Utility of the Visceral Adiposity Index and Hypertriglyceridemic Waist Phenotype for Predicting Incident Hypertension

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1 Originl Article Endocrinol Metb 2017;32: pissn X eissn Utility of the Viscerl Adiposity Index nd Hypertriglyceridemic Wist Phenotype for Predicting Incident Hypertension Mohsen Jnghorbni 1, Mohmmd Rez Slmt 2, Ashrf Aminorroy 1, Msoud Amini 1 1 Isfhn Endocrine nd Metbolism Reserch Center, 2 Deprtment of Medicl Physics nd Medicl Engineering, Isfhn University of Medicl Sciences, Isfhn, Irn Bckground: The im of this study ws to ssess the utility of the viscerl diposity index (VAI) nd the hypertriglyceridemic wist (HTGW) phenotype s possible hypertension (HTN) predictors in high-risk popultion without dibetes nd HTN. Methods: Incident HTN over 7-yer follow-up ws ssessed mong 1,375 first-degree non-dibetic nd non-hypertensive reltives of consecutive ptients with type 2 dibetes who were 30 to 70 yers of ge. HTN ws defined s blood pressure reding 140/90 mm Hg or the use of ntihypertensive medictions. We exmined the incidence of HTN cross VAI quintiles nd four groups defined ccording to bseline fsting serum triglyceride (TG) levels nd wist circumference (WC). Results: The VAI nd the HTGW phenotype t bseline were relted to n incresed risk for HTN. In comprison with the lowest VAI quintile, the highest VAI quintile showed significnt ssocited with HTN in n ge- nd gender-djusted model (odds rtio [OR], 1.65; 95% confidence intervl [CI], 1.07 to 2.55). Those with HTGW were 2.3 times (OR, 2.27; 95% CI, 1.54 to 3.35) more likely to develop HTN thn those with norml WC nd norml TG levels. Conclusion: Greter VAI vlues wekly predicted HTN, wheres the HTGW phenotype ws stronger predictor of incident HTN in n Irnin high-risk popultion. Keywords: Viscerl diposity index; Hypertension; Incidence; Risk fctors; Hypertriglyceridemic wist INTRODUCTION Hypertension (HTN) is rpidly growing helth problem worldwide [1]. The prevlence of HTN hs incresed nd remins high in Irn, s pproximtely 27% of Irnin dults hve HTN [2]. Therefore, it is importnt to identify individuls who re t higher risk of HTN. Mny studies hve exmined the link between obesity, prticulrly bdominl obesity, nd HTN [3-7]. The reltionship between bdominl obesity nd HTN remins inconclusive [3-7]. Nevertheless, becuse nthropometric mesures such s body mss index (BMI), wist circumference (WC), nd wist-to-hip rtio (WHR) cnnot differentite between viscerl nd subcutneous ft, Amto et l. [8] creted gender-specific index bsed Received: 9 December 2016, Revised: 25 Jnury 2017, Accepted: 9 Februry 2017 Corresponding uthor: Mohsen Jnghorbni Isfhn Endocrine nd Metbolism Reserch Center, Isfhn University of Medicl Sciences, Khorrm Av, Sedigheh Thereh Reserch Complex, Isfhn , Irn Tel: , Fx: , E-mil: jnghorbni@hlth.mui.c.ir Copyright 2017 Koren Endocrine Society This is n Open Access rticle distributed under the terms of the Cretive Commons Attribution Non-Commercil License ( licenses/by-nc/4.0/) which permits unrestricted non-commercil use, distribution, nd reproduction in ny medium, provided the originl work is properly cited

2 Jnghorbni M, et l. on WC, BMI, triglycerides (TGs), nd high density lipoprotein cholesterol (HDL-C) nd termed it the viscerl diposity index (VAI). For similr resons, Lemieux et l. [9] estblished phenotype bsed on combintion of bdominl obesity nd elevted fsting TG levels nd termed it the hypertriglyceridemic wist (HTGW) phenotype, in order to distinguish viscerl ft from subcutneous ft. They observed tht VAI nd HTGW were closely relted to viscerl diposity mesured by mgnetic resonnce imging [10]. Mgnetic resonnce imging nd computed tomogrphy (CT) re gold stndrds for the mesurement of viscerl ft, but they re not pproprite for epidemiologicl studies nd everydy prctice for prcticl, ethicl, nd economic resons. Only limited investigtions hve exmined the ssocition between viscerl diposity mesured by CT nd the risk of HTN [11-19], with inconclusive results. Some studies showed significnt or borderline significnt ssocition [11,13,15-18], wheres others reported no ssocition [19] or n ssocition in women but not men [14]. No longitudinl study hs inspected the reltionships of the VAI nd the HTGW phenotype with HTN risk, nd the clinicl utility of the VAI nd the HTGW phenotype in predicting HTN hs not been investigted. Therefore, the objective of this ongoing longitudinl study ws to ssess the bility of the VAI nd/or the HTGW phenotype to predict HTN incidence in high-risk popultion without dibetes or HTN. METHODS Dt were drwn from the Isfhn Dibetes Prevention Study (IDPS), the detils of which hve been presented elsewhere [20]. In brief, the IDPS, initited in 2003, is n ongoing longitudinl study crried out in cohort of first-degree reltives (FDRs) of ptients with type 2 dibetes mellitus (T2DM) in centrl Irn to mesure severl possible risk fctors for dibetes in individuls with fmily history of T2DM. At bseline, our smple comprised 3,483 FDRs of consecutive ptients with T2DM (919 men nd 2,564 women). All prticipnts were seen t the Isfhn Endocrine nd Metbolism Reserch Center, which is prt of the Isfhn University of Medicl Sciences, Irn. The study ws strted between 2003 nd At the time of ech exmintion, subjects underwent nthropometric mesurements nd lbortory tests, including stndrd 75-g 2-hour orl glucose tolernce test (OGTT), nd lso completed questionnire on their helth sttus nd severl possible risk fctors of dibetes. Prticipnts were followed up consistently ccording to the stndrd of medicl cre for dibetes [21], nd informtion ws obtined regrding demogrphic, nthropometric, nd lifestyle fctors, s well s new dignoses of dibetes nd HTN. If the OGTT ws norml t bseline, then repet testing ws crried out t lest t 3-yer intervls. Otherwise, repet testing ws usully crried out every yer. Ethics sttement The protocols for the IDPS were pproved by the Isfhn University of Medicl Sciences Ethicl Committee. All prticipnts provided written informed consent. Follow-up nd dignosis of HTN Of the 3,483 prticipnts who took prt t bseline, 2,108 were excluded for one or more of the following resons t bseline: prevlent T2DM (n=329), prevlent HTN (n=632), nd filure to ttend follow-up exmintions (n=1,009); further 138 prticipnts who took prt in follow-up but hd missing dt on blood pressure (BP) nd the necessry components of the VAI were lso excluded, resulting in 1,375 prticipnts who were ultimtely included in the study. The men ge±stndrd devi- 3,483 (919 men nd 2,564 women) 3,154 Without T2DM 2,522 Without T2DM or hypertension 1,513 Without T2DM or hypertension who ttended follow-up 1,375 Finlly included 329 Excluded becuse of dignosis of T2DM t bseline 632 Excluded becuse of dignosis of hypertension t bseline 1,009 Did not ttend ny follow-up exmintions 138 Excluded due to missing dt on blood pressure nd VAI components Fig. 1. Flow digrm of inclusion nd exclusion criteri in the Isfhn Dibetes Prevention Study. A totl of 1,375 individuls were included in this study. T2DM, type 2 dibetes mellitus; VAI, viscerl diposity index Copyright 2017 Koren Endocrine Society

3 VAI nd HTGW Phenotype nd Hypertension Risk tion (SD) of prticipnts ws 42.6±6.4 yers (rnge, 30 to 70), nd ll prticipnts underwent t lest one subsequent dditionl exmintion during men±sd follow-up period of 7.3±2.1 yers (rnge, 1 to 10). Pregnnt women were excluded (Fig. 1). Mesurements At bseline nd t follow-up visits, dt on ge, sex, BMI, hemoglobin A1c (HbA1c), totl cholesterol (TC), low density lipoprotein cholesterol (LDL-C), HDL-C, TG, BP, nd fmily nd personl medicl history were collected. The sme methodology ws used t bseline nd t follow-up visits. The prticipnts were the siblings nd children of ptients with T2DM. They were requested to refrin from intense exercise the evening before nd the morning of their visit when they reported to clinic in the morning fter n overnight fst. Smokers were sked to refrin from smoking on the morning of the investigtions. First, fter the prticipnts rrived t the clinic, the dt provided by the prticipnts in the questionnire on fmily history were checked. Then, height, weight, WC, nd hip circumference (HC) were ssessed without shoes or hevy clothing using stndrd devices, nd recorded to the nerest 0.1 kg nd 0.5 cm. The WC ws determined midwy between the lower rib mrgin nd the ilic-crest t the end of gentle expirtion in the upright position. HC ws determined over the greter trochnters directly over the underwer. BMI ws clculted s weight (kg) divided by height squred (m 2 ). Resting systolic (phse I) nd distolic (phse V) BP were recorded t ech exmintion by physicin with the prticipnts in sitting position, fter they hd rested in this position for t lest 10 minutes, using mercury column sphygmomnometer nd ppropritely sized cuffs. A blood smple ws drwn between 7:00 nd 9:00 AM. Fsting plsm glucose (FPG) ws ssessed by the glucose oxidse method. T2DM ws defined s 2-hour plsm glucose (PG) reding of 200 mg/dl with phrmcologicl tretment, or 2 FPG redings of 126 mg/dl [22]. Those with FPG <126 mg/dl underwent stndrd OGTT (75-g of glucose, 2 hours) t bseline nd follow-up visits. Venous blood ws smpled 0, 30, 60, nd 120 minutes fter orl glucose dministrtion. According to the Eighth Joint Ntionl Committee guidelines [23], HTN ws defined s BP reding 140/90 mm Hg, or by the use of ntihypertensive gents. HbA1c, TC, TG, HDL-C, nd LDL-C were recorded. LDL-C levels were estimted by the Friedewld eqution [24]. Non- HDL-C ws clculted by subtrcting HDL-C from TC. All blood nlyses were performed t the centrl lbortory of the Isfhn Endocrine nd Metbolism Reserch Center on the dy of blood collection using the enzyme-linked method. Definitions VAI ws defined s follows [8]: Men: VAI =[WC/39.68+(1.88 BMI)] (TG/1.03) (1.31/ HDL-C) Women: VAI=[WC/36.58+(1.89 BMI)] (TG/0.81) (1.52/ HDL-C) The HTGW phenotype ws defined s the concurrent presence of WC 102 or 88 cm in men nd women, respectively, nd TG 150 mg/dl for both genders. Abdominl obesity ws defined s the presence of WC 102 or 88 cm in men nd women, respectively. Anlysis Prticipnts were followed until the occurrence of HTN, the dte of the lst completed follow-up, deth, or end of follow-up on Mrch 21, 2014, whichever event occurred first. We used the dte of the exmintion in which new cse of HTN ws recognized s the dte of dignosis. Sttisticl methods included the following: the Student t test or the Mnn-Whitney U test; one wy nlysis of vrince (ANOVA) or the Kruskl-Wllis test for continuous vribles; the chi-squre test, Person correltion or the Spermn rnk correltion; nd binry logistic regression. Differences between more thn two groups were ssessed using one wy ANOVA with the Bonferroni post hoc test. Person correltion nlysis or the Spermn rnk correltion ws used to exmine the liner reltionships between the VAI nd other vribles, holding the effect of ge nd gender constnt. Univrite nd multivrite logistic regression were used to identify predictors of new-onset HTN. We did not djust for WC, TG, or HDL-C, which re components of the VAI nd HTGW, becuse it ws not pproprite to djust for these vribles in prediction models tht lredy incorported the VAI nd HTGW. The VAI ws re-coded into quintiles, nd we compred the risk of developing HTN in ech quintile with the lowest ctegory of risk (reference group). To test the significnce of HTGW s predictor of the incidence of HTN, the incidence of HTN ws clculted ccording to the four phenotypic groups, nd we compred the risk of developing HTN in ech group with the norml-wist nd norml-tg group (reference group). A generl liner model ws used to exmine the significnce of trends in potentil predictors of HTN cross VAI quintiles nd compred ge-djusted mens. SPSS version 18 (SPSS Inc., Chicgo, IL, USA) were used for dt nlysis. The reported P vlues re 2-tiled, nd P vlues <0.05 were considered to indicte sttisticl significnce. Copyright 2017 Koren Endocrine Society 223

4 Jnghorbni M, et l. RESULTS Chrcteristics Most of the bseline chrcteristics of the individuls who did not return for follow-up visit (non-respondents), such s ge, height, weight, BMI, WC, HC, WHR, wist-to-height rtio, LDL-C, TC, TG, systolic BP, nd obesity, were similr to those who ttended follow-up visits (dt not shown). However, nonrespondents hd lower bseline vlues of FPG (95.4 mg/dl vs mg/dl, P<0.001); PG t 30 minutes (143.0 mg/dl vs mg/dl, P<0.001), 60 minutes (148.0 mg/dl vs mg/dl, (P<0.001), nd 120 minutes (119.2 mg/dl vs mg/dl, P<0.001); levels of HbA1c (5.0% vs. 5.3%, P<0.001); nd distolic BP (72.0 mm Hg vs mm Hg, P<0.001); nd higher HDL-C (46.4 mg/dl vs mg/dl, P<0.05) thn respondents. Over 9,954 person-yers of follow-up, 281 (19.8%) incident cses of HTN occurred. The men±sd VAI ws 2.8±1.9. Prticipnts on verge were overweight with men±sd BMI of 28.6±4.1 kg/m 2. Tble 1 shows the bseline chrcteristics of the 281 prticipnts (19.8%) who did nd the 1,138 (80.2%) who did not progress to HTN. As expected, compred with prticipnts who did not progress to HTN, those who progressed to HTN were older nd hd higher ge-djusted men weight, BMI, WC, WHR, wist-to-height rtio, HC, follow-up durtion, systolic nd distolic BP, PG t 30 minutes, TG, non-hdl-c, nd VAI t bseline, nd higher proportion of obesity nd the HTGW phenotype. The men±sd ge ws 44.8±6.9 yers for those who progressed to HTN nd 42.0±6.2 yers for those who did not progress to HTN. The men±sd VAI ws 3.1±2.1 for those who progressed to HTN nd 2.7±1.9 for those who did not progress to HTN. The HTGW phenotype ws present t bseline in 22.1% of those progressed to HTN nd 14.6% of those who did not. Tble 2 presents the bseline chrcteristics of the study prticipnts by VAI quintile. In comprisons of the vribles t bseline, ll vribles, except ge nd height, were greter in higher VAI quintiles. However, HDL-C ws inversely ssocited with VAI quintiles. The VAI showed significnt positive correltions with WC, BMI, WHR, systolic nd distolic BP, PG, TG, nd non-hdl- C, nd negtive correltion with LDL-C nd HDL-C (Tble 3). Incidence of HTN The totl incidence of HTN during the study ws 28.2 (95% Tble 1. Age-Adjusted Men±SE nd Proportions of Selected Bseline Chrcteristics in 281 Prticipnts Who Did Develop HTN nd 1,136 Who Did Not Develop HTN Vrible Progressed to HTN Did not progress to HTN Age, yr 44.8± ±0.19 Height, cm 159.3± ±0.24 Weight, kg 75.5± ±0.34 BMI, kg/m ± ±0.12 Wist circumference, cm 90.8± ±0.27 Wist-to-hip rtio 0.83± ±0.002 b Hip circumference, cm 109.2± ±0.26 Wist-to-height rtio 0.57± ±0.002 Follow-up durtion, yr 7.9± ±0.06 SBP, mm Hg 115.0± ±0.32 DBP, mm Hg 74.2± ±0.26 Fsting plsm glucose, mg/dl 95.7± ±0.35 Plsm glucose, mg/dl At 30 minutes 147.6± ±0.95 c At 60 minutes 151.6± ±1.28 At 120 minutes 121.2± ±0.98 HbA1c, % 5.0± ±0.02 Triglycerides, mg/dl 174.3± ±2.67 c Cholesterol, mg/dl 196.1± ±1.14 HDL-C, mg/dl 45.0± ±0.36 LDL-C, mg/dl 116.9± ±1.01 Non-HDL-C, mg/dl 150.6± ±1.08 Viscerl diposity index 3.1± ±0.06 c Women Norml (BMI <25 kg/m 2 ) Overweight (BMI kg/m 2 ) Obese (BMI 30 kg/m 2 ) Abdominl obesity Norml wist nd norml triglycerides Norml wist nd high triglycerides Enlrged wist nd norml triglycerides Hypertriglyceridemic wist phenotype Vlues re expressed s men±se or percentge. Age-djusted mens were clculted using generl liner models. HTN, hypertension; BMI, body mss index; SBP, systolic blood pressure; DBP, distolic blood pressure; HbA1c, hemoglobin A1c; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol. P<0.001; b P<0.05; c P< Copyright 2017 Koren Endocrine Society

5 VAI nd HTGW Phenotype nd Hypertension Risk Tble 2. Age nd Age-Adjusted Men±SE nd Proportions of the Bseline Chrcteristics of Prticipnts by Viscerl Adiposity Index Quintile Chrcteristic Totl 1st quintile ( 1.36) 2nd quintile ( ) Viscerl diposity index t bseline 3rd quintile ( ) 4th quintile ( ) 5th quintile ( 3.72) Prticipnts 1,362 (100) 273 (20.0) 270 (19.8) 274 (20.1) 272 (20.0) 273 (20.0) Age, yr 42.5± ± ± ± ± ±0.38 Height, cm 159.6± ± ± ± ± ±0.50 Weight, kg 72.9± ± ± ± ± ±0.69 Wist circumference, cm 88.3± ± ± ± ± ±0.54 Hip circumference, cm 107.1± ± ± ± ± ±0.52 b Wist-to-hip rtio 0.83± ± ± ± ± ±0.004 Body mss index, kg/m ± ± ± ± ± ±0.24 Wist-to-height rtio 0.55± ± ± ± ± ±0.003 FPG, mg/dl 95.5± ± ± ± ± ±0.72 Plsm glucose, mg/dl At 30 minutes 142.9± ± ± ± ± ±1.95 c At 60 minutes 148.0± ± ± ± ± ±2.59 At 120 minutes 119.5± ± ± ± ± ±1.99 HbA1c, % 5.0± ± ± ± ± ±0.05 Cholesterol, mg/dl 194.9± ± ± ± ± ±2.28 b LDL-C, mg/dl 118.5± ± ± ± ± ±2.09 HDL-C, mg/dl 45.5± ± ± ± ± ±0.60 Triglycerides, mg/dl 159.2± ± ± ± ± ±3.85 Non-HDL-C, mg/dl 3.9± ± ± ± ± ±0.05 SBP, mm Hg 110.6± ± ± ± ± ±0.67 DBP, mm Hg 71.9± ± ± ± ± ±0.54 c Viscerl diposity index 2.8± ± ± ± ± ±0.07 Women 1,042 (75.8) 209 (76.0) 209 (76.0) 212 (77.1) 209 (76.0) 203 (73.8) Overweight (BMI 25 kg/m 2 ) 1,128 (82.3) 198 (72.0) 217 (79.5) 230 (83.6) 238 (86.9) 245 (89.7) Abdominl obesity 490 (35.6) 69 (25.1) 86 (31.3) 92 (33.5) 117 (42.5) 126 (45.8) Hypertriglyceridemic wist 235 (17.1) 0 4 (1.5) 23 (8.4) 86 (31.3) 122 (44.4) Vlues re expressed s number (%) or men±se. Age-djusted mens were clculted using generl liner models. FPG, fsting plsm glucose; HbA1c; hemoglobin A1c; LDL-C, low density lipoprotein cholesterol; HDL-C, high density lipoprotein cholesterol; SBP, systolic blood pressure; DBP, distolic blood pressure; BMI, body mss index. P<0.001; b P<0.01; c P<0.05 in comprisons cross ll five groups. confidence intervl [CI], 25.0 to 31.5) per 1,000 person-yers. The incidence ws lower in women (27.8; 95% CI, 24.1 to 31.5 per 1,000 person-yers) thn in men (29.6; 95% CI, 23.1 to 37.3), but the difference ws not sttisticlly significnt. The risk for incident HTN ccording to VAI quintiles HTN incidence ws 20.8 per 1,000 person-yers (95% CI, 15.0 to 28.0) for prticipnts in the lowest quintile, nd 33.8 per 1,000 person-yers (95% CI, 26.3 to 42.9) for those in the highest quintile. The risk of HTN ws greter in higher VAI quintiles. Compred with prticipnts in the lowest quintile, the risk of HTN ws 75% greter for those in the highest quintile t bseline (odds rtio [OR], 1.75; 95% CI, 1.14 to 2.70), 45% higher for those in the fourth quintile (OR, 1.45; 95% CI, 0.93 to 2.25), 6% higher for those in the third quintile (OR, 1.06; 95% CI, 0.67 to 1.68), nd 10% higher for those in the second quintile (OR, Copyright 2017 Koren Endocrine Society 225

6 Jnghorbni M, et l. 1.10; 95% CI, 0.69 to 1.73) in undjusted models. Controlling for gender did not lter the ORs compred to the undjusted model. Further controlling for ge nd FPG did not pprecibly Tble 3. Age- nd Gender-Adjusted Correltions between the Viscerl Adiposity Index nd Metbolic Prmeters Prmeter Wist circumference, cm Body mss index, kg/m 2 Wist-to-hip rtio Correltion coefficient Age, yr SBP, mm Hg DBP, mm Hg b HbA1c, % Fsting glucose, mg/dl Plsm glucose, mg/dl At 30 minutes At 60 minutes At 120 minutes c Cholesterol, mg/dl LDL-C, mg/dl HDL-C, mg/dl Triglycerides, mg/dl Non-HDL-C, mg/dl SBP, systolic blood pressure; DBP, distolic blood pressure; HbA1c, hemoglobin A1c; LDL-C, low density lipoprotein cholesterol; HDL-C, high density lipoprotein cholesterol. P<0.001; b P<0.01; c P<0.05. lter the ssocitions (Tbles 4, 5). The risk for incident HTN ccording to HTGW HTN incidence ws 17.0 per 1,000 person-yers (95% CI, 13.2 to 20.8) for prticipnts in the norml-wist nd norml-tg group, nd 36.5 per 1,000 person-yers (95% CI, 28.1 to 46.6) for those with the HTGW phenotype. Compred with prticipnts in the norml-wist nd norml-tg group, the risk of HTN ws 75% greter in those in the norml-wist nd high- TG group t bseline (OR, 1.75; 95% CI, 1.22 to 2.51), 2.3 times higher in those in the enlrged-wist nd norml-tg group (OR, 2.33; 95% CI, 1.59 to 3.40), nd 2.3 times higher in those with the HTGW phenotype (OR, 2.27; 95% CI, 1.54 to 3.35) in n ge- nd gender-djusted model. DISCUSSION This study showed tht high VAI ws wek predictor of HTN independently of ge nd gender, while the HTGW phenotype ws stronger predictor of incident HTN in lrge cohort of non-hypertensive nd non-dibetic FDRs of ptients with T2DM in Irn, s reflected by multivrite nlysis. This result suggests tht high VAI levels should be recognized s wek risk fctor for HTN. Although the VAI could be n lterntive index to predict HTN, the HTGW phenotype ppered to be stronger predictor thn the VAI. Our findings re consistent with the limited number of cross-sectionl studies [12-16] nd longitudinl study [11] showing tht viscerl diposity mesured by CT ws n independent predictor of HTN. In cross- Tble 4. Incidence Rtes nd OR of Hypertension by Viscerl Adiposity Index Quintile Vrible Viscerl diposity index t bseline 1st quintile ( 1.36) 2nd quintile ( ) 3rd quintile ( ) 4th quintile ( ) 5th quintile ( 3.72) No. of cses (%) 42 (15.8) 46 (17.0) 44 (16.5) 57 (21.3) 66 (24.7) Person-yers 2,021 2,013 1,983 1,987 1,950 Incidence/1,000 person-yers, OR (95% CI) OR (95% CI) 20.8 ( ) 22.9 ( ) 22.2 ( ) 28.7 ( ) 33.8 ( ) Undjusted ( ) 1.06 ( ) 1.45 ( ) 1.75 ( ) b Gender-djusted ( ) 1.06 ( ) 1.45 ( ) 1.75 ( ) b Age- nd gender-djusted ( ) 1.01 ( ) 1.33 ( ) 1.65 ( ) b Age-, gender-, nd FPG-djusted OR, odds rtio; CI, confidence intervl; FPG, fsting plsm glucose. OR (95% CI) clculted by multiple logistic regression; b P< ( ) 1.00 ( ) 1.32 ( ) 1.65 ( ) b Copyright 2017 Koren Endocrine Society

7 VAI nd HTGW Phenotype nd Hypertension Risk Tble 5. Incidence Rtes nd OR of Hypertension by the Four Hypertriglyceridemic Wist Phenotype Groups, the Isfhn Dibetes Prevention Study Vrible Hypertriglyceridemic wist phenotype groups NWNT NWHT EWNT HTGW No. of cses (%) 75 (12.9) 77 (21.9) 67 (25.2) 62 (27.1) Person-yers 4,417 2,612 1,997 1,699 Incidence/1000 person-yers (95% CI) 17.0 ( ) 29.5 ( ) 33.6 ( ) 36.5 ( ) OR (95% CI) Undjusted ( ) b 2.27 ( ) b 2.50 ( ) b Gender-djusted ( ) c 2.30 ( ) b 2.52 ( ) b Age- nd gender-djusted ( ) c 2.33 ( ) b 2.27 ( ) b Age-, gender-, nd FPG-djusted ( ) c 2.32 ( ) b 2.29 ( ) b OR, odds rtio; NWNT, norml wist nd norml triglycerides; NWHT, norml wist nd high triglycerides; EWNT, enlrged wist nd norml triglycerides; HTGW, hypertriglyceridemic wist phenotype; CI, confidence intervl; FPG, fsting plsm glucose. OR (95% CI) clculted by multiple logistic regression; b P<0.001; c P<0.01. sectionl nd cohort studies of Jpnese-Americns [11,12,17], viscerl diposity mesured by CT, but not the bdominl subcutneous dipose tissue, ws ssocited with the prevlence nd incidence of HTN. Boyko et l. [17], in cross-sectionl study of Jpnese-Americns in 1995, demonstrted tht, mong individuls without T2DM nd who did not tke ntihypertensive mediction, viscerl diposity s mesured by CT ws not independently relted to systolic or distolic BP fter djusting for ge, fsting plsm insulin, nd BMI. In their more recent study in 2003, they reported, bsed on cross-sectionl dt from the sme popultion, tht greter viscerl diposity incresed the odds of HTN independently of other mesures of totl or regionl diposity, fsting insulin, 2-hour PG, ge, nd gender [12]. Fox et l. [13] demonstrted tht both viscerl nd subcutneous ft volume were ssocited with the prevlence of HTN. In contrst, Foy et l. [14] showed significnt reltionship between bdominl subcutneous ft re, but not intr-bdominl ft re, nd the prevlence of HTN mong Africn- Americn nd Hispnic-Americn men. Ok et l. [15] reported in ntive Jpnese subjects tht both viscerl nd subcutneous dipose tissue were correlted with systolic nd distolic BP. Kni et l. [18] showed tht, mong severely obese women in Jpn, the rtio of the intr-bdominl ft re to subcutneous ft re mesured by CT ws ssocited with BP, independently of ge nd BMI. In contrst, Johnson et l. [19] reported tht, mong individuls without dibetes or HTN, CT-mesured intr-bdominl ft re ws not correlted with systolic or distolic BP. Differences in body composition by ethnicity nd/or djustments for other potentilly confounding vribles my prtilly explin these inconclusive findings. Bsed on comprison of ORs, the reltionship of HTN incidence with the VAI ws weker thn the reltionship of incident HTN with the HTGW phenotype. Therefore, the HTGW phenotype ppered to be stronger predictor of HTN in our study popultion. In our recent study in the sme popultion, the HTGW phenotype ws lso ssocited with n incresed risk of T2DM [25]. There re limittions relted to this study. While the smple size is believed to hve been dequte for the nlysis s whole, the follow-up rte ws reltively low. However, the prticipnts who did not complete follow-up did not differ from those who did in terms of mjor risk fctors for the development of HTN, except for FPG. We do not believe tht there ws high likelihood for bis due to differentil loss to follow-up. Regrding our definition of HTN incidence, some selection bis my hve been present, s prticipnts who ttended screenings my hve been more likely to be tested nd consequently dignosed s hving HTN. Thus, prticipnts with HTN who were t lower risk my hve been missed through lck of testing. Becuse our definition of HTN ws bsed on BP mesurement t single visit, it is possible tht mesurement error existed regrding the presence or bsence of HTN. We did not consider gender-specific nlyses becuse there were n insufficient number of events in some subgroups to clculte stble risk estimtes, lthough we used gender s n djustment fctor in ll nlyses. The current findings were drwn from n Irnin popultion composed of FDRs of ptients with T2DM nd the results my therefore not be pplicble to ll popultions. Residu- Copyright 2017 Koren Endocrine Society 227

8 Jnghorbni M, et l. l confounders could not be eliminted, incresing the possibility tht uncontrolled or indequtely mesured confounders ffected our results. It is thus necessry to vlidte the ssocitions of the VAI nd the HTGW phenotype with incident HTN in other popultions nd/or with more dt. In conclusion, the VAI nd the HTGW phenotypes were found to be predictors of HTN in high-risk individuls in Irn, nd the HTGW phenotype showed stronger predictive power. The role of viscerl diposity in the pthogenesis of HTN requires more investigtion. CONFLICTS OF INTEREST No potentil conflict of interest relevnt to this rticle ws reported. ORCID Mohsen Jnghorbni ACKNOWLEDGMENTS We thnk Mr. M. Abyr for technicl nd computer ssistnce nd ll the prticipting FDRs. This study ws prtly funded by the Isfhn Endocrine nd Metbolism Reserch Center, Irn. REFERENCES 1. Poulter NR, Prbhkrn D, Culfield M. Hypertension. Lncet 2015;386: Esteghmti A, Meysmie A, Khlilzdeh O, Rshidi A, Hghzli M, Asgri F, et l. Third ntionl Surveillnce of Risk Fctors of Non-Communicble Diseses (SuRF- NCD-2007) in Irn: methods nd results on prevlence of dibetes, hypertension, obesity, centrl obesity, nd dyslipidemi. BMC Public Helth 2009;9: Gillum RF, Mussolino ME, Mdns JH. Body ft distribution nd hypertension incidence in women nd men. The NHANES I Epidemiologic Follow-up Study. Int J Obes Relt Metb Disord 1998;22: Hrris MM, Stevens J, Thoms N, Schreiner P, Folsom AR. Associtions of ft distribution nd obesity with hypertension in bi-ethnic popultion: the ARIC study. Atherosclerosis Risk in Communities Study. Obes Res 2000;8: Folsom AR, Prines RJ, Kye SA, Munger RG. Incidence of hypertension nd stroke in reltion to body ft distribution nd other risk fctors in older women. Stroke 1990;21: Cssno PA, Segl MR, Vokons PS, Weiss ST. Body ft distribution, blood pressure, nd hypertension. A prospective cohort study of men in the normtive ging study. Ann Epidemiol 1990;1: Troisi RJ, Weiss ST, Segl MR, Cssno PA, Vokons PS, Lndsberg L. The reltionship of body ft distribution to blood pressure in normotensive men: the normtive ging study. Int J Obes 1990;14: Amto MC, Giordno C, Gli M, Criscimnn A, Vitbile S, Midiri M, et l. Viscerl diposity index: relible indictor of viscerl ft function ssocited with crdiometbolic risk. Dibetes Cre 2010;33: Lemieux I, Poirier P, Bergeron J, Almers N, Lmrche B, Cntin B, et l. Hypertriglyceridemic wist: useful screening phenotype in preventive crdiology? Cn J Crdiol 2007;23 Suppl B:23B-31B. 10. Elish B, Messier V, Krelis A, Coderre L, Bernrd S, Prud homme D, et l. The viscerl diposity index: reltionship with crdiometbolic risk fctors in obese nd overweight postmenopusl women: MONET group study. Appl Physiol Nutr Metb 2013;38: Hyshi T, Boyko EJ, Leonetti DL, McNeely MJ, Newell- Morris L, Khn SE, et l. Viscerl diposity is n independent predictor of incident hypertension in Jpnese Americns. Ann Intern Med 2004;140: Hyshi T, Boyko EJ, Leonetti DL, McNeely MJ, Newell- Morris L, Khn SE, et l. Viscerl diposity nd the prevlence of hypertension in Jpnese Americns. Circultion 2003;108: Fox CS, Mssro JM, Hoffmnn U, Pou KM, Murovich- Horvt P, Liu CY, et l. Abdominl viscerl nd subcutneous dipose tissue comprtments: ssocition with metbolic risk fctors in the Frminghm Hert Study. Circultion 2007;116: Foy CG, Hsu FC, Hffner SM, Norris JM, Rotter JI, Henkin LF, et l. Viscerl ft nd prevlence of hypertension mong Africn Americns nd Hispnic Americns: findings from the IRAS fmily study. Am J Hypertens 2008;21: Ok R, Miur K, Skuri M, Nkmur K, Ygi K, Miymoto S, et l. Impcts of viscerl dipose tissue nd subcutneous dipose tissue on metbolic risk fctors in middleged Jpnese. Obesity (Silver Spring) 2010;18: Koh H, Hyshi T, Sto KK, Hrit N, Med I, Nishizw Y, et l. Viscerl diposity, not bdominl subcutneous ft Copyright 2017 Koren Endocrine Society

9 VAI nd HTGW Phenotype nd Hypertension Risk re, is ssocited with high blood pressure in Jpnese men: the Ohtori study. Hypertens Res 2011;34: Boyko EJ, Leonetti DL, Bergstrom RW, Newell-Morris L, Fujimoto WY. Viscerl diposity, fsting plsm insulin, nd blood pressure in Jpnese-Americns. Dibetes Cre 1995; 18: Kni H, Mtsuzw Y, Kotni K, Keno Y, Kobtke T, Ngi Y, et l. Close correltion of intr-bdominl ft ccumultion to hypertension in obese women. Hypertension 1990;16: Johnson D, Prud homme D, Despres JP, Ndeu A, Trembly A, Bouchrd C. Reltion of bdominl obesity to hyperinsulinemi nd high blood pressure in men. Int J Obes Relt Metb Disord 1992;16: Amini M, Jnghorbni M. Dibetes nd impired glucose regultion in first-degree reltives of ptients with type 2 dibetes in isfhn, irn: prevlence nd risk fctors. Rev Dibet Stud 2007;4: Executive summry: stndrds of medicl cre in dibetes Dibetes Cre 2013;36 Suppl 1:S Expert Committee on the Dignosis nd Clssifiction of Dibetes Mellitus. Report of the expert committee on the dignosis nd clssifiction of dibetes mellitus. Dibetes Cre 2003;26 Suppl 1:S Jmes PA, Opril S, Crter BL, Cushmn WC, Dennison- Himmelfrb C, Hndler J, et l Evidence-bsed guideline for the mngement of high blood pressure in dults: report from the pnel members ppointed to the Eighth Joint Ntionl Committee (JNC 8). JAMA 2014;311: Friedewld WT, Levy RI, Fredrickson DS. Estimtion of the concentrtion of low-density lipoprotein cholesterol in plsm, without use of the preprtive ultrcentrifuge. Clin Chem 1972;18: Jnghorbni M, Amini M. Utility of hypertriglyceridemic wist phenotype for predicting incident type 2 dibetes: the Isfhn Dibetes Prevention Study. J Dibetes Investig 2016;7: Copyright 2017 Koren Endocrine Society 229