Gender-specific associations between weight-adjusted-waist index and peripheral arterial disease in adults: Evidence from NHANES 1999-2004

Abstract

The relationship between weight-adjusted-waist index (WWI, a newly developed obesity index) and peripheral arterial disease (PAD) is unclear. We aimed to explore the association between WWI and the prevalence of PAD in US adults. A total of 7,344 participants (males: 50.60%; females: 49.40%) from the 1999–2004 National Health and Nutrition Examination Survey (NHANES) were included in this study. WWI was calculated as waist circumference (WC) divided by the square root of weight. PAD was defined as an ankle-brachial index < 0.90 in either leg. The prevalence of PAD was 7.84%, which was respectively 3.72%, 7.23%, and 12.58% in WWI tertiles 1–3 (P < 0.001). WWI was positively associated with an elevated likelihood of PAD (OR = 1.25, 95% CI: 1.06–1.48), and the association was robust in stratified subgroups (all P for trend > 0.05). For male participants, there was a nearly linear relationship between WWI and PAD (OR = 1.35, 95% CI: 1.01–1.82). However, non-linear positive relationships were detected in females with an inflection point of 10.98 cm/√kg. A positive association was observed on the left of the inflection point (OR = 2.71, 95% CI: 1.27–5.78), while the association on the right was of no statistical significance (OR = 1.01, 95% CI: 0.77–1.33). In summary, WWI was significantly associated with an increased likelihood of PAD in US adults, with a differential association between males and females.

Introduction

Peripheral artery disease (PAD) is a growing public health challenge characterized by atherosclerotic narrowing and occlusion of the peripheral arteries ¹. It was reported in 2015 that more than 200 million people aged ≥ 25 years worldwide suffer from PAD, with the majority occurring in low- and middle-income countries ². Previous evidence has established that PAD is associated with an increased risk of various adverse clinical outcomes, such as ischemic stroke, acute myocardial infarction (AMI), and non-traumatic amputation ^{3, 4}. In a prospective cohort analysis, Criqui et al. discovered that PAD increased the mortality from cardiovascular disease by 5.9-fold and that of coronary artery disease by 6.6-fold ⁵. Hence, screening for the presence of PAD and implementing effective interventions are critical to reducing the burden of this condition.

Obesity, a state of abnormal fat accumulation induced by an impaired energy balance, has been recognized as a well-established and modifiable risk factor for atherosclerosis ^{6, 7}. Indeed, much evidence indicates that obesity—assessed by body mass index (BMI)—is associated with a significantly increased risk of PAD ^8–10. However, in recent years, an increasing number of studies have observed the “obesity survival paradox”, in which obese PAD patients exhibit better survival than their normal-weight counterparts ^11–13. This may be partly due to the fact that BMI does not differentiate between lean mass and fat mass ¹⁴. Although waist circumference (WC) has been proposed to more accurately reflect central obesity, it is also limited as a good obesity-related index due to its high correlation with BMI ¹⁵.

In this context, some investigators have proposed a new anthropometric index, the weight-adjusted-waist index (WWI), which standardizes WC for weight ¹⁶. Thus, WWI may combine the advantages of WC but weaken the correlation with BMI. Indeed, several studies have consistently revealed that WWI is a better predictor of albuminuria, hypertension (HTN), and cardiovascular death than traditional indicators ^17–19. Unfortunately, no previous research has examined the effect of WWI on PAD. Therefore, our study sought to investigate the association between WWI and PAD in adults using data from the National Health and Nutrition Examination Survey (NHANES).

Methods

Results

Baseline characteristics 

The baseline characteristics of the study population stratified by WWI tertiles are shown in Table 1. A total of 7,344 participants (males: 50.60%; females: 49.40%) with an average age of 60.18 ± 13.03 years were included in this study. The mean WWI was 11.16 ± 0.78 cm/√kg, and the ranges of tertiles 1-3 were 8.36- 10.81, 10.81-11.49, and 11.49-15.52 cm/√kg, respectively. Moreover, the prevalence of PAD was 7.84% (576 participants), which was respectively 3.72% (91 participants), 7.23% (177 participants), and 12.58% (308 participants) in WWI tertiles 1-3 (P <0.001). Individuals in the highest WWI tertile were predominated by older participants, and had higher BMI, WC, SBP, HbA1c, TC, TG, and SUA; higher prevalence of HTN, DM, and CHD; less alcohol intake; and lower educational level and DBP values (all P <0.001). 

Table 1. Baseline characteristics of the study population according to weight-adjusted-waist index tertiles.

Abbreviations: WWI, weight-adjusted-waist index; BMI, body mass index; WC, waist circumference; SBP, systolic blood pressure; DBP, diastolic blood pressure; TBiL, total bilirubin; AST, aspartate transaminase; ALT, alanine transaminase.

Associations between WWI and PAD

As shown in Table 2, elevated WWI was associated with an increased likelihood of PAD. After full adjustment (Model 3), every one unit increase in WWI was associated with 25% increased odds of PAD (OR = 1.25; 95% CI: 1.06-1.48). We further transformed WWI into categorical variables for sensitivity analysis. The adjusted OR was 1.53 (95% CI: 1.10-2.12) for Tertile 2 and 1.77 (95% CI: 1.26-2.49) for Tertile 3, indicating a stable positive association between WWI and increased risk of PAD with statistical significance (P for trend = 0.002).

Table 2. The association between weight-adjusted-waist index and peripheral arterial disease in total samples.

Abbreviations: WWI, weight-adjusted-waist index; PAD, peripheral arterial disease; 95% CI: 95% confidence interval; OR: odds ratio;

Model 1: No covariates were adjusted. 

Model 2: Adjusted for gender, age, race, education level, body mass index, systolic and diastolic blood pressure.

Model 3: Adjusted for model 2 + smoking status, alcohol intake, hemoglobin A1c, total bilirubin, aspartate transaminase, alanine transaminase, total cholesterol, triglycerides, serum creatinine, serum uric acid, hypertension, diabetes mellitus, and coronary heart disease.

Besides, the smooth curve fitting indicated that there was a nearly linear relationship between WWI and the risk of PAD in the total population (Figure 1).

Subgroup analysis

Subgroup analyses were conducted to explore the robustness of the association between WWI and PAD in different population settings. None of the stratifications, including gender (male and female), age (<60 years and ≥60 years), race (Mexican American, other Hispanic, non-Hispanic black, non-Hispanic white, and other races), education level (< high school, high school, and > high school), BMI (<30 kg/m² and ≥30 kg/m²), HTN (yes and no), DM (yes and no), and CHD (yes and no), significantly modified the association between WWI and PAD prevalence (all P for interaction > 0.05). The results indicated that the positive WWI-PAD association was stable in stratified subgroups and could be appropriate for various populations (Figure 2).

Non-linear positive association of WWI and PAD in females

Given the difference in body composition between males and females, analyses stratified by sex were further conducted. As shown in Table S1 (Supplementary Information), a significantly positive association between WWI and PAD prevalence was observed in male participants (Model 3: OR = 1.35, 95% CI: 1.01-1.82). Although there were similar trends in female participants, the difference was not statistically significant (Model 3: OR = 1.23, 95% CI: 0.99-1.52). 

We then used GAM and smooth curve fitting to evaluate the non-linearity for different sexes. The results show that there was a non-linear relationship between WWI and the prevalence of PAD in female participants, with a log-likelihood ratio test of 0.021 (Table 3; Figure 3). The inflection point was determined to be 10.98 cm/√kg using the two-piecewise linear regression model. On the left of the inflection point, a positive association between WWI and PAD was observed, with the adjusted OR being 2.71 (95% CI: 1.27-5.78). Nevertheless, no relationship with statistical significance was observed on the right of the inflection point (OR = 1.01, 95% CI: 0.77-1.33). Unlike females, a nearly linear relationship was detected in males (OR = 1.35, 95% CI: 1.01-1.82), with a log-likelihood ratio test of 0.317 (Table 3; Figure 3).

Table 3. Threshold effect analysis of WWI on PAD using a two-piecewise linear regression model.

Abbreviations: WWI, weight-adjusted-waist index; PAD, peripheral arterial disease; 95% CI: 95% confidence interval; OR: odds ratio.

^*Adjusted for gender (only for all participants), age, race, education level, body mass index, systolic and diastolic blood pressure, smoking status, alcohol intake, hemoglobin A1c, total bilirubin, aspartate transaminase, alanine transaminase, total cholesterol, triglycerides, serum creatinine, serum uric acid, hypertension, diabetes mellitus, and coronary heart disease.

WWI predicts PAD better than BMI and WC

The ROC curves were used to evaluate the discriminative ability of different indicators for PAD. As shown in Table 4 and Figure S2 (Supplementary Information), WWI showed the highest area under the curve (AUC) in both males (0.647; 95% CI: 0.615-0.680) and females (0.654; 95% CI: 0.623-0.685), with cut-off values of 11.12 and 11.36 cm/√kg, respectively. 

Table 4. Comparison of the ability of different obesity-related indices to predict peripheral artery disease.

Abbreviations: WWI, weight-adjusted-waist index; BMI, body mass index; WC, waist circumference; AUC, area under the curve; 95% CI, 95% confidence interval.

Discussion

In this nationally representative cross-sectional study, we observed that participants with increased WWI were significantly associated with an increased likelihood of PAD. The relationship was independent of multiple potential covariates including demographics, laboratory measurements, cardiovascular risk factors, and others. Subgroup analysis indicated that the WWI-PAD association was stable in different populations. Furthermore, non-linear positive relationships between WWI and the prevalence of PAD were detected in females, and the different correlations were found on the left and right sides of the inflection point (10.98 cm/√kg). Besides, WWI was superior to BMI and WC in predicting PAD, suggesting that the management of obesity evaluated by WWI may reduce the risk of PAD. 

To our knowledge, this is the first report assessing the association between WWI and PAD in a nationally representative population. As a new simple adiposity index, WWI has been investigated in various fields, especially related to cardiometabolic diseases ^{17-19, 22}. In a cohort study involving 465,629 individuals, Park et al. found that WWI was positively associated with cardiometabolic morbidity and cardiovascular death ¹⁶. Moreover, when compared to the lowest WWI subgroup (< 9.94 cm/√kg), Li et al. discovered that the highest WWI subgroup (≥ 10.91 cm/√kg) was associated with 50% increased risk of HTN ¹⁸. In addition, a cross-sectional study of 14,078 hypertensive patients by Zhao et al. aimed to investigate the relationship between WWI and hyperuricemia ²³. The results show that per one unit increase in WWI (Model 3), the risk of hyperuricemia increased by 37% (95% CI: 1.25-1.49) in males and by 35% (95% CI: 1.26-1.45) in females. In this study, we first reported the positive association and gender differences between WWI and the prevalence of PAD, and the relationship was stable in different subgroups evaluated by the stratified analyses.

Previous studies have shown that the traditional obesity-related index, BMI, is related to PAD. A population-based study involving 11,477 Chinese community-dwelling adults suggested that each standard deviation (3.60 kg/m²) increase in BMI was correlated with 23% (95% CI: 1.13-1.33) incremental PAD risk. Moreover, the categorical analysis showed that compared with the lowest quartile of BMI, the highest quartile was associated with 31% (95% CI: 1.03-1.67) increased PAD risk (P for trend = 0.008) ⁹. In the China Hypertension Registry study, Li et al. found that BMI was positively associated with the risk of PAD (OR = 1.52; 95% CI: 1.52-1.93) in those with BMI greater than 25.7 kg/m^{2 24}. However, some studies indicate an inverse association between BMI and the prevalence of PAD ²⁵. A meta-analysis including 5,729,272 individuals further demonstrated that higher BMI values were associated with a lower mortality risk in PAD patients ¹³. Because BMI does not distinguish between lean mass and fat mass, this phenomenon may be due to the limitations of BMI and the existence of the “obesity survival paradox”. Although WC was proposed as a surrogate measure for the indirect evaluation of visceral adipose tissue that more accurately reflects adverse metabolic profiles, it is also limited by its high correlation with BMI. In this context, some nontraditional obesity indicators were also performed to explore the association with PAD. A cross-sectional study of 1,872 patients with diabetes mellitus by Wung et al. showed that the body roundness index (BRI) was significantly associated with peripheral artery occlusive disease (P = 0.021), and the AUC was 0.630 (95 CI%: 0.567-0.692) ²⁶. Another cross-sectional study using data from the China H-type Hypertension Registry demonstrated that visceral adiposity index (VAI) was positively associated with PAD in normal-weight adults with HTN ²⁷. However, most of these nontraditional indicators are based on relatively complicated mathematical models, and therefore routine examinations in the general population would be limited. 

Notably, WWI is a new and simple indicator based on the formula [In(WC) = β₀ + β₁ In(weight) + ε] that has the potential to combine the advantages of WC while weakening the correlation with BMI, enabling it to assess both fat and muscle mass components ¹⁶. Using a cross-sectional sample of 602 participants aged ≥ 65 years from the Ansan Geriatric Study, Kim et al. found that WWI was positively correlated with total abdominal fat area but negatively correlated with appendicular skeletal muscle mass ²⁸. Moreover, several prospective cohort studies further confirmed that WWI rather than BMI and WC better predicted the risk of all-cause and cardiovascular death ^{16, 19}. Consistent with our current results, WWI was superior to BMI and WC in predicting PAD, indicating that WWI might be a better predictor of PAD than other obesity parameters. These findings suggest that WWI may be a comprehensive and superior indicator of obesity and could be used to predict obesity-related disorders in clinical settings.

Given that WWI has been shown to more accurately estimate total body fat percentage, the potential mechanism of the positive WWI-PAD association could be related to metabolic abnormalities. There is evidence that even normal-weight individuals are metabolically obese ²⁹. Moreover, even with a similar degree of obesity, WWI was significantly higher in metabolically unhealthy groups than in metabolically healthy groups ³⁰. Hence, elevated WWI may reflect a state of metabolic disorder with excessive adipose tissue accumulation. The dysfunction of adipose tissue secretes various inflammatory cytokines and adipocytokines (such as interleukin-6 and resistin), leading to insulin resistance, endothelial dysfunction, and inflammation response, which are correlated with an increased risk of HTN, DM, and PAD ^31-33. Besides, we observed gender differences in WWI-PAD association, which may be explained by the specific fat distribution. As previous studies have shown that total abdominal fat and visceral fat were both significantly lower in females than in males ³⁴. Other potential reasons are that estrogen may slow down the adverse effects of adipose tissue on the progression of atherosclerosis ³⁵. 

Our study has the strengths of a large population-based sample size, rigorous study protocols and quality controls, and data available on many important covariates by integrating the NHANES survey. By adjusting for multiple potential covariates, we confirmed the robustness of the results. Furthermore, we explored the dose-response relationship between WWI and PAD and found significant gender differences, which are very easily overlooked in clinical practice. Despite that, the limitations of this study should also be declared. First, although we adjusted for many important variables, we could not completely rule out the influence of other potential confounders, such as medications and hormones, which may affect the progression of atherosclerosis. Second, the cross-sectional nature of this investigation made it impossible to determine the causal relationship between WWI and PAD. Third, all participants were recruited from a single country, thus limiting the ability to generalize our findings to the general population. 

Conclusion

This cross-sectional study suggested that WWI levels were significantly associated with an increased likelihood of PAD in United States adults, with a differential association between males and females. WWI was superior to BMI and WC in predicting PAD, indicating that the management of obesity evaluated by WWI may reduce the risk of PAD. Despite that, further large-scale longitudinal studies are still needed to verify our findings.

Declarations

Acknowledgments

We thank all National Health and Nutrition Examination Survey (NHANES) participants and staff for their valuable efforts and contributions.

Author contributions

F.X. and Y.W. conceived and designed the study. R.G., H.F., and J.X. contributed to data collection and statistical analysis. F.X. drafted the manuscript. Y.W. had primary responsibility for the final content of the manuscript. All authors interpreted the results, and reviewed and approved the manuscript.

Funding

This work was supported by the National Key Research and Development Plan of China (No. 20212BBG71004), the National Natural Science Foundation of China (No. 82160085), the Jiangxi Provincial Department of Science and Technology Foundation (No. 20181BCB24013), the Natural science funding (No. 20202BAB206005), and the Jiangxi Provincial Natural Science Foundation (20192BAB205012).

Competing interests 

The authors declare no competing interests.

Additional information 

Correspondence and requests for materials should be addressed to Y.W. 

Reprints and permissions information is available at www.nature.com/reprints. 

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Data availability 

Publicly available datasets were analyzed in this study. These data can be found at: www.cdc.gov/nchs/nhanes/index.htm.

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