AbstractBackgroundRegarding diet’s contribution to cardiovascular disease, Ancel Keys, MD proposed his “lipid hypothesis” in the 1950s. Despite USDA Dietary Guidelines endorsing the lipid hypothesis, debate about whether dietary saturated fat and cholesterol cause cardiovascular disease has continued.MethodsUsing Global Burden of Disease (GBD 2017) data on cardiovascular disease deaths/100k/year, ages 15-69 years old in male and female cohorts (CVD) and dietary and other risk factors, we formatted and population weighted data from 195 countries. Each of the resulting 7846 rows of data (cohorts) represented about 1 million people, projected to total about 7.8 billion people in 2020. We correlated CVD with dietary and other risk factors worldwide and in appropriate subsets.FindingsAll foods were expressed in kilocalories/day (KC/d). We summed the KC/d of processed meat, red meat, fish, milk, poultry, eggs, and added (saturated fatty acid, polyunsaturated fatty acid, and trans fatty acid) to create a “fat-soluble vitamins variable” (FSVV) high in vitamins A, D, E, and K2 (menaquinones). Low density lipoprotein cholesterol (LDL-c) correlated positively with LSVV worldwide (r=0.780, 95% CI 0.771 to 0.788, p<0.0001, n=7846 cohorts), so we considered LSVV our marker variable to test the lipid hypothesis as well as our fat-soluble vitamin hypothesis. The FSVV correlated negatively with CVD worldwide (r= -0.329, 95% CI -0.349 to -0.309, p<0.0001), and FSVV correlated positively with CVD in high FSVV cohorts (when FSVV≥567.3 KC/d: r=0.523, 95% CI 0.476 to 0.567, p<0.0001, n=974 cohorts). Meat and poultry negatively correlated with CVD worldwide (e.g., red meat mean=50.27 KC/d, r= -0.232, 95% CI -0.253 to -0.211, p<0.0001) and positively with CVD in high FSVV cohorts (e.g., red meat mean=122.2 KC/d, r=0.655, 95% CI 0.618 to 0.690, p<0.0001, n=974 cohorts).InterpretationSince FSVV correlated positively with CVD in high FSVV cohorts (FSVV≥567.3 KC/d, n=974 cohorts), the lipid hypothesis is supported only in GBD cohorts and individuals with high FSVV intake. These data support the fat-soluble vitamins hypothesis because FSVV correlated negatively with CVD worldwide, meaning the more fat-soluble vitamin containing animal foods and fat for gut absorption the less the CVD. In high FSVV countries, reducing meat and poultry intake by at least half would likely reduce CVD significantly. This GBD cohort methodology could supplement prospective observational studies of individuals to be used in developing food policy and education strategies for reducing CVD and improving public health.FundingNoneResearch in contextEvidence before this studyIn the field of nutritional epidemiology, controversies abound. The lipid hypothesis that dietary saturated fat and cholesterol promote cardiovascular diseases has been disputed recently with no scientific consensus on the outcome.Added value of this studyWith worldwide GBD data, we created a fat-soluble vitamins variable (FSVV) with animal foods—the primary source of fat-soluble vitamins—and fatty acids—the vehicle for absorption of vitamins A, D, E, and K. We found a strong positive correlation between LDLc and FSVV worldwide. Consequently, we used FSVV to test both the lipid hypothesis and our fat-soluble vitamin hypothesis. CVD correlated negatively with FSVV worldwide, meaning insufficient fat-soluble vitamin containing animal food and added fatty acid intake associated with increased CVD. In the subset with high FSVV (FSVV≥567.3, n=974 cohorts), CVD positively correlated with FSVV, suggesting that excessive saturated fat and cholesterol containing food and added fatty acids associates with increased CVD.Low poultry and meat intake associated with higher CVD worldwide (i.e., mean processed meat=5.3 KC/d, red meat=50.3 KC/d, poultry=44.3 KC/d). However, in high FSVV countries, high meat and poultry intakes associated with higher CVD (i.e., with FSVV≥567.3 KC/d, mean processed meat=25.0 KC/d, mean red meat=122.2 KC/d, mean poultry=130.0 KC/d, n=974 cohorts). Eggs, fish, and milk products in any amount associated with lower CVD.Implications of all the available evidenceThe data support the fat-soluble vitamin hypothesis worldwide and the lipid hypothesis only in high FSVV cohorts and individuals. These findings are plausible because deficiencies of vitamins A, D, E, and K (fat soluble vitamins) and fatty acids, required for gut absorption, have been documented to lead to cardiovascular adverse effects. These findings are consistent with the lipid hypothesis in individuals within high FSVV intake countries (e.g., Seven Country Study and Framingham Heart Study). In high FSVV countries, such as in the USA and Europe, the data suggest that public health strategies should endeavor to promote reduction of animal foods and added fats, particularly meat and poultry consumption. In developing countries with low FSVV intake, supplemental fat-soluble vitamin intake should be studied. This GBD data-based methodology can enhance understanding of the complex interrelationships of dietary and other risk factors with CVD and other health endpoints.
Relationship between red meat metabolite trimethylamine N-oxide and cardiovascular disease