Central Adiposity and Mortality after First-Ever Acute Ischemic Stroke

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Erwin Chiquete a José L. Ruiz-Sandoval c Luis Murillo-Bonilla e
Carolina León-Jiménez g Bertha Ruiz-Madrigal d, f Erika Martínez-López d, f
Sonia Román d, f Arturo Panduro d, f Alma Ramos b Carlos Cantú-Brito

Background: The waist-to-height ratio (WHtR) may be a better
adiposity measure than the body mass index (BMI). We
evaluated the prognostic performance of WHtR in patients
with acute ischemic stroke (AIS). Methods: First, we compared
WHtR and BMI as adiposity measures in 712 healthy
adults by tetrapolar bioimpedance analysis. Thereafter,
baseline WHtR was analyzed as predictor of 12-month allcause
mortality in 821 Mexican mestizo adults with first-ever
AIS by a Cox proportional hazards model adjusted for baseline
predictors. Results: In healthy individuals, WHtR correlated
higher than BMI with total fat mass and showed a higher
accuracy in identifying a high percentage of body fat (p <
0.01). In AIS patients a U-shaped relationship was observed
between baseline WHtR and mortality (fatality rate 29.1%).
On multivariate analysis, baseline WHtR ≤ 0.300 or >0.800 independently
predicted 12-month all-cause mortality (h

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Central Adiposity and Mortality after First-Ever Acute Ischemic Stroke

  1. 1. Original Paper Received: February 15, 2013 Accepted: March 18, 2013 Published online: July 13, 2013 Eur Neurol 2013;70:117–123 DOI: 10.1159/000350762 Central Adiposity and Mortality after First-Ever Acute Ischemic Stroke Erwin Chiquete a José L. Ruiz-Sandoval c Luis Murillo-Bonilla e Carolina León-Jiménez g Bertha Ruiz-Madrigal d, f Erika Martínez-López d, f Sonia Román d, f Arturo Panduro d, f Alma Ramos b Carlos Cantú-Brito a             a         Department of Neurology and Psychiatry, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, and Scientific Area, Sanofi-Aventis, Mexico City, Departments of c Neurology and d Molecular Biology, Hospital Civil de Guadalajara ‘Fray Antonio Alcalde’, e Departments of Neurology, Facultad de Medicina, Universidad Autónoma de Guadalajara, and f Department of Molecular Biology, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, and g Department of Neurology, Hospital Valentín Gomez Farías, Zapopan, Mexico   b             Abstract Background: The waist-to-height ratio (WHtR) may be a better adiposity measure than the body mass index (BMI). We evaluated the prognostic performance of WHtR in patients with acute ischemic stroke (AIS). Methods: First, we compared WHtR and BMI as adiposity measures in 712 healthy adults by tetrapolar bioimpedance analysis. Thereafter, baseline WHtR was analyzed as predictor of 12-month allcause mortality in 821 Mexican mestizo adults with first-ever AIS by a Cox proportional hazards model adjusted for baseline predictors. Results: In healthy individuals, WHtR correlated higher than BMI with total fat mass and showed a higher accuracy in identifying a high percentage of body fat (p < 0.01). In AIS patients a U-shaped relationship was observed between baseline WHtR and mortality (fatality rate 29.1%). On multivariate analysis, baseline WHtR ≤0.300 or >0.800 independently predicted 12-month all-cause mortality (hazard ratio 1.91, 95% confidence interval 1.04–3.51). BMI was © 2013 S. Karger AG, Basel 0014–3022/13/0702–0117$38.00/0 E-Mail karger@karger.com www.karger.com/ene not associated with mortality, tested either as continuous, binomial or stratified variable. Conclusion: WHtR is a modifiable risk factor that accurately demonstrates body fat excess. Extreme WHtR values were associated with increased 12-month all-cause mortality in Mexican mestizo patients with AIS. No survival advantage was found with high WHtR as the pragmatic indicator of obesity in this population. Copyright © 2013 S. Karger AG, Basel Introduction Obesity is a well-recognized risk factor for acute ischemic stroke (AIS) [1, 2], however when BMI is tested as predictor of mortality in people with atherothrombotic complications such as myocardial infarction, stroke or heart failure, a high body mass index (BMI) has been associated with a survival advantage (the so-called obesity paradox) [3–6]. BMI is an index of both lean and fat tissues (i.e. total body mass) as a function of height squared and therefore BMI is not the ideal indicator of obesity [7, 8]. Other anthropometric measures, such as the waist-to-height ratio Dr. Carlos Cantú-Brito Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán Vasco de Quiroga 15 Tlalpan, Mexico City, CP 14439 (Mexico) E-Mail carloscantu_brito @ hotmail.com Downloaded by: 201.141.112.10 - 7/25/2013 1:35:20 PM Key Words Adiposity · Body composition · Body fat · Body mass index · Obesity paradox · Overweight · Stroke
  2. 2. Methods We compared WHtR, BMI and other anthropometric measures as references of body adiposity in healthy adults in order to find the best adiposity index of general adiposity that can be applied in AIS patients to evaluate whether the excessive body fat is a predictor of 12-month all-cause mortality. To find the best anthropometric measure of body adiposity, a total of 712 Mexican mestizo adults without a history of stroke were invited to receive body composition evaluation at the Department of Molecular Biology in Medicine, Hospital Civil de Guadalajara ‘Fray Antonio Alcalde’, Guadalajara, Mexico. The institutional committee of ethics of the Hospital Civil de Guadalajara approved this part of the study. Informed consent was required for all subjects. These individuals underwent evaluation by means of bioimpedance analysis (BIA) with a computerized multifrequency tetrapolar 8-point tactile electrode BIA system (Inbody 720; analyzing software: Inbody 3.0; Biospace Co., Ltd, Seoul, Korea). Participating subjects were evaluated in the morning, with cotton underwear without metal or synthetic textiles, in overnight fasting and having evacuated bladder and rectum. The individuals were asked to remove their clothes, excepting underwear, and they were provided with a disposable cotton-made coat for use during BIA. Hands and soles were cleaned up and impregnated with an electrolyte solution. BMI was calculated as weight (kg) divided by height (m). WHtR was calculated as waist circumference (WC) (cm) divided by height (cm), by using the waist measurement of the narrowest point between the lower costal border and the top of the iliac crest. Waist-to-hip ratio (WHR) was calculated as WC (cm) divided by the hip circumference (cm). Body fat and lean mass content were estimated by using the standard built-in prediction algorithms for adults (Biospace Co., Ltd.). Among 1,376 participants with AIS or transient ischemic attack (TIA) registered in the PREMIER study [8, 10–12], a total of 821 first-ever AIS patients with complete anthropometric evaluations and 12-month follow-up outcome information were selected for this part of the study. TIA cases were not included in this analysis. A central institutional review board and the local committee of ethics of each participating center approved the study. In brief, consecutive patients with AIS or TIA aged ≥18 years were included. All patients received medical care within 7 days of AIS onset. Data collection was prospectively performed during 1 year (in six planned research visits) by using a standardized structured questionnaire outlined in a procedure manual. All participating physicians were instructed on stroke guidelines, classification and management. Stroke subtypes were registered according to Trial of ORG 10172 in Acute Stroke (TOAST) and Oxfordshire Community Stroke Project (OCSP) classifications. AIS severity was assessed by the National Institutes of Health Stroke Scale (NIHSS) at 118 Eur Neurol 2013;70:117–123 DOI: 10.1159/000350762 baseline, and the modified Rankin scale (mRS) was used to evaluate the functional outcome at hospital discharge, 30 and 90 days, 6, and 12 months after AIS (the six research visits). Weight, height, and WC were measured at baseline by direct assessment with scales, stadiometer or flexible metric rulers, with standard procedures for either supine or stand-up positions, as corresponded. Hip circumference was not measured in this cohort. BMI and WHtR were calculated as described above. The investigator ascertained every fatality case either directly during hospitalization, or at each follow-up visit by telephone interview with caregivers. The exact day of death was recorded. The information of the standardized structured questionnaires was saved on independent electronic files in data capture software developed and revised periodically by a contract research organization (CRO; Innoval Co.). Members of the CRO analyzed information on every patient for completeness and plausibility. Missing or implausible variables were referred to the investigator for clarification. Data quality was ascertained by periodic statistical reports and clinical site visits by CRO monitors. Parametric continuous variables are expressed as geometric means and standard deviations (SD), or minimum and maximum. Non-parametric continuous variables are expressed as medians and interquartile range (IQR). Categorical variables are expressed as percentages. To compare quantitative variables distributed between two groups, Student’s t test and Mann-Whitney U test were performed in distributions of parametric and nonparametric variables, respectively. χ2 statistics were used to compare nominal variables in bivariate analyses. Pearson’s ρ correlation was used to test the continuous association between two quantitative variables. An r-to-z transformation was performed to calculate a ‘z’ score that can be applied to assess the significance of the difference between two correlation coefficients. Different WHtR, BMI cutoffs, NIHSS cutoffs, and demographic as well as clinical variables were tested as predictors of 12-month all-cause mortality in univariate analyses. Variables significantly associated with mortality were selected to integrate a multivariate prediction model. Kaplan-Meyer survival estimates and Cox proportional hazards models at 12-month follow-up were constructed to find independent baseline risk factors for all-cause mortality after AIS, testing the WHtR and BMI cutoffs selected in univariate analyses. Multivariate hazard ratios (HR) and their respective 95% confidence intervals (CI) are provided. In healthy subjects, BMI, WC and WHtR were evaluated by a receiver-operating characteristic (ROC) curve for discrimination of a percentage of body fat (%BF) >20 and >30, regarding as superior the index with the largest area under the curve (AUC) without overlapping 95% CIs. All p values are two-sided and considered significant when p < 0.05. SPSS version 17.0 software was used for all statistical calculations. Results WHtR Is Better than BMI as an Index of Adiposity A total of 712 healthy adults (mean age 38.2, median 38, IQR 28–45 years; 60.5% women) underwent BIA for body composition assessment. Significant differences were observed between men and women with respect to Chiquete  et al.   Downloaded by: 201.141.112.10 - 7/25/2013 1:35:20 PM (WHtR), may denote more precisely the excess of body adiposity [9]. Growing evidence suggests that WHtR is stronger than BMI as a risk factor for stroke [2]. In this study we tested the hypotheses that WHtR is better than BMI as an index of adiposity in healthy adults and stronger than BMI as predictor of death in Mexican patients with a first-ever AIS.
  3. 3. Color version available online 80 60 40 AUC (95% CI) WHtR: 0.908 (0.883–0.932) BMI: 0.769 (0.729–0.810) WC: 0.808 (0.771–0.845) WHR: 0.775 (0.734–0.816) 20 0 0 a 20 40 60 80 100 False positives (%) True positives (%) 100 80 True positives (%) 100 60 40 AUC (95% CI) WHtR: 0.961 (0.949–0.973) BMI: 0.889 (0.866–0.912) WC: 0.907 (0.886–0.928) WHR: 0.842 (0.812–0.872) 20 0 0 20 b 40 60 80 100 False positives (%) Mexican mestizo adults who underwent tetrapolar BIA. b ROC curve on the discriminatory function of anthropometric indices for %BF >30. Table 1. Univariate Pearson’s correlation of several indices of adi- mean %BF (27.7 vs. 31.8%, respectively; p < 0.001), BMI (28.5 vs. 25.9, respectively; p < 0.001), WC (93.6 vs. 89.3 cm, respectively; p = 0.001) and WHR (0.880 vs. 0.890, respectively; p = 0.03), but not with respect to age (38.6 vs. 38.0 years, respectively; p = 0.52) or, more importantly, the WHtR (0.550 vs. 0.560, respectively; p = 0.53). In healthy adults, WHtR correlated significantly higher than  BMI with total body fat within each BMI interval (table 1). Moreover, WHtR showed higher accuracy than BMI, WC or WHR in identifying both a %BF >20 or >30 (fig. 1a, b). WHtR Is a Predictor of 12-Month All-Cause Mortality after a First-Ever AIS A total of 821 Mexican mestizo patients with AIS (52.6% women, mean age 67.9, median 70, IQR 57–79 years) were analyzed for the association of baseline adiposity measures with 12-month all-cause mortality (table  2). At the 12-month follow-up, a total of 90 (11.0%) patients achieved a mRS = 0; 191 (23.3%) had a mRS = 1; 109 (13.3%) had a mRS = 2; 89 (10.8%) had a mRS = 3; 74 (9.0) had a mRS = 4; 29 (3.5%) had a mRS = 5, and 239 (29.1%) patients died. A U-shaped relationship was observed between WHtR intervals and 12-month all-cause mortality risk (fig. 2a), so that both low or high baseline WHtR measurements were associated with an increased 12-month mortality rate. Notably, mean BMI increased as a function of WHtR, but BMI ranges significantly overlapped across WHtR intervals (fig. 2a). An inverse relationship was found between the frequency of hypercholesterolemia and 12-month allcause mortality (table 2), possibly explained by the higher use of statins among patients with dyslipidemia than among non-dyslipidemic individuals (9.1 vs. 5.2%, respectively; p = 0.04). Kaplan-Meier estimates showed a significantly lower survival in patients with baseline WHtR ≤0.300 or >0.800 (fig. 2b). Differences in mortality rates were significant since the first 6 months after AIS (p = 0.03). In a multivariate analysis by the Cox proportional hazards method adjusted for relevant baseline confounders (table 3), WHtR ≤0.300 or >0.800, age >65 years, to- Central Adiposity and Mortality in Acute Stroke Eur Neurol 2013;70:117–123 DOI: 10.1159/000350762 posity with %BF, according to BMI strata, in 712 healthy adults who received tetrapolar BIAa Characteristic BMI <20 BMI 20–25 BMI 25.1–30 BMI >30 (n = 48) (n = 285) (n = 197) (n = 182) WHtR BMI WC WHR 0.773b 0.401b 0.614b 0.597b 0.702b 0.237b 0.396b 0.355b 0.864b 0.460b 0.557b 0.530b –0.715b –0.666b –0.423b –0.026 a p < 0.05 for comparison of Pearson’s correlation between BMI and total body fat with that of WHtR and total body fat. b p < 0.001 for significance of univariate Pearson’s correlation. 119 Downloaded by: 201.141.112.10 - 7/25/2013 1:35:20 PM Fig. 1. Accuracy of anthropometric measures in identifying excessive adiposity in healthy adults. a ROC curve on the discriminatory function of anthropometric indices for %BF >20 in 712 healthy
  4. 4. Table 2. Main characteristics of patients with a first-ever acute cerebral infarction (n = 821) and their association with 12-month allcause mortality Variable 12-Month all-cause mortality absent (n = 582) Median age, years Male NIHSS at hospital admission, median Major vascular risk factors Hypertension Diabetes mellitus Hypercholesterolemia Atrial fibrillation Coronary artery disease Heart failure Past or current smoking Ischemic stroke syndromes Total anterior circulation cerebral infarction Partial anterior circulation cerebral infarction Lacunar cerebral infarction Posterior circulation cerebral infarction Ischemic stroke mechanisms Large-artery atherothrombosis Lacunar Cardioembolism Mixed mechanism Other determined mechanisms Undetermined mechanism Baseline anthropometric measures Weight, kg Height, m WC, cm WHtR Body mass index >25 >27 >30 >35 68.0 [56.0–77.0] 282 (48.5) 8.0 [5.0–13.0] p value present (n = 239) 77.00 [65.0–85.0] 107 (44.8) 19.0 [14.0–26.5] 373 (64.1) 199 (34.2) 136 (23.4) 44 (7.6) 70 (12.0) 40 (6.9) 212 (36.4) 157 (65.7) 84 (35.1) 29 (12.1) 46 (19.2) 36 (15.1) 38 (15.9) 93 (38.9) 54 (9.3) 238 (40.9) 190 (32.6) 100 (17.2) 119 (49.8) 72 (30.1) 13 (5.4) 35 (14.6) 56 (9.6) 140 (24.1) 91 (15.6) 33 (5.7) 35 (6.0) 227 (39.0) 9 (3.8) 12 (5.0) 65 (27.2) 12 (5.0) 9 (3.8) 132 (55.2) 71.8±4.6 1.62±0.09 93.3±15.4 0.577±0.096 27.35±4.66 406 (69.8) 290 (49.8) 138 (23.7) 30 (5.2) 70.4±15.3 1.61±0.09 93.7±17.4 0.584±0.105 27.19±5.20 153 (64.0) 120 (50.2) 62 (25.9) 15 (6.3) <0.001 <0.34 <0.001 <0.66 <0.79 <0.001 <0.001 <0.24 <0.001 <0.50 <0.001 <0.001 <0.19 <0.10 <0.75 <0.41 <0.67 <0.11 <0.92 <0.50 <0.52 Values are mean ± SD, n (%) or IQR in brackets. Discussion When compared with BMI these results demonstrate that WHtR is a better measure of adiposity and a stronger predictor of 12-month all-cause mortality in Mexican 120 Eur Neurol 2013;70:117–123 DOI: 10.1159/000350762 mestizo patients with AIS. We found a U-shaped relationship between WHtR and mortality, and therefore did not observe any protective effect of a high BMI or high WHtR in this first-ever AIS cohort. WHtR has been traditionally considered an anthropometric measure of central adiposity adjusted for a given height [7, 9]. Here we show that WHtR can accurately indicate general adiposity as well. Central adiposity has been found to be associated with an adverse metabolic profile that traduce into a high cardiovascular risk [9]. If WC parallels with increments of visceral fat tissue when weight gain occurs at the expense of positive energy balChiquete  et al.   Downloaded by: 201.141.112.10 - 7/25/2013 1:35:20 PM tal anterior circulation cerebral infarction syndrome, and NIHSS were significant predictors of 12-month all-cause mortality (table  3). BMI was not significantly associated with 12-month mortality, tested either as a continuous, binomial or stratified variable (table 3).
  5. 5. 2 20 0 0 Deaths, n Number at risk a BMI Mean SD Range 100 80 WHtR 0.301–0.800 60 40 WHtR 20 Fig. 2. All-cause mortality after a first-ever AIS. a One-year all-cause mortality ac- cording to baseline WHtR: in circles, relative frequency; in triangles, age- and sexadjusted HRs. The corresponding BMI for every WHtR interval is also shown. b Kaplan-Meier estimates according to baseline WHtR ≤0.300 or >0.800. Rhombuses indicate censored cases. 0 Number at risk WHtR 0.301–0.800 b WHtR 0 802 19 100 200 300 Days after first-ever AIS 614 11 593 10 400 570 8 As reflected by WHtR, in the present study both a reduced and an excessive central adiposity increase the probability of death after a first-ever cerebral infarction. Indeed, on the one hand it is possible that certain energy stores are necessary to cope with metabolic demands that follow AIS [8, 13, 14], and on the other hand, an excessive visceral fat could be associated with an adverse risk profile. When analyzing a high BMI as a predictor of mortality in subjects who have survived an atherothrombotic Central Adiposity and Mortality in Acute Stroke Eur Neurol 2013;70:117–123 DOI: 10.1159/000350762 121 Downloaded by: 201.141.112.10 - 7/25/2013 1:35:20 PM ance, then WHtR may denote more accurately the most important body mass in terms of chronic risks. Both obese and muscled persons can have the same BMI if weight (with different proportions of lean and fat masses) and height are the same, but with radically different risks. On the other hand, WC does not increase significantly in muscled individuals; hence, the adjustment of WC for height provides the opportunity of correcting central adiposity for variations of height.
  6. 6. Table 3. Multivariate analysis on baseline factors associated with 12-month all-cause mortality in patients with a first-ever acute cerebral infarction (n = 821): a Cox proportional hazards modela Predictor HR (95% CI) p value TACI NIHSSb WHtR ≤0.300 or >0.800 Agec 2.435 (1.759−3.371) 2.182 (1.751−2.720) 1.911 (1.040−3.514) 1.018 (1.008−1.027) <0.001 <0.001 <0.037 <0.001 a   Adjusted for atrial fibrillation, hypercholesterolemia, statin use, heart failure, stroke mechanisms, stroke syndromes, BMI (tested as a continuous, stratified or binomial variable with different cutoffs), WC and total body weight. b  NIHSS <9, 9–18 and >18 points. c  Age per 1-year increment. complication (i.e. stroke, myocardial infarction, heart failure, and other complications), it can be erroneously concluded that obesity provides a survival advantage, a concept that may be misinterpreted by the general population, with potential negative consequences for public health. Our findings are in conflict with the obesity paradox concept. In a previous analysis of the PREMIER cohort, we originally found that a high BMI was apparently associated with a good functional outcome in stroke survivors exclusively [8], confirming the obesity paradox in the context of functional recovery. However, when WHtR was analyzed as a measure of adiposity excess (i.e. obesity), no functional advantage was found with high WHtR or high BMI in adjusted multivariate analyses [8]. It is possible that the elimination of patients with a previous stroke can reduce the bias of survival selection for the obese individuals, then reducing the apparent advantage with high BMI values. In other words, it remains unquestionable that a high BMI is strongly associated with increased mortality and cardiovascular risks [15–17], but when studying persons who already have a cardiovascular event, and the onset of such an event is the new ‘zero point’ for mortality analysis, the inclusion of obese patients who had survived several cardiovascular events may bias towards the selection of strong body constitutions that may be more ‘resistant’ to the metabolic challenges after atherothrombotic events in the long run. So far, no indisputable explanation to the obesity paradox concept has been put forward [18]. The main limitation of our study is the lack of direct body composition analysis in the cohort with AIS, which would allow for estimation of the exact predictive value of adiposity in diseased persons. Another limitation is the relatively small sample size that might hamper robust analyses. At the population level different WHtR cutoffs may apply in terms of long-term cardiometabolic risks, if we consider that the present study was only about patients with arterial disease at baseline. Given the body composition characteristics of the Mexican mestizo population, our findings should be tested in different bioethnic groups and other forms of cerebrovascular and cardiometabolic diseases. In conclusion, extreme WHtR values are modestly, but significantly associated with an increased all-cause mortality risk in Mexican mestizos, in the late part of the evolution after a first-ever AIS. These findings should be retested in different scenarios. Disclosure Statement This study received unrestricted funds from Sanofi-Aventis for the registering of patients with stroke. The company did not participate, either directly or indirectly in study design, selection of patients, data analysis, manuscript draft or the decision to summit for publication. Mrs. A. 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