The Association of Pediatric Obesity With Nocturnal Non- Dipping on 24-Hour Ambulatory Blood Pressure Monitoring

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1 Originl Article The Assocition of Peditric Obesity With Nocturnl Non- Dipping on 24-Hour Ambultory Blood Pressure Monitoring In R. Mcumber, 1 Noel S. Weiss, 2 Susn M. Hlbch, 1 Corl D. Hnevold, 1 nd Joseph T. Flynn, 1 BACKGROUND Obesity hs been linked with bnorml nocturnl dipping of blood pressure (BP) in dults, which in turn is ssocited with poor crdiovsculr outcomes. There re few dt regrding bnorml dipping sttus in the obese peditric popultion. The gol of this study ws to further describe the reltionship between obesity nd nondipping sttus on mbultory blood pressure monitor (ABPM) in children. METHODS We conducted cross-sectionl study using dtbse of ptients ged 5 21 yers who hd undergone 24-hour ABPM t Settle Children s Hospitl from Jnury 2008 through My Subjects were grouped by body mss index (BMI) into len (BMI 15th 85th percentile) nd obese (BMI >95th percentile) groups. RESULTS Compred to len subjects (n = 161), obese subjects (n = 247) hd prevlence rtio (PR) for non-dipping of 2.15, djusted for rce (95% confidence intervl (CI) = ). Incresing severity of obesity ws not further ssocited with nocturnl non-dipping. Nocturnl non-dipping ws not ssocited with left ventriculr hypertrophy (PR = 1.01, 95% CI = ). CONCLUSIONS These results suggest tht in children, just s in dults, obesity is relted to reltively decresed dipping in nocturnl BP. Keywords: mbultory blood pressure monitor; ABPM; blood pressure; hypertension; nocturnl dipping; obesity; peditrics. doi: /jh/hpv147 The prevlence of hypertension in peditrics is incresing 1 prticulrly in the obese. 2 Obese children with hypertension re likely to remin hypertensive s they rech dulthood 3 nd hypertension hs been shown to hve significnt effects on future crdiovsculr helth 4 s well s development of chronic kidney disese. 5 Twenty-four-hour mbultory blood pressure monitoring (ABPM) hs been immensely helpful in dignosing hypertension in children, llowing physicins to identify white cot hypertension, msked hypertension, nd evlute nocturnl dipping sttus. 6 In dults, obesity is ssocited with nocturnl hypertension nd bnorml dipping sttus on 24-hour ABPM. 7 Nocturnl hypertension specificlly hs been shown to significntly ffect prognosis in dults 8 nd children. 9 In dults, bnorml dipping sttus noted on ABPM hs likewise been independently ssocited with development of chronic kidney disese 10 nd worsening kidney injury, 11 elevted left ventriculr mss nd impired left ventriculr function, 12 nd incresed risk of crdiovsculr disese in generl. 13 There re few dt regrding BP dipping sttus in the obese peditric popultion. The studies tht hve been performed to dte hve either been limited by smll numbers of subjects or were conducted in ptient popultions with significnt medicl conditions such s dibetes. 17 The gol of this study ws to further describe the reltionship between obesity nd non-dipping sttus on ABPM, which my eventully led to better tretments nd prevention methods. METHODS Dt source We conducted cross-sectionl study using dtbse of ptients ged 5 21 yers who hd undergone first-time 24-hour ABPM t Settle Children s Hospitl from Jnury 2008, through My Retrospective dt collection ws pproved by the Institutionl Review Bord t Settle Children s Hospitl. Subject selection/methods Subjects were selected by querying the electronic medicl record to identify ll ptients who hd undergone 24-hour ABPM during the study period. Demogrphic informtion collected included ge, rce, gender, pst medicl history, nd current medictions t time of ABPM study. Exclusion criteri included conditions tht could ffect BP (chronic kidney disese, thyroid disese, congenitl hert disese, history of premturity <34 weeks of gesttion, sleep disordered brething dignosed by no lter thn 90 dys fter ABPM study, etc.), nd medictions tht could ffect BPs Correspondence: In R. Mcumber (inmcumber@gmil.com) Initilly submitted June 5, 2015; dte of first revision June 26, 2015; ccepted for publiction August 1, 2015; online publiction August 26, Division of Nephrology, Settle Children s Hospitl, Settle, Wshington, USA; 2 Deprtment of Epidemiology, University of Wshington, Settle, Wshington, USA. Americn Journl of Hypertension, Ltd All rights reserved. For Permissions, plese emil: journls.permissions@oup.com Americn Journl of Hypertension 29(5) My

2 Mcumber et l. (ntihypertensives, glucocorticoids, immunosuppressnts, stimulnts). All ABPMs were performed using Spcelbs (Issquh, WA) monitor. The monitor ws plced by nursing stff in our office t the time of clinic visit. Approprite cuff size ws determined using guidelines from the 4th report on dignosis, evlution, nd tretment of peditric hypertension. 18 Redings were tken every 20 minutes while wke nd every 30 minutes while sleep. Ptients were sked to keep diry showing sleep nd wke times. The dequcy of the ABPM study ws determined by the interpreting physicin t the time of ABPM evlution ccording to AHA criteri. 6 Subjects were grouped into ctegories bsed on body mss index (BMI): len (15th 85th BMI percentile), overweight (>85th 95th percentile), nd obese ( 95th percentile). 19 The primry outcome ws the prevlence of dequte nocturnl dipping in the len group vs. the obese group. Adequte nocturnl dipping ws defined s decrese in both systolic nd distolic men nocturnl BP of t lest 10% from men systolic nd distolic wke BP. A secondry nlysis ws performed exmining the reltionship between the severity of obesity nd prevlence of non-dipping sttus. Obesity ctegories generted using BMI z-scores, bsed on previous studies 20 : obesity ctegory I (BMI z-score to <2), obesity ctegory II (BMI z-score 2 to <2.5), obesity ctegory III (BMI z-score 2.5). Lstly, we evluted the reltionship between obesity nd the prevlence of isolted nocturnl hypertension or prehypertension, nd the reltionship between nocturnl non-dipping nd the prevlence of left ventriculr hypertrophy. Hypertension ws defined s men systolic or distolic mbultory BP 95th percentile for ge, sex, nd height 21 during either the wke or sleep period. Prehypertension ws defined s men mbultory BP less thn the 95th percentile for ge, sex, nd height, but with BP lod (percentge of individul BP redings >95th percentile) between 25% nd 50%. Elevted men BPs tht met criteri for hypertension or prehypertension but occurred only during sleep hours were designted nocturnl hypertension nd prehypertension, respectively. Left ventriculr hypertrophy ws defined s LV mss indexed to height in meters to the 2.7 power tht is greter thn the 95th percentile for ge nd sex, s defined in 2009 by Khoury et l. 22 strtified nlysis using PR estimtes. A P-vlue of <0.05 ws considered significnt. STATA (Stt, College Sttion, TX) version 13.1 ws used for sttisticl nlysis. RESULTS Generl chrcteristics of subjects A totl of 1,620 ABPMs were completed during the study period; 248 of these were repet ABPMs on n individul subject, thus 1,372 first-time ABPMs were identified. Of these, 98 were of indequte qulity for interprettion. Following ppliction of exclusion criteri, there were 408 subjects included in the primry nlysis, of whom 161 were len nd 247 obese (Figure 1). Ninety subjects in the overweight group were not included in the nlysis s we were interested in compring only obese to len subjects. Distributions were generlly similr for ge nd gender between the 2 groups (Tble 1). There were differences noted in rce, with 49% of subjects in the len group being Cucsin, compred to 36% in the obese group. There were 15% of subjects in the len group clssified s Other, compred to 28% in the obese group. All other rcil bckgrounds were distributed evenly between the 2 groups. Sttisticl nlysis Continuous vribles were expressed s the men ± SD. Differences in mens between continuous outcomes were determined using 2-smple t-tests. Our primry nlysis of the ssocition of obesity with nocturnl non-dipping ws performed using log-binomil regression to clculte prevlence rtio (PR) estimtes nd test-bsed 95% confidence intervls (CIs). Only fctors tht ltered estimtes substntilly (10% or more) were considered to be confounders nd djusted for in our nlysis. Vribles tht were considered for djustment were subject ge, rce, gender, nd dytime BP sttus. Assessment of effect modifiction ws bsed on biologicl plusibility nd cliniclly relevnt differences in PRs cross strt. Secondry nlyses were lso evluted by Figure 1. A totl of 1,620 ABPMs were performed between Jnury 2008 nd My 2014, of which 1,372 were first-time ABPMs. Ninety eight of these were of indequte qulity to be interpretble. Following ppliction of exclusion criteri, 408 first-time ABPMs were eligible for nlysis including 161 in len subjects nd 247 in obese subjects. Ninety overweight subjects were not included. Abbrevitions: ABPM, mbultory blood pressure monitor. 648 Americn Journl of Hypertension 29(5) My 2016

3 Blunted Dipping in Obese Children Tble 1. Chrcteristics of len nd obese subjects Len Obese N = 161 % N = 247 % Rce White Blck Ntive Americn/Alskn Asin Hwiin/Pcific Islnder Other Unknown Gender Mle Femle Age (yers; men ± SD) 14.6 ± ± 2.9 Height (cm; men ± SD) ± ± 16.0 BMI (kg/m 2, men ± SD) 20.8 ± ± 6.4 Abbrevition: BMI, body mss index. Len group defined s 15th-85th BMI percentile, obese group defined s 95th BMI percentile. Tble 2. ABPM findings in len nd obese subjects, djusted for rce Len b Obese b P-vlue Nocturnl Systolic Dip (%) Nocturnl Distolic Dip (%) Len Group Len Group Obese Group Obese Group 24-hour SBP (mm Hg) 123 ± ± hour DBP (mm Hg) 71 ± 7 69 ± Awke SBP (mm Hg) 130 ± ± Awke DBP (mm Hg) 77 ± 8 74 ± 7 <0.001 Asleep SBP (mm Hg) 110 ± ± Asleep DBP (mm Hg) 60 ± 7 60 ± SBP Noct. Dipping (%) 15 ± 5 12 ± 6 <0.001 DBP Noct. Dipping (%) 22 ± 6 19 ± 7 <0.001 Abbrevitions: SBP, systolic blood pressure; DBP, distolic blood pressure. Dt displyed s men ± SD. b Len group defined s 15th 85th BMI percentile, obese group defined s 95th BMI percentile. Prevlence of non-dipping Men wke nd sleep systolic nd distolic BPs nd dipping sttus re shown in Tble 2. The prevlence of hypertension ws 40.3% in the len group nd 43.7% in the obese group, which is not significntly different (PR = 1.14, 95% CI = ). Both systolic nd distolic nocturnl dipping were significntly blunted (Figure 2) in the obese group compred to the len group (P < ). Of the 161 subjects in the len group, 22 were clssified s non-dippers (13.6%) (Tble 3). Of the 247 subjects in the obese group, 85 were clssified s non-dippers (34.4%). The Figure 2. Men nocturnl dipping ws decresed in the obese group compred to the len group. (A) Men systolic dip ws 15.1% ± 4.6% in len subjects compred to 12.4 ± 5.6% in obese subjects (P-vlue < 0.001). (B) Men distolic dip ws 22.2 ± 6.0% in len subjects compred to 18.5 ± 7.0% in obese subjects (P-vlue < 0.001). Tble 3. Prevlence rtio of the ssocition between obesity nd non-dipping Sttus, djusted for rce Non-dipping Yes % No % crude PR of non-dipping ws 2.51 (95% CI = ) in obese subjects compred to len subjects. The PR djusted for rce ws 2.15 (95% CI = ). The PR ws significntly incresed in the obese group for both systolic dipping cses (N = 313, PR = 2.28, 95% CI = ) nd distolic dipping cses (N = 113, PR = 3.35, 95% CI = ). The PR ws not ffected by djustment for dytime BP, ge, or gender of the subjects, lthough there ws slightly higher PR in femles (PR = 2.37, 95% CI = ) compred to mles (PR = 2.08, 95% CI = ), which is presented in Tble 4. PR 95% CI Len Ref Obese Abbrevition: CI, confidence intervl; PR, prevlence rtio. Len group defined s 15th 85th BMI percentile, obese group defined s 95th BMI percentile. Americn Journl of Hypertension 29(5) My

4 Mcumber et l. Tble 4. Prevlence rtio of non-dipping by gender nd ge, djusted for rce Secondry nlyses Obesity ws found to be significntly ssocited with isolted nocturnl hypertension; 44 of 247 subjects in the obese group hd isolted nocturnl hypertension or prehypertension, compred to 12 of 161 subjects in the len group. This resulted in crude PR of 2.37 (95% CI = ). This ws not ffected by djustment for ge, rce, or gender. Incresing severity of obesity ws not significntly ssocited with nocturnl non-dipping sttus. Compred to the reference group of obese ctegory I (BMI z-score 1.65 to <2), subjects in obese ctegory II (BMI z-score 2 to <2.5) hd non-dipping PR of 1.28 (95% CI = ) nd subjects in obese ctegory III (BMI z-score 2.5) hd PR of 1.16 (95% CI = ). Nocturnl dipping sttus ws not found to be significntly ssocited with left ventriculr hypertrophy (LVH). Although there ws crude PR of 1.26 (95% CI = ), this decresed to 1.01 (95% CI = ) when djusted for obesity sttus. DISCUSSION Len non-dippers Obese non-dippers N % N % PR 95% CI By sex Mle Femle By ge (yers) Len group defined s 15th 85th BMI percentile, obese group defined s 95th BMI percentile. In this lrge study of children referred for evlution of suspected hypertension, obesity ws significntly ssocited with non-dipping sttus nd nocturnl hypertension. We did not find significnt ssocition between non-dipping sttus nd incresing severity of obesity, or nocturnl dipping sttus nd the prevlence of LVH. Non-dipping sttus hs been shown to hve significnt effects on helth outcomes. In dults, specificlly, nondipping hs been ssocited with poor crdiovsculr, 12,13 renl, 10,11 nd dibetic outcomes. 23 The dt in the peditric popultion re not s strong. Nocturnl hypertension nd non-dipping hve been ssocited in dolescent dibetics with dibetic nephropthy, 24 LVH, 25 nd incresed crotid intiml-medi thickness. 9 Non-dipping hs lso been ssocited with worsening GFR in children with CKD. 26 There re few vilble dt on the prevlence of dipping sttus in the generl peditric popultion. Previous studies tht hve looked t the ssocition between obesity nd nocturnl dipping hve been much lesser. Frmme et l. found similr ssocition s ours, 14 with totl of 80 subjects (25 in the len group nd 55 in the obese group). Their study, however, found tht tht obesity only hd significnt effect on nocturnl dipping in femles, wheres we sw strong ssocition between obesity nd nocturnl dipping in both genders. A recent 2014 study by Westersthl et l. looked t the prevlence of non-dipping in 76 obese children nd dolescents. 27 Westersthl et l. found the prevlence of nondipping in obese children to be bout twice tht in children overll. We found similr prevlence of non-dipping in the obese group compred to this study: 34% in our obese group compred to 40% in the Westersthl et l. s study. The Westersthl et l. s study did not hve len subjects s control, however, insted using estblished normtive peditric ABPM dt s their comprison group. 28 The lck of significnce in the reltionship between incresing severity of obesity nd prevlence of nocturnl dipping demonstrted here could be due to lck of sttisticl power, s the PR for both more obese ctegories ws greter thn 1. In ddition, it is quite possible tht the reltionship ws underestimted secondry to undignosed obstructive sleep pne (OSA). OSA is positively ssocited with both obesity nd nocturnl hypertension. 29 There seems to be n ssocition between OSA nd nocturnl non-dipping, 30 lthough the dt re inconsistent. 31 Poor sleep qulity hs lso been linked with non-dipping. 32 It is likely tht there were subjects with undignosed OSA in our study. One surprising finding of this study ws the significntly higher wke nd 24-hour DBP in len subjects compred to obese subjects. In ddition, there were no significnt differences between the systolic BPs of the 2 groups. This my reflect selection bis, s ll subjects were referred to Settle Children s Hospitl for evlution of elevted BP, which my decrese the generlizbility of our results to generl peditric popultion. However, our findings would pertin to children referred to other peditric hypertension clinics. These results lso rise the question of whether the higher prevlence of non-dipping in the obese popultion ws due to the lower men wke DBP in the obese group compred to the len group. The higher prevlence of non-dipping in the obese group ws seen with both systolic nd distolic dipping, however. In ddition, there were lmost 3 times s mny cses of systolic non-dipping (N = 313) s distolic non-dipping (N = 113). The incresed prevlence of systolic non-dipping in the obese group cnnot be ttributed to BP differences in the 24-hour ABPM findings, s the len nd obese groups did not hve significnt different wke men SBPs. The cusl mechnism between obesity nd nocturnl non-dipping is still subject of ctive reserch nd is likely to be complex. 33 Activtion of the sympthetic nervous system is thought to ply significnt role. Compred to len children, obese children hve reduced crdic vgl function nd overll incresed sympthetic ctivity. 34 Insulin resistnce nd impired glucose tolernce re possible mechnisms by which sympthetic ctivtion occurs. 35 Obesity-ssocited elevtion of leptin, 36 reduction of diponectin, 37 nd ltertion of other neuropeptides 33 hve lso been ssocited with 650 Americn Journl of Hypertension 29(5) My 2016

5 Blunted Dipping in Obese Children hypertension. Nocturnl ntriuresis, which is incresed by hyperinsulinemi nd elevted leptin levels, is elevted in non-dippers compred to norml dippers. 38 Finlly, the renin-ngiotensin-ldosterone system (RAAS) ctivity, which is upregulted in obesity, plys role in circdin BP ptterns. 39 Our study hd severl limittions. Given the cross-sectionl design, we cnnot mke inference bout cuslity. We do not hve informtion regrding Hispnics subjects, s tht ws not recorded in our dtbse. This is importnt s the Hispnic popultion hs been shown to hve incresed obesity-ssocited hypertension 20 nd my respond to tretment of nocturnl hypertension differently thn Cucsin popultions. 40 We lso did not hve informtion regrding sodium intke or exercise hbits of subjects, both of which could ffect BP results. Finlly, s mentioned bove, our subjects were ll referred for hypertension evlutions, which my decrese the generlizbility of our results. Despite these weknesses, we feel tht this nlysis dds significntly to this literture regrding obesity nd non-dipping in the peditric popultion. Strengths of this study include its size, s it is one of the lrgest ABPM studies performed in the peditric popultion, nd the fct tht we were ble to clerly seprte len nd obese groups ccording to BMI percentile. In conclusion, we found significnt nd robust ssocition between obesity nd nocturnl non-dipping. This provides bsis for further prospective study into this reltionship, s well s dds to the public helth importnce of childhood obesity. As non-dipping is so clerly linked to worse helth outcomes in dults, it is importnt for us to continue to describe the reltionship between obesity nd non-dipping, s well s continue to investigte helth outcomes in the peditric popultion. Our dt lso further support the benefit of utilizing ABPM in the evlution of childhood hypertension, s it offers vluble informtion tht cnnot be scertined from office or home BP mesurements. ACKNOWLEDGMENTS We thnk the Ntionl Institute of Dibetes nd Digestive nd Kidney Diseses for providing fellowship funding (Grnt # T32 DK007662) nd Dt Informtion Services t Settle Children s Hospitl for technicl support. DISCLOSURE The uthors declred no conflict of interest. REFERENCES 1. McNiece KL, Poffenbrger TS, Turner JL, Frnco KD, Sorof JM, Portmn RJ. Prevlence of hypertension nd pre-hypertension mong dolescents. J Peditr 2007; 150: e1. 2. Sorof JM, Li D, Turner J, Poffenbrger T, Portmn RJ. Overweight, ethnicity, nd the prevlence of hypertension in school-ged children. Peditrics 2004; 113: Chen X, Wng Y. Trcking of blood pressure from childhood to dulthood: systemtic review nd met-regression nlysis. Circultion 2008; 117: Hymn LL. 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