
- Low DA, Shibasaki M, Davis SL, Keller DM, Crandall CG. Does local heating‐induced nitric oxide production attenuate vasoconstrictor responsiveness to lower body negative pressure in human skin. J Appl Physiol (1985). 2007;102:1839–1843. DOI: 10.1152/japplphysiol.01181.2006.
- Okamoto LE, Shibao C, Gamboa A, Choi L, Diedrich A, Raj SR, Black BK, Robertson D, Biaggioni I. Synergistic effect of norepinephrine transporter blockade and α‐2 antagonism on blood pressure in autonomic failure. Hypertension. 2012;59:650–656. DOI: 10.1161/HYPERTENSIONAHA.111.184812.
- Faul F, Erdfelder E, Lang AG, Buchner A. G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods. 2007;39:175–191. DOI: 10.3758/BF03193146.
- Minson CT, Berry LT, Joyner MJ. Nitric oxide and neurally mediated regulation of skin blood flow during local heating. J Appl Physiol (1985). 2001;91:1619–1626. DOI: 10.1152/jappl.2001.91.4.1619.
- Charkoudian N, Eisenach JH, Atkinson JL, Fealey RD, Joyner MJ. Effects of chronic sympathectomy on locally mediated cutaneous vasodilation in humans. J Appl Physiol (1985). 2002;92:685–690. DOI: 10.1152/japplphysiol.00758.2001.
- Wilson TE, Brothers RM, Tollund C, Dawson EA, Nissen P, Yoshiga CC, Jons C, Secher NH, Crandall CG. Effect of thermal stress on Frank‐Starling relations in humans. J Physiol. 2009;587:3383–3392. DOI: 10.1113/jphysiol.2009.170381.
- Coon EA, Cheshire WP. Sweating disorders. Continuum (Minneap Minn). 2020;26:116–137. DOI: 10.1212/CON.0000000000000813.
- Yamanaka Y, Asahina M, Mathias CJ, Akaogi Y, Koyama Y, Hattori T. Skin vasodilator response to local heating in multiple system atrophy. Mov Disord. 2007;22:2405–2408. DOI: 10.1002/mds.21742.
- Okamoto LE, Diedrich A, Baudenbacher FJ, Harder R, Whitfield JS, Iqbal F, Gamboa A, Shibao CA, Black BK, Raj SR, et al. Efficacy of servo‐controlled splanchnic venous compression in the treatment of orthostatic hypotension: a randomized comparison with midodrine. Hypertension. 2016;68:418–426. DOI: 10.1161/HYPERTENSIONAHA.116.07199.
- Shibao C, Gamboa A, Diedrich A, Dossett C, Choi L, Farley G, Biaggioni I. Acarbose, an alpha‐glucosidase inhibitor, attenuates postprandial hypotension in autonomic failure. Hypertension. 2007;50:54–61.
- Deschamps A, Magder S. Effects of heat stress on vascular capacitance. Am J Physiol. 1994;266:H2122–H2129. DOI: 10.1152/ajpheart.1994.266.5.H2122.
- Kregel KC, Gisolfi CV. Circulatory responses to heat after celiac ganglionectomy or adrenal demedullation. J Appl Physiol (1985). 1989;66:1359–1363. DOI: 10.1152/jappl.1989.66.3.1359.
- Choi MS, Lee HJ, Lee JH. Early intervention for low‐temperature burns: comparison between early and late hospital visit patients. Arch Plast Surg. 2015;42:173–178. DOI: 10.5999/aps.2015.42.2.173.
- Ten Harkel AD, Van Lieshout JJ, Wieling W. Treatment of orthostatic hypotension with sleeping in the head‐up tilt position, alone and in combination with fludrocortisone. J Intern Med. 1992;232:139–145. DOI: 10.1111/j.1365-2796.1992.tb00563.x.
- Laukkanen T, Khan H, Zaccardi F, Laukkanen JA. Association between sauna bathing and fatal cardiovascular and all‐cause mortality events. JAMA Intern Med. 2015;175:542–548. DOI: 10.1001/jamainternmed.2014.8187.
- Li Z, Jiang W, Chen Y, Wang G, Yan F, Zeng T, Fan H. Acute and short‐term efficacy of sauna treatment on cardiovascular function: a meta‐analysis. Eur J Cardiovasc Nurs. 2020;1474515120944584. DOI: 10.1177/1474515120944584.
- Shannon JR, Jordan J, Diedrich A, Pohar B, Black BK, Robertson D, Biaggioni I. Sympathetically mediated hypertension in autonomic failure. Circulation. 2000;101:2710–2715. DOI: 10.1161/01.CIR.101.23.2710.
Source: PubMed