# Sex Differences in the Relationship between Abdominal Obesity and Cardiovascular Death in Elderly Patients with Permanent Pacemakers Implantation: A Retrospective Cohort Study

Authors: Xiaodi Xue; Xiaoyao Li; Shuang Zhao; Keping Chen; Wei Hua; Yan-Gang Su; Zhaoguang Liang; Wei Xu; Shu Zhang
Journal: Evidence-Based Complementary and Alternative Medicine
 (2023)

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## Abstract

Objectives. This study aims to investigate the association between waist circumference (WC) and cardiovascular death in patients with permanent pacemakers (PPMs). Methods. This is a retrospective cohort study that enrolled patients who underwent PPM implantation in Fuwai Hospital from May 2010 to April 2014, according to the BIOTRONIK Home Monitoring database. The WC was treated as sex-specific quartiles, and patients were divided into three groups according to body mass index (BMI): normal (≤22.9 kg/m2), overweight (23–24.9 kg/m2), and obese (≥25 kg/m2). Cox proportional hazards models were used to calculate hazard ratios and 95% confidence intervals for cardiovascular death according to WC and BMI in patients. Results. 492 patients with PPMs implantation were analyzed (mean age: 71.9 ± 10.8 years; 55.1% men (n = 271)). Data showed that after a mean follow-up 67.2 ± 17.5 months, 24 (4.9%) patients had experienced cardiovascular death and 71 (14.4%) were cases of all-cause mortality. Men in the third quartile of WC had an HR of 10.67 (Model 4, 95% CI: 1.00–115.21, p trend = 0.04) for cardiovascular death. However, the association disappeared in female patients (Model 4, HR = 3.99, 95% CI: 0.37–42.87, p trend = 0.25). There was no association between BMI and cardiovascular death or all-cause mortality in both male and female patients. Conclusions. Abdominal obesity was associated with an increased risk of cardiovascular death in patients with PPMs, and this relationship was only in male patients.


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## Body

## 1. Introduction

Obesity is a worldwide problem; approximately, a third of the world’s population is considered obese [1]. Previous studies have found that obesity can lead to left atrial enlargement, atrial fibrosis, atrioventricular block, and even sudden cardiac death [2]. Cardiac implantable electronic devices (CIEDs), which include permanent pacemakers (PPMs), implantable cardioverter-defibrillators (ICDs), and cardiac resynchronization therapy (CRT), are well-known methods in the treatment of cardiac arrhythmia diseases. PPMs among those are the most widely used [3]. Obesity is considered a risk factor for mortality [4]. However, there is still ongoing debate regarding the effect of obesity in patients implanted with CIEDs. Some epidemiologic studies demonstrated that obese or overweight patients with ICD may have better clinical outcomes, a phenomenon termed the “obesity paradox” [5, 6]. Nowadays, most studies define obesity using the body mass index (BMI), which is an imperfect measure of obesity because it does not reflect body fat distribution or discriminate by body shape [7].Compared to BMI, waist circumference (WC) is a more effective measure of obesity because it strongly correlates with visceral adipose tissue [8]. Many epidemiologic and clinical studies have demonstrated the association between WC and mortality [9–11]. Due to the fact that adipose tissue distribution varies between the sexes [12], some studies show that men with larger WC are at higher risk of mortality or cardiovascular events than women [9, 13]. Therefore, it is also necessary to investigate the role of sex differences in the relationship between WC and cardiovascular outcome among patients with CIEDs.In this study, we aimed to determine the relationship between WC and cardiovascular outcome in patients with PPMs and investigate the sex difference in the relationship between WC and cardiovascular death. We hypothesized that, compared to patients with higher WC, patients with lower WC would have better outcomes, especially among male patients.


## 2. Methods

### 2.1. Study Design and Population

We conducted a retrospective cohort from the BIOTRONIK Home Monitoring (HM) database, which collected data from patients who prepared to implant PPMs (BIOTRONIK, Berlin, Germany) with BIOTRONIK HM function from May 2010 to April 2014 in China. After implantation, all equipment was programmed to provide continuous patient monitoring data. Regular follow-up was conducted for all enrolled patients after they were discharged. The clinical research coordinator confirmed the status of the patient immediately by contacting the family if the patient’s daily transmission was interrupted. In our study, patients from Fuwai Hospital were analyzed. The present study complied with the Declaration of Helsinki and was approved by the Ethics Committee of Fuwai Hospital. All study participants provided oral informed consent.We retrospectively reviewed records of patients in the HM database who were hospitalized at Fuwai Hospital. The clinical characteristics, comorbidities, echocardiography at admission, medication at discharge, and WC were collected from the Fuwai hospital medical record system. Among the 2009 patients with PPMs implantation in database, 534 hospitalized in Fuwai hospital, 40 patients with incomplete medical record, 2 patients with a single-chamber PPM, and finally, 492 patients constituted the study population.


### 2.2. WC Measurement and Groups

WC was measured over bare skin at the smallest point between the iliac crest and the tenth rib [14]. Because the relationship between adverse outcomes and WC was not completely linear [15], patients were classified into 3 groups according to WC as sex-specific quartiles. BMI was calculated as weight in kilograms divided by the square of the person’s height in meters. The patients were classified as normal (≤22.9 kg/m2), overweight (23–24.9 kg/m2), and obese (≥25 kg/m2) according to the WHO definition for Asian populations [16].


### 2.3. Endpoints

We abstracted death dates and causes of death from the HM database through May 2018. The cause of death was abstracted from the death certificate form that was submitted to the HM database. If the exact cause of death was unknown but the date of death was known, we classified these deaths as other causes of death. The primary endpoint of the present study was cardiovascular death (including acute myocardial infarction, sudden cardiac death, death due to heart failure, stroke, cardiovascular procedures, cardiovascular hemorrhage, and other cardiovascular causes) [17], and the secondary endpoint was all-cause mortality.


### 2.4. Statistical Methods

Continuous variables are presented as means ± standard deviations, and categorical variables are presented as numbers and percentages. Baseline characteristics were compared among the groups using one-way analysis of variance (one-way ANOVA) for continuous variables or theχ2 test or Fisher exact tests for categorical variables. Rates of cardiovascular death and all-cause mortality were calculated, and between-group differences were compared using the chi-squared test. Cox proportional hazard regression analysis was used to evaluate the association between endpoint events in the different WC and BMI groups. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to evaluate the impact of WC and BMI. Model 1 was unadjusted, model 2 was adjusted for age, model 3 was adjusted for age and WC/BMI, while model 4 was adjusted for factors listed in model 3 and potential mediators of causal pathways, such as New York Heart Association class, structure heart disease, hypertension, diabetes, atrial fibrillation, heart rate, atrial pacing, ventricular pacing, left ventricular ejection fraction, left atrial dimension, left ventricular end-systolic dimension, and medication (including angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, beta-blocker, amiodarone, calcium channel clockers, digitalis, statins, and aspirin).Interaction and stratified analyses were performed for age, New York Heart Association classes I–II, structural heart disease, hypertension, diabetes, atrial fibrillation, and medication. We also performed several sensitivity analyses to test the relationship between WC and the endpoints using various WC cut-offs provided by the Joint Committee for Developing Chinese Guidelines (JCDCG) [18], and by excluding participants with BMI < 18.5 kg/m2 or those with follow-up time of less than 1 year because these patients might have had other unknown conditions.A value ofp<0.05 was considered significant, and all statistical analyses were performed using R, Version 3.4.3 (R Foundation for Statistical Computing, Vienna, Austria).


## 2.1. Study Design and Population

We conducted a retrospective cohort from the BIOTRONIK Home Monitoring (HM) database, which collected data from patients who prepared to implant PPMs (BIOTRONIK, Berlin, Germany) with BIOTRONIK HM function from May 2010 to April 2014 in China. After implantation, all equipment was programmed to provide continuous patient monitoring data. Regular follow-up was conducted for all enrolled patients after they were discharged. The clinical research coordinator confirmed the status of the patient immediately by contacting the family if the patient’s daily transmission was interrupted. In our study, patients from Fuwai Hospital were analyzed. The present study complied with the Declaration of Helsinki and was approved by the Ethics Committee of Fuwai Hospital. All study participants provided oral informed consent.We retrospectively reviewed records of patients in the HM database who were hospitalized at Fuwai Hospital. The clinical characteristics, comorbidities, echocardiography at admission, medication at discharge, and WC were collected from the Fuwai hospital medical record system. Among the 2009 patients with PPMs implantation in database, 534 hospitalized in Fuwai hospital, 40 patients with incomplete medical record, 2 patients with a single-chamber PPM, and finally, 492 patients constituted the study population.


## 2.2. WC Measurement and Groups

WC was measured over bare skin at the smallest point between the iliac crest and the tenth rib [14]. Because the relationship between adverse outcomes and WC was not completely linear [15], patients were classified into 3 groups according to WC as sex-specific quartiles. BMI was calculated as weight in kilograms divided by the square of the person’s height in meters. The patients were classified as normal (≤22.9 kg/m2), overweight (23–24.9 kg/m2), and obese (≥25 kg/m2) according to the WHO definition for Asian populations [16].


## 2.3. Endpoints

We abstracted death dates and causes of death from the HM database through May 2018. The cause of death was abstracted from the death certificate form that was submitted to the HM database. If the exact cause of death was unknown but the date of death was known, we classified these deaths as other causes of death. The primary endpoint of the present study was cardiovascular death (including acute myocardial infarction, sudden cardiac death, death due to heart failure, stroke, cardiovascular procedures, cardiovascular hemorrhage, and other cardiovascular causes) [17], and the secondary endpoint was all-cause mortality.


## 2.4. Statistical Methods

Continuous variables are presented as means ± standard deviations, and categorical variables are presented as numbers and percentages. Baseline characteristics were compared among the groups using one-way analysis of variance (one-way ANOVA) for continuous variables or theχ2 test or Fisher exact tests for categorical variables. Rates of cardiovascular death and all-cause mortality were calculated, and between-group differences were compared using the chi-squared test. Cox proportional hazard regression analysis was used to evaluate the association between endpoint events in the different WC and BMI groups. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to evaluate the impact of WC and BMI. Model 1 was unadjusted, model 2 was adjusted for age, model 3 was adjusted for age and WC/BMI, while model 4 was adjusted for factors listed in model 3 and potential mediators of causal pathways, such as New York Heart Association class, structure heart disease, hypertension, diabetes, atrial fibrillation, heart rate, atrial pacing, ventricular pacing, left ventricular ejection fraction, left atrial dimension, left ventricular end-systolic dimension, and medication (including angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, beta-blocker, amiodarone, calcium channel clockers, digitalis, statins, and aspirin).Interaction and stratified analyses were performed for age, New York Heart Association classes I–II, structural heart disease, hypertension, diabetes, atrial fibrillation, and medication. We also performed several sensitivity analyses to test the relationship between WC and the endpoints using various WC cut-offs provided by the Joint Committee for Developing Chinese Guidelines (JCDCG) [18], and by excluding participants with BMI < 18.5 kg/m2 or those with follow-up time of less than 1 year because these patients might have had other unknown conditions.A value ofp<0.05 was considered significant, and all statistical analyses were performed using R, Version 3.4.3 (R Foundation for Statistical Computing, Vienna, Austria).


## 3. Results

### 3.1. Baseline Characteristics of the Included Patients

Detailed baseline characteristics of the patients included in the study are provided in Table1. The mean age of the study cohort was 71.9 ± 10.8 years and it had 271 men (55.1%) more than women. Men patients had more WC (as continue variable or categorical variable), older, heart rate, left ventricular ejection fraction and left ventricular end-systolic dimension (p value for all ≤0.05).Table 1
Baseline clinical characteristics.
TotalMenWomenp valueN492271221WC (cm; mean ± SD)84.5 ± 12.787.4 ± 12.580.1 ± 11.8<0.001WC quartiles0.031131 (26.6)60 (22.1)71 (32.1)2174 (35.4)98 (36.2)76 (34.4)3187 (38.0)113 (41.7)74 (33.5)BMI (kg/m2; mean ± SD)23.5 ± 2.723.8 ± 2.623.3 ± 2.90.07Age at implantation (year; mean ± SD)71.9 ± 10.873.8 ± 10.369.7 ± 11.0<0.01NYHA class I-II (%)461 (93.7)252 (93.0)209 (94.6)0.48Structure heart disease (%)235 (47.8)133 (49.1)102 (46.2)0.52Hypertension (%)253 (51.4)139 (51.3)114 (51.6)0.95Diabetes (%)67 (13.6)35 (12.9)32 (14.5)0.62Atrial fibrillation (%)70 (14.2)40 (14.8)30 (13.6)0.71Heart rate (bpm)54.5 ± 10.555.7 ± 13.953.2 ± 15.20.01Atrial pacing (%)41.2 ± 36.239.2 ± 36.243.7 ± 36.10.17Ventricular pacing (%)59.7 ± 41.661.3 ± 40.357.7 ± 43.20.87LVEF (%)42.7 ± 14.959.2 ± 10.961.6 ± 9.8<0.01LAD (mm)35.1 ± 7.035.2 ± 7.034.9 ± 7.00.58LVEDD (mm)48.9 ± 7.549.4 ± 5.748.2 ± 9.3<0.01Medications at discharge (%)ACEI/ARB126 (25.6)70 (25.8)56 (25.3)0.90Beta-blockers143 (29.1)84 (31.0)59 (26.7)0.26Amiodarone40 (8.1)19 (7.0)21 (9.5)0.32CCB109 (22.2)62 (22.9)47 (21.3)0.67Digitalis23 (4.7)12 (4.4)11 (5.0)Statins115 (23.4)64 (23.6)51 (23.1)0.89Aspirin152 (30.9)82 (30.3)70 (31.7)0.74Abbreviations: ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; BMI = body mass index; LVEF = left ventricular ejection fraction; LAD = left atrial dimension; LVEDD = left ventricular end-systolic dimension; NYHA = New York heart association; CCB = calcium channel clockers; WC = waist circumference.


### 3.2. Association of WC with Cardiovascular Death and All-Cause Mortality

Table2 shows the association between WC quartiles and cardiovascular death in the study population. Multivariable Cox regression analyses showed that compared with those in the first quartile of WC, men in the third quartile of WC had a HR of 10.67 for cardiovascular death (model 4, 95 CI% = 1.00–115.21; p trend = 0.04). Interestingly, higher WC was not associated with a greater risk of cardiovascular death in women PPM patients (model 4; HR = 3.99, 95% CI = 0.37–42.87; p trend = 0.25). For all-cause mortality, higher WC was significantly related to a greater risk of all-cause mortality in men (quartile 3 vs. quartile 1; HR = 5.42, 95% CI = 1.72–17.07; quartile 2 vs. quartile 1; HR = 3.28, 95% CI = 1.05–10.23) in a linear fashion (model 4, p trend = 0.003). However, this association disappeared in female patients after adjusting for confounds (model 4: HR = 2.30, 95% CI = 0.44–11.92, p trend = 0.51) (Table 3).Table 2
Quartiles of waist circumference and cardiovascular death.
WCHazard radio (95% CI)Model 1Model 2Model 3Model 4Men1st quartileRefRefRefRef2nd quartile3.60 (0.43, 29.93)3.90 (0.47, 32.44)4.54 (0.53, 39.18)4.64 (0.44, 49.27)3rd quartile4.81 (0.61, 37.96)5.51 (0.70, 43.66)6.75 (0.80, 56.71)10.67 (1.00, 115.21)p value for trend0.130.090.070.04Women1st quartileRefRefRefRef2nd quartile1.48 (0.25, 8.90)1.50 (0.25, 9.01)1.65 (0.26, 10.45)2.26 (0.20, 26.22)3rd quartile1.50 (0.25, 8.97)1.57 (0.26, 9.53)1.92 (0.26, 14.07)3.99 (0.37, 42.87)p value for trend0.690.650.540.25Model 1: unadjusted; model 2: adjusted for age; model 3: adjusted for age and BMI; model 4: adjusted for factors in model 3 and NYHA class, structure heart disease, hypertension, diabetes, atrial fibrillation, heart rate, atrial pacing, ventricular pacing, LVEF, LAD, LVEDD, and medication at discharge (including ACEI/ARB, beta-blockers, amiodarone, CCB, digitalis, statins, and aspirin). Abbreviations: ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; BMI = body mass index; LVEF = left ventricular ejection fraction; LAD = left atrial dimension; LVEDD = left ventricular end-systolic dimension; NYHA = New York heart association; CCB = calcium channel clockers.Table 3
Quartiles of waist circumference and all-cause mortality.
WCHazard radio (95% CI)Model 1Model 2Model 3Model 4Men1st quartileRefRefRefRef2nd quartile3.22 (1.10, 9.43)3.63 (1.24, 10.64)3.71 (1.23, 11.12)3.28 (1.05, 10.23)3rd quartile3.95 (1.38, 11.25)4.73 (1.65, 13.53)4.85 (1.63, 14.44)5.42 (1.72, 17.07)p value for trend0.010.0040.0070.003Women1st quartileRefRefRefRef2nd quartile2.57 (0.80, 8.23)2.73 (0.85, 8.83)3.14 (0.94, 10.46)3.11 (0.73, 13.32)3rd quartile1.29 (0.35, 4.82)1.5 (0.40, 5.69)1.96 (0.47, 8.15)2.30 (0.44, 11.92)p value for trend0.900.700.470.51Model 1: unadjusted; model 2: adjusted for age; model 3: adjusted for age and BMI; model 4: adjusted for factors in model 3 and NYHA class, structure heart disease, hypertension, diabetes, atrial fibrillation, heart rate, atrial pacing, ventricular pacing, LVEF, LAD, LVEDD, and medication at discharge (including ACEI/ARB, beta-blockers, amiodarone, CCB, digitalis, statins, and aspirin). Abbreviations: ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; BMI = body mass index; LVEF = left ventricular ejection fraction; LAD = left atrial dimension; LVEDD = left ventricular end-systolic dimension; NYHA = New York heart association; CCB = calcium channel clockers.


### 3.3. Association of BMI with Cardiovascular Death and All-Cause Mortality

Table4 shows the association between BMI and cardiovascular death in different sexes of patients. There was no association between BMI and cardiovascular death in both male and female patients (men: model 4, overweight vs. normal: HR = 2.07, 95 CI% = 0.48–9.03; obesity vs. normal: HR = 1.86, 95 CI% = 0.42–8.18; p trend = 0.40; women: model 4, overweight vs. normal: HR = 1.19, 95 CI% = 0.17–8.12; obesity vs. normal: HR = 0.56, 95 CI% = 0.04–8.41; p trend = 0.77). The results are the same in all-cause mortality (men: model 4, overweight vs. normal: HR = 1.70, 95 CI% = 0.82–3.51; obesity vs. normal: HR = 1.27, 95 CI% = 0.58–2.78; p trend = 0.53; women: model 4, overweight vs. normal: HR = 0.64, 95 CI% = 0.20–2.06; obesity vs. normal: HR = 0.20, 95 CI% = 0.03–1.15; p trend = 0.07) (Table 5).Table 4
Association between body mass index and cardiovascular death.
WCHazard radio (95% CI)Model 1Model 2Model 3Model 4MenNormalRefRefRefRefOverweight0.86 (0.24, 3.06)0.93 (0.26, 3.30)0.86 (0.24, 3.11)2.07 (0.48, 9.03)Obesity1.45 (0.47, 4.49)1.83 (0.58, 5.79)1.53 (0.44, 5.34)1.86 (0.42, 8.18)p value for trend0.530.320.510.40WomenNormalRefRefRefRefOverweight1.07 (0.24, 4.79)1.06 (0.24, 4.74)0.88 (0.19, 4.17)1.19 (0.17, 8.12)Obesity0.47 (0.05, 4.25)0.48 (0.05, 4.26)0.35 (0.04, 3.49)0.56 (0.04, 8.41)p value for trend0.560.560.390.77Model 1: unadjusted; model 2: adjusted for age; model 3: adjusted for age and WC; model 4: adjusted for factors in model 3 and NYHA class, structure heart disease, hypertension, diabetes, atrial fibrillation, heart rate, atrial pacing, ventricular pacing, LVEF, LAD, LVEDD, and medication at discharge (including ACEI/ARB, beta-blockers, amiodarone, CCB, digitalis, statins, and aspirin). Abbreviations: ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; LVEF = left ventricular ejection fraction; LAD = left atrial dimension; LVEDD = left ventricular end-systolic dimension; NYHA = New York heart association; CCB = calcium channel clockers; WC = waist circumference.Table 5
Association between body mass index and all-cause mortality.
WCHazard radio (95% CI)Model 1Model 2Model 3Model 4MenNormalRefRefRefRefOverweight1.41 (0.73, 2.74)1.63 (0.84, 3.18)1.47 (0.75, 2.89)1.70 (0.82, 3.51)Obesity1.44 (0.73, 2.82)1.93 (0.97, 3.83)1.52 (0.73, 3.17)1.27 (0.58, 2.78)p value for trend0.280.060.260.53WomenNormalRefRefRefRefOverweight0.77 (0.29, 2.09)0.78 (0.29, 2.11)0.67 (0.24, 1.86)0.64 (0.20, 2.06)Obesity0.34 (0.08, 1.54)0.36 (0.08, 1.63)0.28 (0.06, 1.33)0.20 (0.03, 1.15)p value for trend0.150.180.100.07Model 1: unadjusted; model 2: adjusted for age; model 3: adjusted for age and WC; model 4: adjusted for factors in model 3 and NYHA class, structure heart disease, hypertension, diabetes, atrial fibrillation, heart rate, atrial pacing, ventricular pacing, LVEF, LAD, LVEDD, and medication at discharge (including ACEI/ARB, beta-blockers, amiodarone, CCB, digitalis, statins, and aspirin). Abbreviations: ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; LVEF = left ventricular ejection fraction; LAD = left atrial dimension; LVEDD = left ventricular end-systolic dimension; NYHA = New York heart association; CCB = calcium channel clockers; WC = waist circumference.


### 3.4. Interaction and Sensitivity Analyses

Figures1 and 2 show the association between WC and the clinical endpoints in different sexes. In the study, we did not detect any interaction between WC and age, New York Heart Association classes I–II, structural heart disease, hypertension, diabetes, atrial fibrillation, angiotensin-converting enzyme inhibitor/angiotensin receptor blockers, beta-blockers, amiodarone, calcium channel clockers, digitalis, statins, and aspirin use in cardiovascular death and all-cause mortality for men (Figures 1(a) and 1(b)). However, we did find use of amiodarone moderated the associated an effect of WC and cardiovascular death not in all-cause mortality in women, which suggested that an effect of WC on cardiovascular death among those women use of amiodarone than those without (Figures 2(a) and 2(b)).Figure 1
Analyses of cardiovascular death according to sex. (a) Data for male patients are shown. (b) Data for female patients are shown. Each stratification was adjusted for all factors in Model 4, except for the stratification factor. Abbreviation: ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor; NYHA = New York Heart Association; CCB = calcium channel clockers; WC = waist circumference.
(a)(b)Figure 2
Analyses of all-cause mortality according to sex. (a) Data for male patients are shown. (b) Data for female patients are shown. Each stratification was adjusted for all factors in Model 4, except for the stratification factor. Abbreviation: ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor; NYHA = New York Heart Association; CCB = calcium channel clockers; WC = waist circumference.
(a)(b)In supplements, to verify the association between WC and clinical endpoints, namely cause-specific mortality among men and women patients, we first used a cut-off that was different from that issued by the JCDCG, even though it is more suitable for the Chinese population. Next, we excluded cases with a BMI < 18.5 or those with follow-up less than 1 year as they may have a greater risk mortality due to other reasons. Despite these exclusions, sensitive analysis showed that our results on WC and cardiovascular death remained robust among both male and female patients with PPMs (TablesS1 and S2).


## 3.1. Baseline Characteristics of the Included Patients

Detailed baseline characteristics of the patients included in the study are provided in Table1. The mean age of the study cohort was 71.9 ± 10.8 years and it had 271 men (55.1%) more than women. Men patients had more WC (as continue variable or categorical variable), older, heart rate, left ventricular ejection fraction and left ventricular end-systolic dimension (p value for all ≤0.05).Table 1
Baseline clinical characteristics.
TotalMenWomenp valueN492271221WC (cm; mean ± SD)84.5 ± 12.787.4 ± 12.580.1 ± 11.8<0.001WC quartiles0.031131 (26.6)60 (22.1)71 (32.1)2174 (35.4)98 (36.2)76 (34.4)3187 (38.0)113 (41.7)74 (33.5)BMI (kg/m2; mean ± SD)23.5 ± 2.723.8 ± 2.623.3 ± 2.90.07Age at implantation (year; mean ± SD)71.9 ± 10.873.8 ± 10.369.7 ± 11.0<0.01NYHA class I-II (%)461 (93.7)252 (93.0)209 (94.6)0.48Structure heart disease (%)235 (47.8)133 (49.1)102 (46.2)0.52Hypertension (%)253 (51.4)139 (51.3)114 (51.6)0.95Diabetes (%)67 (13.6)35 (12.9)32 (14.5)0.62Atrial fibrillation (%)70 (14.2)40 (14.8)30 (13.6)0.71Heart rate (bpm)54.5 ± 10.555.7 ± 13.953.2 ± 15.20.01Atrial pacing (%)41.2 ± 36.239.2 ± 36.243.7 ± 36.10.17Ventricular pacing (%)59.7 ± 41.661.3 ± 40.357.7 ± 43.20.87LVEF (%)42.7 ± 14.959.2 ± 10.961.6 ± 9.8<0.01LAD (mm)35.1 ± 7.035.2 ± 7.034.9 ± 7.00.58LVEDD (mm)48.9 ± 7.549.4 ± 5.748.2 ± 9.3<0.01Medications at discharge (%)ACEI/ARB126 (25.6)70 (25.8)56 (25.3)0.90Beta-blockers143 (29.1)84 (31.0)59 (26.7)0.26Amiodarone40 (8.1)19 (7.0)21 (9.5)0.32CCB109 (22.2)62 (22.9)47 (21.3)0.67Digitalis23 (4.7)12 (4.4)11 (5.0)Statins115 (23.4)64 (23.6)51 (23.1)0.89Aspirin152 (30.9)82 (30.3)70 (31.7)0.74Abbreviations: ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; BMI = body mass index; LVEF = left ventricular ejection fraction; LAD = left atrial dimension; LVEDD = left ventricular end-systolic dimension; NYHA = New York heart association; CCB = calcium channel clockers; WC = waist circumference.


## 3.2. Association of WC with Cardiovascular Death and All-Cause Mortality

Table2 shows the association between WC quartiles and cardiovascular death in the study population. Multivariable Cox regression analyses showed that compared with those in the first quartile of WC, men in the third quartile of WC had a HR of 10.67 for cardiovascular death (model 4, 95 CI% = 1.00–115.21; p trend = 0.04). Interestingly, higher WC was not associated with a greater risk of cardiovascular death in women PPM patients (model 4; HR = 3.99, 95% CI = 0.37–42.87; p trend = 0.25). For all-cause mortality, higher WC was significantly related to a greater risk of all-cause mortality in men (quartile 3 vs. quartile 1; HR = 5.42, 95% CI = 1.72–17.07; quartile 2 vs. quartile 1; HR = 3.28, 95% CI = 1.05–10.23) in a linear fashion (model 4, p trend = 0.003). However, this association disappeared in female patients after adjusting for confounds (model 4: HR = 2.30, 95% CI = 0.44–11.92, p trend = 0.51) (Table 3).Table 2
Quartiles of waist circumference and cardiovascular death.
WCHazard radio (95% CI)Model 1Model 2Model 3Model 4Men1st quartileRefRefRefRef2nd quartile3.60 (0.43, 29.93)3.90 (0.47, 32.44)4.54 (0.53, 39.18)4.64 (0.44, 49.27)3rd quartile4.81 (0.61, 37.96)5.51 (0.70, 43.66)6.75 (0.80, 56.71)10.67 (1.00, 115.21)p value for trend0.130.090.070.04Women1st quartileRefRefRefRef2nd quartile1.48 (0.25, 8.90)1.50 (0.25, 9.01)1.65 (0.26, 10.45)2.26 (0.20, 26.22)3rd quartile1.50 (0.25, 8.97)1.57 (0.26, 9.53)1.92 (0.26, 14.07)3.99 (0.37, 42.87)p value for trend0.690.650.540.25Model 1: unadjusted; model 2: adjusted for age; model 3: adjusted for age and BMI; model 4: adjusted for factors in model 3 and NYHA class, structure heart disease, hypertension, diabetes, atrial fibrillation, heart rate, atrial pacing, ventricular pacing, LVEF, LAD, LVEDD, and medication at discharge (including ACEI/ARB, beta-blockers, amiodarone, CCB, digitalis, statins, and aspirin). Abbreviations: ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; BMI = body mass index; LVEF = left ventricular ejection fraction; LAD = left atrial dimension; LVEDD = left ventricular end-systolic dimension; NYHA = New York heart association; CCB = calcium channel clockers.Table 3
Quartiles of waist circumference and all-cause mortality.
WCHazard radio (95% CI)Model 1Model 2Model 3Model 4Men1st quartileRefRefRefRef2nd quartile3.22 (1.10, 9.43)3.63 (1.24, 10.64)3.71 (1.23, 11.12)3.28 (1.05, 10.23)3rd quartile3.95 (1.38, 11.25)4.73 (1.65, 13.53)4.85 (1.63, 14.44)5.42 (1.72, 17.07)p value for trend0.010.0040.0070.003Women1st quartileRefRefRefRef2nd quartile2.57 (0.80, 8.23)2.73 (0.85, 8.83)3.14 (0.94, 10.46)3.11 (0.73, 13.32)3rd quartile1.29 (0.35, 4.82)1.5 (0.40, 5.69)1.96 (0.47, 8.15)2.30 (0.44, 11.92)p value for trend0.900.700.470.51Model 1: unadjusted; model 2: adjusted for age; model 3: adjusted for age and BMI; model 4: adjusted for factors in model 3 and NYHA class, structure heart disease, hypertension, diabetes, atrial fibrillation, heart rate, atrial pacing, ventricular pacing, LVEF, LAD, LVEDD, and medication at discharge (including ACEI/ARB, beta-blockers, amiodarone, CCB, digitalis, statins, and aspirin). Abbreviations: ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; BMI = body mass index; LVEF = left ventricular ejection fraction; LAD = left atrial dimension; LVEDD = left ventricular end-systolic dimension; NYHA = New York heart association; CCB = calcium channel clockers.


## 3.3. Association of BMI with Cardiovascular Death and All-Cause Mortality

Table4 shows the association between BMI and cardiovascular death in different sexes of patients. There was no association between BMI and cardiovascular death in both male and female patients (men: model 4, overweight vs. normal: HR = 2.07, 95 CI% = 0.48–9.03; obesity vs. normal: HR = 1.86, 95 CI% = 0.42–8.18; p trend = 0.40; women: model 4, overweight vs. normal: HR = 1.19, 95 CI% = 0.17–8.12; obesity vs. normal: HR = 0.56, 95 CI% = 0.04–8.41; p trend = 0.77). The results are the same in all-cause mortality (men: model 4, overweight vs. normal: HR = 1.70, 95 CI% = 0.82–3.51; obesity vs. normal: HR = 1.27, 95 CI% = 0.58–2.78; p trend = 0.53; women: model 4, overweight vs. normal: HR = 0.64, 95 CI% = 0.20–2.06; obesity vs. normal: HR = 0.20, 95 CI% = 0.03–1.15; p trend = 0.07) (Table 5).Table 4
Association between body mass index and cardiovascular death.
WCHazard radio (95% CI)Model 1Model 2Model 3Model 4MenNormalRefRefRefRefOverweight0.86 (0.24, 3.06)0.93 (0.26, 3.30)0.86 (0.24, 3.11)2.07 (0.48, 9.03)Obesity1.45 (0.47, 4.49)1.83 (0.58, 5.79)1.53 (0.44, 5.34)1.86 (0.42, 8.18)p value for trend0.530.320.510.40WomenNormalRefRefRefRefOverweight1.07 (0.24, 4.79)1.06 (0.24, 4.74)0.88 (0.19, 4.17)1.19 (0.17, 8.12)Obesity0.47 (0.05, 4.25)0.48 (0.05, 4.26)0.35 (0.04, 3.49)0.56 (0.04, 8.41)p value for trend0.560.560.390.77Model 1: unadjusted; model 2: adjusted for age; model 3: adjusted for age and WC; model 4: adjusted for factors in model 3 and NYHA class, structure heart disease, hypertension, diabetes, atrial fibrillation, heart rate, atrial pacing, ventricular pacing, LVEF, LAD, LVEDD, and medication at discharge (including ACEI/ARB, beta-blockers, amiodarone, CCB, digitalis, statins, and aspirin). Abbreviations: ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; LVEF = left ventricular ejection fraction; LAD = left atrial dimension; LVEDD = left ventricular end-systolic dimension; NYHA = New York heart association; CCB = calcium channel clockers; WC = waist circumference.Table 5
Association between body mass index and all-cause mortality.
WCHazard radio (95% CI)Model 1Model 2Model 3Model 4MenNormalRefRefRefRefOverweight1.41 (0.73, 2.74)1.63 (0.84, 3.18)1.47 (0.75, 2.89)1.70 (0.82, 3.51)Obesity1.44 (0.73, 2.82)1.93 (0.97, 3.83)1.52 (0.73, 3.17)1.27 (0.58, 2.78)p value for trend0.280.060.260.53WomenNormalRefRefRefRefOverweight0.77 (0.29, 2.09)0.78 (0.29, 2.11)0.67 (0.24, 1.86)0.64 (0.20, 2.06)Obesity0.34 (0.08, 1.54)0.36 (0.08, 1.63)0.28 (0.06, 1.33)0.20 (0.03, 1.15)p value for trend0.150.180.100.07Model 1: unadjusted; model 2: adjusted for age; model 3: adjusted for age and WC; model 4: adjusted for factors in model 3 and NYHA class, structure heart disease, hypertension, diabetes, atrial fibrillation, heart rate, atrial pacing, ventricular pacing, LVEF, LAD, LVEDD, and medication at discharge (including ACEI/ARB, beta-blockers, amiodarone, CCB, digitalis, statins, and aspirin). Abbreviations: ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; LVEF = left ventricular ejection fraction; LAD = left atrial dimension; LVEDD = left ventricular end-systolic dimension; NYHA = New York heart association; CCB = calcium channel clockers; WC = waist circumference.


## 3.4. Interaction and Sensitivity Analyses

Figures1 and 2 show the association between WC and the clinical endpoints in different sexes. In the study, we did not detect any interaction between WC and age, New York Heart Association classes I–II, structural heart disease, hypertension, diabetes, atrial fibrillation, angiotensin-converting enzyme inhibitor/angiotensin receptor blockers, beta-blockers, amiodarone, calcium channel clockers, digitalis, statins, and aspirin use in cardiovascular death and all-cause mortality for men (Figures 1(a) and 1(b)). However, we did find use of amiodarone moderated the associated an effect of WC and cardiovascular death not in all-cause mortality in women, which suggested that an effect of WC on cardiovascular death among those women use of amiodarone than those without (Figures 2(a) and 2(b)).Figure 1
Analyses of cardiovascular death according to sex. (a) Data for male patients are shown. (b) Data for female patients are shown. Each stratification was adjusted for all factors in Model 4, except for the stratification factor. Abbreviation: ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor; NYHA = New York Heart Association; CCB = calcium channel clockers; WC = waist circumference.
(a)(b)Figure 2
Analyses of all-cause mortality according to sex. (a) Data for male patients are shown. (b) Data for female patients are shown. Each stratification was adjusted for all factors in Model 4, except for the stratification factor. Abbreviation: ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor; NYHA = New York Heart Association; CCB = calcium channel clockers; WC = waist circumference.
(a)(b)In supplements, to verify the association between WC and clinical endpoints, namely cause-specific mortality among men and women patients, we first used a cut-off that was different from that issued by the JCDCG, even though it is more suitable for the Chinese population. Next, we excluded cases with a BMI < 18.5 or those with follow-up less than 1 year as they may have a greater risk mortality due to other reasons. Despite these exclusions, sensitive analysis showed that our results on WC and cardiovascular death remained robust among both male and female patients with PPMs (TablesS1 and S2).


## 4. Discussion

In our post-hoc analysis involving patients with PPMs, cases showed that unlike BMI, a higher WC was associated with a higher risk of cardiovascular death. This relationship was only observed in male patients.To the best of our knowledge, this is the first study to specifically examine the association between WC and clinical outcomes and focus on the gender difference between abdominal obesity and cardiovascular death in patients with PPMs. Our finding expands on existing knowledge from previous studies on CIED recipients.Easier studies conducted in this field focused on obese patients with ICD, and the results showed an “obesity paradox” [19, 20]. In the study by Echouffo-Tcheugui et al. found that compared to normal-weight individuals, ≥65 years old patients with CRT-D who were underweight (BMI: 25–29.9 kg/m2) had greater risks of mortality and hospitalization, while those who were overweight (BMI ≥ 30 kg/m2) or obese had a lower mortality risk [19]. In a similar study by Zhou et al., BMI ≥ 24 kg/m2 patients with ICD experienced a decreased all-cause death [20]. In our study, we found that BMI had no association with cardiovascular death. The result was consisted with previous study. Gregory et al. analyzed 8,079 patients who underwent coronary angiography in the APPROACH-NL database, and they found that there was no significant association between BMI and all-cause or cardiac-specific mortality after adjusting for potential confounders [21]. Also, several studies have demonstrated that cardiovascular risk is linked to body fat storage and not to BMI itself [22, 23]. Therefore, results using BMI as a criterion for determining obesity must be evaluated in light of the inherent limitations of BMI as an index of adiposity. Further, methodological biases and the presence of confounding factors, such as physical activity, smoking, and cardiorespiratory fitness, may have resulted in erroneous findings [24].In contrast, WC, as a clinically useful and easy method of assessing central obesity, has been shown to have an excellent correlation with abdominal imaging, cardiovascular disease risk, and mortality with or without adjustment for BMI [25]. Recently, a consensus statement from the International Atherosclerosis Society (IAS) and International Chair on Cardiometabolic Risk (ICCR) Working Group suggests that BMI alone is insufficient to properly assess adiposity in patients and that WC should be adopted as a routine measure in clinical practice alongside BMI to classify obesity [26]. In addition to this, compared to BMI, WC is an easier and more intuitive measure to demonstrate a patient’s health status.Although the mechanism underlying the association between WC and cardiovascular death has not been elucidated, several factors can explain this phenomenon. First, compared to fat stored in other parts of the body, abdominal fat greatly affects inflammation [27]. Further, recently, inflammatory markers such as C-reactive protein have been reported to be associated with cardiovascular mortality [28]. Second, abdominal visceral adiposity is associated with impaired inhibition of adipocyte lipolysis and elevated levels of non-esterified fatty acids, leading to vascular endothelial dysfunction [29]. Third, adipose tissue also releases a variety of cytokines, such as leptin, adiponectin, and interleukin-6, which result in insulin resistance, thereby causing hypercholesterolemia and glucose intolerance [30].In our study, we also found that WC had a strong positive association with cardiovascular death only in men but not in female patients. This result is consistent with that of a previous study. Xing et al. [31] found that a higher WC in male T2DM patients alone was significantly associated with a higher risk of cardiovascular events. Similarly, Song et al. [32] used data from four European national registries to estimate cardiovascular death in relation to obesity and sex and found that men had higher cardiovascular death than women when obesity was defined by WC. Importantly, these associations remained statistically significant even after adjustment for other cardiac risk factors. A prospective study from Korea followed 23,263,878 subjects over a period of 6 years via the National Insurance Service health checkup and showed that WC increased all-cause mortality and that men had higher HRs for mortality than women [33].The observed sex differences in the association between WC and mortality in patients with PPMs may be related to the following factors: first, there are significant sex differences in body content and fat distribution. Women have more subcutaneous adipose tissue, while men have predominantly visceral adipose tissues [34]. Additionally, higher visceral adipose tissue in men is associated with elevated postprandial insulin and higher free fatty acid and triglyceride levels [35]. In women, the subcutaneous adipose tissue is associated with very little inflammation during obesity and has a greater capacity to absorb circulating free fatty acids and triglycerides, thereby providing a protective effect against obesity-related diseases [35]. Second, sex hormones may also play an important role in cardiovascular disease. Specifically, higher total testosterone in males is associated with an increased risk of coronary heart disease, while higher estradiol levels in females are associated with a lower risk of coronary heart disease [36].Due to the development of life expectancy and technology, the speed of CIEDs’ utilization increases annually. Recently, a worldwide report showed that nearly 40,728 patients per year were treated with PPMs implantation, and this number was larger than any other CIEDs in China [37]. Thus, it is important to effectively perform health management and assess accurately cardiovascular risk for these patients. Obesity is one of the most important indicators of cardiovascular health. However, most medical institutions still use BMI as the main criterion for determining obesity. This can lead to a missed opportunity to figure out the high-risk but neglected patients (i.e., those with a high WC but a normal BMI). Weight management is a crucial component of patients’ healthy lifestyle. And our results confirmed the importance of keeping fit.


### 4.1. Limitations

The present study has some limitations. First, we calculated WC only at baseline and did not reevaluate WC either after implantation or during follow-up. However, a previous study reported that changes in WC are not significantly associated with mortality [38]. Second, some residual confounding caused by unmeasured variables such as physical activity, dietary factors, and smoking may have affected the relation between WC and mortality. Third, our study is a single retrospective analysis, which might result in selective biases. Fourth, the follow-up time in our study was not quite long, so there were not too many clinical outcomes. We hope to continue this study to see whether this association will be more pronounced for different sexes in the future.


## 4.1. Limitations

The present study has some limitations. First, we calculated WC only at baseline and did not reevaluate WC either after implantation or during follow-up. However, a previous study reported that changes in WC are not significantly associated with mortality [38]. Second, some residual confounding caused by unmeasured variables such as physical activity, dietary factors, and smoking may have affected the relation between WC and mortality. Third, our study is a single retrospective analysis, which might result in selective biases. Fourth, the follow-up time in our study was not quite long, so there were not too many clinical outcomes. We hope to continue this study to see whether this association will be more pronounced for different sexes in the future.


## 5. Conclusion

The study demonstrates that abdominal obesity was associated with an increased risk of cardiovascular death in patients with PPMs, and this relationship was only in male patients.



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*Source: 4383508-2023-02-17.xml*