The hypothesis that a behavioral intervention augments

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1 Behavioal Neuocadiac Taining in Hypetension A Randomized, Contolled Tial Robet P. Nolan, John S. Floas, Paula J. Havey, Makad V. Kamath, Pete E. Picton, Caoline Chessex, Natalie Hiscock, Jonathan Powell, Michael Catt, Hilde Hendickx, Duncan Talbot, Maggie H. Chen Downloaded fom by guest on May 2, 2018 Abstact It is not established whethe behavioal inteventions add benefit to phamacological theapy fo hypetension. We hypothesized that behavioal neuocadiac taining (BNT) with heat ate vaiability biofeedback would educe blood pessue futhe by modifying vagal heat ate modulation duing eactivity and ecovey fom standadized cognitive tasks ( mental stess ). This andomized, contolled tial enolled 65 patients with uncomplicated hypetension to BNT o active contol (autogenic elaxation), with six 1-hou sessions ove 2 months with home pactice. Outcomes wee analyzed with linea mixed models that adjusted fo antihypetensive dugs. BNT educed daytime and 24-hou systolic blood pessues ( mm Hg, P 0.009, and mm Hg, P 0.03, espectively) and pulse pessues ( mm Hg, P 0.004, and mm Hg, P 0.02, espectively). No effect was obseved fo contols (P 0.10 fo all indices). BNT also inceased RR-high-fequency powe (0.15 to 0.40 Hz; P 0.01) and RR inteval (P 0.001) duing cognitive tasks. Among contols, high-fequency powe was unchanged (P 0.29), and RR inteval deceased (P 0.03). Neithe intevention alteed spontaneous baoeflex sensitivity (P 0.10). In contast to elaxation theapy, BNT with heat ate vaiability biofeedback modestly lowes ambulatoy blood pessue duing wakefulness, and it augments tonic vagal heat ate modulation. It is unknown whethe efficacy of this teatment can be impoved with biofeedback of baoeflex gain. BNT, alone o as an adjunct to dug theapy, may epesent a pomising new intevention fo hypetension. (Hypetension. 2010;55:00-00.) Key Wods: hypetension heat ate vaiability baoeflex clinical tials biofeedback elaxation stess The hypothesis that a behavioal intevention augments the hypotensive effect of phamacological teatment of hypetension was tested in a andomized, contolled tial fist by Patel and Noth. 1 Taining in yoga-induced elaxation with electodemal biofeedback significantly educed systolic and diastolic blood pessues (BPs; SBP and DBP), wheeas no change was obseved with self-guided elaxation as the contol intevention. The theapeutic model fo this appoach can be taced to ealy eseach by Smik, who ecognized that BP could be loweed to a basal level by an emotionally calm o desensitized state and that emotional and envionmental factos contibuted to the supplemental elevation that was obseved duing casual BP measuements. 2 It was subsequently asseted that epeated exposue to a hypometabolic state, populaly known as the elaxation esponse, could lowe BP by educing envionmentally diven sympathetic oveactivity. 1,3 Commentay at the time concening a behavioal teatment fo hypetension focused on 2 issues: the need fo diffeentiation between the depesso effect of biofeedback-assisted elaxation and any placebo esponse 4 and whethe active taining with biofeedback augmented o intefeed with the passive mental attitude that was consideed necessay fo theapeutic elaxation. 3 Concening hypetension, clinical tial evidence since Patel and Noth 1 has been equivocal with egad to an association between BP eduction and elaxation theapy o stess management. Meta-analysis indicates that elaxation taining significantly educes SBP and DBP in compaison with no-teatment contol conditions. 5 Howeve, in compaison with an active contol (AC) o behavioal placebo, only biofeedback taining combined with behavioal elaxation educed SBP and DBP 6 o SBP alone. 5 Impotantly, the 2 above-noted issues cental to the behavioal eseach agenda wee not addessed. Consequently, it is not established whethe a behavioal intevention will exet an additional hypotensive effect among subjects eceiving antihypetensive Received Octobe 20, 2009; fist decision Novembe 8, 2009; evision accepted Januay 22, Fom the Division of Cadiology (R.P.N., J.S.F., P.J.H., C.C.), Univesity Health Netwok and Faculty of Medicine, Univesity of Toonto, Toonto, Ontaio, Canada; Depatments of Medicine and Electical and Compute Engineeing (M.V.K.), McMaste Univesity, Hamilton, Ontaio, Canada; Unileve Copoate Reseach Biosciences (N.H., J.P., M.C., H.H., D.T.), Bedfod, United Kingdom; Univesity Health Netwok (M.H.C.), Toonto, Ontaio, Canada. This tial has been egisteed at (identifie NCT ). Coespondence to Robet P. Nolan, Behavioal Cadiology Reseach Unit, 6N-618, Univesity Health Netwok, 585 Univesity Ave, Toonto, Ontaio, Canada M5G 2N2. nolan@uhnes.utoonto.ca 2010 Ameican Heat Association, Inc. Hypetension is available at DOI: /HYPERTENSIONAHA

2 2 Hypetension Apil 2010 Downloaded fom by guest on May 2, 2018 medications, in compaison with an AC o behavioal placebo. In addition, it is unknown whethe passive elaxation is citical to an antihypetensive behavioal stategy that aims to augment autonomic egulation of BP by counteing emotional-envionmental challenges. Ou pimay objective was to evaluate whethe, in compaison with passive elaxation taining which seved as an AC, behavioal neuocadiac taining (BNT) with heat ate vaiability (HRV) biofeedback 7 educes significantly ambulatoy SBP, DBP, o pulse pessue (PP) among subjects with hypetension afte adjusting fo medications. Ou seconday objective was to assess whethe BNT o AC impoved cadiovagal contibutions to the dynamic egulation of BP, as assessed by tonic vagal-heat ate (HR) modulation and spontaneous baoeflex sensitivity (BRS) duing cognitive eactivity-ecovey testing. Methods Study Design We used a andomized, placebo-contolled, 2-paallel goup design to assess BNT vesus AC befoe intevention (within 2 weeks of initiation) and afte intevention (1 week afte the 8-week potocol, which allowed fo completion of home pactice). Randomization was conducted by a compute algoithm that statified fo sex, age (35 to 49 vesus 50 to 64 yeas), and hypetension seveity (SBP: 140 to 159 mm Hg o DBP: 90 to 99 mm Hg vesus SBP: 160 to 180 mm Hg o DBP: 100 to 110 mm Hg). The behavioal natue of the inteventions pemitted only blinding of subjects, but the teatment andomization code emained hidden duing pocessing of BP and ECG data. AC povided taining in autogenic elaxation, which is not associated with BP eduction. 5 Theefoe, it seved as a behavioal placebo with egad to pimay outcomes. Appoval was obtained fom the eseach ethics boad of the Univesity Health Netwok, and all of the subjects povided infomed witten consent. Patient Population Subjects wee 35 to 64 yeas of age and diagnosed with stage 1 o 2 hypetension (SBP: 140 to 180 mm Hg; DBP: 90 to 110 mm Hg). 8 Among subjects not pescibed medication, hypetension status was confimed by ambulatoy BP monitoing: daytime SBP/DBP 135/ 85 mm Hg o 24-hou SBP/DBP 130/80 mm Hg. 8 Subjects pescibed antihypetensive dugs wee equied to have a pesciption unchanged fo 4 months befoe enollment. Exclusion citeia wee as follows: diagnosis of cadiovascula disease, clinically significant ahythmia, sleep apnea, majo psychiatic illness (eg, psychosis), alcohol/dug dependence in the pevious yea, o an inability to compehend English o Fench. Assessment Potocol Assessments befoe and afte inteventions wee conducted on 2 successive days, between 8:00 AM and 12:00 PM. On day 1 befoe inteventions, anthopometic measues (age, sex, height, weight, and body mass index [BMI; in kilogams pe mete squaed]) and medical and medication histoies wee obtained. Subjects wee then fitted with an ambulatoy BP monito (SpaceLabs model , SpaceLabs Medical Inc) with its inflatable cuff fitted to the nondominant am. BP was measued evey 15 minutes between 8:00 AM and 10:00 PM and evey 30 minutes between 10:00 PM and 8:00 AM. Subjects wee instucted to engage in typical daily activities, with the exception of showeing o stenuous execise. On day 2, subjects wee instucted to efain fom caffeine and smoking fo 12 hous befoe pesenting to ou laboatoy, whee they wee seated in a semiecumbent position. RR inteval was ecoded continuously fom lead II of the ECG. A finge cuff was placed on the thid digit of the left hand to assess continuous vaiations in systolic ateial pessue (Finomete, Finapes Medical Systems). ECG and SBP data wee digitized at 500 Hz and late esampled at 1000 Hz fo offline analysis. Spontaneous BRS was estimated fo each 3-minute inteval of the assessment potocol by the sequence method, as descibed peviously. 9 We used customized softwae (LabView 7.1, National Instuments) to identify sequences of 3 cadiac cycles whee SBP inceased o deceased by 1 mm Hg and RR inteval inceased o deceased concodantly by 4 ms within 2 cadiac cycles afte the onset of SBP changes (lag 0, 1, o 2). BRS was quantified as the slope of the linea egession line elating RR to SBP (in milliseconds pe millimete of mecuy). Powe spectal analysis of the RR inteval was pefomed with fast Fouie tansfomation ove each 3-minute segment of cognitive eactivity-ecovey testing. Spectal powe (in milliseconds squaed pe hetz) was quantified fo conventional bandwidths, including the high-fequency (HF) bandwidth (0.15 to 0.40 Hz), which seved as a make of vagal-hr modulation. Respiation ate (beaths pe minute) was sensed by the ECG electodes as changes in tansthoacic impedance. Cognitive eactivity-ecovey testing began with a 10-minute adaptation that was followed by 2 successive 3-minute esting intevals (baseline 1 and baseline 2). The initial 3-minute task was a cognitive contol pocedue. Subjects viewed 18 neutal slides (Intenational Affective Pictue System 10 [IAPS]) on a compute sceen in 10-second intevals, followed by a 3-minute ecovey. Subjects next pefomed 2 andomly odeed tasks in 3-minute intevals, with each followed by 3-minute ecovey. The Paced Auditoy Seial Addition Test (PASAT) 11 used audio-taped instuction to test attentional ability and memoy. Thee potential answes to each seial addition wee pesented on a compute sceen, and subjects esponded by pessing 1 of 3 coesponding keys on a handheld device that was synchonized to the compute. Pefomance demands wee pogessively inceased by educing the inteval between seial digits fom 2.5 to 2.0 seconds. 7 The emotional Stoop test 12 (estoop) equied subjects to pess 1 of 4 coloed buttons on a handheld device (ed, yellow, geen, and blue) that coesponded with the colo in which 8 neutal wods and 10 negatively valanced wods (eg, mude and ape) wee displayed on a compute sceen. Each wod was displayed fo 1.5 seconds, with a esponse inteval of 8.5 seconds. Neutal and negative wods wee andomly odeed. Inteventions Subjects eceived 4 weekly and then 2 biweekly 1-hou sessions of BNT o AC. Each session began with a 10-minute eview of cognitive-behavioal guidelines fo managing daily stess. 7 Taining in BNT and AC was supplemented by 20-minute audio-taped execises fo daily home pactice, which eplicated pocedues used in the 1-hou teatment sessions. AC subjects wee infomed that they would be tained in autogenic elaxation to buffe the effect of daily stess on BP. Each session included a 30-minute audio-taped autogenic elaxation pocedue. 7 The stated taining goal was to evoke passive elaxation by silently epeating autogenic (self-initiated) phases that focused attention on sensations of heaviness, calm, and wamth in majo skeletal muscle goups. BNT subjects wee infomed that they would lean an active counteing skill with HRV biofeedback to decease the influence of stess on BP. As descibed peviously, 7 each session pesented subjects with a standadized psychological task (eg, seial 7 subtaction) and physical challenge (sitting-to-standing) to evoke mild-tomodeate psychophysiologic aousal. On completing each task, subjects wee tained to cognitively disengage fom negative o aoused affect and to focus attention on slowing espiation within thei comfot zone to 10-second cycles (6 beaths pe minute). The taining goal fo each counteing execise was to incease RR spectal powe at 0.1 Hz, as guided by the biofeedback display of the RR powe spectum (0.003 to Hz) and beaths pe minute. The biofeedback display also included eal-time vaiations in HR and BRS, which wee not the focus of taining in this study. These

3 Nolan et al Behavioal Neuocadiac Taining and Hypetension 3 Telephone sceening inteview: n = 185 Scheduled fo 2-day Lab Assessment: n = 87 Excluded: n = declined to paticipate 19 failed to meet inclusion citeia Excluded: n = withdew 12 failed to confim inclusion citeia Figue 1. Patient flow diagam. Randomized: n = 65 Active Contol: n = 30 Withdew: n = 2 Behavioal Neuocadiac Taining: n = 35 Withdew: n = 4 Analyzed fo efficacy assessment: n = 30 Analyzed fo efficacy assessment: n = 35 Downloaded fom by guest on May 2, 2018 indices wee initially sampled acoss a window of 120 seconds, and the compute display was updated continuously. All of the physiological data wee time synchonized and digitized at 1000 Hz by a customized biofeedback pogam (LabView 7.1, National Instuments). Pimay efficacy outcomes included daytime (8:00 AM to 10:00 PM) and 24-hou ambulatoy measues fo SBP, DBP and PP. Seconday efficacy outcomes included RR inteval, HF powe, and BRS duing cognitive eactivity-ecovey testing. Statistical Methods On the basis of the method poposed by Rochon 13 and findings fom ou pevious tial of BNT, 7 it was estimated that 62 subjects wee equied to detect a significant diffeence between BNT and AC, with statistical powe of 80% and a type 1 eo of 5%, with espect to RR-HF powe duing cognitive eactivity-ecovey testing and BP eduction. Baseline chaacteistics of BNT and AC goups wee examined by Peason 2 tests and ANOVA. The effects of BNT and AC on daytime and 24-hou SBP, DBP, and PP wee evaluated by an intention-to-teat appoach using linea mixed models (LMMs) with andom intecept and adjustment fo age, sex, BMI, and antihypetensive medications ( -blockes, calcium channel blockes, angiotensin-conveting enzyme inhibitos, angiotensin II ecepto blockes, o diuetics; 0: not pescibed, 1: pescibed, and 2: pescibed but modified duing this tial). Main-effect models contasted each ambulatoy BP vaiable befoe intevention with outcomes afte BNT and AC. The use of the andom intecept adjusted fo vaiability in BP between individual subjects. Absolute isk eduction and numbe-needed-to-teat statistics wee used to exploe whethe BNT vesus AC deceased the numbe of subjects with uncontolled BP (24-hou SBP 130 mm Hg) in compaison with peteatment. Repeated-measues LMM with a andom intecept evaluated whethe BNT vesus AC augmented cadiovagal functioning acoss each 3-minute segment of cognitive eactivity-ecovey testing, in contast to a esting baseline (baseline 2). The tasks included a cognitive contol (neutal IAPS slides 10 ), ecovey, PASAT, 11 ecovey, estoop, 12 and ecovey. Each analysis adjusted fo esting baseline 1 fo each seconday outcome vaiable, age, sex, BMI, antihypetensive medications, beaths pe minute, and tasks. LMM analyses also adjusted fo the seial coelation between epeated measues acoss the testing potocol. Seconday outcomes included RR inteval, HF powe, and BRS. A log-10 tansfomation was applied to HF powe and BRS to contol fo skewness. Each LMM tested the main effect fo inteventions (befoe vesus afte BNT and AC), tasks (esting baseline 2 vesus each eactivity and ecovey inteval), and the teatment-by-tasks inteaction. Only those effects with P 0.1 wee included in the final model. Use of the andom intecept contolled fo vaiability between individual subjects. The association between postteatment measues of log-hf and log-brs duing the cognitive eactivity tests (PASAT 11 and estoop 12 ) and 24-hou SBP and PP was exploed with patial coelations that adjusted fo antihypetensive medications, SBP o PP befoe intevention, and esting baseline fo log-hf o log-brs. Results ae epoted as the mean SE unless othewise noted. Statistical significance was defined by 2-tailed tests at P Analyses wee conducted on SAS 9.1 (SAS Institute Inc) and SPSS 17.0 (SPSS Inc). Results The sample included 65 subjects (BNT: n 35; AC: n 30; Figue 1). Baseline chaacteistics did not diffe between goups (Table 1). Among subjects pescibed antihypetensive medications (n 46; 70.8%), 5 BNT and 2 AC subjects epoted a change in medication dose o numbe (P 0.32). Withdawals did not diffe between goups (BNT: n 4; AC: n 2; P 0.51). Table 1. Chaacteistic Baseline Chaacteistics BNT (n 35) AC (n 30) Age, y Female sex 20 (57.1) 17 (56.7) 0.97 BMI, kg/m Diabetes mellitus 8 (22.9) 5 (16.7) 0.53 Smokes 2 (5.7) 2 (6.7) 0.87 Antihypetensive medications -blocke 10 (28.6) 3 (10.0) 0.06 Calcium channel 6 (17.1) 6 (20.0) 0.77 blocke ACE inhibito 12 (34.3) 11 (36.7) 0.84 Angiotensin II ecepto 5 (14.3) 3 (10.0) 0.60 blocke Diuetic 18 (51.4) 13 (43.3) antihypetensive dug 25 (71.4) 21 (70.0) 0.25 Data ae shown as mean SE o n (%). ACE indicates angiotensin-conveting enzyme. P

4 4 Hypetension Apil 2010 Downloaded fom by guest on May 2, 2018 Table 2. Unadjusted Means fo Ambulatoy BP Befoe and Afte Inteventions Ambulatoy BP, mm Hg Befoe Intevention BNT Afte Intevention Befoe Intevention Ambulatoy BP Unadjusted means fo daytime and 24-hou SBP, DBP, and PP, befoe and afte intevention, ae pesented in Table 2. Table 3 indicates that BNT was associated independently with a significant eduction in daytime and 24-hou SBP ( mm Hg, P 0.009; and mm Hg, P 0.03, espectively) and daytime and 24-hou PP ( mm Hg, P 0.004; and mm Hg, P 0.02, espectively) but not DBP (P 0.10 fo both). Significant main effects indicated that daytime and 24-hou SBP wee lowe among subjects without (vesus with) antihypetensive medications, subjects with pescibed medications that wee not changed (vesus changed), and subjects who wee younge o who had a lowe BMI. AC did not evoke significant change on any ambulatoy BP measue (P 0.10 fo all). Table S1 (available in the online Data Supplement, please see pesents unadjusted means fo nighttime SBP, DBP, and PP, wheeas Table S2 indicates that these measues wee not significantly educed afte BNT o AC. The numbe of subjects with uncontolled BP (24- hou SBP: 130 mm Hg) deceased fom peteatment afte BNT (n 17 of 35 to 12 of 35) but not AC (n 15 of 30 to 15 AC Afte Intevention Daytime SBP Daytime DBP Daytime PP h SBP h DBP h PP Data ae shown as mean SE. of 30; absolute isk eduction: 0.14 [95% CI: 0.01 to 0.27]; numbe needed to teat: 7 [95% CI: 4 to 57]). Vagal Modulation of HR and BP Figue 2 displays unadjusted means duing cognitive eactivity-ecovey testing fo espiation, RR inteval, HF powe, and BRS. Baseline values fo these vaiables did not diffe significantly befoe vesus afte BNT o AC (P 0.30 fo each). Table 4 pesents the covaiate-adjusted effects of BNT and AC on RR inteval, log-hf, and log-brs duing cognitive eactivity-ecovey testing. RR inteval inceased significantly fom peteatment afte BNT (P ) and in compaison with AC (P ), wheeas RR inteval deceased fom peteatment afte AC (P 0.01). The intevention-by-task inteaction was not significant (P 0.30). Log-HF inceased significantly afte BNT in compaison with both peteatment (P 0.01) and AC (P 0.005). Log-HF did not change significantly afte AC (P 0.18). The intevention-by-task inteaction was not significant (P 0.51). Log-BRS did not change significantly afte vesus befoe BNT o AC (P 0.35 fo both compaisons). The intevention-by-task inteaction was not significant (P 0.93). Table S3 pesents the complete LMMs fo RR inteval, log-hf, and log-brs with main-effect compaisons between baseline 1 and each cognitive eactivity-ecovey task (please see the online Data Supplement). Association Between Ambulatoy BP and Cadiovagal Response to Cognitive Tasks Table 5 indicates that daytime and 24-hou SBP and PP wee invesely associated with log-hf duing the PASAT 11 and estoop 12 afte BNT (P 0.05 in each case) but not afte AC (P 0.05 in each case). Neithe BNT no AC demonstated a stable invese association between ambulatoy BP and BRS (P 0.05). Table 3. Linea Mixed Model fo the Effect of Inteventions on Ambulatoy BP Daytime SBP Daytime DBP Daytime PP 24-Hou SBP 24-Hou DBP 24-Hou PP Pedictos SE P SE P SE P SE P SE P SE P Sex Age BMI Stable antihypetensive dugs vs not pescibed Stable antihypetensive dugs vs changed AC vs befoe intevention BNT vs befoe intevention

5 Nolan et al Behavioal Neuocadiac Taining and Hypetension 5 Respiation: Beaths/Minute Baseline 1 Baseline 2 IAPS PASAT estoop RR Inteval (ms) Baseline 1 Baseline 2 IAPS PASAT estoop Downloaded fom by guest on May 2, 2018 log10 Baoeflex Sensitivity (mmhg/ms) Baseline 1 Baseline 2 IAPS PASAT Befoe Intevention estoop log10 RR-High Fequency Powe (ms 2 /Hz) Afte: BFB Goup Baseline 1 Baseline 2 IAPS PASAT Afte: Active Contol Goup Figue 2. Cadiovagal esponse to cognitive eactivity-ecovey testing as shown by unadjusted means. IAPS indicates Intenational Affective Pictue System;, ecovey. Discussion The pesent findings help to esolve 2 issues that ae tied histoically to effots to develop a behavioal intevention fo hypetension. Whethe such an intevention can futhe lowe BP once subjects eceive antihypetensive medications has become an inceasingly impotant challenge, because combination dug theapy is now ecommended fo most patients with hypetension. 14 Recent meta-analyses have epoted that the combination of biofeedback and elaxation taining educed SBP and DBP 6 o SBP only 5 in compaison with an AC o behavioal placebo. Howeve, the efficacy of this complementay behavioal teatment was not evaluated diectly fo estoop Table 4. Linea Mixed Model fo the Effect of Inteventions on RR Inteval, Log-HF and Log-BRS Pedictos Baseline 1 (RR/log-HF/log-BRS) RR Inteval Log-HF Log-BRS SE P SE P SE P Respiation Sex Age BMI Stable antihypetensive dugs vs not pescibed Stable antihypetensive dugs vs changed AC vs befoe intevention BNT vs befoe intevention BNT vs AC Data ae shown as mean SE. IAPS indicates Intenational Affective Pictue System; HF, RR high-fequency powe.

6 6 Hypetension Apil 2010 Table 5. Patial Coelation Coefficients fo Ambulatoy BP and Cadiovagal Response to Cognitive Reactivity Tasks BNT Subjects Afte Intevention AC Subjects Afte Intevention Cadiovagal 24-h SBP 24-h PP 24-h SBP 24-h PP Response to Tasks R P R P R P R P Log-HF PASAT Log-HF estoop Log-BRS PASAT Log-BRS estoop R indicates patial coelations adjusted fo antihypetensive medications, SBP o PP (espectively) befoe intevention, and esting baseline fo log-hf o log-brs (espectively). Downloaded fom by guest on May 2, 2018 patients who wee pescibed antihypetensive medications. Impotantly, these meta-analyses included 8 tials that enolled medicated subjects, of which 6 tials epoted null findings. In the pesent tial, 71% of subjects wee pescibed 1 antihypetensive medication on enollment with phamacotheapy stable fo 4 months to incease the likelihood that theapeutic benefit had been achieved. Nevetheless, BNT futhe educed ambulatoy SBP and PP afte adjusting statistically fo antihypetensive medications, wheeas no change was obseved fo AC. The second issue concens whethe epeated exposue to passive elaxation 3 is necessay o sufficient to modify symptoms of sympathetic oveactivity associated with emotional o envionmental challenges. Autonomic dysfunction in hypetension is chaacteized by inhibition of vagal-hr modulation, attenuated BRS, heightened sympathetic modulation of cadiac function and vasomoto tone, and inceased BP vaiability. 21,22 In the pesent study, passive elaxation with autogenic taining did not significantly change tonic o eflex vagal modulation of the heat. In contast, BNT 7 significantly inceased tonic vagal-hr modulation. This was achieved by epeatedly exposing subjects to standadized psychological and physical challenges to povide active taining in counteing skills that included focused attention, affect egulation, and slow-paced beathing. HRV biofeedback einfoced and guided the development of counteing skills towad the goal of inceasing vagal-hr modulation duing the psychological and physical challenges. To ou knowledge, this is the fist behavioal tial with hypetensive patients to demonstate a concomitant impovement in ambulatoy SBP and PP (as a suogate, in the pesent context, fo stoke volume) in association with inceased vagal-hr modulation, as evidenced by RR-HF powe and lengthening of the RR inteval. Pevious tials have epoted an incease in vagal-hr modulation among subjects with coonay heat disease afte BNT and HRV biofeedback 7 o a combination of beathing execises with elaxation taining o meditation. 23 The pesent tial extends these findings by demonstating this theapeutic effect in association with educed ambulatoy SBP and PP among subjects with hypetension. This outcome was obseved afte only an 8-week intevention, which may undeestimate a potential benefit of BNT fo long-tem pognosis. Clinical tial evidence has shown that impoved vagal-hr modulation o BRS independently contibutes to educed isk fo cadiovascula events among patients with coonay heat disease 24,25 o with hypetension. 26 In heat failue, whee chonic -adenegic antagonism has been demonstated to impove longevity, this dug class augments eflex vagal-hr modulation at an effeent site of inteaction involving blockade of cadiac sympathetic pejunctional 2 adenoceptos that facilitate noepinephine elease. 27 The potential use of BNT as a complementay antihypetensive teatment is futhe suppoted by the exploatoy finding, albeit in a small sample, that ambulatoy 24-hou SBP was educed below the clinical theshold of 130 mm Hg fo 1 of evey 7 BNT subjects, epesenting an absolute isk eduction of 14% in compaison with AC. This modest exploatoy outcome suggests that thee is meit in conducting a lage scale tial to evaluate the long-tem clinical efficacy of BNT. Findings fom the pesent study ae limited by the shot (8-week) intevention peiod. In addition, subjects wee studied 1 week afte the final session, at which time the maximum impact of teatment may have dissipated. Evidence of an independent association between BNT and BP eduction ove at least a 6-month follow-up is needed to confim its potential ole as a complementay teatment fo hypetension. 5 In addition, BNT and AC inteventions wee supplemented with instuctions fo daily home pactice using 20-minute audio-taped execises. Adheence to home pactice was not objectively monitoed; theefoe, the dose-esponse association between BNT and BP eduction cannot be accuately established in this tial. Finally, spontaneous BRS did not incease significantly afte BNT and HRV biofeedback. Futue eseach is needed to detemine whethe BNT and BRS biofeedback can educe BP while impoving baoeflex gain among patients with hypetension. Pespectives Ou pesent tial demonstates that, in contast to passive elaxation, BNT with HRV biofeedback 7 modestly educes ambulatoy SBP and PP while impoving tonic vagal-hr modulation, independent of antihypetensive medications. BNT is well suited to physiologically define teatment objectives, to specify mechanisms of theapeutic change, and, theefoe, to eplicate teatment outcomes. Fo this eason, we popose BNT as a novel advance in the development of behavioal inteventions fo hypetension.

7 Nolan et al Behavioal Neuocadiac Taining and Hypetension 7 Downloaded fom by guest on May 2, 2018 Acknowledgments We ae gateful to D Adiana Mechetiuc, D Susan Bay- Bianchi, Nazia Siddiqui, Caley Hamilton, and Samantha Young fo thei assistance. Souces of Funding This tial was suppoted by an unesticted eseach gant fom Unileve Copoate Reseach Biosciences. J.S.F. holds the Canada Reseach Chai in Integative Cadiovascula Biology and is a caee investigato of the Heat and Stoke Foundation of Ontaio. None. Disclosues Refeences 1. Patel C, Noth WR. Randomised contolled tial of yoga and bio-feedback in management of hypetension. Lancet. 1975;2: Alam GM, Smik FH. Casual and basal blood pessues II: in essential hypetension. B Heat J. 1943;5: Benson H, Rosne BA, Mazetta BR, Klemchuk HM. Deceased bloodpessue in phamacologically teated hypetensive patients who egulaly elicited the elaxation esponse. Lancet. 1974;1: Pickeing T. Lette: yoga and bio-feedback in hypetension. Lancet. 1973;2: Dickinson HO, Campbell F, Beye FR, Nicolson DJ, Cook JV, Fod GA, Mason JM. Relaxation theapies fo the management of pimay hypetension in adults. Cochane Database Syst Rev. 2008;(1):CD Nakao M, Yano E, Nomua S, Kuboki T. Blood pessue-loweing effects of biofeedback teatment in hypetension: a meta-analysis of andomized contolled tials. Hypetens Res. 2003;26: Nolan RP, Kamath MV, Floas JS, Stanley J, Pang C, Picton P, Young QR. Heat ate vaiability biofeedback as a behavioal neuocadiac intevention to enhance vagal heat ate contol. Am Heat J. 2005;149: Padwal RS, Hemmelgan BR, McAliste FA, McKay DW, Gove S, Wilson T, Penne B, Bugess E, Bolli P, Hill M, Mahon J, Myes MG, Abbott C, Schiffin EL, Honos G, Mann K, Temblay G, Milot A, Cloutie L, Chockalingam A, Khan NA, Rabkin SW, Dawes M, Touyz RM, Tobe SW. The 2007 Canadian Hypetension Education Pogam ecommendations fo the management of hypetension: pat 1 blood pessue measuement, diagnosis and assessment of isk. Can J Cadiol. 2007;23: Butle GC, Senn BL, Floas JS. Influence of atial natiuetic facto on spontaneous baoeflex sensitivity fo heat ate in humans. Hypetension. 1995;25: Cente fo the Study of Emotion and Attention-National Institute of Mental Health. Intenational Affective Pictue System (IAPS): Technical Manual and Affective Ratings. Gainesville, FL: NIMH-Cente fo the Study of Emotion and Attention, Univesity of Floida; Wiens AN, Fulle KH, Cossen JR. Paced Auditoy Seial Addition Test: adult noms and modeato vaiables. J Clin Exp Neuopsychol. 1997;19: Whalen PJ, Bush G, McNally RJ, Wilhelm S, McIneney SC, Jenike MA, Rauch SL. The emotional counting Stoop paadigm: a functional magnetic esonance imaging pobe of the anteio cingulate affective division. Biol Psychiaty. 1998;44: Rochon J. Sample size calculations fo two-goup epeated-measues expeiments. Biometics. 1991;47: Chobanian AV, Bakis GL, Black HR, Cushman WC, Geen LA, Izzo JL J, Jones DW, Mateson BJ, Opail S, Wight JT J, Roccella EJ. Seventh epot of the Joint National Committee on Pevention, Detection, Evaluation, and Teatment of High Blood Pessue. Hypetension. 2003;42: Blanchad EB, Mille ST, Abel GG, Haynes MR, Wicke R. Evaluation of biofeedback in the teatment of bodeline essential hypetension. J Appl Behav Anal. 1979;12: Fankel BL, Patel DJ, Howitz D, Fiedewald WT, Gaade KR. Teatment of hypetension with biofeedback and elaxation techniques. Psychosom Med. 1978;40: Ivine MJ, Johnston DW, Jenne DA, Maie GV. Relaxation and stess management in the teatment of essential hypetension. J Psychosom Res. 1986;30: Jacob RG, Shapio AP, O Haa P, Potse S, Kuge A, Gatsonis C, Ding Y. Relaxation theapy fo hypetension: setting-specific effects. Psychosom Med. 1992;54: Hafne RJ. Psychological teatment of essential hypetension: a contolled compaison of meditation and meditation plus biofeedback. Biofeedback Self Regul. 1982;7: Juek IE, Higgins JT J, McGady A. 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8 Behavioal Neuocadiac Taining in Hypetension. A Randomized, Contolled Tial Robet P. Nolan, John S. Floas, Paula J. Havey, Makad V. Kamath, Pete E. Picton, Caoline Chessex, Natalie Hiscock, Jonathan Powell, Michael Catt, Hilde Hendickx, Duncan Talbot and Maggie H. Chen Downloaded fom by guest on May 2, 2018 Hypetension. published online Mach 1, 2010; Hypetension is published by the Ameican Heat Association, 7272 Geenville Avenue, Dallas, TX Copyight 2010 Ameican Heat Association, Inc. All ights eseved. Pint ISSN: X. Online ISSN: The online vesion of this aticle, along with updated infomation and sevices, is located on the Wold Wide Web at: Data Supplement (unedited) at: Pemissions: Requests fo pemissions to epoduce figues, tables, o potions of aticles oiginally published in Hypetension can be obtained via RightsLink, a sevice of the Copyight Cleaance Cente, not the Editoial Office. Once the online vesion of the published aticle fo which pemission is being equested is located, click Request Pemissions in the middle column of the Web page unde Sevices. Futhe infomation about this pocess is available in the Pemissions and Rights Question and Answe document. Repints: Infomation about epints can be found online at: Subsciptions: Infomation about subscibing to Hypetension is online at:

9 Online Supplement to: BEHAVIORAL NEUROCARDIAC TRAINING IN HYPERTENSION: A RANDOMIZED CONTROLLED TRIAL Robet P. Nolan 1 ; John S. Floas 1 ; Paula J. Havey 1 ; Makad V. Kamath 2 ; Pete E. Picton 4 ; Caoline Chessex 1 ; Natalie Hiscock 3 ; Jonathan Powell 3 ; Michael Catt 3 ; Hilde Hendickx 3 ; Duncan Talbot 3 ; Maggie H. Chen 4 1 Division of Cadiology, Univesity Health Netwok and Faculty of Medicine, Univesity of Toonto, Toonto, Canada 2 Depatments of Medicine and Electical and Compute Engineeing, McMaste Univesity, Hamilton, Canada 3 Unileve Copoate Reseach Biosciences, Colwoth Pak, UK 4 Univesity Health Netwok, Toonto, Ontaio Canada Shot title: Behavioal Neuocadiac Taining and Hypetension Addess fo Coespondence: Robet P. Nolan, PhD; Behavioual Cadiology Reseach Unit, 6N-618; Univesity Health Netwok; 585 Univesity Avenue, Toonto, Ontaio, Canada, M5G 2N2; Tel ext. 6400; Fax ; nolan@uhnes.utoonto.ca.

10 Table S1. Unadjusted Means fo Ambulatoy Nighttime Blood Pessue. BNT AC Befoe Afte Befoe Afte Ambulatoy Blood Pessue Intevention Intevention Intevention Intevention Nighttime SBP (mm Hg) ± ± ± ±2.3 Nighttime DBP (mm Hg) 69.7 ± ± ± ±1.3 Nighttime PP (mm Hg) 50.0 ± ± ± ±1.6 Data ae shown as M ±SE. AC indicates Active Contol intevention; BNT, Behavioal Neuocadiac Taining; SBP, systolic BP; DBP, diastolic BP; PP, pulse pessue;

11 Table S2. Linea Mixed Model fo the Effect of Inteventions on Ambulatoy Nighttime Blood Pessue Nighttime SBP Nighttime DBP Nighttime PP Pedictos ß ±SE P ß ±SE P ß ±SE P Sex ± ± ± Age 0.36 ± ± ± Body Mass Index 0.65 ± ± ±0.2 < Stable Antihypetensive ± ± ± Dugs vs. Not Pescibed Stable Antihypetensive ± ± ± Dugs vs. Change AC vs. Befoe Intevention ± ± ± BNT vs. Befoe Intevention ± ± ± Data ae shown as M ±SE. AC indicates Active Contol intevention; BNT, Behavioal Neuocadiac Taining; SBP, systolic BP; DBP, diastolic BP; PP, pulse pessue

12 Table S3. Complete Linea Mixed Model fo the Effect of Inteventions on RR Inteval, loghf and logbrs RR Inteval loghf logbrs Pedictos ß ±SE P ß ±SE P ß ±SE P Baseline-1 (RR/logHF/logBRS) 0.85 ±0.02 < ±0.03 < ±0.04 < Respiation ± ± ± Sex ± ± ± Age 0.62 ± ± ± Body Mass Index ± ± ± Medication vs. No medication ± ± ± Stable Medication vs. Change ± ± ± Assessment Tasks: IAPS 1 vs. Baseline ±5.60 < ± ± IAPS 1 ecovey vs. Baseline ± ± ± PASAT 2 vs. Baseline ±5.95 < ±0.04 < ±0.02 < PASAT 2 ecovey vs. Baseline ± ± ± estoop 3 vs. Baseline ±6.05 < ±0.04 < ± estoop 3 ecovey vs. Baseline ± ± ± Inteventions: AC vs. Befoe Intevention ± ± ± BNT vs. Befoe Intevention ±4.02 < ± ± BNT vs. AC ±5.56 < ± ± IAPS 1 indicates Intenational Affective Pictue System; PASAT 2, Paced Auditoy Seial Addition Test; estoop 3, Emotional Stoop test; HF, RR high fequency powe; BRS, baoeflex sensitivity; AC, Active Contol intevention; BNT, Behavioal Neuocadiac Taining.

13 REFERENCES: 1. Cente fo the Study of Emotion and Attention-National Institute of Mental Health. Intenational affective pictue system (IAPS): Technical manusal and affective atings. NIMH-Cente fo the Study of Emotion and Attention, Univesity of Floida; Wiens AN, Fulle KH, Cossen JR. Paced Auditoy Seial Addition Test: adult noms and modeato vaiables. J Clin Exp Neuopsychol. 1997;19: Whalen PJ, Bush G, McNally RJ, Wilhelm S, McIneney SC, Jenike MA, Rauch SL. The emotional counting Stoop paadigm: a functional magnetic esonance imaging pobe of the anteio cingulate affective division. Biol Psychiaty. 1998;44: