Effects of transcutaneous electrical nerve stimulation (TENS) on arterial stiffness and blood pressure in resistant hypertensive individuals: study protocol for a randomized controlled trial

José Fernando Vilela-Martin, Luiz Tadeu Giollo-Junior, Gaspar Rogério Chiappa, Gerson Cipriano-Junior, Paulo José Cardoso Vieira, Fábio dos Santos Ricardi, Manoel Ildefonso Paz-Landim, Days Oliveira de Andrade, Elizabeth do Espírito Santo Cestário, Luciana Neves Cosenso-Martin, Juan Carlos Yugar-Toledo, José Paulo Cipullo, José Fernando Vilela-Martin, Luiz Tadeu Giollo-Junior, Gaspar Rogério Chiappa, Gerson Cipriano-Junior, Paulo José Cardoso Vieira, Fábio dos Santos Ricardi, Manoel Ildefonso Paz-Landim, Days Oliveira de Andrade, Elizabeth do Espírito Santo Cestário, Luciana Neves Cosenso-Martin, Juan Carlos Yugar-Toledo, José Paulo Cipullo

Abstract

Background: Resistant hypertension (RH) treatment requires an adequate and intense therapeutic approach. However, the results are not always satisfactory despite intensive treatment. Of the different pathophysiological mechanisms involved in the pathogenesis of RH, sympathetic overstimulation and therapies that block the sympathetic system have been widely studied. These approaches, however, are invasive and expensive. Another possible approach is by transcutaneous electrical nerve stimulation (TENS), a noninvasive method that modulates activity by using low-frequency transcutaneous electrical stimulation to inhibit primary afferent pathways. Thus, the current study will evaluate the effect of applying TENS in the cervicothoracic region of subjects with RH and will seek to develop a new low-cost and readily available therapy to treat this group of hypertensive individuals.

Methods/design: This is a randomized, single blind (subject), parallel-assignment study controlled with a sham group and including participants aged 40 to 70 years with resistant hypertension. The trial has two arms: the treatment and control (sham group). The treatment group will be submitted to the stimulation procedure (TENS). The sham group will not be submitted to stimulation. The primary outcomes will be a reduction in the peripheral blood pressure and adverse events. The secondary outcomes will be a reduction the central blood pressure. The study will last 30 days. The sample size was calculated assuming an alpha error of 5 % to reject the null hypothesis with a statistical power of 80 %, thereby resulting in 28 participants per group (intervention versus sham).

Discussion: In recent decades, RH has become very common and costly. Adequate control requires several drugs, and in many cases, treatment is not successful. Sympathetic nervous system inhibition by renal denervation and central inhibition have significant effects in reducing BP; however, these treatments are costly and invasive. Another type of sympathetic nervous system inhibition can also be noninvasively achieved by electric current. Therefore, the application of TENS may be a new therapeutic option for treating resistant hypertensive individuals.

Trial registration: Clinical Trials NCT02365974.

Keywords: Arterial stiffness; Blood pressure; Resistant hypertension; Sympathetic system; Transcutaneous electrical nerve stimulation.

Figures

Fig. 1
Fig. 1
Flowchart of study
Fig. 2
Fig. 2
Diagram showing the location for application of the transcutaneous electrical nerve stimulation (TENS)

References

    1. Brazilian Society of Cardiology, Brazilian Society of Hypertension, Brazilian Society of Nephrology VI Brazilian guidelines on hypertension. Arq Bras Cardiol. 2010;95(1 Supl 1):1–51.
    1. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, et al. Heart disease and stroke statistics - 2015 update: a report from the American Heart Association. Circulation. 2015;131:e29–322. doi: 10.1161/CIR.0000000000000152.
    1. Oppenheimer GM. Framingham heart study: the first 20 years. Prog Cardiovasc Dis. 2010;53:55–61. doi: 10.1016/j.pcad.2010.03.003.
    1. Calhoun DA, Jones D, Textor S, Goff DC, Murphy TP, Toto RD, et al. Resistant hypertension: diagnosis, evaluation, and treatment: a scientific statement from the American Heart Association. Hypertension. 2008;51:1403–19. doi: 10.1161/HYPERTENSIONAHA.108.189141.
    1. Pimenta E, Calhoun DA. Resistant hypertension: incidence, prevalence and prognosis. Circulation. 2012;125(13):1635–42. doi: 10.1161/CIRCULATIONAHA.112.097345.
    1. Suwaidi JA, Hamasaki S, Higano ST, Nishimura RA, David H, Lerman A. Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation. 2000;101:948–54. doi: 10.1161/01.CIR.101.9.948.
    1. Perrone-Filardi P, Cuocolo A, Brevetti G, et al. Relation of artery flow-mediated vasodilatation to significant coronary arterial disease in patients with peripheral arterial disease. Am J Cardiol. 2005;96:1337–41. doi: 10.1016/j.amjcard.2005.06.084.
    1. Quyuumi AA, Dakak N, Andrews NP, et al. Nitric oxide activity in the human coronary circulation: impact of risks factors for coronary atherosclerosis. J Clin Invest. 1995;95:1747–55. doi: 10.1172/JCI117852.
    1. Bakker W, Eringa EC, Sipkema P, van Hinsbergh VW. Endothelial dysfunction and diabetes: roles of hyperglycemia, impaired insulin signaling and obesity. Cell Tissue Res. 2009;335:165–89. doi: 10.1007/s00441-008-0685-6.
    1. Melo SESFC, Toledo JCY, Coca AP, Moreno H., Jr Arterial hypertension, atherosclerosis and inflammation: the endothelium as target organ. Rev Bras Hipertens. 2007;14:234–8.
    1. Gomes F, Telo DF, Souza HP, Nicolau JC, Halpern A, Serrano CV., Jr Obesity and coronary artery disease: role of vascular inflammation. Arq Bras Cardiol. 2009;94:273–9. doi: 10.1590/S0066-782X2010000200021.
    1. Savoia C, Sada L, Zezza L, Pucci L, Lauri FM, Befani A, et al. Vascular inflammation and endothelial dysfunction in experimental hypertension. Int J Hyperten. 2011. doi: 10.4061/2011/281240.
    1. Lopes HF. Inflammatories markers and arterial hypertension. Rev Bras Hipertens. 2005;12:112–3.
    1. Yamakawa K, Matsunaga M, Isowa T, Kimura K, Kasugai K, Yoneda M, et al. Transient responses of inflammatory cytokines in acute stress. Biol Psychol. 2009;82:25–32. doi: 10.1016/j.biopsycho.2009.05.001.
    1. Monteiro FC, Jr, Anunciação FAC, Filho NS, Silva MA, Barbosa JB, Silva WS., Jr Prevalence of true hypertensive crises and appropriateness of the medical management in patients with high blood pressure seen in a general emergency room. Arq Bras Cardiol. 2007;90:269–73. doi: 10.1590/S0066-782X2008000400006.
    1. Ramos AM, Pellanda LC, Gus I, Portal VL. Inflammatory markers of cardiovascular disease in the elderly. Arq Bras Cardiol. 2009;92:233–40. doi: 10.1590/S0066-782X2009000300012.
    1. Balanescu S, Calmac L, Constantinescu D, Marinescu M, Onut R, Dorobantu M. Systemic inflammation and early atheroma formation: are they related? J Clin Med. 2010;5:292–301.
    1. Cavusoglu E, Marmur JD, Hojjati MR, Chopra V, Butala M, Subnani R, et al. Plasma interleukin-10 levels and adverse outcomes in acute coronary syndrome. Am J Med. 2011;124:724–30. doi: 10.1016/j.amjmed.2011.02.040.
    1. Marchesi C, Paradis P, Schiffrin EL. Role of the renin–angiotensin system in vascular inflammation. Trends Pharmacol Sci. 2008;29:367–74. doi: 10.1016/j.tips.2008.05.003.
    1. Rabkin SW. The role of interleukin 18 in the pathogenesis of hypertension-induced vascular disease. Nat Clin Pract C. 2009;6:192–9. doi: 10.1038/ncpcardio1453.
    1. Tretjakovs P, Jurka A, Bormane I, Mikelsone I, Elksne K, Krievina G, et al. Circulating adhesion molecules, matrix metalloproteinase-9, plasminogen activator inhibitor-1, and myeloperoxidase in coronary artery disease patients with stable and unstable angina. Clin Chim Acta. 2012;413:25–9. doi: 10.1016/j.cca.2011.10.009.
    1. Dumer CD, Thomé FS, Veronese FS. Chronic renal disease, inflammation and atherosclerosis: new concepts about an old problem. Rev Assoc Med Bras. 2007;53:446–50. doi: 10.1590/S0104-42302007000500022.
    1. Jin HY, Song B, Oudit GY, Davidge ST, Yu HM, Jiang YY, et al. ACE2 deficiency enhances angiotensin ii-mediated aortic profilin-1 expression, inflammation and peroxynitrite production. PLoS One. 2012;7:1–10.
    1. Raffetto JD, Khalil RA. Matrix metalloproteinases and their inhibitors in vascular remodeling and vascular disease. Biochem Pharmacol. 2008;75:346–59. doi: 10.1016/j.bcp.2007.07.004.
    1. Chow AK, Cena J, Schulz R. Acute actions and novel targets of matrix metalloproteinases in the heart and vasculature. Br J Pharmacol. 2007;152:189–205. doi: 10.1038/sj.bjp.0707344.
    1. Schulz R. Intracellular targets of matrix metalloproteinase-2 in cardiac disease: rationale and therapeutic approaches. Annu Rev Pharmacol Toxicol. 2007;47:211–42. doi: 10.1146/annurev.pharmtox.47.120505.105230.
    1. Nagase H, Woessner JF., Jr Matrix metalloproteinases. J Biol Chem. 1999;274:21491–4. doi: 10.1074/jbc.274.31.21491.
    1. Murphy G, Nagase H. Progress in matrix metalloproteinase research. Mol Aspects Med. 2008;29:290–308. doi: 10.1016/j.mam.2008.05.002.
    1. Visse R, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res. 2003;92:827–39. doi: 10.1161/01.RES.0000070112.80711.3D.
    1. Castro MM, Rizzi E, Figueiredo-Lopes L, Fernandes K, Bendhack LM, Pitol DL, et al. Metalloproteinase inhibition ameliorates hypertension and prevents vascular dysfunction and remodeling in renovascular hypertensive rats. Atherosclerosis. 2008;198:320–31. doi: 10.1016/j.atherosclerosis.2007.10.011.
    1. Dollery CM, McEwan JR, Henney AM. Matrix metalloproteinases and cardiovascular disease. Circ Res. 1995;77:863–8. doi: 10.1161/01.RES.77.5.863.
    1. Creemers EE, Cleutjens JP, Smits JF, Daemen MJ. Matrix metalloproteinase inhibition after myocardial infarction: a new approach to prevent heart failure? Circ Res. 2001;89:201–10. doi: 10.1161/hh1501.094396.
    1. Ahmed SH, Clark LL, Pennington WR, Webb CS, Bonnema DD, Leonardi AH, et al. Matrix metalloproteinases/tissue inhibitors of metalloproteinases: relationship between changes in proteolytic determinants of matrix composition and structural, functional, and clinical manifestations of hypertensive heart disease. Circulation. 2006;113:2089–96. doi: 10.1161/CIRCULATIONAHA.105.573865.
    1. Yasmin SW, McEniery CM, Wallace S, Dakham Z, Pulsalkar P, Maki-Petaja K, et al. Matrix metalloproteinase-9 (MMP-9), MMP-2, and serum elastase activity are associated with systolic hypertension and arterial stiffness. Arterioscler Thromb Vasc Biol. 2005;25:372–8. doi: 10.1161/01.ATV.0000151373.33830.41.
    1. Castro MM, Rizzi E, Prado CM, Rossi MA, Tanus-Santos JE, Gerlach RF. Imbalance between matrix metalloproteinases and tissue inhibitor of metalloproteinases in hypertensive vascular remodeling. Matrix Biol. 2010;29:194–201. doi: 10.1016/j.matbio.2009.11.005.
    1. Palei AC, Sandrim VC, Cavalli RC, Tanus-Santos JE. Comparative assessment of matrix metalloproteinase (MMP)-2 and MMP-9, and their inhibitors, tissue inhibitors of metalloproteinase (TIMP)-1 and TIMP-2 in preeclampsia and gestational hypertension. Clin Biochem. 2008;41:875–80. doi: 10.1016/j.clinbiochem.2008.04.015.
    1. Alessi A, Brandão AA, Coca A, Cordeiro AC, Nogueira AR. Diógenes de Magalhães, et al. First Brazilian position on resistant hypertension. Arq Bras Cardiol. 2012;99:576–85. doi: 10.1590/S0066-782X2012000700002.
    1. Willians B, Lacy PS, Thom SM, Cruikshanki K, Stanton A, Collier D, et al. Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: principal results of the conduit artery function evaluation (CAFE) study. Circulation. 2006;113:1213–25. doi: 10.1161/CIRCULATIONAHA.105.595496.
    1. O’Rourke MF, Staessen JA, Vlachopoulos C, Duprez D, Plante GE. Clinical applications of arterial stiffness; definitions and reference values. Am J Hypertens. 2002;15:426–44. doi: 10.1016/S0895-7061(01)02319-6.
    1. Heitmar R. Total arterial compliance: the future of cardiovascular risk assessment? J Hum Hypertens. 2010;24:227–9. doi: 10.1038/jhh.2009.106.
    1. Mendonça MI, Palma Reis R, Sousa AC, Gomes S, Faria P, Pereira A, et al. Pulse wave velocity and coronary risk stratification. Rev Port Cardiol. 2009;28:155–71.
    1. Safar ME, Levy BI, Struijker-Boudier H. Current perspectives on arterial stiffness and pulse pressure in hypertension and cardiovascular diseases. Circulation. 2003;107:2864–9. doi: 10.1161/01.CIR.0000069826.36125.B4.
    1. O’Rourke MF, Nichols WW. Aortic diameter, aortic stiffness, and wave reflection increase with age and isolated systolic hypertension. Hypertension. 2005;45:652–8. doi: 10.1161/01.HYP.0000153793.84859.b8.
    1. Dart AM, Kingwell BA. Pulse pressure - a review of mechanisms and clinical relevance. J Am Coll Cardiol. 2001;37:975–84. doi: 10.1016/S0735-1097(01)01108-1.
    1. Laurent S, Cockroft J. Central aortic blood pressure. Paris: Elsevier; 2008.
    1. Mota-Gomes MA, Feitosa AM, Brandão MC, et al. Augmentation Index – a new predictor of cardiovascular risk. Rev Bras Hipertens. 2006;13:63–4.
    1. Vaz-de-Melo RO, Pimenta AG, Giollo Júnior LT, et al. Factors associated with increased radial augmentation index in hypertensive individuals. Arq Bras Cardiol. 2011;97:241–8. doi: 10.1590/S0066-782X2011005000087.
    1. Fisher JP, Paton JFR. The sympathetic nervous system and blood pressure in humans: implications for hypertension. J Hum Hypertens. 2012;26:463–75. doi: 10.1038/jhh.2011.66.
    1. Hoppe UC, Brandt MC, Wachter R, Beige J, Rump LC, Kroon AA, et al. Minimally invasive system for baroreflex activation therapy chronically lowers blood pressure with pacemaker-like safety profile: results from the Barostim neo trial. J Am Soc Hyperten. 2012;6:270–6. doi: 10.1016/j.jash.2012.04.004.
    1. Gregorini C, Cipriano Junior G, Aquino LM, Branco JNR, Bernardelli GF. Estimulação elétrica nervosa transcutânea de curta duração no pós-operatório de cirurgia cardíaca. Arq Bras Cardiol. 2010;94:345–51. doi: 10.1590/S0066-782X2010000300011.
    1. Jhonson M. Transcutaneous electrical nerve stimulation: mechanisms, clinical application and evidence. Rev Pain. 2007;1:7.
    1. Malliani A. The autonomic nervous system: a Sherringtonian revision of its integrated properties in the control of circulation. J Auton Nerv Syst. 1997;64:158. doi: 10.1016/S0165-1838(97)00022-2.
    1. Mannheimer C, Emanuelsson H, Waagstein F. The effect of transcutaneous electrical nerve stimulation (TENS) on catecholamine metabolism during pacing-induced angina pectoris and the influence of naloxone. Pain. 1990;41:27–34. doi: 10.1016/0304-3959(90)91105-R.
    1. Sanderson JE, Tomlinson B, Lau MSW, So KWH, Cheung AHK, Critchley JAJH, et al. The effect of transcutaneous electrical nerve stimulation (TENS) on autonomic cardiovascular reflexes. Clin Auton Res. 1995;5:81–4. doi: 10.1007/BF01827467.
    1. Kaada B. Vasodilation induced by transcutaneous nerve stimulation in peripheral ischemia (Raynaud‘s phenomenon and diabetic polyneuropathy) Eur Heart J. 1982;3:303.
    1. Twist DJ. Acrocyanosis in a spinal cord injured patient—effects of computer-controlled neuromuscular electrical stimulation: a case report. Phys Ther. 1990;70:45.
    1. Barker R, Lang T, Hager H, Steinlechner B, Hoerauf K, Zimpfer M, et al. The influence of stellate ganglion transcutaneous electrical nerve stimulation on signal quality of pulse oximetry in prehospital trauma care. Anesth Analg. 2007;104:1150. doi: 10.1213/01.ane.0000260564.52592.63.
    1. da Silva ML, Chiappa GR, da Silva VM, Neves LM, de Lima AC, Tomasi FP, et al. Effect of transcutaneous electrical nerve stimulation on peripheral to central blood pressure ratio in healthy subjects. Clin Physiol Funct Imaging. 2015. doi:10.1111/cpf.12227.
    1. Jones CR, Taylor K, Chowienczyk P, Poston L, Shennan AH. A Validation of the Mobil O Graph (version 12) ambulatory blood pressure monitor. Blood Press Monit. 2000;5:233–8. doi: 10.1097/00126097-200008000-00007.
    1. Brazilian Society of Cardiology, Brazilian Society of Hypertension, Brazilian Society of Nephrology V Guidelines for ambulatory blood pressure monitoring (ABPM) and III guidelines for home blood pressure monitoring (HBPM) Arq Bras Cardiol. 2011;97(3 Suppl 3):1–24.
    1. Scanavacca MI, de Brito FS, Maia I, Hachul D, Gizzi J, Lorga A, et al. Guidelines for the evaluation and treatment of patients with cardiac arrhythmias. Arq Bras Cardiol. 2002;79(Suppl 5):1–50.
    1. Crawford MH, Bernstein SJ, Deedwania PC, DiMarco JP, Ferrick KJ, Garson A, Jr, et al. ACC/AHA Guidelines for ambulatory eletrocardiography: a report of the American College of Cardiology/American Heart Association task force on practice guidelines (Committee to Revise the Guidelines for Ambulatory Eletrocardiography) developed in collaboration with the North American Society for Pacing and Electrophysiology. J Am Coll Cardiol. 1999;34:912–48. doi: 10.1016/S0735-1097(99)00354-X.
    1. Stein C, Dal Lago P, Ferreira JB, Casali KR, Plentz RD. Transcutaneous electrical nerve stimulation at different frequencies on heart rate variability in healthy subjects. Auton Neurosci. 2011;165:205–8. doi: 10.1016/j.autneu.2011.07.003.
    1. Jíra M, Závodná E, Nováková Z, Fiser B, Honzíková N. Reproducibility of blood pressure and inter-beat interval variability in man. Physiol Res. 2010;59:S113–21.
    1. Bonetti PO, Pumper GM, Higano ST, Holmes JDR, Kuvin JT, Lerman A. Noninvasive identification of patients with early coronary atherosclerosis by assessment of digital reactive hyperemia. J Am Coll Cardiol. 2004;44:2137–41. doi: 10.1016/j.jacc.2004.08.062.
    1. Bonetti PO, Barsness GW, Keelan PC, Schnell TI, Pumper GM, Kuvin JT, et al. Enhanced external counterpulsation improves endothelial function in patients with symptomatic coronary artery disease. J Am Coll Cardiol. 2003;41:1761–8. doi: 10.1016/S0735-1097(03)00329-2.
    1. Gargiulo P, Marciano C, Savarese G, D’Amore C, Paolillo S, Esposito G, et al. Endothelial dysfunction in type 2 diabetic patients with normal coronary arteries: a digital reactive hyperemia study. Int J Cardiol. 2013;165:67–71. doi: 10.1016/j.ijcard.2011.07.076.
    1. American Diabetes Association Diagnosis and classification of diabetes mellitus. Diabetes Care. 2007;30:S42–7. doi: 10.2337/dc07-S042.
    1. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18:499–502.
    1. Geloneze B, Repetto EM, Geloneze SR, Tambascia MA, Ermetice MN. The threshold value for insulin resistance (HOMA-IR) in admixtured population IR in the Brazilian metabolic syndrome study. Diabetes Res Clin Pract. 2006;72:219–20. doi: 10.1016/j.diabres.2005.10.017.
    1. Lessa I. Serum creatinine levels: hypercreatinemia in a segment of the adult population of Salvador, Brazil. Rev Bras Epidemiol. 2004;7:176–86. doi: 10.1590/S1415-790X2004000200007.
    1. Kochi AC, Martins AS, Balbi AL, Moraes e Silva MA, Lima MC, Martins LC, et al. Preoperative risk factors for the development of acute renal failure in cardiac surgery. Braz J Cardiovasc Surg. 2007;22:33–40.
    1. Bisi Molina MC, Cunha RS, Herkenhoff LF, Mill JG. Hypertension and salt intake in an urban population. Rev Saude Publica. 2003;37:743–50. doi: 10.1590/S0034-89102003000600009.
    1. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999;130:461–70. doi: 10.7326/0003-4819-130-6-199903160-00002.
    1. Li JJ, Wang HR, Huang CX, Xue JL, Li GS. Enhanced inflammatory response of blood monocytes to C-reactive protein in patients with unstable angina. Clin Chim Acta. 2005;352:127–33. doi: 10.1016/j.cccn.2004.08.019.
    1. Kater CE. Screening, confirmation and differential diagnosis of primary aldosteronism. Arq Bras Endocrinol Metab. 2002;46:106–15. doi: 10.1590/S0004-27302002000100015.
    1. Moshage H, Kok B, Huizenga JR, Jansen PLM. Nitrite and nitrate determination in plasma: a critical evaluation. Clin Chem. 1995;41:892–6.
    1. Félétou M, Vanhoutte PM. Endothelial dysfunction: a multifaceted disorder. Am J Physiol Heart Circ Physiol. 2006;291:H985–1002. doi: 10.1152/ajpheart.00292.2006.
    1. Endemann DH, Schiffrin EL. Endothelial dysfunction. J Am Soc Nephrol. 2004;15:1983–92. doi: 10.1097/01.ASN.0000132474.50966.DA.

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi