ambulatory blood pressure changes after renal sympathetic

DOI: 10.1161/CIRCULATIONAHA.112.000949

1

Ambulatory Blood Pressure Changes after Renal Sympathetic Denervation in

Patients with Resistant Hypertension

Running title: Mahfoud et al.; ABPM after renal denervation

Felix Mahfoud, MD1*; Christian Ukena, MD1*; Roland E. Schmieder, MD2; Bodo Cremers, MD1; Lars C. Rump, MD3; Oliver Vonend, MD3; Joachim Weil, MD4; Martin Schmidt, MD5;

Uta C. Hoppe, MD6; Thomas Zeller, MD7; Axel Bauer, MD8; Christian Ott, MD2; Erwin Blessing, MD9; Paul A. Sobotka, MD10; Henry Krum, MBBS, PhD11; Markus Schlaich, MD12;

Murray Esler, MBBS, PhD, FRACP12; Michael Böhm, MD1

1Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar; 2Medizinische Klinik IV, Universitätsklinikum

Erlangen, Erlangen; 3Klinik für Nephrologie, Universitätsklinikum Düsseldorf, Düsseldorf; 4Medizinische Klinik 2, Universitätsklinikum Schleswig-Holstein, Lübeck, Lübeck; 5Klinik für Kardiologie, Klinikum

München-Bogenhausen, München-Bogenhausen, Germany; 6Dept für Innere Medizin II, Paracelsus Medical University Salzburg, Salzburg, Austria; 7Klinik für Angiologie, Universitäts-Herzzentrum Bad

Krozingen-Freiburg, Bad Krozingen-Freiburg, Germany; 8Innere Medizin III, Universitätsklinikum Tübingen, Tübingen; 9Medizinische Klinik III, Universitätsklinikum Heidelberg, Heidelberg, Germany; 10The Ohio State University, Columbus, OH & Ardian, Inc, Palo Alto, CA; 11Centre of Cardiovascular

Research and Education in Therapeutics, Dept of Epidemiology and Preventive Medicine, Monash University, Melbourne; 12Baker IDI Heart and Diabetes Research Institute, Melbourne, Australia

*Both first authors contributed equally

Address for Correspondence:

Felix Mahfoud, MD

Klinik für Innere Medizin III

Kardiologie, Angiologie und Internistische Intensivmedizin

Universitätsklinikum des Saarlandes

Kirrberger Str., Geb. 40

66421 Homburg/Saar, Germany

Tel: +49 6841 16 21346

Fax: +49 6841 16 13211

E-mail: [email protected]

Journal Subject Code: Hypertension:[14] Other hypertension

g g gUniversitätsklinikum des Saarlandes, Homburg/Saar; 2Medizinische Klinik IV, Univererrsisisitätätätstst klklklinininikikikumumum

Erlangen, Erlangen; 3Klinik für Nephrologie, Universitätsklinikum Düsseldorf, Düsselddoororf;f;f; 4MeMeMedididizizizininniscschehKlinik 2, Universitätsklinikum Schleswig-Holstein, Lübeck, Lübeck; 5Klinik für Kardiiollogiei , KlKliinikikum

München-Bogenhausen, München-Bogenhausen, Germany; 6Dept für Innere Medizin II, Paracelsus Medid cal Unnivversisityty Salzburg, Salzburg, Austria; 7KlK inik für Angiologie, Uninivev rsitäts-Herzzentrum Bad

KrKrKrozozozininingegegen-n-n-Freieieibbuburgr , Bad Krozingen-Freiburg, GeGeGermrmrmany; 8Innere MMedee izininn IIIIIIII , Universitätsklinikum TTüTübbibingn en, TüTüTübingnggenen;; 9MeMedidiziziniiscschehe KKlilininik k IIIII,I, UUniniveveerrssitättsksklilinnikikummm HHHeeidedelblberere g, HHeieidedelblbererg,g, GGerermamanyn ; 10TTThe Ohio SStataatetete UUUniniivvev rsrsrsititityy,y, CCColoolumummbbubuss,, OOHOH &&& AAArdiiannn, Innnc,, PaPaalooo AAltltl o,o CCA;A;A; 111Ceentntntrrere oof f f CCaCardrdrdioiovavavasccsculullar

RReR search and EEEddducaattiooon inn TThherappeueutiicscss, Deeepttt of EEEpppideemimimiololologogo yy annndd Prevvvf ennntivvve MMedicccinnne,e MMMonaasshh h UnUnU ivi erersisiitytyty,, MMeMelblbououurnnne;e; 1212BaBaBakekek r r IDIDIDI I HeHeHearart t aanandd DiDiabbbeteteeses RResesseaaarrchchh Innsnstititutuutee,, MMeMelblbbouournrnnee,e, AAusustrtralaliia

*B*BBoototh h fifirsrsrstt t auauauthththoororss cococontntntriribububutetetedd d eqeqequauallllllyy y

by guest on February 15, 2018http://circ.ahajournals.org/

Dow

nloaded from

http://circ.ahajournals.org/


2

Abstract:

Background—Catheter-based renal sympathetic denervation (RDN) reduces office blood

pressure (BP) in patients with resistant hypertension according to office BP. Less is known about

the effect of RDN on 24-hour BP measured by ambulatory blood pressure monitoring (ABPM)

and correlates of response in individuals with true or pseudo-resistant hypertension.

Methods and Results—A total of 346 uncontrolled hypertensive patients, separated according to

daytime ABPM into 303 with true resistant (office SBP 172.2 ± 22 mmHg; 24-hour SBP 154 ±

16.2 mmHg) and 43 with pseudo-resistant hypertension (office SBP 161.2 ± 20.3 mmHg; 24-

hour SBP 121.1 ± 19.6 mmHg), from 10 centers were studied. At 3, 6 and 12 months follow-up

office SBP was reduced by 21.5/23.7/27.3 mmHg, office DBP by 8.9/9.5/11.7 mmHg, and pulse

pressure by 13.4/14.2/14.9 mmHg (n=245/236/90; p for all <0.001), respectively. In patients

with true treatment resistance there was a significant reduction with RDN in 24-hour SBP (-

10.1/-10.2/-11.7 mmHg, p<0.001), DBP (-4.8/-4.9/-7.4 mmHg, p<0.001), maximum SBP (-

11.7/-10.0/-6.1 mmHg, p<0.001) and minimum SBP (-6.0/-9.4/-13.1 mmHg, p<0.001) at 3, 6 and

12 months, respectively. There was no effect on ABPM in pseudo-resistant patients, while office

BP was reduced to a similar extent. RDN was equally effective in reducing BP in different

subgroups of patients. OSBP at baseline was the only independent correlate of BP response.

Conclusions—RDN reduced office BP and improved relevant aspects of ABPM, commonly

linked to high cardiovascular risk, in patients with true-treatment resistant hypertension while it

only affected office BP in pseudo-resistant hypertension.

Clinical Trial Registration Information—http://www.clinicaltrials.gov. Identifiers:

NCT00664638 and NCT00888433

Key words: hypertension, clinical trial, hypertension, renal, renal denervation

pressure by 13.4/14.2/14.9 mmHg (n=245/236/90; p for all <0.001), respectivelyy... InInIn pppatatatieieientntntss s

with true treatment resistance there was a significant reduction with RDN in 24-hohooururur SSBPBPBP ((--

10.1/-10.2/-11.7 mmHg, p<0.001), DBP (-4.8/-4.9/-7.4 mmHg, p<0.001), maximum SBP (-

111.7.77/-/-/-101010 0.0.0/-/-/-6.6.6 1 mmmmmmHgH , p<0.001) and minimum SSSBPBP (-6.0/-9.4/-13133.1 mmmmmHmHg, p<0.001) at 3, 6 and

12122 mmmonths, rresespepepectcttivvvelelely.y. TTTheheh rerere wwwasass nnnoo o efefe fefeectctc ooon n ABABABPMMM iiinn n pspspseueuudodod r-r-resesesisisistatantt pppatatatieieientntnts,s,s wwwhihihilelele oooffffffici e

BBPBP wwwas reducuced ttooo a ssiimmmilaarr r exexxteentn .. RDRDRDNNN waass equuaualllly y efefeffefefectcc iivve iinin reduuuciiningg BBPBP in didiffffeeereent

uubgbggrororoupupupsss ofoof ppatatatieieienntnts.ss. OOOSBSBS P P atatat bbbaasaselelinine ee wwawasss thththe ee onononlylyly iiindndndepepepenenenddedentntnt cccorororrererelalalatete oooff f BPBPBP rresesspopoponsnsnse.ee

Conclusionss——RDRDRDN N N rereedudd ceceed d d ofofffifificecec BBBP P P ananand d d imimimprprprovovovededed reeelelel vavavantntnt aaaspsps ececectststs ooof f f ABABABPMPMPM,, cococommmm only


Dow

nloaded from



3

Ambulatory blood pressure monitoring (ABPM) is important for the management of patients

with hypertension as it allows more sensitive and specific cardiovascular risk stratification

compared to office blood pressure (BP) measurement.1-3 International guidelines recommend

ABPM in patients with resistant hypertension to exclude pseudo-resistance and to more

accurately assess BP control by treatment.4 ABPM with 24-hour, day and night average BP

values correlate more closely to hypertensive or diabetic end-organ damage than office BP

values.5-7 Nighttime BP is more closely related to cardiovascular morbidity and mortality than

daytime BP.3, 8 High nighttime BP and non-dipping patterns have been associated with increased

sympathetic activity in hypertensives.9

Catheter-based renal denervation (RDN) offers a new approach to interrupt renal

sympathetic innervation and has been shown to reduce renal and total body norepinephrine

spillover.10-12 RDN significantly reduced office systolic and diastolic BP in patients with

resistant hypertension,13, 14 reduced left ventricular mass and improved diastolic function15 and

glucose metabolism16 without negatively affecting renal function17 or causing chronotropic

incompetence during exercise.18 However, only limited information about the impact of RDN on

daytime, nighttime and average BP from the Symplicity HTN-2 trial is available.13 Furthermore,

information about the effectiveness of RDN according to patients’ baseline characteristics and

predictors of response are lacking. This study aimed to investigate the effects of RDN on out-of-

office BP by 24-hour ABPM and assessed the potential correlates of response to treatment in the

largest cohort of patients with true resistant and pseudo-resistant hypertension analyzed so far.

Methods

Local ethic committees approved the study. All patients gave written informed consent and were

Catheter-based renal denervation (RDN) offers a new approach to interruuptppt rrrennnalala ff

ympathetic innervation and has been shown to reduce renal and total body norepinephrine

ppililllololoveveverr.10-10-10-121212 RDNDNDN significantly reduced office sysysyssttolic and diasttoloo ic BBBPPP in patients with

eesiiststant hypeertrteennsssionon,,13,3,, 141414 rredededucucededed llefefft vventttriicculaaar mamasssss anannd d imimpprprovovededed ddiaiaststtolololicic fffunununctctc ioioi nnn151515 aaanddd

glglucucucosososee e memeetatatabbobolliismmm1616 wwitithoh uutut nnnegegegatatativiveeely yy aaaffffffeccctitit ngngng rrrenennalall fffuununctctctioioi nnn177 ooor r ccacauususininng g g chchc rororonnnotrtrropppicic

ncompetencecee dddurururinining gg exexexercicicisesese.181818 HHHowowowevevevererer,,, onononlylyly lllimimimitititeded iiinfnfnfororormamamatitit onnn aaaboboboututut tttheheh iimpmpmpacacactt t of RDN onnn


Dow

nloaded from



4

treated between March 2009 and December 2011 with subsequent follow-up to 12 months.

Eligible patients were 18 years and had an office systolic blood pressure (SBP) 160 mmHg

( 150 mmHg for type 2 diabetic patients), despite being treated with 3 antihypertensive drugs

(including one diuretic) at maximum or maximum tolerated doses, with no changes in

medication for a minimum of two weeks prior to enrolment. Optimization of antihypertensive

therapy was considered in all patients prior to RDN. A total of 346 patients from 9 centers in

Germany and 1 center in Australia were enrolled following protocols of ongoing therapeutic

renal denervation trials. 71 patients were included in the Symplicity HTN-1 or HTN-2 trial. In all

other patients the measurements were performed as an extension to the Symplicity protocol

(NCT00664638 and NCT00888433), using the same inclusion and exclusion criteria. Patients

were excluded if they had an estimated glomerular filtration rate (eGFR) of <45 mL/min per 1.73

m2 or a known secondary cause of hypertension other than sleep apnea or chronic kidney disease.

All patients underwent a complete history and physical examination, assessment of vital signs,

and review of medication. Patients were interviewed whether they had taken their complete

medication at defined doses. Treating physicians and patients were instructed not to change

medications except when medically required.

Office SBP, DBP and PP as well as ABPM readings were obtained at entry, and 3, 6, and

12 months following treatment. Office BP readings were taken in a seated position with an

automatic oscillometric Omron HEM-705 monitor (Omron Healthcare, Vernon Hills, IL, USA)

after 5 minutes of rest according to the Standard Joint National Committee VII Guidelines.19 At

baseline, BP was measured at each arm and the arm with the higher BP was used for all

subsequent readings. Averages of the triplicate measures were calculated and used for analysis.

ABPM was performed using an oscillometric Spacelabs 90207 monitor (Spacelabs Healthcare,

NCT00664638 and NCT00888433), using the same inclusion and exclusion crititeeriaiai . PaPaPatititienenentsts

were excluded if they had an estimated glomerular filtration rate (eGFR) of <45 mL/min per 1.73

mm2 ooor r aaa knknknowowownn seseeccocondn ary cause of hypertensionn ooothhher than sleep apapa neaeaa ooorr chronic kidney disease

AAAll pap tients undnddeeerwwewentnnt aaa cccomomomplppletetee e hhihistttorry annnddd physysysicaalal eeexaxaammiminanatioonon, aassseesssssmemem ntnt ooof ff vivivitttal l sissigngnnss,s,

anndd d rereeviviv eweww ooofff mmeeddidicacatttioonon.. PaPaatitienenentststs wwwererre e ininintetetervvvieiei wwewedd whwhwhetetethhher rr ththt eeyey hhhadadd taakakenenn tttheheh irirr cccomommpllletete e

medication aat t dededefifiinenened d dododoseees.s.s TTTrereeatata ininng g phphphysysysiciciciaiaiansnsn ananandd d paaatitit enenentstst wwwerere e e inininstststruruructctctedede nnnototot ttto oo chcc ange


Dow

nloaded from



5

Issaqua, WA, USA) with readings taken every 15 minutes in daytime and every 30 minutes at

nighttime. ABP readings were averaged for 24 hours, day (7 AM to 10 PM), and night (10 PM to

7 AM). Patients were assessed while adhering to their usual diurnal activity and nocturnal sleep

routine. Pseudo-resistance was prospectively defined as mean ambulatory 24-hour SBP <130

mmHg (n=43), despite elevated office SBP readings.20 Patients were graded according to their

baseline-dipping pattern into 4 groups: extreme dippers (nighttime BP fall >20%, n=42), dippers

(nighttime BP fall >10% and <20%, n=92), non-dippers (nighttime BP fall <10% and >0%,

n=125), and reverse-dippers (nighttime BP > daytime BP, n=40). Data on baseline dipping

pattern was missing in 47 patients due to missing nighttime average values. The BP was

considered at target when daytime and nighttime values were <135/85 and <120/70 mmHg,

respectively. The RDN procedure was performed as previously described.13

Statistical analysis

Data are presented as mean ± standard deviation (SD) unless otherwise specified. Comparisons

between groups were performed using the Pearson chi-square test for categorical variables and

the Wilcoxon rank sum test or a paired t-test for continuous variables where appropriate. Linear

mixed-effects models were used to assess changes within groups over follow-up time. A two-

tailed p value of <0.05 was regarded as statistically significant. Multivariable unconditional

logistic regression analysis was performed for risk analyses with response (reduction of office

SBP 10 mmHg and reduction of SBP on ABPM 5mmHg at 6 months) as outcome variable.

All statistical analyses were performed with SPSS statistical software (version 15.0, SPSS Inc.,

Chicago, Illinois).

Results

Patient characteristics of the entire patient population (true resistant and pseudo-resistant) are

considered at target when daytime and nighttime values were <135/85 and <1200/7/7/7000 mmmmmHgHgHg, ,

espectively. The RDN procedure was performed as previously described.13

Sttatatatisisistititicacaalll anananalysysysiisis

DDattata are preseentntededed aass memeeananan ±±± ssstatandndndaararddd dddeviaaatiion ((S(SDD) uunnlnleesss otothhherrwrwisiseee ssppececcifififieied.d. CCComomompaaaririsosonnns

beetwtwtweeeeeenn grgrgrouououpsps wweerere e pepeerfrfoormmemeddd usususiniing g thhhee e PPPearararsososonn cchii-i sqsqsquuauareee tttesesst fofoforr cccattetegogooririicacac l l vavavariaabablleless aaanddd

he Wilcoxonn rrranana k k k susus m m m tet ststst ooor r a a a papap iririrededd ttt-t-ttesesest t t fofofor r cococontntntininuououoususus vvvararariaiaiabllleseses wwwhhhererere ee apappprprpropopopriririata e. Linear


Dow

nloaded from



6

depicted in Table 1. Patients mean age was 62.7 ± 10.8 years, 64% were male, with a mean body

mass index of 30.4 ± 5.6 kg/m2. Type 2 diabetes was diagnosed in 135 patients (39%). Diagnosis

was confirmed as recommended by the American Diabetes Association.21 Coronary artery

disease was prevalent in 83 patients (24%). Patients were treated with 5.2 ± 1.6 antihypertensive

drugs on average (Table 1). True resistant hypertensive patients were less often treated with

beta-blockers compared to pseudo-resistant (75% vs. 93%; p=0.008). Despite antihypertensive

drug treatment, baseline SBP, DBP and PP was 170.7 ± 22.1 mmHg, 91.3 ± 15.2 mmHg and

79.3 ± 18.7 mmHg, respectively, with a heart rate of 70.2 ± 13.6 beats per minute (bpm). Office

and 24-hour mean SBP at baseline was 172.2 ± 22 and 154 ± 16.2 mmHg in true resistant

hypertension and 161.2 ± 20.3 and 121.1 ± 19.6 mmHg in pseudo-resistant hypertension,

respectively. Except for the use of beta-blockers, SBP and APBM values, the baseline

characteristics between true treatment-resistant and pseudo-resistant patients were well matched

regarding their baseline characteristics (Table 1 and 2).

Office-based BP at 3, 6 and 12 months were significantly reduced in the overall cohort:

SBP by 21.5/23.7/27.3 mmHg, DBP by 8.9/9.5/11.7 mmHg, and PP by 13.4/14.2/14.9 mmHg

(n=245/236/90; p for all <0.001), respectively. At 3, 6 and 12 month follow-up 24-hour SBP

decreased by 8.4/8.7/9.9 mmHg and DBP by 4.2/4.3/6.6 mmHg (n=245/236/90; p for all

<0.001), respectively. Changes in office SBP and DBP were significantly more pronounced than

changes in 24-hour SBP and DBP (p<0.0001 for SBP and DBP at each time point). While office

BP reduction were comparable between treatment resistant and pseudo-resistant hypertensive

patients (Figure 1), only in patients with true treatment resistance were 24-hour mean SBP and

DBP significantly reduced 3, 6 and 12 months after treatment (SBP: -10.1/-10.2/-11.7 mmHg,

p<0.001 vs. +2.7/+1.2/-4.4 mmHg, p=0.362/0.465/ 0.386; DBP: -4.8/-4.9/-7.4 mmHg, p<0.001

hypertension and 161.2 ± 20.3 and 121.1 ± 19.6 mmHg in pseudo-resistant hypererrtetensnn ioioion,n,n,

espectively. Except for the use of beta-blockers, SBP and APBM values, the baseline

chharararacaccteteteririristststiicics bebeetwtwtween true treatment-resistant ananandd pseudo-resisttanana t papaatititieents were well matched

eegaaardr ing theiir r bbab ssseliliinnne ccchahaharraracctctererisisi ttiticscss ((TTabbbleee 1 aanandd 222).).)

OfOffifificecec -b-baaaseeded BBBP P atat 33, 6 6 ananand d d 1212 mmmononontthths ss wewewereee siiigngngnififificicicananntltlt yyy rereedudud ccceddd ininn tthhehe oooveveveraallll cccohohooortt:t:

SBP by 21.5/5/232323.7.7/2/2/27.77 3 3 3 mmmmmmHgHgHg, DBDBDBP P P bybyy 888.9.99/9/9/9.5.5.5/1/1/ 1.1..777 mmmmmHgHgHg, , ananand d d PPPP bbby y y 131313.4.4.4/1/114.4.4.2/2/2/141414.9.9. mmHg


Dow

nloaded from



7

vs. +0.3/-0.3/-0.2, p=0.757/0.991/0.906). In those patients changes of office SBP correlated

poorly with changes of 24-hour mean SBP, even if this limited correlation achieved statistical

significance (3 months: r=0.198, p<0.001). Even in the subgroup of patients treated with an

aldosterone antagonist (n=78), specifically recommended in patients with resistant hypertension,

RDN significantly lowered office SBP/DBP/PP (-29.0/-11.4/-15.2 mmHg, p for all <0.001) and

24-hour SBP/DBP (-11.9/-7.1 mmHg, p for both <0.001) 6 month after RDN. At 3, 6 and 12

months maximum and minimum 24-hour SBP (-11.7/-10.0/-6.1 mmHg and -6.0/-9.4/-13.1

mmHg, p<0.001 compared to baseline) as well as minimum 24-hour DBP (-3.8/-3.9/-7.6 mmHg,

p<0.001 compared to baseline; n=175/153/48) declined. In patients with true resistance daytime

and nighttime ABPM were similarly reduced (Figure 2). In the overall cohort the percentage of

non-dippers and reverse dippers was not altered after RDN (baseline: 43.2%/14.7%; 3 months:

43.3%/20.1%, p=0.201; 6 months: 45.4%/12.6%, p=0.105; 12 months: 37.9%/17.2%, p=0.233).

Patients with a SBP reduction of 10 mmHg in office-based measurements and 5

mmHg in ABPM average were subsequently defined as responders to RDN. Although, these

thresholds were not provided by guidelines they represent clinical relevant BP reductions and

were used in the Symplicity trials. Figure 3 depicts rates of responders according to office and

24-hour BP at 3, 6 and 12 months follow-up. Odds ratios (OR) for response at 6 months

according to gender, age >75 years, per 1 kg/m2 increase in body mass index (BMI), diabetes

type 2, GFR >60 ml/min/1.73 m2, number of antihypertensive >median, treatment with

aldosterone antagonists, treatment with central sympatholytics, office SBP >median, office DBP

>median, office PP >median, ABPM average >median, and dipping pattern are shown in Table

3, indicating that RDN was equally effective in terms of blood pressure lowering in all of the

analyzed subgroups. After adjusting for covariates as age, sex, body mass index, diabetes, and

and nighttime ABPM were similarly reduced (Figure 2). In the overall cohort thehee pppere cececentntntagagage e e oof

non-dippers and reverse dippers was not altered after RDN (baseline: 43.2%/14.7%; 3 months:

433.3.33%/%/%/202020.1.11%,%% pp=0=0=0.2.201; 6 months: 45.4%/12.6%,%,% pp==0.105; 12 mooontn hss:: 33737.9%/17.2%, p=0.233).

Patientsts wwwiitth h aa a SBSBBPPP rreredduductcttioioionn ofof 1000 mmmmHHHggg innn oooffffiiccee-e-babaaseeed d memeeaassururremememenentststs aaandndnd 555

mmmmmHgHgHg iinn ABABABPMPMM aaaveverrraggege wweerere e sususubsbsbseqeqqueueentntntlylyly dddeeefifiinenened d aasa rrresesespopopondndnderersss totot RRDNDNDN.. AAlAlththhouououghghh,, ththheseseee

hresholds wwererere e e nonoot t t prprprovovvidddededed by y y gugug idididelllinini esese ttthehehey y y rerereprprprese enenent t t clclclinininicicicalaa rrreleleleeevavavantntnt BBBPPP rerereduduductctctioi ns and


Dow

nloaded from



8

GFR, office SBP at baseline was identified as a correlate of response at 6 months follow-up (as

continuous variable (per 1 mmHg): OR 1.026, 95% confidence interval (CI) 1.005-1.048,

p=0.017; office SBP >170 mmHg: OR 2.32, 95%-CI 1.09-4.85, p=0.029).

Patients and physicians were instructed not to change antihypertensive medication during

the study period. However, antihypertensive drug regimen was reduced during follow-up in 118

patients (34%), due to confirmed BP levels below respective target BP or the development of

symptoms of hypotension and confirmed low BP. Antihypertensive treatment was increased in

23 patients (7%) who remained above target BP. When excluding those 23 patients, BP effects

remained unchanged: reduction of office SBP by 21.9/23.8/26.9 mmHg and 24-hour SBP by

8.6/8.6/9.7 mmHg at 3, 6, and 12 months, respectively (p<0.001 for all). No differences existed

concerning medication reductions (p=0.524) or increases (p=0.399) between true-resistant and

pseudo-resistant patients. Figure 4 illustrates the distribution of office and daytime BP levels at

baseline pre-procedure and at 3, 6, and 12 months post-procedure.

Discussion

Renal denervation offers a novel and well-tolerated approach to selectively interrupt sympathetic

fibers and effectively reduce systolic and diastolic office BP.11, 12 Recently, concerns have been

raised that RDN might not reduce ABP equally effective.22 The results of the present multi-

center study in more than 300 patients now confirm that RDN significantly reduces office and

24-hour average, daytime and nighttime BP in patients with true-resistant hypertension and

increases the rate of patients controlled to target BP values, both according to office BP and

ABPM. Of note, office BP also declined in pseudo-resistant patients.

Blood pressure varies throughout the circadian period with a prolonged decrease during

8.6/8.6/9.7 mmHg at 3, 6, and 12 months, respectively (p<0.001 for all). No difffefeereencnn esese eeexixixiststs eed

concerning medication reductions (p=0.524) or increases (p=0.399) between true-resistant and

psseueuudododo-r-resesesisisistattantt pppaatatients. Figure 4 illustrates thehee ddiistribution of ofofofficee aaannnd daytime BP levels at

bbaaseeelil ne pre-pprorocecec dudurree aaandndnd aaatt 33,3, 6,6,6, aaandndd 1112 mmomonnthsss pppostt-t-pprproocceededururre..

Discussion


Dow

nloaded from



9

nocturnal sleep.1 Daytime BP is more variable than nighttime BP in terms of different physical

and mental activity and nighttime BP is closely related to sympathetic outflow to the heart and

the muscle vasculature.23 Sympathetic activation has been shown to be a major contributor in the

development and progression of hypertension and represents a potential mechanism for the day-

night BP difference.24 Recently, a close inverse relationship between the degree of sympathetic

activation and the magnitude of the nighttime drop in SBP and DBP has been reported.9 The day-

night BP differences correlated inversely with sympathetic nerve activity (r = -0.76, p<0.0001)

with the highest sympathetic activity observed in patients with reverse dipping.9 The Dublin

Outcome Study included 5292 hypertensive patients and demonstrated that nocturnal BP was an

independent predictor of cardiovascular mortality.25 A 10-mmHg increase in mean nighttime

SBP corresponded to a 21% increase in cardiovascular mortality. The Anglo-Scandinavian

Cardiac Outcome Trial (ASCOT) ABPM substudy has demonstrated that nighttime SBP is

superior compared to office SBP in predicting stroke.26 Herein, RDN significantly reduced both

nighttime SBP by 11.9 mmHg, 10.9 mmHg and 12.6 mmHg (p<0.0001) and daytime SBP by

13.6 mmHg, 10.7 mmHg, and 11.6 mmHg (p<0.0001) at 3, 6 and 12 months, respectively.

However, no clear improvement in dipping status was found after RDN, which might be related

i) to the poor reproducibility of the classification of patients into dippers and non-dippers over

time 27, 28 and ii) to the fact that ABPM was performed as usually done in clinical practice with

fixed time intervals for day and night time periods, which might affect the calculation of

nocturnal dipping.

The office BP reductions were more pronounced than the reduction in ABPM, a plausible

finding which has been consistently demonstrated in antihypertensive drug treatment trial.29 In a

meta-analysis including 44 studies with >5800 patients, the averaged weighted reductions in 24-

ndependent predictor of cardiovascular mortality.25 A 10-mmHg increase in meaeaan nnin ghghghttttttimimime e e

SBP corresponded to a 21% increase in cardiovascular mortality. The Anglo-Scandinavian

CaCardrdrdiaiaiaccc OuOuOutcttcomomeee TTrTrial (ASCOT) ABPM substudududy y hhas demonstratata ed tthahahatt nighttime SBP is

uupeeperir or compaparreeddd too oofffffficicicee e SBSBSBPP ininin pprreedddictininnggg strookkke.26266 HHHererreieiin,n RRRDDNDN sssiggninififificacantntlylyly rrredededuucucededed bbboototh

ninighghghttttttimimimee SBSBSBPP bbyby 111.1.999 mmmmmHgHgHg, 101010.9.9.9 mmmmHmHmHggg annnd d d 1112.66. mmmmHmHmHg g (p(p(p<<<0.0000000011) anand dd dadadaytytytimimime SBSBSBP P bbyby

13.6 mmHg,g,, 1110.0.0 77 mmmmmmHgHgH , ananand dd 111111.6.6. mmmmHmHmHg g g (p(p(p<0<0<0.0.000000001)1 atatat 333,,, 6 66 ananand dd 121212 mmmonononththths,s rrresesespepepectctctivi ely.


Dow

nloaded from



10

hour SBP or DBP were 36.5% and 36.8% less than the reduction in the office based values.29

The differences between office BP and 24-hour BP reductions found herein might be partially

influenced by other factors, including a possible regression to the mean of office BP readings

over repeated visits, a phenomenon which by definition cannot affect mean ABP. Furthermore, it

can be hypothesized that the disparity might be partially mediated by a suppression of the white-

coat effect, frequently encountered in resistant hypertension and associated with increased

sympathetic activity.30 However, the differences between the entire population and the group of

patients with true resistant hypertension were comparable, indicating that this cannot only be

attributed to the inclusion of patients with pseudo-resistant hypertension whose ABPM values

after RDN remain unchanged.

The ASPIRANT (Addition of Spironolactone in Patients With Resistant Arterial

Hypertension) trial 31 demonstrated in patients treated with a mean of 4.5 antihypertensive drugs

a reduction of daytime BP by 5.4 mmHg (p=0.024), nighttime by 8.6 mmHg (p=0.011) and 24-h

SBP by 9.8 mmHg (p=0.004) without significantly influencing DBP by addition of 25 mg

spironolactone once daily. However, the different effects of spironolactone on BP in the

ASPIRANT trial and RDN herein has to be interpreted in view of the different baseline BP

values (office BP: 154/92 vs. 171/91 mmHg, 24-hour ABP: 141/80 vs. 150/85 mmHg, day-time

ABP: 142/82 vs. 154/88, and night-time ABP: 136/77 vs. 141/78 mmHg). Despite the fact that

the patients analyzed herein were intensively treated (mean 5.2 ± 1.6 antihypertensive drugs),

RDN was more effective in lowering 24-hour BP on top of concomitant antihypertensive

medication, even in the subgroup of patients (n=78) who were already treated with

spironolactone (mean 24-hour BP changes 6 months after RDN: -11.9/-7.1 mmHg, p for both

<0.001). Maximum daytime SBP has been shown to predict risk of stroke and coronary events,

after RDN remain unchanged.

The ASPIRANT (Addition of Spironolactone in Patients With Resistant Arterial

HyHyypepepertrtrtenensisisiononon) trriaiaialll 331 demonstrated in patients trrreaee tted with a meaan nn off 444 5.5.5 antihypertensive drugs

a reeedduction off dddaaaytttimemee BBBPPP bybyby 555.4.4 mmmmHmHmHggg (p=0=0=0.02444)),, niiighghghttttimimime e bbyy 88.66 mmmmHmHmHgg g ((p(p=0=00.00011111)) anananddd 24244-h

SBSBBPPP bybyby 99.8.88 mmmmHmHHg g g (p(pp=0=0=0.0.004044))) wiwiwithththouoout t sisigngngnififificcananantltlly ini ffflueueuenncncinnng gg DBDBDBP P P bybyby aaadddddititi ioioion n ofofof 2255 mmgmg

pironolactonenee oooncncnce e e dadadailili y.y. HHHowowowevevevererr,, thhheee didid ffffffererereeentntnt eeeffffffecectststs ooof f f spspspiririronono olololacacactototonenene oon n n BPBPBP iiin n n tht e


Dow

nloaded from



11

particularly after adjustment for mean daytime SBP.32 At 3, 6, and 12 months follow-up, RDN

significantly reduced maximum SBP. Both the office and 24-hour BP reductions and the

improvement in control rates after RDN found herein, may have relevant implications for

cardiovascular morbidity and mortality in patients at risk.

Although it was not mandatory to exclude pseudo-resistant hypertension according to the

Symplicity protocol,13, 14 the percentage was rather small (approx. 12%). Not surprisingly, in

patients with pseudo-resistant hypertension office BP was significantly reduced, while ABPM

was not influenced following RDN. Our findings are in line with recent recommendation of

several national 33 and international societies (including the European Society of Cardiology 34

and the European Society of Hypertension 35), aimed at avoiding to treat patients with RDN if

only office BP but not ABP is elevated. However, it has been shown that pseudo-resistant

hypertension is a risk indicator of sustained hypertension and is associated with an increased risk

for cardiovascular endpoints, including cardiovascular death, stroke and hypertensive organ

damage.36, 37 Therefore, further investigations are deserved to assess the effects of office BP

reductions by RDN on cardiovascular morbidity, mortality and the development of sustained

hypertension in patients with elevated clinic and normal 24-hour BP.

Response to RDN has been defined as a reduction in office SBP 10 mmHg six months

after treatment. In order to avoid invasive treatment by RDN in patients with low probability of

BP lowering afterwards, identification of correlates of response are essential. In different

subgroups, according to patients’ baseline characteristics, RDN was similarly effective in terms

of blood pressure reductions. Office SBP at baseline was the only correlate of response identified

herein (per 1 mmHg OR 1.026, 95%-CI 1.005-1.048, p=0.017). Of note, current medication with

spironolactone or central sympathetic agents were no correlates.

and the European Society of Hypertension 35), aimed at avoiding to treat patientsts wwititi hh h RDRDRDN N N ifiif

only office BP but not ABP is elevated. However, it has been shown that pseudo-resistant

hyhypepepertrtrteenensisisionono is aa a rririsks indicator of sustained hypepeerrtr eeension and is asasssociciatatateeed with an increased risk

ffoor cac rdiovascculullarara endndndpoooininintststs, iininclcludududiningg ccardddiooovassccuuularr r ddedeatatth,, sstrtrrokokkee anannd hyhyypepepertrtenennsisisivveve ooorgrgganan

dadamamamagegege..36,6, 37377 TTheheereeefoforrere, fufurtr hheher r inininveveveststigiggatatatioioionsnsn aaarere ddeeseeervvvededed to oo asasa sesessssss tthhhe eefffffeecectststs ooff f oofoffiiccece BBPPP

eductions by y y RDRDR N N N ononon cccarrdidid ovovo asasascucuc lalalar momomorbrbrbidididititity,y,y, momomortr alallititi y y y ananand d d thththe dededevevevelololopmpmpmenenent t t ofofof sssusuu tained


Dow

nloaded from



12

Our study might have some limitations. Despite the advantages of ABPM, it is not

generally used in prospective trials investigating cardiovascular protection by antihypertensive

treatments. Actually there is not a single prospective study relating BP changes by ABPM to

future cardiovascular outcome, which might be due to difficulties of the procedure (time

consumption, repeated device checking, data heterogeneity, costs, etc.).29 It can be speculated

that such a profound reduction of BP after RDN might have increased patient’s exercise capacity

and daily physical workload and thereby also increased ABP, especially during daytime, which

might explain the similar BP reductions during daytime and nighttime. Although, preliminary

data suggest that RDN reduces BP variability,38 assessment of BP variability was not part of the

study protocol. As the study was mainly focused on the BP changes after 3 or 6 months, the

number of patients completing 12-month follow-up is lower compared to the other time points.

Therefore, the group of patients with 12-month follow-up should be regarded as a subgroup,

illustrating that the effects of RDN on BP are sustained over a longer time period. Changes in

antihypertensive drug treatment might also have influenced ABP measurements. During the

study period antihypertensive treatment was reduced in 24.6% (85 patients), due to symptomatic

hypotension with SBP <120 mmHg, and increased in 4.6% (16 patients, all non-responders).

Even after censoring for post-procedural medication changes, no significant differences were

found, making a relevant influence of treatment intensification unlikely.

Conclusions

Renal denervation reduces office, 24-hour, daytime, nighttime, maximum and minimum BP in

patients with true-treatment resistant hypertension on top of background antihypertensive

medication. In the largest cohort of patients analyzed so far, RDN was equally effective in terms

tudy protocol. As the study was mainly focused on the BP changes after 3 or 6 mmmononnthhhs,s,s, ttthehehe

number of patients completing 12-month follow-up is lower compared to the other time points.

Thherererefefefoorore,ee, tttheheh ggrororouupup of patients with 12-month fofofollloow-up shouldd bbbe reregagagardr ed as a subgroup,

lllluusststrating thaatt ththt eee efefffeff ctctctss s ofofof RRRDNDNN ooonn BBPP arrre sustttaaiineddd ovoveeer aa lloonongeger titit mmeme pppererrioiod.d.d CCChahah ngnggeses iiin n

anntititihyhyhypepepertrtenenensissiveve ddrurur g gg trreaeae tmtmmenene ttt mimimighgght t alallsososo hhhaaavevev iiinfffluluenenencececeddd ABABABPPP mememeasassurrrememmenenentstst .. DuDuDurinngng tthehee

tudy periodd aaantntntihihhypypypererrteteenssivivive e e trrreaeaeatmtmmenenntt t wawawass s rereredududuceceed d d inin 2224.4.4.6%6%6% (((8588 pppaaatitit enenentststs),),) dddueueue tttooo sysysymptomaticcc


Dow

nloaded from



13

of BP reduction in different subgroups. Additional trials with longer-term follow-up are needed

to investigate the impact of these alterations on cardiovascular outcome in patients with resistant

hypertension.

Funding Sources: The Symplicity HTN1 and HTN2 were sponsored by Medtronic/Ardian Inc.

Conflict of Interest Disclosures: FM, CU, and MB are supported by the Ministry of Science

and Economy of the Saarland. FM is supported by the Deutsche Hochdruckliga and Deutsche

Gesellschaft für Kardiologie. FM, CU and MB are supported by the Deutsche

Forschungsgemeinschaft (KFO 196). MS is supported by an NHMRC Senior Research

Fellowship. PAS was an employee of Medtronic Ardian Inc. All authors received scientific

support and speaker honorarium from Medtronic Ardian Inc.

References: 1. Pickering TG, Shimbo D, Haas D. Ambulatory blood-pressure monitoring. N Engl J Med. 2006;354:2368-2374. 2. Ohkubo T, Imai Y, Tsuji I, Nagai K, Watanabe N, Minami N, Itoh O, Bando T, Sakuma M, Fukao A, Satoh H, Hisamichi S, Abe K. Prediction of mortality by ambulatory blood pressure monitoring versus screening blood pressure measurements: A pilot study in ohasama. JHypertens. 1997;15:357-364.

3. Fagard RH, Celis H, Thijs L, Staessen JA, Clement DL, De Buyzere ML, De Bacquer DA. Daytime and nighttime blood pressure as predictors of death and cause-specific cardiovascular events in hypertension. Hypertension. 2008;51:55-61. 4. Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, Grassi G, Heagerty AM, Kjeldsen SE, Laurent S, Narkiewicz K, Ruilope L, Rynkiewicz A, Schmieder RE, Boudier HA, Zanchetti A, Vahanian A, Camm J, De Caterina R, Dean V, Dickstein K, Filippatos G, Funck-Brentano C, Hellemans I, Kristensen SD, McGregor K, Sechtem U, Silber S, Tendera M, Widimsky P, Zamorano JL, Erdine S, Kiowski W, Agabiti-Rosei E, Ambrosioni E, Lindholm LH, Viigimaa M, Adamopoulos S, Bertomeu V, Clement D, Farsang C, Gaita D, Lip G, Mallion JM, Manolis AJ, Nilsson PM, O'Brien E, Ponikowski P, Redon J, Ruschitzka F, Tamargo J, van Zwieten P, Waeber B, Williams B. 2007 guidelines for the management of arterial hypertension: The task force for the management of arterial hypertension of the european society of hypertension (esh) and of the european society of cardiology (esc). J Hypertens. 2007;25:1105-1187.

Fellowship. PAS was an employee of Medtronic Ardian Inc. All authors receivedd sscicicienentitifificc

upport and speaker honorarium from Medtronic Ardian Inc.

Refeferererencncnceseses::

1.1.. PPPicickeringg TTTG,G,G, SSShihimbmbmbooo D,D,D HHHaaaaaas ss D.D.D AAAmbmbmbulululattatororyy bblooood-d-d-prprpresesessusuurerer mmmonononitititoorinng.g.g. N N N EnEnEnglglgl JJJ MMMededed. 2002 00606;354:2368-2322374.

2.2 OOOhkhkhkubububooo T,TT, IImamamaii i Y,Y,Y TTTsususujij II,, NaNaNaggagaii K,K WWWaatatanananabababeee NNN,, MiMiMinananamimimi NNN, ItItItohohoh OOO, BaBaB ndndndooo T,T,T SSakakkumumumaa a M,MMFuFuFukakakaooo AAA, SSSatatatohohoh HHH, HiHiHisasasamimimichchchiii SSS, AAAbebebe KKK. PrPrPredededicicictititiononon ooofff momomortrtrtalalalititityyy bybyby aaambmbmbulululatatatorororyyy blblblooooooddd prprpresesessususurerere monitoringg vvvererersusususss scsccrerereenene innng g g bblb oooodd d prppresesssussureree mememeasasa ururrememmenenntsts:: AAA pipipillol t tt stststudududyy y ininin oohahahasasaamamama. J


Dow

nloaded from



14

5. Mancia G, Parati G. Ambulatory blood pressure monitoring and organ damage. Hypertension. 2000;36:894-900. 6. Mancia G, Zanchetti A, Agabiti-Rosei E, Benemio G, De Cesaris R, Fogari R, Pessina A, Porcellati C, Rappelli A, Salvetti A, Trimarco B. Ambulatory blood pressure is superior to clinic blood pressure in predicting treatment-induced regression of left ventricular hypertrophy. Sample study group. Study on ambulatory monitoring of blood pressure and lisinopril evaluation. Circulation. 1997;95:1464-1470. 7. Jula A, Puukka P, Karanko H. Multiple clinic and home blood pressure measurements versus ambulatory blood pressure monitoring. Hypertension. 1999;34:261-266. 8. Metoki H, Ohkubo T, Kikuya M, Asayama K, Obara T, Hashimoto J, Totsune K, Hoshi H, Satoh H, Imai Y. Prognostic significance for stroke of a morning pressor surge and a nocturnal blood pressure decline: The ohasama study. Hypertension. 2006;47:149-154.

9. Grassi G, Seravalle G, Quarti-Trevano F, Dell'Oro R, Bombelli M, Cuspidi C, Facchetti R, Bolla G, Mancia G. Adrenergic, metabolic, and reflex abnormalities in reverse and extreme dipper hypertensives. Hypertension. 2008;52:925-931.

10. Krum H, Schlaich M, Whitbourn R, Sobotka PA, Sadowski J, Bartus K, Kapelak B, Walton A, Sievert H, Thambar S, Abraham WT, Esler M. Catheter-based renal sympathetic denervation for resistant hypertension: A multicentre safety and proof-of-principle cohort study. Lancet. 2009;373:1275-1281.

11. Krum H, Sobotka P, Mahfoud F, Böhm M, Esler M, Schlaich M. Device-based antihypertensive therapy: Therapeutic modulation of the autonomic nervous system. Circulation. 2011;123:209-215. 12. Schlaich MP, Sobotka PA, Krum H, Lambert E, Esler MD. Renal sympathetic-nerve ablation for uncontrolled hypertension. N Engl J Med. 2009;361:932-934. 13. Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE, Böhm M. Renal sympathetic denervation in patients with treatment-resistant hypertension (the symplicity htn-2 trial): A randomised controlled trial. Lancet. 2010;376:1903-1909.

14. Krum H, Barman N, Schlaich M, Sobotka P, Esler M, Mahfoud F, Böhm M, Dunlap M. Catheter-based renal sympathetic denervation for resistant hypertension: Durability of blood pressure reduction out to 24 months. Hypertension. 2011;57:911-917.

15. Brandt MC, Mahfoud F, Reda S, Schirmer SH, Erdmann E, Böhm M, Hoppe UC. Renal sympathetic denervation reduces left ventricular hypertrophy and improves cardiac function in patients with resistant hypertension. J Am Coll Cardiol. 2012;59:901-909.

16. Mahfoud F, Schlaich M, Kindermann I, Ukena C, Cremers B, Brandt MC, Hoppe UC, Vonend O, Rump LC, Sobotka PA, Krum H, Esler M, Böhm M. Effect of renal sympathetic

Bolla G, Mancia G. Adrenergic, metabolic, and reflex abnormalities in reverse andnd eeextxtrerememe dipper hypertensives. Hypertension. 2008;52:925-931.

10. Krum H, Schlaich M, Whitbourn R, Sobotka PA, Sadowski J, Bartus K, Kapelak B, Walton A, Sievert H,, Thambar S, Abraham WT, Esler M. Catheter-based renal sysympathetic denervation foor r rerresisisi tststananant t t hhhypepeertrtrtene sion: A multicentre safety aaandndnd proof-of-prinncicc ple e cococohoh rt study. Lancet. 2020009099;3373:112727275--121228181..

1111. KKrK um HH, , SoS bbobottka P,P, MMaahahffofoudud FFF,, BBöBöhhm MMM, Esssleerer MMM, , ScScSchlhllaicchh MM. DDeDeviviccce--bbasa eddd anntititihyhyhypepepertrtenenensissiveve thheheraraapypyy:: ThThheere apapapeueueuttitic c momomodududulaaatititiononn ooof f tththeee auauautotoononon mimimiccc neneervrvouous ss sysyyststememem. CCCircrccululaaatiioonn201111;1;12323:2:2090 -2-2155.

1212 ScSchlhlaiaichch MMPP SSobobototkaka PPAA KKrurumm HH LLamambebertrt EE EEslslerer MMDD RRenenalal ssymympapaththeteticic n-nererveve aablblatatioionnn


Dow

nloaded from



15

denervation on glucose metabolism in patients with resistant hypertension: A pilot study. Circulation. 2011;123:1940-1946.

17. Mahfoud F, Cremers B, Janker J, Link B, Vonend O, Ukena C, Linz D, Schmieder R, Rump LC, Kindermann I, Sobotka PA, Krum H, Scheller B, Schlaich M, Laufs U, Böhm M. Renal hemodynamics and renal function after catheter-based renal sympathetic denervation in patients with resistant hypertension. Hypertension. 2012;60:419-424. 18. Ukena C, Mahfoud F, Kindermann I, Barth C, Lenski M, Kindermann M, Brandt MC, Hoppe UC, Krum H, Esler M, Sobotka PA, Böhm M. Cardiorespiratory response to exercise after renal sympathetic denervation in patients with resistant hypertension. J Am Coll Cardiol. 2011;58:1176-1182.

19. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL, Jr., Jones DW, Materson BJ, Oparil S, Wright JT, Jr., Roccella EJ. The seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure: The jnc 7 report. JAMA. 2003;289:2560-2572. 20. de la Sierra A, Segura J, Banegas JR, Gorostidi M, de la Cruz JJ, Armario P, Oliveras A, Ruilope LM. Clinical features of 8295 patients with resistant hypertension classified on the basis of ambulatory blood pressure monitoring. Hypertension. 2011;57:898-902. 21. International expert committee report on the role of the a1c assay in the diagnosis of diabetes. Diabetes Care. 2009;32:1327-1334. 22. Petidis K, Anyfanti P, Doumas M. Renal sympathetic denervation: Renal function concerns. Hypertension. 2011;58:e19. 23. Sayk F, Becker C, Teckentrup C, Fehm HL, Struck J, Wellhoener JP, Dodt C. To dip or not to dip: On the physiology of blood pressure decrease during nocturnal sleep in healthy humans. Hypertension. 2007;49:1070-1076. 24. Sobotka PA, Mahfoud F, Schlaich MP, Hoppe UC, Böhm M, Krum H. Sympatho-renal axis in chronic disease. Clin Res Cardiol. 2011;100:1049-1057. 25. Dolan E, Stanton A, Thijs L, Hinedi K, Atkins N, McClory S, Den Hond E, McCormack P, Staessen JA, O'Brien E. Superiority of ambulatory over clinic blood pressure measurement in predicting mortality: The dublin outcome study. Hypertension. 2005;46:156-161. 26. Dolan E, Stanton AV, Thom S, Caulfield M, Atkins N, McInnes G, Collier D, Dicker P, O'Brien E. Ambulatory blood pressure monitoring predicts cardiovascular events in treated hypertensive patients--an anglo-scandinavian cardiac outcomes trial substudy. J Hypertens. 2009;27:876-885.

27. Omboni S, Parati G, Palatini P, Vanasia A, Muiesan ML, Cuspidi C, Mancia G. Reproducibility and clinical value of nocturnal hypotension: Prospective evidence from the

20. de la Sierra A, Segura J, Banegas JR, Gorostidi M, de la Cruz JJ, Armario P,P, OOOlililiveeerararasss A,A,A, Ruilope LM. Clinical features of 8295 patients with resistant hypef rtension classififieieieddd ononn ttthehehe bbbasasasisissof ambulatory blood pressure monitoring. Hypertension. 2011;57:898-902.

211. . InInInteteternrnatatatioioional l exexexppert committee report on thee rrrolole of the a1c aasssss ayy iiin n n tththe diagnosis of diabetesDiDiDiababbetes CCararre. 202000909;3;32:2:2 1313132727-1-113333334.4.

22222. PPeP tidis K,K,, Anynynyfanntti PP, DDDououumamas M.M.M RRRenaal sssymmppaatatheheetititiccc dedd nnnervvvaattion:: RRReennnall fufuncttioonon cooonceeernnns. HyHyypepepertrtrtenensisiiononon.. 20200111;5;588:ee1e19.9

23. Sayk F, BeBeeckckc ererer CCC,, , TeTT ckckkenenentrrrupupup CCC,, FeFeFehmhmhm HHHL,L,L SSStrtrt uuuckck JJJ,, WeWeWellllllhohohoennnererer JJJP,P,P, DDDododdt tt C.C.C. TTTooo dip or not oo ddipip:: OnOn tthehe pphyhysisiolologogyy ofof bbloloodod ppreressssururee ddececrereasasee duduriringng nnococtuturnrnalal sslleeeepp inin hheaealtlthyhy hhumumananss


Dow

nloaded from



16

sample study. Study on ambulatory monitoring of pressure and lisinopril evaluation. JHypertens. 1998;16:733-738.

28. Fedecostante M, Barbatelli P, Guerra F, Espinosa E, Dessi-Fulgheri P, Sarzani R. Summer does not always mean lower: Seasonality of 24 h, daytime, and night-time blood pressure. JHypertens. 2012;30:1392-1398. 29. Mancia G, Parati G. Office compared with ambulatory blood pressure in assessing response to antihypertensive treatment: A meta-analysis. J Hypertens. 2004;22:435-445. 30. Doumas M, Anyfanti P, Bakris G. Should ambulatory blood pressure monitoring be mandatory for future studies in resistant hypertension: A perspective. J Hypertens. 2012;30:874-876. 31. Vaclavik J, Sedlak R, Plachy M, Navratil K, Plasek J, Jarkovsky J, Vaclavik T, Husar R, Kocianova E, Taborsky M. Addition of spironolactone in patients with resistant arterial hypertension (aspirant): A randomized, double-blind, placebo-controlled trial. Hypertension. 2011;57:1069-1075. 32. Rothwell PM, Howard SC, Dolan E, O'Brien E, Dobson JE, Dahlof B, Sever PS, Poulter NR. Prognostic significance of visit-to-visit variability, maximum systolic blood pressure, and episodic hypertension. Lancet. 2010;375:895-905. 33. Mahfoud F, Vonend O, Bruck H, Clasen W, Eckert S, Frye B, Haller H, Hausberg M, Hoppe UC, Hoyer J, Hahn K, Keller T, Krämer BK, Kreutz R, Potthoff SA, Reinecke H, Schmieder R, Schwenger V, Kintscher U, Böhm M, Rump LC. [expert consensus statement on interventional renal sympathetic denervation for hypertension treatment]. Dtsch Med Wochenschr. 2011;136:2418. 34. Mahfoud F, Lüscher TF, Andersson B, Baumgartner I, Cifkova R, Dimario C, Doevendans P, Fagard R, Fajadet J, Komajda M, Lefevre T, Lotan C, Sievert H, Volpe M, Widimsky P, Wijns W, Williams B, Windecker S, Witkowski A, Zeller T, Böhm M. Expert consensus document from the european society of cardiology on catheter-based renal denervation. Eur Heart J. 2013 In press.

35. Schmieder RE, Redon J, Grassi G, Kjeldsen SE, Mancia G, Narkiewicz K, Parati G, Ruilope L, van de Borne P, Tsioufis C. Esh position paper: Renal denervation - an interventional therapy of resistant hypertension. J Hypertens. 2012;30:837-841. 36. Verdecchia P, Reboldi GP, Angeli F, Schillaci G, Schwartz JE, Pickering TG, Imai Y, Ohkubo T, Kario K. Short- and long-term incidence of stroke in white-coat hypertension. Hypertension. 2005;45:203-208. 37. Mancia G, Bombelli M, Facchetti R, Madotto F, Quarti-Trevano F, Polo Friz H, Grassi G, Sega R. Long-term risk of sustained hypertension in white-coat or masked hypertension. Hypertension. 2009;54:226-232.

2011;57:1069-1075.

32. Rothwell PM, Howard SC, Dolan E, O'Brien E, Dobson JE, Dahlof B, Severr PPPSSS, PPououo ltltlterrer NNNRRRPrognostic significance of visit-to-visit variability, maximum systolic blood pressure, and episodic hyppertension. Lancet. 2010;375:895-905.

33333. MMaMahfoud d d F,, VVVonono enennd d d O,O,O, BBruruuckckck HH,,, ClClasasenen WW,, EEcEckkertt SSS,,, FrFrF yee BBB,, HaHallllererer H, , HaHaHausususbebergrgg MMM, , HoHoHoppp eUCUC, , Hoyer J, HHaaha nnn KK,K, KKKelelelllelerrr TT,T, KKKräräämmeerr BKKK, KKKreuuttzz RRR,,, PoPotttt hhohofffff SSA,A, RRReiineneckckckee H,H, SSSchchchmimimiedeedereer RRR,SScSchwhwwenger V,V,, KKKininntschhherrr UU,, BöBöhmm MMM,, RuRumppp LLLC. [eeexpxpererert t t cocoonnsennnsuuus staaateememeenentt ono iiintnterervvevenntiooonaaaleenananalll sysysympmpmpatatathhehetitic deded nennervrvvatatiooonn n fofoforrr hyhyhypepeertrttenenensssiononon ttrerreaatatmmementntnt].].]. DtDtDtscscs hh h MeMeMed d d WWoWochchhenennscschrhrhr..

201111;1;13636:2:2414 8.8.

3434 MaMahfhfououdd FF LLüsüschcherer TTFF AAndndererssssonon BB BaBaumumgagartrtnenerr II CCififkokovava RR DiDimamaririoo CC DDoeoevevendndananss PPP


Dow

nloaded from



17

38. Zuern CS, Rizas KD, Eick C, Stoleriu C, Bunk L, Barthel P, Balletshofer B, Gawaz M, Bauer A. Effects of renal sympathetic denervation on 24-hour blood pressure variability. Front Physiol. 2012;3:134.

Table 1. Patient characteristics

All patients n = 346

True resistant n = 303

Pseudo-resistantn = 43

P*

Demographics Age (years) 62.7 ± 10.8 62.6 ± 10.8 63.3 ± 11 0.641 Male gender 223 (64%) 194 (64%) 29 (67%) 0.661 Body mass index (kg/m²) 30.4 ± 5.6 30.5 ± 5.8 29.6 ± 4.3 0.381 Risk factors and target organ damage Type II diabetes 135 (39%) 124 (41%) 11 (26%) 0.054 CAD 83 (24%) 70 (23%) 13 (30%) 0.305 Cystatin C GFR (mL/min) 79.8 ± 29.2 80.3 ± 30.3 76.4 ± 20.6 0.419 Office blood pressure and heart rate measurements SBP (mmHg) 170.8 ± 22.1 172.2 ± 22 161.2 ± 20.3 0.013 DBP (mmHg) 91.3 ± 15.2 92.1 ± 15.2 87.2 ± 14.4 0.128 PP (mmHg) 79.3 ± 18.7 80.1 ± 18.9 74 ± 16.6 0.057 Heart rate (bpm) 70.2 ± 13.6 70 ± 13.4 71.7 ± 17.2 0.758 Antihypertensive treatment No. of antihypertensive drugs 5.2 ± 1.6 5.2 ± 1.6 5.3 ± 1.3 0.867 ACE-I/ARB 304 (88%) 264 (87%) 40 (93%) 0.268 Beta-blockers 267 (77%) 227 (75%) 40 (93%) 0.008 Calcium channel blockers 261 (75%) 224 (74%) 37 (86%) 0.084 Diuretics 318 (92%) 239 (79%) 38 (88%) 0.145 Aldosterone antagonists 88 (25%) 78 (25%) 10 (24%) 0.726 Central sympatholytics 190 (55%) 167 (55%) 23 (54%) 0.841 Direct vasodilators 100 (29%) 88 (29%) 12 (28%) 0.876 CAD: coronary artery disease. GFR: glomerular filtration rate. SBP: systolic blood pressure. DBP: diastolic blood pressure. PP: pulse pressure (mmHg). ACE-I: Angiotensin-converting enzyme inhibitors. ARB: Angiotensin receptor blockers. *P-values for comparison between true resistant and pseudo-resistant.

Type II diabetes 135 (39%) 124 (41%) 11 (26%)%) 00.0.054 CAD 83 (24%) 70 (23%) 13 (300%%)%) 000.3.3005 Cystatin C GFR (mL/min) 79.8 ± 29.2 80.3 ± 30.3 76.4 ± 20200 66.6 000 44.4191919

Office blood pressure and heart rate measurements SBPP (((mmm HgHg) 170.8 ± 22.1 172.2 ± 22 161 1.2 ± 20.3 0.013DDDBPBPBP ((mmmmmHHHg) ) 91.3 ± 15.2 92.1 ± 15.2 878 .2 ± 14.4 0.128PPPPP (mmHHg)g)g) 797979.3.3.3 ±±± 1118.8.8.77 7 80800.1.1.1 ±±± 118.8.999 744 ±±± 1116.6.6.6 6 6 00.0.0500 7HHHeae rt rate (bbpmmm)) 77070.222 ±±± 133.66 707070 ±±± 133.3.44 7171.7.7 ±± 11777.222 000.77758

AnAnAntitiihyhyh pepertrtenenensisivveve ttrereatattmem nntnt NNo.o. ooofff ananantitihyhypepepertrtrtenenensisisiveveve ddruugggsss 5.5 22 ±±± 111.6 6 6 555.222 ±±± 11.1.66 5.5 333 ±±± 1.11 333 0.00 86868677AAACECECE II-I/A/A/ARBRBRB 303030444 (8(8(88%8%8%))) 26262644 4 (8(8(87%7%7%) ) ) 404040 (((939393%)%)%) 000 22.2686868BBeteta-a-blblocockekersrs 262677 (7(77%7%)) 222277 (7(75%5%)) 4040 ((9393%)%) 00 0.008088


Dow

nloaded from



18

Table 2. ABPM parameters

All patients True resistant Pseudo-resistant P*Baseline n = 346 n = 303 n = 43 Mean SBP 149.9 ± 19.9 154 ± 16.2 121.1 ± 19.6 <0.0001 Mean DBP 84.9 ± 13.1 86.5 ± 12.8 73.6 ± 8.6 <0.0001 Daytime SBP 153.9 ± 18.7 157.7 ± 16.9 129.9 ± 8.7 <0.0001 Daytime DBP 87.8 ± 13.7 89.5 ± 13.6 76.9 ± 8.7 <0.0001 Nighttime SBP 141.3 ± 22.9 145.6 ± 21.2 113.9 ± 11.4 <0.0001 Nighttime DBP 77.6 ± 14.3 79.7 ± 14.1 64.6 ± 7 <0.0001 Non-dippers 165 (55%) 150 (58%) 15 (38%) 0.0072 Maximum SBP 191.3 ± 29.1 195.3 ± 28.4 166.7 ± 20.3 <0.0001 Maximum DBP 113.6 ± 23.4 115.7 ± 24 101.1 ± 14.4 <0.0001 Minimum SBP 111.3 ± 20 115 ± 18.8 89.3 ± 11.8 <0.0001 Minimum DBP 57.6 ± 12.4 59.2 ± 12.3 48.5 ± 8.7 <0.0001 3 months n = 245 n = 213 n = 32 Mean SBP 141.9 ± 19.2 144.3 ± 18.8 126.2 ± 13.5 <0.0001 Mean DBP 80 ± 13.2 81 ± 13.3 73.3 ± 10.2 <0.0001 Daytime SBP 141.8 ± 23.8 144.1 ± 24.3 127.3 ± 13.6 <0.0001 Daytime DBP 85.6 ± 19.1 86.7 ± 19.6 78.2 ± 13.4 <0.0001 Nighttime SBP 132 ± 24 134.5 ± 24.1 116.1 ± 15.1 <0.0001 Nighttime DBP 73.5 ± 13.4 74.7 ± 13.5 65.8 ± 10.1 <0.0001 6 months n = 236 n = 206 n = 30 Mean SBP 141.9 ± 17.4 144.2 ± 17 125.9 ± 10.3 <0.0001 Mean DBP 80.6 ± 12.8 81.6 ± 12.9 73.1 ± 9.1 <0.0001 Daytime SBP 144.6 ± 17.8 146.9 ± 17.5 130.1 ± 11.7 <0.0001 Daytime DBP 82.4 ± 13.7 83.4 ± 13.8 76.3 ± 11 <0.0001 Nighttime SBP 133.5 ± 19.9 135.5 ± 19.8 121.2 ± 15.8 <0.0001 Nighttime DBP 73 ± 13.5 73.9 ± 13.9 67.6 ± 9.9 <0.0001 12 months n = 90 n = 80 n = 10 Mean SBP 140.8 ± 16.3 142 ± 16.1 130.8 ± 15.2 <0.0001 Mean DBP 79.4 ± 10.5 80 ± 10.6 74.5 ± 7.6 <0.0001 Daytime SBP 143.7 ± 15.7 145.2 ± 15.2 134.2 ± 16.1 <0.0001 Daytime DBP 82 ± 10.3 82.8 ± 10.4 77.4 ± 9 <0.0001 Nighttime SBP 130.2 ± 16.8 131.6 ± 16.8 121.6 ± 15.3 <0.0001 Nighttime DBP 71.1 ± 10.5 72 ± 10.9 65.7 ± 5.8 <0.0001 SBP: systolic blood pressure. DBP: diastolic blood pressure. *P-values for comparison of true resistant and pseudo-resistant.

n-dippers 165 (55%) 150 (58%) 15 (38%) 0.0.000 72ximum SBP 191.3 ± 29.1 195.3 ± 28.4 166.7 ± 20.3 <0<0<0.0.000ximum DBP 113.6 ± 23.4 115.7 ± 24 101.1 ± 14.4 <0<0<0.0.00000imum SBP 111.3 ± 20 115 ± 18.8 89.3 ± 11.8 <0<0 0.00000imum DBP 57.6 ± 12.4 59.2 ± 12.3 48.5 ± 8.7 <0.000

nths n = 245 n = 213 n = 32 an SBP P 141.9 ± 19.2 14144.4.3 ± 18.8 12126.6 2 ± 13.5 <0.000an n DBDBDBP P 80 ± 13.2 181 ± 13.3 37373.3. ± 10.2 <0.000titimemm SSSBPBP 141.88 ± ± 232 .88 4141 .4.4 1 ± 2424.3.3 12127.7 3 ± 1313.6.6 <00.0.000ititi eeme DDBP 8585.66.6 ±±± 11199.9.111 8688 7.7. ± 1199.9.6 6 6 78878.2 ±± 1113.3.3.4 4 4 <0<0<0.0.000

hth timemem SBP 1313322 ± ± 42424 331 .4.4 5 ± 242424.1.1 1116.6 11 ± ±± 15151 .1.1 <0<< 00. 00hthh timemem DBP 7377 5.5. ± 113.44 7477 7.7. ± 113.3.3.55 5 5565.8 ±±± 110.0 11 <0<< 00. 00tntnthshh n === 232 6 n n = 020206 6 n === 030

aan n BSBSBPP 4141.1.1 9 ±± 17177.4.4 141 4.4.4 22 ±± ± 7717 2125.5.5 9 9 ±± 1010.3.3.3 <0<< 00.0000an DBDBP P 800.6.6 ±± 112.2.88 818 .6 ±± 112.2.99 733.1.1 ±± 99.1.1 <0< .000000tititimeme SSSBPBPBP 141414444.666 ±±± 171717 88.8 141414666.999 ±±± 171717 55.5 131313000.111 ±±± 111111 77.7 0<0<0 00.0000000time DBP 828282.4 ±±± 1133.3 777 838383.44.4 ±±± 13.3.3 8 88 767676.33.3 ±± 11111 <0.0 0000hthttitime SSBPBP 131333 55 ±± 1919 99 131355 55 ±± 1919 88 121211 22 ±± 1515 88 <0<0 00 00000


Dow

nloaded from



19

Table 3. Correlate of response

Univariable analysis Multivariable analysis* Variable Wald OR 95% CI p Wald OR 95% CI p All patients Male Gender 0.74 1.33 0.-70-2.54 0.388 Age >75 years 0.43 1.47 0.47-4.64 0.51 Per 1 kg/m² increase in BMI 0.66 1.03 0.96-1.09 0.418 Diabetes 0.63 1.30 0.68-2.48 0.428 GFR >60 ml/min/1.73m² 0.31 0.82 0.41-1.65 0.58 >5 antihypertensive drugs (m) 0.69 1.32 0.69-2.51 0.406 Use of an aldosterone antagonist 1.39 1.6 0.73-3.5 0.238 Use of a central sympatholytic 0.98 1.38 0.73-2.61 0.322 Office SBP >170 mmHg (m) 6.62 2.33 1.22-4.44 0.01 7.2 2.59 1.29-5.18 0.007 Office DBP >91 mmHg (m) 0.01 0.98 0.53-1.82 0.943 Office PP >79 mmHg (m) 2.71 1.67 0.90-3.19 0.101 ABPM >151 mmHg (m) 0.33 0.83 0.45-1.55 0.833 Non-/reverse-dipping 0.01 1.03 0.54-1.96 0.934

True resistant hypertension Male Gender 0.01 1.03 0.51-2.09 0.936 Age >75 years 0.57 1.65 0.45-6.07 0.452 Per 1 kg/m² increase in BMI 0.1 1.01 0.95-1.08 0.75 Diabetes 0.01 1.0 0.5-1.99 0.997 GFR >60 ml/min/1.73m² 0.09 0.89 0.43-1.86 0.761 >5 antihypertensive drugs (m) 0.95 1.42 0.7-2.86 0.33 Use of an aldosterone antagonist 1.57 1.73 0.73-4.11 0.211 Use of a central sympatholytic 3.3 1.9 095-3.79 0.07 2.2 1.77 0.83-3.74 0.138 Office SBP >170 mmHg (m) 4.2 2.7 1.03-4.13 0.041 4.79 2.3 1.09-4.85 0.029 Office DBP >91 mmHg (m) 0.88 0.72 0.37-1.42 0.347 Office PP >79 mmHg (m) 0.22 0.70 0.23-2.51 0.64 ABPM >151 mmHg (m) 0.72 0.75 0.38-1.47 0.396 Non-/reverse-dipping 0.75 1.36 0.68-2.75 0.386

Odds ratios for response (office SBP 10 mmHg) at 6 months in all patients and in patients with true resistant hypertension. OR: odds ratio; CI: confidence interval; m: variable was dichotomized according to the median; BMI: body mass index; GFR: glomerular filtration rate; SBP: systolic blood pressure; DBP: diastolic blood pressure; PP: pulse pressure; ABPM: ambulatory blood pressure 24-h average. *Variables entered the multivariate analysis were age, gender, BMI, GFR, diabetes, and variables with p<0.1 in the univariable analysis

>60 ml/min/1.73m 0.31 0.82 0.41 1.65 0.58 ntihypertensive drugs (m) 0.69 1.32 0.69-2.51 0.406 of an aldosterone antagonist 1.39 1.6 0.73-3.5 0.238 of a central sympatholytic 0.98 1.38 0.73-2.61 0.322 ce SBP >170 mmHg (m) 6.62 2.33 1.22-4.44 0.01 7.2 2.59 1.29-5.18 0.0ce DBP >91 mmHg (m) 0.01 0.98 0.53-1.82 0.943 ce PP >7>79 mmm HgHg ((m)) 2.71 1.67 0.0 9090-3.19 0.101 MM >>>151515111 mmmmmmHgHgHg ((m)mm 0.33 0.83 0.00 5454 -1.55 0.833 --/r/rrevee erere sese-dippipi gngng 0.0.0101 11.0.033 0.00 4545 -1.966 0.934 4 rrres ssistatant hyperrtetensnsioioionn

e G nene ded r 0.0 1101 1.03 0.00 1515 -2 00.0999 .00 93936 6 >7>> 5 yey ars 0.575 1.655 0.00 5454 -6.00777 .00 452 2

11 kgkgkg mm/m²² inncrc eaasesee iiin n n MBMBMI 0.0.11 1.1.01011 000 9.95-5 .1.0808 000.7755 etetess 000.0.00111 1.1.1.00 0 00.0.5-5-5-1.1.1 99999 00.0.99999 7 7

6>600 mll/min/1/1.73mm² 0.0 099 00 8.899 0.43-11.886 0.0 767 1 ntihypertensive drdrugugugs s s (m(mm) ) ) 0.0.0.959595 111.4.4.4222 0.0..7-7 2.2.2 8686 00.3.33333 of an aldosterone antagog ini tst 11.57577 11 7.733 00.7373-444.111 0.0 212111


Dow

nloaded from



20

Figure Legends:

Figure 1. Office and 24-hour BP changes 3, 6 and 12 months after renal denervation. SBP:

systolic blood pressure; DBP: diastolic blood pressure. Whiskers indicate 5 and 95 percentile. P-

values are for comparison with baseline values. *p-value are comparison of within group

changes over time using linear mixed-effects models.

Figure 2. Daytime and nighttime BP changes in patients with true-treatment resistant

hypertension at 3-, 6- and 12-months follow-up. SBP: systolic blood pressure; DBP: diastolic

blood pressure. Whiskers indicate 5 and 95 percentile. P-values are for comparison with baseline

values. *p-value are comparison of within group changes over time using linear mixed-effects

models.

Figure 3. Rates of responders in patients with true-treatment resistant hypertension, defined as a

SBP reduction of 10 mmHg in office-based measurements or 5 mmHg in ABPM average at 3

months, 6 months and 12 months follow-up.

Figure 4. Distribution of office and BP levels at baseline pre-procedure and at 3, 6, and 12

months post-procedure in patients with true resistant hypertension.

blood pressure. Whiskers indicate 5 and 95 percentile. P-values are for comparissonoon wwititith h h bababaseses liline

values. *p-value are comparison of within group changes over time using linear mixed-effects

momodededelslsls.

FiFigugugurerere 33.. RRRatatateses ooff f reresspspoonondederrsrs iiinnn papapattitienenntstss wwwiiith hh trtrt uueue--ttrereeatatmemementnt rrresessiiststtananant t hyhyhypepep rtrtrtenennsisiononon, , dedeefiiinenedd d asass a

SBP reductioon n n ofofo 10101 mmmmHmHHg g g innn oooffffficicice---bababasesesed d d memem asasasurururememmenenentstst oor r r 55 mmmmmmHgHgHg iiin nn ABABABPMPMPM aaavev rage at 33


Dow

nloaded from


-80

-60

-40

-20

0

20

40

3M (n=245)

6M (n=236)

12M (n=90)

3M (n=213)

6M (n=206)

12M (n=80)

3M (n=32)

6M (n=30)

12M (n=10)

SBP DBP

BP

chan

ges (

mm

Hg)

p<0.0001

p<0.0001

p<0.0001

p<0.0001

p<0.0001

p<0.0001

p<0.0001

p<0.0001

p<0.0001

p<0.0001

p<0.0001

p<0.0001

p=0.906 p=0.757 p=0.465 p=0.991 p=0.386

p=0.362

-80

-60

-40

-20

0

20

40

BP

chan

ges (

mm

Hg)

3M (n=245)

6M (n=236)

12M (n=90)

3M (n=213)

6M (n=206)

12M (n=80)

3M (n=32)

6M (n=30)

12M (n=10)

SBP DBP

All patients (n=346) True resistant hypertension (n=303)

Pseudo-resistant hypertension (n=43)

Office BP changes

p<0.0001

p<0.0001

p<0.0001

p<0.0001

p<0.0001

p<0.0001

p<0.0001

p<0.0001

p<0.0001

p<0.0001

p<0.0001

p<0.0001

p<0.0001

p<0.0001

p<0.0001

p<0.0001

p<0.0001 p<0.0001

24h-BP changes All patients (n=346) True resistant

hypertension (n=303)Pseudo-resistant

hypertension (n=43)

SBP p<0.0001* DBP p<0.0001*

SBP p<0.0001* DBP p<0.0001*

SBP p<0.0001* DBP p=0.015*

SBP p<0.0001* DBP p<0.0001*

SBP p<0.0001* DBP p<0.0001*

SBP p=0.218* DBP p=0.977*

Figure 1

00

202020

40 40

g)H

g

-800

-60

-40

-20

BP

chan

ges (

3M 3(n=(n=245)

6M(n=236)

12M (n=90)

3M(n=213)

6M6M6(n= 620620 )

12M (n=80)

3M(n= ))32)

M6M6M(n=n=30)30)

12M (n=10)

SBSBPP DBPP

p<0.0001

p<0.0001

p<0.0001

p<0.0001

p<0.0001 p

p<0.0001

p<0.0001

p<0.0001

p<0.0001

p<0.0001

p<0.0001

p<0.0001

p<0.0001

p<0.0001

p<0.0001

p<0.0001

p<0.0001 p<0.0001

24h- PBP chahh ng seellAlA aap tientss n(n( 434=346)6) rurTr e r iesistas nt nt

pyphy trter ens nion n(n=30= ))3)PseP udo rer-r ssistantant pyphy ertens onioi n(n( 43=43)))

SBP pSBP pSB <0.00<0 *01* DBP pDBP pDBP <0.00< 01*

P pSBP pSBP .00<0.0<0.0 01*DBP pDBP p<0 00<0.00< 01*01

SBP pSBP pS =0.21=0=0 *8*DBP ppDBP p=0 97=0.977*7


Dow

nloaded from


3M (n=183)

6M (n=161)

12M (n=54) 3M

(n=183) 6M

(n=161) 12M

(n=54) -80

-60

-40

-20

0

20

40

SBP DBP

BP

chan

ges (

mm

Hg)

Daytime change Nighttime change

p<0.0001

p<0.0001

p<0.0001

p<0.0001

p<0.0001

p<0.0001

p<0.0001

p<0.0001

p<0.0001

p<0.0001

p<0.0001

p<0.0001

SBP p<0.0001* DBP p<0.0001*

SBP p<0.0001* DBP p<0.0001*

Figure 2

-6-6-600

-4000

-2000

0

BPP

ccchahahng

es (m

m H

g)

pp<0.0001

p<0p<0<0.00.00.000101

<0p<0p< .00. 01

p<0p<0p<0.00.00.0 0101

p<0p<0p<0.00.00010101

p<0pp 0.00010

p<0p<0p< .00.00010101

0p<0p<0.00.00.0 01 1

p<0p<0p< .0000.00010101

<0p<p .00.0000100

p<0p .0001

<0<0p< 00.00010


Dow

nloaded from


Reduction of ABP 5 mm Hg Reduction of office SBP 10 mm Hg

0

20

40

60

80

100

Prop

ortio

n (%

)

3M (n=213)

6M(n=206)

12M (n=80)

71.3 73.3 76.7

58.3 65

70

Figure 3

00

2000

40

60

80

Prop

ortio

n (%

)

33MMM (((nnn==222111333)))

666MMM(((nnn==222000666)))

111222MMM (((nnn==888000)))

71.3 73.376.7

58.3 65

70


Dow

nloaded from


Baseline 3M 6M 12M 0

20

40

60

80

100

SBP 140-160 mm Hg

SBP >160 mm Hg

SBP <140 mm Hg

Prop

ortio

n (%

)

Baseline 3M 6M 12M 0

20

40

60

80

100

SBP 130-150 mm Hg

SBP >150 mm Hg

SBP <130 mm Hg

Prop

ortio

n (%

)

Office BP

24h-BP

27

73

33

39

28

27

36

37

31

45

24

56

44

36

46

18

36

46

20

30

49

21

Figure 4

Baseline 3M 6M 12M0

SBP 140-160 mm Hg

SBP >160 mm Hg

BSBPPP <1<1404 mm Hg

6060

80

1000 0

onon((%

)

222444hhh--BBBPPP

27 28 37 24

565656 363 3636 3030


Dow

nloaded from


Erwin Blessing, Paul A. Sobotka, Henry Krum, Markus Schlaich, Murray Esler and Michael BöhmVonend, Joachim Weil, Martin Schmidt, Uta C. Hoppe, Thomas Zeller, Axel Bauer, Christian Ott,

Felix Mahfoud, Christian Ukena, Roland E. Schmieder, Bodo Cremers, Lars C. Rump, OliverResistant Hypertension

Ambulatory Blood Pressure Changes after Renal Sympathetic Denervation in Patients with

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 2013 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation published online June 18, 2013;Circulation.

http://circ.ahajournals.org/content/early/2013/06/18/CIRCULATIONAHA.112.000949World Wide Web at:

The online version of this article, along with updated information and services, is located on the

http://circ.ahajournals.org//subscriptions/

is online at: Circulation Information about subscribing to Subscriptions:

http://www.lww.com/reprints Information about reprints can be found online at: Reprints:

document. Permissions and Rights Question and Answer available in the

Permissions in the middle column of the Web page under Services. Further information about this process isOnce the online version of the published article for which permission is being requested is located, click Request

can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office.Circulation Requests for permissions to reproduce figures, tables, or portions of articles originally published inPermissions:


Dow

nloaded from

http://circ.ahajournals.org/content/early/2013/06/18/CIRCULATIONAHA.112.000949

http://www.ahajournals.org/site/rights/

http://www.lww.com/reprints

http://circ.ahajournals.org//subscriptions/


ambulatory blood pressure changes after renal sympathetic

Documents