Red Meat Intake and the Risk of Cardiovascular Diseases: A Prospective Cohort Study in the Million Veteran Program.

BACKGROUND: Red meat consumption was associated with an increased risk of cardiovascular disease (CVD) in prospective cohort studies and a profile of biomarkers favoring high CVD risk in short-term controlled trials. However, several recent systematic reviews and meta-analyses concluded with no or weak evidence for limiting red meat intake. OBJECTIVES: To prospectively examine the associations between red meat intake and incident CVD in an ongoing cohort study with diverse socioeconomic and racial or ethnic backgrounds. METHODS: Our study included 148,506 participants [17,804 female (12.0%)] who were free of cancer, diabetes, and CVD at baseline from the Million Veteran Program. A food frequency questionnaire measured red meat intakes at baseline. Nonfatal myocardial infarction and acute ischemic stroke were identified through a high-throughput phenotyping algorithm, and fatal CVD events were identified by searching the National Death Index. RESULTS: Comparing the extreme categories of intake, the multivariate-adjusted relative risks of CVD was 1.18 (95% CI: 1.01, 1.38; P-trend < 0.0001) for total red meat, 1.14 (95% CI: 0.96, 1.36; P-trend = 0.01) for unprocessed red meat, and 1.29 (95% CI: 1.04, 1.60; P-trend = 0.003) for processed red meat. We observed a more pronounced positive association between red meat intake and CVD in African American participants than in White participants (P-interaction = 0.01). Replacing 0.5 servings/d of red meat with 0.5 servings/d of nuts, whole grains, and skimmed milk was associated with 14% (RR: 0.86; 95% CI: 0.83, 0.90), 7% (RR: 0.93; 95% CI: 0.89, 0.96), and 4% (RR: 0.96; 95% CI: 0.94, 0.99) lower risks of CVD, respectively. CONCLUSIONS: Red meat consumption is associated with an increased risk of CVD. Our findings support lowering red meat intake and replacing red meat with plant-based protein sources or low-fat dairy foods as a key dietary recommendation for the prevention of CVD.

Impact of 8 lifestyle factors on mortality and life expectancy among United States veterans: The Million Veteran Program.

BACKGROUND: Lifestyle medicine has been proposed as a way to address the root causes of chronic disease and their associated health care costs. OBJECTIVE: This study aimed to estimate mortality risk and longevity associated with individual lifestyle factors and comprehensive lifestyle therapy. METHODS: Age- and sex-specific mortality rates were calculated on the basis of 719,147 veterans aged 40-99 y enrolled in the Veteran Affairs Million Veteran Program (2011-2019). Hazard ratios and estimated increase in life expectancy were examined among a subgroup of 276,132 veterans with complete data on 8 lifestyle factors at baseline. The 8 lifestyle factors included never smoking, physical activity, no excessive alcohol consumption, restorative sleep, nutrition, stress management, social connections, and no opioid use disorder. RESULTS: On the basis of 1.12 million person-years of follow-up, 34,247 deaths were recorded. Among veterans who adopted 1, 2, 3, 4, 5, 6, 7, and 8 lifestyle factors, the adjusted hazard ratios for mortality were 0.74 (0.60-0.90), 0.60 (95% CI: 0.49, 0.73), 0.50 (95% CI: 0.41, 0.61), 0.43 (95% CI: 0.35, 0.52), 0.35 (95% CI: 0.29, 0.43), 0.27 (95% CI: 0.22, 0.33), 0.21 (95% CI: 0.17, 0.26), and 0.13 (95% CI: 0.10, 0.16), respectively, as compared with veterans with no adopted lifestyle factors. The estimated life expectancy at age 40 y was 23.0, 26.5, 28.8, 30.8, 32.7, 35.1, 38.3, 41.3, and 47.0 y among males and 27.0, 28.8, 33.1, 38.0, 39.2, 41.4, 43.8, 46.3, and 47.5 y for females who adopted 0, 1, 2, 3, 4, 5, 6, 7, and 8 lifestyle factors, respectively. The difference in life expectancy at age 40 y was 24.0 y for male veterans and 20.5 y for female veterans when comparing adoption of 8-9 lifestyle factors. CONCLUSIONS: A combination of 8 lifestyle factors is associated with a significantly lower risk of premature mortality and an estimated prolonged life expectancy.

Correction for Collider Bias in the Genome-wide Association Study of Diabetes-Related Heart Failure due to Bidirectional Relationship between Heart Failure and Type 2 Diabetes.

Aims: Type 2 diabetes (T2D) is a major risk factor for heart failure (HF) across demographic groups. On the other hand, metabolic impairment, including elevated T2D incidence is a hallmark of HF pathophysiology. We investigated the bidirectional relationship between T2D and HF, and identified genetic associations with diabetes-related HF after correction for potential collider bias. Methods: We performed a genome-wide association study (GWAS) of HF to identify genetic instrumental variables (GIVs) for HF, and to enable bidirectional Mendelian Randomization (MR) analysis between T2D and HF. Since genetics and HF can independently influence T2D, collider bias may occur when T2D (i.e., collider) is controlled for by design or analysis. Thus, we conducted GWAS of diabetes-related HF with correction for collider bias. Results: We first identified 61 genomic loci, including 24 novel loci, significantly associated with all-cause HF in 114,275 HF cases and over 1.5 million controls of European ancestry. Combined with the summary statistics of a T2D GWAS, we obtained 59 and 82 GIVs for HF and T2D, respectively. Using a two-sample bidirectional MR approach, we estimated that T2D increased HF risk (OR 1.07, 95% CI 1.04-1.10), while HF also increased T2D risk (OR 1.60, 95% CI 1.36-1.88). Then we performed a GWAS of diabetes-related HF corrected for collider bias due to prevalent HF affecting incidence of T2D. After removing the spurious association of TCF7L2 locus due to collider bias, we identified two genome-wide significant loci close to PITX2 (chromosome 4) and CDKN2B-AS1 (chromosome 9) associated with diabetes-related HF in the Million Veteran Program, and replicated the associations in the UK Biobank study. Conclusion: We identified novel HF-associated loci to enable bidirectional MR study of T2D and HF. Our MR findings support T2D as a HF risk factor and provide strong evidence that HF increases T2D risk. As a result, collider bias leads to spurious genetic associations of diabetes-related HF, which can be effectively corrected to identify true positive loci. Evaluation of collider bias should be a critical component when conducting GWAS of complex disease phenotypes such as diabetes-related cardiovascular complications.

Association of dietary fatty acids with the risk of atherosclerotic cardiovascular disease in a prospective cohort of United States veterans.

BACKGROUND: Atherosclerotic cardiovascular diseases (ASCVDs) are the leading cause of worldwide adult mortality. Although broad classes of dietary fats have been shown to alter ASCVD risk, the roles that individual dietary fatty acids play in influencing ASCVD risk are unclear. OBJECTIVES: The aim of this prospective cohort study was to examine the relationships of the total fat classes and individual fatty acids with the risk of ASCVD. METHODS: The Million Veteran Program is a prospective cohort whereby dietary intake of fatty acids was assessed in 158,198 participants that had enrolled between January 2011 and November 2018 and were free of ASCVD at baseline. Incident ASCVD was ascertained from the Veterans Affairs electronic health records and the National Death Index. Multivariable-adjusted hazard ratios (HRs) for the relationship between fat intake and ASCVD risk were computed using Cox regression models. RESULTS: The mean age was 61 years, 88% were males. A total of 11,771 ASCVD events were identified during the follow-up. When compared with the lowest quintile, participants in the highest quintile of dietary trans-monounsaturated fats and conjugated linoleic acids had an increased risk (HR [95% CI]) of ASCVD events: 1.10 (1.04, 1.17) and 1.11 (1.05, 1.18), respectively. When compared with low consumers, participants in the highest quintile of total cis-polyunsaturated fatty acid intake had a lower risk of experiencing an ASCVD event 0.93 (0.87, 0.99). CONCLUSION: Although higher intakes of specific trans-fatty acids and conjugated linoleic were associated with an increased risk of ASCVD, the same cannot be said for all other fat classes. This work suggests that care must be taken when drawing general conclusions regarding the health effects of dietary individual fatty acids.

Egg consumption and risk of acute stroke in the Million Veteran Program.

BACKGROUND: While observational data suggest a higher risk of coronary artery disease with frequent egg consumption, only limited and inconsistent data are available on the relation of egg consumption with stroke. OBJECTIVE: The primary objective was to assess whether egg consumption is associated with a higher risk of ischemic and hemorrhagic stroke among US veterans. METHODS: In a prospective cohort study of US veterans from the Million Veteran Program (MVP), egg intake was collected through a self-reported food frequency questionnaire at baseline. Incidence of stroke was ascertained via ICD9/ICD10 codes from the electronic health records. Multivariable Cox proportional hazard models were used to estimate the multivariable adjusted hazard ratios. RESULTS: A total of 233,792 veterans (91.6% men) were studied with a mean age of 65.6 ± 11.7 years. During a mean follow-up of 3.3 years, a total of 5740 cases of fatal and non-fatal ischemic stroke and 423 cases of fatal and non-fatal hemorrhagic stroke occurred. Median egg consumption was 2-4 eggs/week. Crude incidence rates for acute ischemic stroke were 6.5, 7.2, 7.1, 7.4, 8.0, 8.1, and 8.6 cases per 1000 person-years for egg consumption of <1/month, 1-3/month, 1/week, 2-4/week, 5-6/week, 1/day, and ≥2/day, respectively. Corresponding multivariable adjusted hazard ratios (95% CI) were 1.00 (ref), 1.10 (0.96-1.25), 1.09 (0.96-1.23), 1.10 (0.98-1.25), 1.16 (1.01-1.33), 1.20 (1.03-1.40), and 1.22 (1.03-1.45) controlling for age, sex, ethnicity, body mass index, diabetes, smoking, alcohol intake, modified DASH score, and education (p linear trend 0.0085). For hemorrhagic stroke, multivariable adjusted hazard ratios (95% CI) after controlling for age, sex, ethnicity, body mass index, modified DASH score, and level of education were 1.00 (ref), 1.28 (0.96-1.72), 1.22 (0.93-1.61), and 1.19 (0.88-1.61) for egg consumption of <1/week, 1/week, 2-4/week, 5+/week, respectively. CONCLUSION: Our data are consistent with a positive association of egg consumption with acute ischemic stroke but not hemorrhagic stroke among veterans.

Chocolate consumption and risk of coronary artery disease: the Million Veteran Program.

Background: Although previous studies have suggested cocoa products may promote cardiovascular health in the general population, no public data are available from patients receiving care in a national integrated health care system. Objectives: We tested the hypothesis that regular chocolate consumption is associated with a lower risk of coronary artery disease (CAD) events among participants of the Million Veteran Program (MVP). Secondary analysis examined if the main hypothesis was observed among participants with type 2 diabetes. Methods: We analyzed data from MVP participants who completed the food frequency section of the MVP Lifestyle Survey and were free of CAD at the time of survey completion. CAD events during follow-up (International Statistical Classification of Diseases Ninth Revision codes 410-411 and 413-414, and Tenth Revision codes I20-I25 except I25.2) were assessed using electronic health records. We fitted a Cox proportional hazard model to estimate the RR of CAD. Results: Of 188,447 MVP enrollees with survey data, mean ± SD age was 64 ± 12.0 y and 90% were men. For regular chocolate (28.3 g/serving) consumption of <1 serving/mo, 1-3 servings/mo, 1 serving/wk, 2-4 servings/wk, and ≥5 servings/wk, crude incidence rates (per 1000 person-years) for fatal and nonfatal CAD events or coronary procedures were 20.2, 17.5, 16.7, 17.1, and 16.9, respectively, during a mean follow-up of 3.2 y. After adjusting for age, sex, race, and lifestyle factors, the corresponding HRs (95% CIs) were 1.00 (ref), 0.92 (0.87, 0.96), 0.88 (0.83, 0.93), 0.89 (0.84, 0.95), and 0.89 (0.84, 0.96), respectively (P for linear trend < 0.0001). In a secondary analysis of 47,265 diabetics, we did not observe a decreasing trend in CAD mortality among those who consumed ≥1 serving of chocolate a month compared with those who consumed <1 serving/mo. Conclusions: Regular chocolate consumption was associated with a lower risk of CAD among veterans, but was not associated with cardiovascular disease risk in veterans with type 2 diabetes.

Dietary yogurt is distinct from other dairy foods in its association with circulating lipid profile: Findings from the Million Veteran Program.

BACKGROUND & AIMS: Dyslipidemia is a major cardiovascular disease risk factor. Research has proposed mechanisms whereby yogurt may improve circulating lipid concentrations. However, at the population level, the association of yogurt, as distinct from other dairy foods, with these important risk factors is poorly understood. This study aimed to determine whether the circulating lipid profile associated with yogurt is different to the circulating lipid profile that is associated with non-yogurt dairy products, specifically milk and cheese. METHODS: The current study included the 192,564 US Veterans enrolled in the Million Veteran Program who reported frequency of yogurt consumption (assessed via food frequency questionnaire) and had lipid concentrations assessed. Trends were evaluated with linear regression. Mean age was 65 (SD = 11) years [20, 100 years]. RESULTS: A one serve/day higher yogurt consumption was positively associated (coefficient ± SE) with the concentration of high-density lipoprotein cholesterol (HDLC) in individuals who were not (0.26 ± 0.12 mg/dL, P value = 0.025), and who were (0.25 ± 0.09, P value = 0.004), using antilipemic agents. Furthermore, higher yogurt consumption was inversely associated with the concentration of triglycerides, but only in individuals who were not using antilipemic agents (-1.46 ± 0.58, P value = 0.012). CONCLUSION: These apparent beneficial associations of yogurt with HDLC and triglycerides were independent of consumption of non-yogurt dairy foods and were not observed for consumption of either milk or cheese. In this prospective cohort study of U.S. Veterans, we found a beneficial relationship between higher frequency of yogurt consumption with circulating HDLC and triglyceride concentrations that was distinct from non-yogurt dairy foods.

A phenotyping algorithm to identify acute ischemic stroke accurately from a national biobank: the Million Veteran Program.

BACKGROUND: Large databases provide an efficient way to analyze patient data. A challenge with these databases is the inconsistency of ICD codes and a potential for inaccurate ascertainment of cases. The purpose of this study was to develop and validate a reliable protocol to identify cases of acute ischemic stroke (AIS) from a large national database. METHODS: Using the national Veterans Affairs electronic health-record system, Center for Medicare and Medicaid Services, and National Death Index data, we developed an algorithm to identify cases of AIS. Using a combination of inpatient and outpatient ICD9 codes, we selected cases of AIS and controls from 1992 to 2014. Diagnoses determined after medical-chart review were considered the gold standard. We used a machine-learning algorithm and a neural network approach to identify AIS from ICD9 codes and electronic health-record information and compared it with a previous rule-based stroke-classification algorithm. RESULTS: We reviewed administrative hospital data, ICD9 codes, and medical records of 268 patients in detail. Compared with the gold standard, this AIS algorithm had a sensitivity of 91%, specificity of 95%, and positive predictive value of 88%. A total of 80,508 highly likely cases of AIS were identified using the algorithm in the Veterans Affairs national cardiovascular disease-risk cohort (n=2,114,458). CONCLUSION: Our algorithm had high specificity for identifying AIS in a nationwide electronic health-record system. This approach may be utilized in other electronic health databases to accurately identify patients with AIS.

Update on Hyperlipidemia in the Elderly: Is This a Risk Factor for Heart Disease?

Results concerning the utility of lipid screening in the elderly are conflicting. Many studies have shown no association between total cholesterol measurements in the elderly and the development of coronary heart disease (CHD). Several recent investigations, with a few exceptions, have demonstrated that high-density lipoprotein-cholesterol (HDL-C) levels and the total/HDL-C ratio are, however, effective markers for CHD in older populations. Although the relative risk associated with lipid measurements tends to decline in older persons, the attributable risk for CHD associated with higher cholesterol and lower HDL-C tends to be greater in older persons because of a greater number of events in this population. Clinical trials with modern lipid-lowering agents have demonstrated efficacy and safety in middle-aged subjects with the newer medications, and it is time to consider a lipid altering clinical trial specifically targeted to persons over the age of 65 years to determine whether morbidity and mortality can be reduced.

Hypercholesterolemia and Coronary Risk in the Elderly: The Framingham Study.

In a follow up of elderly Framingham men and women, and after multivariate adjustment, the total/high-density lipoprotein-cholesterol ratio remained highly associated with the incidence of coronary heart disease in both sexes, whereas total cholesterol level was associated with coronary heart disease only in women. Whereas total cholesterol values decline in the very elderly, and the association of coronary heart disease with total cholesterol level alone is weaker in the elderly than among those of middle age, the total/high-density lipoprotein-cholesterol ratio remains a strong predictor of coronary heart disease. In assessing the elderly for coronary risk, lipid measurements should include high-density lipoprotein-cholesterol and cholesterol determinations.