JAMDA
Volume 12, Issue 1 , Pages 58-61, January 2011

The Relationship of Vitamin D Status to Cardiovascular Risk Factors and Amputation Risk in Veterans With Peripheral Arterial Disease

  • Vamsi C. Gaddipati, BS

      Affiliations

    • Quillen College of Medicine, Johnson City, TN
    • ,
  • Beth A. Bailey, PhD

      Affiliations

    • Department of Family, East Tennessee State University, Johnson City, TN
    • ,
  • Reena Kuriacose, MD

      Affiliations

    • Department of Internal Medicine, East Tennessee State University, Johnson City, TN
    • ,
  • Rebecca J. Copeland, MD

      Affiliations

    • Department of Internal Medicine, East Tennessee State University, Johnson City, TN
    • ,
  • Todd Manning, BA

      Affiliations

    • Medicine Service, Mountain Home VAMC, Mountain Home, TN
    • ,
  • Alan N. Peiris, MD, PhD, MRCP

      Affiliations

    • Department of Internal Medicine, East Tennessee State University, Johnson City, TN
    • Medicine Service, Mountain Home VAMC, Mountain Home, TN
    • Corresponding Author InformationAddress correspondence and reprint requests to Alan N. Peiris, MD, PhD, MRCP, Mountain Home VAMC, Medicine Service-111, Mountain Home, TN 37684.

published online 13 August 2010.

Article Outline

Objectives

Peripheral arterial disease (PAD) is a common and often overlooked entity responsible for considerable morbidity and mortality. Recent evidence suggests that nontraditional risk factors such as vitamin D may contribute to atherosclerosis. We hypothesized that vitamin D status was associated with cardiovascular risk factors and that vitamin D deficiency (25(OH)D <20 ng/mL) enhanced the risk of amputation.

Design

We reviewed medical records of 1435 veterans between 2000 and 2008 in Tennessee via retrospective chart analysis using correlations, logistic regressions, t tests, and χ2 analyses.

Results

Vitamin D status was significantly and inversely correlated with body mass index (BMI), glucose, and triglyceride values. Hypertension and diabetes but not smoking also emerged as significantly associated. Of the sample population, 5.2% (n = 75) had an amputation performed. Those individuals who were vitamin D deficient had a significantly higher amputation rate (6.7%) compared with patients who were nondeficient (4.2%). BMI, triglyceride, total cholesterol, hypertension, and diabetes were found to account for 5.7% of the variation in amputation status. Vitamin D concentration and deficiency status accounted for a nonsignificant amount of additional variance.

Conclusions

We conclude that vitamin D deficiency is closely linked to increased adiposity, triglyceride, and glucose measurements. Vitamin D deficiency was associated with an increased amputation risk in veterans with PAD and appears to mediate its effects through traditional risk factors.

Keywords: Vitamin D deficiency, peripheral arterial disease, amputation

 

Peripheral arterial disease (PAD) is a common clinical concern with current prevalence rates estimated at 4% of the general population older than 401 and 16% of those individuals older than 55.2 The prevalence of the disorder is frequently underestimated3 and has serious monetary4 and quality-of-life implications. The recent emergence of nontraditional risk factors for PAD has been noted.5

Hypovitaminosis D has become a global pandemic influencing approximately 50% of the world's inhabitants.6 Its prevalence rates are similarly high in veteran populations7 and are associated with increased health care costs.8 Recent data suggest that vitamin D may play a significant role in vascular health: its active form, for example, has been demonstrated to decrease blood pressure.9 Vitamin D inadequacy has further been inversely correlated with cardiomyocyte10 and vascular smooth muscle cell11 proliferation, coronary calcification,12 and with increased carotid intima-media thickness (IMT).13 A cross-sectional analysis of the National Health and Nutrition Examination Survey associated hypovitaminosis D with coronary heart disease, heart failure, stroke, and PAD.14 A more specific study of this same data found a strong, graded association between lower concentration of 25(OH)D and PAD. This association persisted following adjustment for potential covariates.15 Moreover, discrepancy in vitamin D status has been suggested as a possible contributor for the wide racial disparity in prevalence of PAD.16

Although vitamin D deficiency has been associated with PAD, the mechanisms by which it may exert an effect on vascular health remain to be defined, and it is currently unknown if there exists a link to a higher prevalence of amputations in PAD patients. The present study was undertaken to assess the relationship of vitamin D status to cardiovascular risk factors and the risk of amputation in veterans with PAD.

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Methods 

Participants and Procedures 

The study was conducted at a Veterans Affairs (VA) facility located in the southeastern United States (Mountain Home, TN). The research and development committee at the VA Medical Center as well as the Institutional Review Board at the affiliated university approved procedures and protocol and issued a waiver of consent. Participants were patients seen at the VA Medical Center from October 2000 to May 2009 with an established diagnosis of PAD and an available vitamin D concentration.

Vitamin D value was obtained via immunochemiluminometric assay (Labcorp, Burlington, NC) for 25(OH)D serum concentration. Vitamin D was examined as both a continuous and dichotomous variable with deficiency classified as 25(OH)D less than 20 ng/mL.17 Cholesterol, lipid, and glucose concentrations were obtained through standard laboratory assays. Serum albumin values were determined as an indicator of frailty/acute illness.18

Data Analysis 

Data were obtained electronically through retrospective medical chart review after redaction of personal information, and statistical analyses performed using SPSS (SPSS Inc., version 14.0; Chicago, IL). All variables were checked for outliers and normality of distribution before analyses were performed. Correlations, logistic regressions, t tests, and χ2 analyses were used to examine the association between vitamin D concentration and/or deficiency with a series of traditional cardiovascular risk factors and amputation risk.

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Results 

A total of 1435 unique patients with diagnosis of PAD and available 25(OH)D concentration were identified during the study period. The sample was predominantly Caucasian (82.2%) with a mean age of 70.8 years (SD = 10.5; range = 38–97). Analysis of vitamin D concentration revealed an average of 24.1 ng/mL (SD = 11.8; range = 4.0–90.0) with 40.8% of the sample found to be deficient. Serum albumin was similar in vitamin D–deficient (4.1 g/L) and vitamin D–replete patients (4.2 g/L).

Body mass index (BMI), total cholesterol, triglycerides, and glucose had a significant inverse correlation with serum vitamin D concentration as presented in Table 1. When classified based on Vitamin D status, BMI, triglycerides, and glucose were significantly higher in the Vitamin D–deficient group. Total cholesterol did not emerge as significantly higher in the Vitamin D–deficient group (P = .197). Low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol values were not significantly linked to either vitamin D concentrations or vitamin D status.

Table 1. Associations between Vitamin D and Metabolic Parameters (N = 1435)
Metabolic ParameterCorrelationVitamin D Status Group Means (SD)
With Vitamin DPDeficientNon-DeficientP∗
BMI–0.127<.00128.8 (6.9)27.6 (5.5)<.001
LDL–0.003.90494.7 (35.5)96.9 (35.7).271
HDL0.024.40241.3 (13.4)42.4 (13.4).161
Total cholesterol–0.078.004174.7 (48.0)171.5 (42.8).197
Triglycerides–0.135<.001205.8 (186.8)171.2 (128.4)<.001
Glucose–0.116<.001127.0 (65.3)112.3 (44.3)<.001

BMI, body mass index; LDL, low-density lipoprotein; HDL, high-density lipoprotein.

∗Two-tailed P value from independent groups t test.

When risk factors were considered as binary variables, the presence of hypertension and diabetes emerge as significant associations with both vitamin D serum concentration and status as shown in Table 2. Smoking was not statistically associated.

Table 2. Associations between Vitamin D and Binary Risk Factors (N = 1435)
Risk FactorVitamin DPercent Vitamin
ng/mL (SD)P∗D DeficientP†
Hypertension .010 .002
Yes23.9 (11.8) 41.9%
No26.9 (11.6) 26.4%
Diabetes <.001 <.001
Yes22.8 (11.0) 45.9%
No25.3 (12.4) 35.9%
Smoking .466 .165
Yes23.8 (12.3) 42.7%
No24.3 (11.3) 39.1%

∗Two-tailed P value from independent groups t test.

†Two-tailed P value from 2 × 2 χ2 test.

Within the total sample of PAD veterans, 5.2% (n = 75) had an amputation performed. Of this subgroup, the average vitamin D value was 22.1 ng/mL and 52% were deficient, whereas nonamputees demonstrated a mean serum concentration of 24.2 ng/mL with 40% deficiency. This difference approached significance (t[1433] = 1.53; P = .063). Those individuals who were vitamin D deficient had a significantly higher amputation rate (6.7%) compared with those patients who were not deficient (4.2%) (χ2[1] = 4.14, P = .029).

A logistical regression analysis was performed to determine if the association between vitamin D deficiency and amputation risk remained significant after adjusting for possible metabolic covariates. Because the glucose value and diabetes status were highly correlated, only diabetes status was included in the analysis. BMI, triglyceride and total cholesterol concentrations, and hypertension and diabetes status were the main covariate factors analyzed, and these parameters were found to account for 5.7% of the variation in amputation status (R = 0.168; χ2 = 80.3; P < .001). When vitamin D concentration and deficiency status were separately entered into the model, each accounted for a nonsignificant amount of additional variance.

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Discussion 

To our knowledge, our study is the first to document the relationship between vitamin D deficiency and risk of amputation in veterans with PAD. Moreover, our data suggest that the effects of vitamin D on vascular health may be mediated through traditional metabolic factors.

Vitamin D deficiency was associated with a 60% increase in risk of amputation in veterans with PAD. It is interesting that although traditional risk factors such as BMI, triglycerides, hypertension, and diabetes were significantly associated with the risk of amputation, these variables accounted for only 5.7% of the variation in amputation status. Adjusting for vitamin D status did not change the risk for amputation, suggesting that if vitamin D plays a role, it may do so through conventional risk factors. This finding is consistent with emerging data that suggest vitamin D deficiency may predict the development of insulin resistance and glycemic status.19 In addition, vitamin D along with calcium may enhance weight loss with associated benefits in lipid parameters.20

Given the plethora of pleiotropic effects that vitamin D appears to exert on the vascular tree, it may be premature to exclude the possibility that vitamin D may have a more direct role in vascular disease. High rates of collinearity between vitamin D and the covariate variables and a large number of existing cardiovascular risk factors in a population with longstanding PAD may have impacted the ability to accurately detect an independent role for vitamin D.

Although serum concentrations of 25(OH)D have not been found to be significantly associated with inflammatory markers such as C-reactive protein, they have been correlated with increased risk for incident coronary artery calcification (CAC).21 Furthermore, vitamin D deficiency is linked to adverse morphological changes in large arteries,22 inflammatory effects upon arterial endothelial cells,23, 24 and enhanced proliferation of aortic smooth muscle cells.25 Low concentrations of 25(OH)D have been shown to affect survival rate independent of vascular calcification and stiffness.26 The influence of vitamin D over additional pathways such as regulation of the renin-angiotensin system27 and control over inflammatory cytokine release from lymphocytes28 may contribute to vascular risk apart from emerging effects on insulin resistance.29

Certain inherent limitations that must be addressed exist in the present study. Being correlative in nature, this investigation cannot prove causality in terms of vitamin D increasing PAD risk: the possibility that patients with PAD may have higher prevalence rates of acute illness and develop subsequent vitamin D deficiency exists. However, we believe this scenario to be less likely because serum albumin was independent of vitamin D status and suggest that acute illness/frailty were not significantly different between study groups. In a study of transgenic rats where vitamin D deficiency was induced by vitamin D-24-hydroxylase, the development of subsequent atherosclerotic lesions suggests vitamin D plays a primary role in promoting atherosclerosis.30 Moreover, treatment with vitamin D in young adults with renal disease has been independently associated with morphological changes in CAC and IMT,31 and supplementation as part of a therapeutic regimen has been revealed to reduce coronary calcium score determined by computerized tomography and level of plaque growth.32 A study of patients referred to coronary angiography concluded that low serum concentrations of 25(OH)D were independently predictive for fatal stroke.33 Given the fact that traditional risk factors and vitamin D accounted for only 5.7% of the variance with regard to risk of amputation, we believe further that there may be hitherto unrecognized factors including duration of variables such as hypertension or diabetes that may account for a greater proportion of the deviation. The current investigation would need to be followed up by a sample with lower levels of other risk factors for amputation or a sample in which those risk factors were not so highly correlated with vitamin D serum concentrations to accurately reach a conclusion.

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Conclusion 

Irrespective of the prospective benefits of a vitamin D–replete state on the vascular tree, the improved sense of well-being, reduced rate of certain malignancies, and potential reduction in the burden of many chronic illnesses suggest that clinicians should actively seek and treat vitamin D deficiency. Additional prospective studies are required to better delineate the role of vitamin D in PAD.

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Acknowledgments 

The invaluable assistance provided by Rick Wallace and Nakia Carter from the East Tennessee State University Quillen College of Medicine Library and Nancy Milligan from the Mountain Home VAMC Medical Library is greatly appreciated. We thank Dr Satyabrata Chatterjee (Internal Medicine and Cardiovascular Disease; Saint Joseph Health System; London, Kentucky) for his helpful review of this article. Vamsi Gaddipati was an American Heart Association Health Science Fellow. This work was supported with resources and the use of facilities at the Mountain Home VAMC. The contents of this paper does not represent the views of the department of Veterans Affairs or the United States Government.

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 We acknowledge the American Heart Association for their funding and support of the Health Science Fellowship program.

 The authors have no conflicts of interest to report.

PII: S1525-8610(10)00063-0

doi:10.1016/j.jamda.2010.02.006

JAMDA
Volume 12, Issue 1 , Pages 58-61, January 2011

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