Nutritional Risk Factors for Peripheral Vascular Disease: Does Diet Play a Role?

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1 Nutritional Risk Factors for Peripheral Vascular Disease: Does Diet Play a Role? John S. Lane MD, Cheryl P. Magno MPH, Karen T. Lane MD, Tyler Chan BS, Sheldon Greenfield MD University of California, Irvine Division of Vascular Surgery Center for Health Policy Research

2 Snake oil salesman: Professor Eustace McGargle (Poppy 1936) Never give a sucker an even break I I think I ve I broken my sacroiliac run run to a golf course and get the nearest doctor

3 Snake oil: (SF Chinatown 1989) 25% oil from Chinese water snakes, itself consisting of: 20% eicosapentaenic acid (EPA) - an omega 3 derivative 48% myristic acid (14:0) 10% stearic acid (18:0) 14% oleic acid (18:1ω9) 7% linoleic acid (18:2ω6) plus arachidonic acid (20:4ω6) Source:

4 Background Treatment and prevention of PVD has focused on early detection and risk factor modification Triad of life-style modification and medical intervention Smoking cessation, low-fat/low fat/low-salt diet, exercise program ASA, Statin, ACE-inhibitor, B-blockerB Dietary invention has been largely overlooked

5 WHO: Nutrition in CV disease low in total fat (<30% of calories), saturated fat (<10% of calories) devoid of trans-fatty (saturated) acids. Salt intake <5 grams (90 mmol) ) per day broad range of fruits, vegetables and grain (>400 grams/day) no recommendation regarding vitamins B, C, E and folic acid, due to a paucity of clinical evidence World Health Organization. Prevention of Cardiovascular Disease: Guidelines for Assessment and Management for Cardiovascular Risk. In: Part 2: Recommendations for Prevention of Cardiovascular Disease; 2007.

6 Nutritional targets Fish oil (ω-3( PUFA), olive oil (ω-6( 6 PUFA) Precursor in AA metabolism, PG/LT ratio Anti-oxidants Vit A, C, E prevent free radical damage Folate, Vit B6, Vit B12 Cofactor in Hcy metabolism Dietary fiber effects cholesterol, insulin/glucose level

7 Hypothesis: Is dietary consumption of certain nutrients associated with a reduced incidence of peripheral vascular disease in the US population, independent of traditional vascular risk factors?

8 Study Design Data from National Health and Nutritional Examination Survey for years Collected data interviews, physical examination, laboratory assays Stratified, multi-stage probability clustered sampling Representative of non-institutionalized civilian population in US

9 Nutritional variables (predictors) NHANES computer assisted dietary interview 24-hour dietary recall listed all food and beverages consumed (time, amount, location) USDA dietary collection instrument (Automated Multiple Pass Method) Linked to database foods/nutritional content Reference nutrient values (RDA s, AI s) US Dept of Health Human Services, US Dept of Agriculture, National Academy of Medicine

10 PVD (outcome) NHANES lower extremity examination (1999) Participants >40 years of age PVD: Ankle-brachial index <0.9 Supine systolic blood pressure ratio (posterior tibial/brachial) Lower of 2 sides used ABI defines and quantifies PVD Strong predictor of cardiovascular morbidity (stroke/mi) and all-cause mortality

11 Covariates Age Gender Smoking: >100 cigs over lifetime Cardiovascular disease: self-report of MI, stroke, or angina HTN: self-report or SBP>140mmHg or DBP>90mmHg Diabetes: self-report Cholesterol NOT included (co-linear)

12 Survey study design Complex probability sampling of US population Incorporates survey weights, stratification, clustered sampling design Reflects probability of selection based on planned over-sampling of subgroups Adjusted for non-response Ensures correct SE s, CI s s and p-valuesp Results can be extrapolated to US population

13 Statistical analyses SAS version 9.1 Nutrient data log-transformed Descriptive: 2-sided 2 t-tests, t tests, Wald χ 2 Univariate, multivariate models Quartile-analysis analysis to analyze dose-response Statistical significance P <0.05 OR and confidence intervals exclude 1

14 Population characteristics (n=7023) PVD (ABI <0.90) Characteristic Yes (n = 422) No (n = 6,781) P-value* Age, years 67.6 (± 0.57) 55.0 (±0.14) <0.001 Gender, % Male 43.9 (± 3.68) 48.4 (± 0.64) Female 56.1 (± 3.68) 51.6 (± 0.64) Hypertension, % 65.6 (± 3.22) 34.6 (± 1.87) <0.001 CAD, % 11.2 (± 1.67) 2.67 (± 0.29) <0.001 Diabetes, % 21.1 (± 2.76) 8.6 (± 0.41) <0.001 Smoking, % 68.6 (± 3.52) 53.3 (± 1.01) <0.001 Obesity, % 18.6 (± 2.11) 18.5 (± 1.02) Body Mass Index (kg/m 2 ) 28.9 (± 0.42) 28.2 (± 0.09) Nutrients Total calories, Kcal 1,742 (± 44.3) 2,100 (± 15.8) <0.001 Vitamin A, ug (± 37.0) (± 10.0) Vitamin C, mg 78.5 (± 4.03) 94.0 (± 1.15) Vitamin E, mg 5.80 (± 0.25) 7.15 (± 0.08) Vitamin B6, mg 1.64 (± 0.05) 1.84 (± 0.01) Vitamin B12, ug 4.96 (± 0.34) 5.15 (± 0.11) Fiber, g 13.9 (± 0.50) 16.3 (± 0.12) <0.001 Folate, ug (± 10.9) (± 2.83) <0.001 Total Polyunsaturated Fatty 13.8 (± 0.45) 16.9 (± 0.14) <0.001 Acids, g Linoleic acid, g (w3) 12.2 (± 0.40) 14.9 (± 0.13) <0.001 Linolenic acid, g (w6) 1.24 (± 0.04) 1.50 (± 0.01) <0.001 Total Saturated Fatty Acids 22.7 (± 0.73) 25.9 (± 0.20) year weight variable used for 2-sided t-test and Wald chi-square analyses. Values are percent ± Standard Error or mean ± Standard Error. *Statistical significance at p<0.05.

15 Unadjusted logistic models Nutrients Beta coefficient OR of PVD 95% CI P-value* Vitamin A, ug , Vitamin C, mg , Vitamin E, mg , 0.78 <0.001 Vitamin B6, mg , 0.83 <0.001 Vitamin B12, ug , Fiber, g , 0.77 <0.001 Folate, ug , 0.75 <0.001 Total Polyunsaturated Fatty Acids, g , 0.80 <0.001 Linoleic acid, g (w6) , 0.81 <0.001 Linolenic acid, g (w3) , 0.85 <0.001 Total Saturated Fatty Acids, g , year weight variable used for analysis. *Statistical significance at p<0.05.

16 Multivariate (adjusted) models Nutrients Beta coefficient OR of PVD 95% CI P-value* Vitamin A, ug , Vitamin C, mg , 0.92 <0.001 Vitamin E, mg , Vitamin B6, mg , Vitamin B12, ug , Fiber, g , 0.79 <0.001 Folate, ug , Total Polyunsaturated Fatty Acids, g , Linoleic acid, g (w6) , Linolenic acid, g (w3) , Total Saturated Fatty Acids, g , year weight variable used for analysis. Models adjusted for age, gender, hypertension, diabetes, and smoking. *Statistical significance at p<0.05.

17 Multivariate models (nutritional quartiles) Nutrients Dietary Health Guidelines* Dietary Reference Intake/day OR of PVD 95% CI P-value Vitamin C, mg < , ug mg , > , 0.75 <0.001 Vitamin E, mg < , , > mg 15 mg , Vitamin B6, mg < mg 1.3 mg , , > , Fiber, g < , , > g g , Folate, ug < , ug 400 ug , > , year weight variable used for analysis; models adjusted for age, gender, hypertension, CAD, diabetes, and smoking. *U.S. Department of Health and Human Services, U.S. Department of Agriculture; based on a 2,000 calorie diet; ranges are female-male values.

18 Summary PVD has prevalence of 5.9% in US population, correlates to 16.5 million Americans Poor nutrition (calories, nutrients) is associated with prevalent PVD in the US population Consumption of specific nutrients are associated with reduced incidence of PVD Nutrients associated irrespective of traditional risk factors: antioxidants (Vit( A,C,E), B vitamins (folate, B6), fiber Vits C, E, B6, fiber, folate supplimentation at or above RDA levels may be additionally protective Omega-3 3 fatty acid consumption may reduce both cardiac and peripheral vascular risk.

19 Nutrients Beta coefficient OR of PVD 95% CI P-value* Vitamin A, ug , Vitamin C, mg , 0.92 <0.001 Vitamin E, mg , Vitamin B6, mg , Vitamin B12, ug , Fiber, g , 0.79 <0.001 Folate, ug , Total Polyunsaturated Fatty Acids, g , Linoleic acid, g (w6) , Linolenic acid, g (w3) , Total Saturated Fatty Acids, g , year weight variable used for analysis. Models adjusted for age, gender, hypertension, diabetes, and smoking. *Statistical significance at p<0.05. Over-adjustment: BMI/kcal/race BMI (kg/m 2 ) Kcal Race Nutrients OR of PVD 95% CI P-value* OR of PVD 95% CI P-value* OR of PVD 95% CI P-value* Vitamin A, ug , , , Vitamin C, mg , , , Vitamin E, mg , , , Vitamin B6, mg , , , Vitamin B12, ug , , , Fiber, g , , , Folate, ug , , , Total PUFA, g , , , Linoleic acid, g , , , Linolenic acid, g , , , Total Saturated Fats, g , , , year weight variable used for analysis. All models adjusted for age, gender, hypertension, diabetes, and smoking. *Statistical significance at p<0.05.

20 Strengths of Study Population-based dataset Results can be generalized to entire US population (disease prevalence) Large number of nutrients covariates collected Large sample size can reveal small difference in effect size

21 Limitations Observational, cross-sectional sectional data Not designed to look at causality or prediction Not longitudinal, no estimation of disease incidence Small effect sizes may not be clinically relevant 24-hour dietary recall method is subject to sampling error and recall bias Manipulation of covariates can alter results

22 Discussion Potential role of nutrition in PVD prevention Dietary modification may have significant effects on prevention and treatment Heart-healthy diet high in fruits (anti- oxidants), vegetables (fiber, folate), fish (ω3( 3 FA) Potential role for nutrient supplementation RCT s needed to confirm these findings

23 Thank you

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