Moderate alcohol consumption on the risk of stroke in the Million Veteran Program.

BACKGROUND: There is inconsistent evidence on the association of moderate alcohol consumption and stroke risk in the general population and is not well studied among U.S. Veterans. Furthermore, it is unclear whether primarily drinking beer, wine, or liquor is associated with a difference in stroke risk. METHODS: The study included 185,323 Million Veteran Program participants who self-reported alcohol consumption on the Lifestyle Survey. Moderate consumption was defined as 1-2 drinks/day and beverage preference of beer, wine or liquor was defined if ≥ 50% of total drinks consumed were from a single type of beverage. Strokes were defined using ICD-9 and ICD-10 codes from the participants' electronic health record. RESULTS: The mean (sd) age of the sample was 64 (13) years and 11% were women. We observed 4,339 (94% ischemic; 6% hemorrhagic) strokes over a median follow-up of 5.2 years. In Cox models adjusted for age, sex, race, education, income, body mass index, smoking, exercise, diet, cholesterol, prevalent diabetes, prevalent hypertension, lipid-lowering medication, antihypertensive medication, and diabetes medication, moderate alcohol consumption (1-2 drinks/day) was associated with a 22% lower risk of total stroke compared with never drinking [Hazards ratio (HR) 95% confidence interval (CI): 0.78 (0.67, 0.92)]. When stratifying by stroke type, we observed a similar protective association with moderate consumption and ischemic stroke [HR (95% CI): 0.76 (0.65, 0.90)], but a non-statistically significant higher risk of hemorrhagic stroke [HR (95% CI): 1.29 (0.64, 2.61)]. We did not observe a difference in ischemic or hemorrhagic stroke risk among those who preferred beer, liquor or wine vs. no beverage preference. When stratifying by prior number of hospital visits (≤ 15, 16-33, 34-64, ≥ 65) as a proxy for health status, we observed attenuation of the protective association with greater number of visits [HR (95% CI): 0.87 (0.63, 1.19) for ≥ 65 visits vs. 0.80 (0.59, 1.08) for ≤ 15 visits]. CONCLUSIONS: We observed a lower risk of ischemic stroke, but not hemorrhagic stroke with moderate alcohol consumption and did not observe substantial differences in risk by beverage preference among a sample of U.S. Veterans. Healthy user bias of moderate alcohol consumption may be driving some of the observed protective association.

Serum Cholesterol and Impact of Age on Coronary Heart Disease Death in More Than 4 Million Veterans.

Background The lipid hypothesis postulates that lower blood cholesterol is associated with reduced coronary heart disease (CHD) risk, which has been challenged by reports of a U-shaped relation between cholesterol and death in recent studies. We sought to examine whether the U-shaped relationship is true and to assess the impact of age on this association. Method and Results We conducted a prospective cohort study of 4 467 942 veterans aged >18 years, with baseline outpatient visits from 2002 to 2007 and follow-up to December 30, 2018, in the Veterans Health Administration electronic health record system. We observed a J-shaped relation between total cholesterol (TC) and CHD mortality after a comprehensive adjustment of confounding factors: flat for TC <180 mg/dL, and greater risk was present at higher cholesterol levels. Compared with veterans with TC between 180 and 199 mg/dL, the multiadjusted hazard ratios (HRs) for CHD death were 1.03 (95% CI, 1.02-1.04), 1.07 (95% CI, 1.06-1.09), 1.15 (95% CI, 1.13-1.18), 1.25 (95% CI, 1.22-1.28), and 1.45 (95% CI, 1.42-1.49) times greater among veterans with TC (mg/dL) of 200 to 219, 220 to 239, 140 to 259, 260 to 279 and ≥280, respectively. Similar J-shaped TC-CHD mortality patterns were observed among veterans with and without statin use at or before baseline. Conclusions The cholesterol paradox, for example, higher CHD death in patients with a low cholesterol level, was a reflection of reverse causality, especially among older participants. Our results support the lipid hypothesis that lower blood cholesterol is associated with reduced CHD. Furthermore, the hypothesis remained true when TC was low due to use of statins or other lipid-lowering medication.

Characterizing longitudinal change in accelerometry-based moderate-to-vigorous physical activity in the Hispanic Community Health Study/Study of Latinos and the Framingham Heart Study.

BACKGROUND: Physical activity promotes health and is particularly important during middle and older age for decreasing morbidity and mortality. We assessed the correlates of changes over time in moderate-to-vigorous physical activity (MVPA) in Hispanic/Latino adults from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL: mean [SD] age 49.2 y [11.5]) and compared them to a cohort of primarily White adults from the Framingham Heart Study (FHS: mean [SD] 46.9 y [9.2]). METHODS: Between 2008 and 2019, we assessed accelerometry-based MVPA at two time points with an average follow-up of: 7.6 y, SD 1.3 for HCHS/SOL, and 7.8 y, SD 0.7 for FHS. We used multinomial logistic regression to relate socio-demographic and health behaviors with changes in compliance with 2018 US recommendations for MVPA from time 1 to time 2 (remained active or inactive; became active or inactive) across the two cohorts. RESULTS: In HCHS/SOL mean MVPA was 22.6 (SD, 23.8) minutes at time 1 and dropped to 16.7 (19.0) minutes at time 2. In FHS Mean MVPA was 21.7 min (SD, 17.7) at time 1 and dropped to 21.3 min (SD, 19.2) at time 2. Across both cohorts, odds of meeting MVPA guidelines over time were about 6% lower in individuals who had lower quality diets vs. higher, about half in older vs. younger adults, about three times lower in women vs. men, and 9% lower in individuals who had a higher vs. lower BMI at baseline. Cohorts differed in how age, gender, income, education, depressive symptoms, marital status and perception of general health and pain associated with changes in physical activity. High income older Hispanics/Latino adults were more likely to become inactive at the follow-up visit as were HCHS/SOL women who were retired and FHS participants who had lower levels of education and income. Higher depressive symptomology was associated with becoming active only in HCHS/SOL women. Being male and married was associated with becoming inactive in both cohorts. Higher perception of general health and lower perception of pain were associated with remaining active only in FHS adults. CONCLUSIONS: These findings highlight potentially high-risk groups for targeted MVPA intervention.

Metabolomic Signatures of Sedentary Behavior and Cardiometabolic Traits in US Hispanics/Latinos: Results from HCHS/SOL.

PURPOSE: The aim of this study was to understand the serum metabolomic signatures of moderate-to-vigorous physical activity (MVPA) and sedentary behavior, and further associate their metabolomic signatures with incident cardiometabolic diseases. METHODS: This analysis included 2711 US Hispanics/Latinos from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) aged 18-74 yr (2008-2011). An untargeted, liquid chromatography-mass spectrometry was used to profile the serum metabolome. The associations of metabolites with accelerometer-measured MVPA and sedentary time were examined using survey linear regressions adjusting for covariates. The weighted correlation network analysis identified modules of correlated metabolites in relation to sedentary time, and the modules were associated with incident diabetes, dyslipidemia, and hypertension over the 6-yr follow-up. RESULTS: Of 624 metabolites, 5 and 102 were associated with MVPA and sedentary behavior at false discovery rate (FDR) <0.05, respectively, after adjusting for socioeconomic and lifestyle factors. The weighted correlation network analysis identified 8 modules from 102 metabolites associated with sedentary time. Four modules (branched-chain amino acids, erythritol, polyunsaturated fatty acid, creatine) were positively, and the other four (acyl choline, plasmalogen glycerol phosphatidyl choline, plasmalogen glycerol phosphatidyl ethanolamine, urea cycle) were negatively correlated with sedentary time. Among these modules, a higher branched-chain amino acid score and a lower plasmalogen glycerol phosphatidyl choline score were associated with increased risks of diabetes and dyslipidemia. A higher erythritol score was associated with an increased risk of diabetes, and a lower acyl choline score was linked to an increased risk of hypertension. CONCLUSIONS: In this study of US Hispanics/Latinos, we identified multiple serum metabolomic signatures of sedentary behavior and their associations with risk of incident diabetes, hypertension, and dyslipidemia. These findings suggest a potential role of circulating metabolites in the links between sedentary behavior and cardiometabolic diseases.

Plant-based diets and the incidence of cardiovascular disease: the Million Veteran Program.

Background: A healthful plant-based diet was associated with lower risks of coronary heart disease and type 2 diabetes, and a favourable profile of adiposity-associated biomarkers, while an unhealthful plant-based diet was associated with elevated risk of cardiometabolic disease in health professional populations. However, little is known about the associations between plant-based dietary patterns and risk of cardiovascular disease (CVD) in US veterans. Methods: The study population consisted of 148 506 participants who were free of diabetes, CVD and cancer at baseline in the Veterans Affairs (VA) Million Veteran Program. Diet was assessed using a Food Frequency Questionnaire at baseline. We calculated an overall Plant-Based Diet Index (PDI), a healthful PDI (hPDI) and an unhealthful PDI (uPDI). The CVD endpoints included non-fatal myocardial infarction (MI) and acute ischaemic stroke (AIS) identified through high-throughput phenotyping algorithms approach and fatal CVD events identified by searching the National Death Index. Results: With up to 8 years of follow-up, we documented 5025 CVD cases. After adjustment for confounding factors, a higher PDI was significantly associated with a lower risk of CVD (HR comparing extreme quintiles=0.75, 95% CI 0.68 to 0.82, P trend<0.0001). We observed an inverse association between hPDI and the risk of CVD (HR comparing extreme quintiles=0.71, 95% CI 0.64 to 0.78, P trend<0.001), whereas uPDI was positively associated with the risk of CVD (HR comparing extreme quintiles=1.12, 95% CI 1.02 to 1.24, P trend<0.001). We found similar associations of hPDI with subtypes of CVD; a 10-unit increment in hPDI was associated with HRs (95% CI) of 0.81 (0.75 to 0.87) for fatal CVD, 0.86 (0.79 to 0.94) for non-fatal MI and 0.86 (0.78 to 0.95) for non-fatal AIS. Conclusions: Plant-based dietary pattern enriched with healthier plant foods was associated with a substantially lower CVD risk in US veterans.

Mild-to-Moderate Kidney Dysfunction and Cardiovascular Disease: Observational and Mendelian Randomization Analyses.

BACKGROUND: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke. METHODS: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition-Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank. RESULTS: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values <60 or >105 mL·min-1·1.73 m-2, compared with those with eGFR between 60 and 105 mL·min-1·1.73 m-2. Mendelian randomization analyses for CHD showed an association among participants with eGFR <60 mL·min-1·1.73 m-2, with a 14% (95% CI, 3%-27%) higher CHD risk per 5 mL·min-1·1.73 m-2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min-1·1.73 m-2. Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD. CONCLUSIONS: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.

Temporal Trends in Incidence of Premature Cardiovascular Disease Over the Past 7 Decades: The Framingham Heart Study.

Background Premature onset of cardiovascular disease (CVD) imposes a significant societal burden and challenges prevention efforts. Methods and Results Trends in the incidence of premature CVD (before age 55, 60, or 65 years, separate analysis for each threshold) were evaluated in 14 464 Framingham Heart Study participants over 7 decades of observation (1950-2019). The change in the incidence of premature CVD (per decade) in men and women was assessed using overdispersed Poisson regression (accounting for cohort effects), adjusting for age at entry and age at onset of premature CVD within each decade. CVD was defined as a composite of fatal or nonfatal coronary heart disease, stroke or transient ischemic attack, peripheral vascular disease, and heart failure. There were 2223 first CVD events (832 in women) before age 65 years during 282 481 person-years of observations (154 587 in women) between 1950 and 2019. The age-adjusted CVD incidence before age 65 years decreased from 14.8 per 1000 person-years (1950-1959) to 4.69 per 1000 person-years (2010-2019) in men and from 7.23 per 1000 person-years (1950-1959) to 1.73 per 1000 person-years (2010-2019) in women. In adjusted analyses, the incidence of premature CVD decreased per decade in men (18.4% [95% CI, 12.0%-24.0%], for onset before age 55 years; 19.5% [95% CI, 12.0%-27.0%], for onset before age 60 years; 21.3% [95% CI, 16.0%-27.0%], for onset before age 65 years) and women (15.1% [95% CI, 7.0%-22.0%], for onset before age 55 years; 14.0% [95% CI, 6.0%-22.0%], for onset before age 60 years; 18.2% [95% CI, 12.0%-24.0%], for onset before age 65 years). The decline in premature CVD was accompanied by a reduction in smoking and increased use of lipid-lowering treatments across the decades. Incidence of premature coronary heart disease decreased, whereas the contribution of stroke to premature CVD burden increased over time. Conclusions The incidence of premature CVD has decreased among White adults in the Framingham cohort over the past 70 years; the residual burden of premature stroke warrants further study. Additional studies of trends in premature CVD in more racially and geographically diverse populations are warranted to elucidate the generalizability of these findings.

Predictors of incident diabetes in two populations: framingham heart study and hispanic community health study / study of latinos.

BACKGROUND: Non-genetic factors contribute to differences in diabetes risk across race/ethnic and socioeconomic groups, which raises the question of whether effects of predictors of diabetes are similar across populations. We studied diabetes incidence in the primarily non-Hispanic White Framingham Heart Study (FHS, N = 4066) and the urban, largely immigrant Hispanic Community Health Study/Study of Latinos (HCHS/SOL, N = 6891) Please check if the affiliations are captured and presented correctly. METHODS: Clinical, behavioral, and socioeconomic characteristics were collected at in-person examinations followed by seven-day accelerometry. Among individuals without diabetes, Cox proportional hazards regression models (both age- and sex-adjusted, and then multivariable-adjusted for all candidate predictors) identified predictors of incident diabetes over a decade of follow-up, defined using clinical history or laboratory assessments. RESULTS: Four independent predictors were shared between FHS and HCHS/SOL. In each cohort, the multivariable-adjusted hazard of diabetes increased by approximately 50% for every ten-year increment of age and every five-unit increment of body mass index (BMI), and was 50-70% higher among hypertensive than among non-hypertensive individuals (all P < 0.01). Compared with full-time employment status, the multivariable-adjusted hazard ratio (HR) and 95% confidence interval (CI) for part-time employment was 0.61 (0.37,1.00) in FHS and 0.62 (0.41,0.95) in HCHS/SOL. Moderate-to-vigorous physical activity (MVPA) was an additional predictor in common observed in age- and sex-adjusted models, which did not persist after adjustment for other covariates (compared with MVPA ≤ 5 min/day, HR for MVPA level ≥ 30 min/day was 0.48 [0.31,0.74] in FHS and 0.74 [0.56,0.97] in HCHS/SOL). Additional predictors found in sex- and age-adjusted analyses among the FHS participants included male gender and lower education, but these predictors were not found to be independent of others in multivariable adjusted models, nor were they associated with diabetes risk among HCHS/SOL adults. CONCLUSIONS: The same four independent predictors - age, body mass index, hypertension and employment status - were associated with diabetes risk across two disparate US populations. While the reason for elevated diabetes risk in full-time workers is unclear, the findings suggest that diabetes may be part of the work-related burden of disease. Our findings also support prior evidence that differences by gender and socioeconomic position in diabetes risk are not universally present across populations.

Notable paradoxical phenomena in associations between cardiovascular health score, subclinical and clinical cardiovascular disease in the community: The Framingham Heart Study.

IMPORTANCE: Cardiovascular Health (CVH) scores are inversely associated with prevalent subclinical (SubDz) and incident cardiovascular disease (CVD). However, the majority of people who develop CVD have intermediate or ideal CVH scores, while many with poor CVH profiles escape CVD development. OBJECTIVE: To describe the prevalence of paradoxical relations among CVH, SubDz, and CVD. DESIGN: Cohort study, Framingham Study data collected prospectively (1995-2016). SETTING: Population-based. PARTICIPANTS: 7,627 participants (mean age 49 years, 53% women) attending Offspring examinations 6/7 and Third Generation examinations 1/2. EXPOSURES: CVH score (range 0-14) constructed from poor, intermediate, or ideal status for each metric (smoking, diet, physical activity, blood pressure, body mass index, fasting glucose, total cholesterol); and prevalent SubDz (≥1 of: increased carotid intimal media thickness, CIMT; left ventricular hypertrophy, LVH; microalbuminuria, MA; elevated ankle brachial index, ABI; coronary artery calcium score ≥100,CAC). MAIN OUTCOME(S) AND MEASURE(S): Ideal CVH (scores 12-14), intermediate CVH (scores 8-11), and poor CVH (0-7). We described three distinct paradoxical phenomena, involving combinations of CVH, SubDz, and CVD, and generated CVD incidence rates and predicted CVD probabilities for all combinations. RESULTS: We observed 842 CVD events (median follow-up 13.7 years); 1,663 participants had SubDz. Most individuals with poor CVH (78%) or SubDz (57% for CIMT to 77% for LVH) did not develop CVD on follow-up. Among participants with incident CVD, the majority had intermediate or ideal CVH (68%) or absent SubDz (46% for CAC to 96% for ABI) at baseline. We observed similar paradoxical results in relations between CVH and prevalent SubDz. Poor CVH and prevalent SubDz were each associated with higher CVD incidence rates compared to intermediate or ideal CVH and absent SubDz, respectively. The predicted CVD probability was nearly three-times greater among participants with poor (22%) versus intermediate or ideal CVH (8%). Mean CVD predicted probabilities were nearly three (26% vs. 10% for MA) to six-times (29% vs. 5% for CAC) greater among participants with SubDz versus without SubDz. Findings were consistent within age and sex strata. CONCLUSIONS AND RELEVANCE: Although poor CVH and SubDz presence are associated with CVD incidence, paradoxical phenomena involving CVH, SubDz, and CVD are frequently prevalent in the community. Further studies to elucidate biological mechanisms underlying these phenomena are warranted.

Million Veteran Program's response to COVID-19: Survey development and preliminary findings.

BACKGROUND: In response to the novel Coronavirus Disease 2019 (COVID-19) pandemic, the Department of Veterans Affairs (VA) Million Veteran Program (MVP) organized efforts to better understand the impact of COVID-19 on Veterans by developing and deploying a self-reported survey. METHODS: The MVP COVID-19 Survey was developed to collect COVID-19 specific elements including symptoms, diagnosis, hospitalization, behavioral and psychosocial factors and to augment existing MVP data with longitudinal collection of key domains in physical and mental health. Due to the rapidly evolving nature of the pandemic, a multipronged strategy was implemented to widely disseminate the COVID-19 Survey and capture data using both the online platform and mailings. RESULTS: We limited the findings of this paper to the initial phase of survey dissemination which began in May 2020. A total of 729,625 eligible MVP Veterans were invited to complete version 1 of the COVID-19 Survey. As of October 31, 2020, 58,159 surveys have been returned. The mean and standard deviation (SD) age of responders was 71 (11) years, 8.6% were female, 8.2% were Black, 5.6% were Hispanic, and 446 (0.8%) self-reported a COVID-19 diagnosis. Over 90% of responders reported wearing masks, practicing social distancing, and frequent hand washing. CONCLUSION: The MVP COVID-19 Survey provides a systematic collection of data regarding COVID-19 behaviors among Veterans and represents one of the first large-scale, national surveillance efforts of COVID-19 in the Veteran population. Continued work will examine the overall response to the survey with comparison to available VA health record data.

Dietary Sodium and Potassium Intake and Risk of Non-Fatal Cardiovascular Diseases: The Million Veteran Program.

Objective: To examine the association between intakes of sodium and potassium and the ratio of sodium to potassium and incident myocardial infarction and stroke. Design, Setting and Participants: Prospective cohort study of 180,156 Veterans aged 19 to 107 years with plausible dietary intake measured by food frequency questionnaire (FFQ) who were free of cardiovascular disease (CVD) and cancer at baseline in the VA Million Veteran Program (MVP). Main outcome measures: CVD defined as non-fatal myocardial infarction (MI) or acute ischemic stroke (AIS) ascertained using high-throughput phenotyping algorithms applied to electronic health records. Results: During up to 8 years of follow-up, we documented 4090 CVD cases (2499 MI and 1712 AIS). After adjustment for confounding factors, a higher sodium intake was associated with a higher risk of CVD, whereas potassium intake was inversely associated with the risk of CVD [hazard ratio (HR) comparing extreme quintiles, 95% confidence interval (CI): 1.09 (95% CI: 0.99−1.21, p trend = 0.01) for sodium and 0.87 (95% CI: 0.79−0.96, p trend = 0.005) for potassium]. In addition, the ratio of sodium to potassium (Na/K ratio) was positively associated with the risk of CVD (HR comparing extreme quintiles = 1.26, 95% CI: 1.14−1.39, p trend < 0.0001). The associations of Na/K ratio were consistent for two subtypes of CVD; one standard deviation increment in the ratio was associated with HRs (95% CI) of 1.12 (1.06−1.19) for MI and 1.11 (1.03−1.19) for AIS. In secondary analyses, the observed associations were consistent across race and status for diabetes, hypertension, and high cholesterol at baseline. Associations appeared to be more pronounced among participants with poor dietary quality. Conclusions: A high sodium intake and a low potassium intake were associated with a higher risk of CVD in this large population of US veterans.

Degree of Adherence to Based Diet and Total and Cause-Specific Mortality: Prospective Cohort Study in the Million Veteran Program.

OBJECTIVE: To examine the associations between adherence to plant-based diets and mortality. DESIGN: prospective study. We calculated a plant-based diet index (PDI) by assigning positive scores to plant foods and reverse scores to animal foods. We also created a healthful PDI (hPDI) and an unhealthful PDI (uPDI) by further separate the healthy plant foods from less-healthy plant foods. SETTING: the VA Million Veteran Program. PARTICIPANTS: 315,919 men and women aged 19 to 104 years who completed a food frequency questionnaire at the baseline. RESULTS: We documented 31,136 deaths during the follow-up. A higher PDI was significantly associated with lower total mortality [hazard ratio (HR) comparing extreme deciles =0.75, 95% confidence interval (CI): 0.71 to 0.79, Ptrend <0.001]. We observed an inverse association between hPDI and total mortality (HR comparing extreme deciles =0.64, 95% CI: 0.61 to 0.68, Ptrend <0.001), whereas uPDI was positively associated with total mortality (HR comparing extreme deciles =1.41, 95% CI: 1.33 to 1.49, Ptrend <0.001). Similar significant associations of PDI, hPDI, and uPDI were also observed for CVD and cancer mortality. The associations between the plant-based diet indices and total mortality were consistent among African and European American participants, and participants free from CVD and cancer and those who were diagnosed with major chronic disease at baseline. CONCLUSIONS: A greater adherence to a plant-based diet was associated with substantially lower total mortality in this large population of veterans. These findings support recommending plant-rich dietary patterns for the prevention of major chronic diseases.

Prevalence, Predictors, Progression, and Prognosis of Hypertension Subtypes in the Framingham Heart Study.

Background The epidemiology of hypertension subtypes has not been well characterized in the recent era. Methods and Results We delineated the prevalence, predictors, progression, and prognostic significance of hypertension subtypes in 8198 Framingham Heart Study participants (mean age, 46.5 years; 54% women). The prevalence of hypertension subtypes was as follows: nonhypertensive (systolic blood pressure [SBP] <140 mm Hg and diastolic blood pressure [DBP] <90 mm Hg), 79%; isolated systolic hypertension (ISH; SBP ≥140 mm Hg and DBP <90 mm Hg), 8%; isolated diastolic hypertension (SBP <140 mm Hg and DBP ≥90 mm Hg), 4%; and systolic-diastolic hypertension (SDH; SBP ≥140 mm Hg and DBP ≥90 mm Hg), 9%. The prevalence of ISH and SDH increased with age. Analysis of a subsample of nonhypertensive participants demonstrated that increasing age, female sex, higher heart rate, left ventricular mass, and greater left ventricular concentricity were predictors of incident ISH and SDH. Higher baseline DBP was associated with the risk of developing isolated diastolic hypertension and SDH, whereas higher SBP was associated with all 3 hypertension subtypes. On follow-up (median, 5.5 years), isolated diastolic hypertension often reverted to nonhypertensive BP (in 42% of participants) and ISH progressed to SDH (in 26% of participants), whereas SDH frequently transitioned to ISH (in 20% of participants). During follow-up (median, 14.6 years), 889 participants developed cardiovascular disease. Compared with the nonhypertensive group (referent), ISH (adjusted hazard ratio [HR], 1.57; 95% CI, 1.30-1.90) and SDH (HR, 1.66; 95% CI, 1.36-2.01) were associated with increased cardiovascular disease risk, whereas isolated diastolic hypertension was not (HR, 1.03; 95% CI, 0.68-1.57). Conclusions Hypertension subtypes vary in prevalence with age, are dynamic during short-term follow-up, and exhibit distinctive prognoses, underscoring the importance of blood pressure subphenotyping.

Hypertension-Mediated Organ Damage: Prevalence, Correlates, and Prognosis in the Community.

BACKGROUND: Guidelines emphasize screening people with elevated BP for the presence of end-organ damage. METHODS: We characterized the prevalence, correlates, and prognosis of hypertension-mediated organ damage (HMOD) in the community-based Framingham Study. 7898 participants (mean age 51.6 years, 54% women) underwent assessment for the following HMOD: electrocardiographic and echocardiographic left ventricular hypertrophy, abnormal brain imaging findings consistent with vascular injury, increased carotid intima-media thickness, elevated carotid-femoral pulse wave velocity, reduced kidney function, microalbuminuria, and low ankle-brachial index. We characterized HMOD prevalence according to blood pressure (BP) categories defined by four international BP guidelines. Participants were followed up for incidence of cardiovascular disease. RESULTS: The prevalence of HMOD varied positively with systolic BP and pulse pressure but negatively with diastolic BP; it increased with age, was similar in both sexes, and varied across BP guidelines based on their thresholds defining hypertension. Among participants with hypertension, elevated carotid-femoral pulse wave velocity was the most prevalent HMOD (40%-60%), whereas low ankle-brachial index was the least prevalent (<5%). Left ventricular hypertrophy, reduced kidney function, microalbuminuria, increased carotid intima-media thickness, and abnormal brain imaging findings had an intermediate prevalence (20%-40%). HMOD frequently clustered within individuals. On follow-up (median, 14.1 years), there were 384 cardiovascular disease events among 5865 participants with concurrent assessment of left ventricular mass, carotid-femoral pulse wave velocity, kidney function, and microalbuminuria. For every BP category above optimal (referent group), the presence of HMOD increased cardiovascular disease risk compared with its absence. CONCLUSIONS: The prevalence of HMOD varies across international BP guidelines based on their different thresholds for defining hypertension. The presence of HMOD confers incremental prognostic information regarding cardiovascular disease risk at every BP category.

Frailty and cardiovascular mortality in more than 3 million US Veterans.

AIMS: Frailty is associated with an increased risk of all-cause mortality and cardiovascular (CV) events. Limited data exist from the modern era of CV prevention on the relationship between frailty and CV mortality. We hypothesized that frailty is associated with an increased risk of CV mortality. METHODS AND RESULTS: All US Veterans aged ≥65 years who were regular users of Veteran Affairs care from 2002 to 2017 were included. Frailty was defined using a 31-item previously validated frailty index, ranging from 0 to 1. The primary outcome was CV mortality with secondary analyses examining the relationship between frailty and CV events (myocardial infarction, stroke, revascularization). Survival analysis models were adjusted for age, sex, ethnicity, geographic region, smoking, hyperlipidaemia, statin use, and blood pressure medication use. There were 3 068 439 US Veterans included in the analysis. Mean age was 74.1 ± 5.8 years in 2002, 76.0 ± 8.3 years in 2014, 98% male, and 87.5% White. In 2002, the median (interquartile range) frailty score was 0.16 (0.10-0.23). This increased and stabilized to 0.19 (0.10-0.32) for 2006-14. The presence of frailty was associated with an increased risk of CV mortality at every stage of frailty. Frailty was associated with an increased risk of myocardial infarction and stroke, but not revascularization. CONCLUSION: In this population, both the presence and severity of frailty are tightly correlated with CV death, independent of underlying CV disease. This study is the largest and most contemporary evaluation of the relationship between frailty and CV mortality to date. Further work is needed to understand how this risk can be diminished. KEY QUESTION: Can an electronic frailty index identify adults aged 65 and older who are at risk of CV mortality and major CV events? KEY FINDING: Among 3 068 439 US Veterans aged 65 and older, frailty was associated with an increased risk of CV mortality at every level of frailty. Frailty was also associated with an increased risk of myocardial infarction and stroke, but not revascularization. TAKE HOME MESSAGE: Both the presence and severity of frailty are associated with CV mortality and major CV events, independent of underlying CV disease.

Aortic Root Diameter and Arterial Stiffness: Conjoint Relations to the Incidence of Cardiovascular Disease in the Framingham Heart Study.

[Figure: see text].

Association of Estimated Cardiorespiratory Fitness in Midlife With Cardiometabolic Outcomes and Mortality.

Importance: The associations of estimated cardiorespiratory fitness (eCRF) during midlife with subclinical atherosclerosis, arterial stiffness, incident cardiometabolic disease, and mortality are not well understood. Objective: To examine associations of midlife eCRF with subclinical atherosclerosis, arterial stiffness, incident cardiometabolic disease, and mortality. Design, Setting, and Participants: This cohort study included 2962 participants in the Framingham Study Second Generation (conducted between 1979 and 2001). Data were analyzed from January 2020 to June 2020. Exposures: eCRF was calculated using sex-specific algorithms (including age, body mass index, waist circumference, physical activity, resting heart rate, and smoking) and was categorized as: (1) tertiles of standardized eCRF at examination cycle 7 (1998 to 2001); (2) tertiles of standardized average eCRF between examination cycles 2 and 7 (1979 to 2001); and (3) eCRF trajectories between examination cycles 2 and 7, with the lowest tertile or trajectory (ie, low eCRF) as referent group. Main Outcomes and Measures: Subclinical atherosclerosis (carotid intima-media thickness [CIMT], coronary artery calcium [CAC] score); arterial stiffness (carotid-femoral pulse wave velocity [-1000/CFPWV]); incident hypertension, diabetes, chronic kidney disease (CKD), cardiovascular disease (CVD), and mortality after examination cycle 7. Results: A total of 2962 participants were included in this cohort study (mean [SD] age, 61.5 [9.2] years; 1562 [52.7%] women). The number of events or participants at risk after examination cycle 7 (at a mean follow-up of 15 years) was 728 of 1506 for hypertension, 214 of 2268 for diabetes, 439 of 2343 for CKD, 500 of 2608 for CVD, and 770 of 2962 for mortality. Compared with the low eCRF reference value, high single examination eCRF was associated with lower CFPWV (ß [SE], -11.13 [1.33] ms/m) and CIMT (ß [SE], -0.12 [0.05] mm), and lower risk of hypertension (hazard ratio [HR], 0.63; 95% CI, 0.46-0.85), diabetes (HR, 0.38; 95% CI, 0.23-0.62), and CVD (HR, 0.71; 95% CI, 0.53-0.95), although it was not associated with CKD or mortality. Similarly, compared with the low eCRF reference, high eCRF trajectories and mean eCRF were associated with lower CFPWV (ß [SE], -11.85 [1.89] ms/m and -10.36 [1.54] ms/m), CIMT (ß [SE], -0.19 [0.06] mm and -0.15 [0.05] mm), CAC scores (ß [SE], -0.67 [0.25] AU and -0.63 [0.20] AU), and lower risk of hypertension (HR, 0.54; 95% CI, 0.34-0.87 and HR, 0.48; 95% CI, 0.34-0.68), diabetes (HR, 0.27; 95% CI, 0.15-0.48 and HR, 0.31; 95% CI, 0.18-0.54), CKD (HR, 0.63; 95% CI, 0.40-0.97 and HR, 0.64; 95% CI, 0.44-0.94), and CVD (HR, 0.46; 95% CI, 0.31-0.68 and HR, 0.43; 95% CI, 0.30-0.60). Compared with the reference value, a high eCRF trajectory was associated with lower risk of mortality (HR, 0.69; 95% CI, 0.50-0.95). Conclusions and Relevance: In this cohort study, higher midlife eCRF was associated with lower burdens of subclinical atherosclerosis and vascular stiffness, and with a lower risk of hypertension, diabetes, chronic kidney disease, cardiovascular disease, and mortality. These findings suggest that midlife eCRF may serve as a prognostic marker for subclinical atherosclerosis, arterial stiffness, cardiometabolic health, and mortality in later life.

Association of Mildly Reduced Kidney Function With Cardiovascular Disease: The Framingham Heart Study.

Background Data are limited on the association of mildly reduced estimated glomerular filtration rate (eGFR 60-89 mL/min per 1.73 m2) with cardiovascular disease (CVD) in the community. Methods and Results We evaluated 3066 Framingham Offspring Study participants (55% women, mean age 58 years), without clinical CVD. Using multivariable regression, we related categories of mildly reduced eGFR (80-89, 70-79, or 60-69 versus ≥90 mL/min per 1.73 m2 [referent]) to prevalent coronary artery calcium, carotid intima media thickness, and left ventricular hypertrophy, and to circulating concentrations of cardiac stress biomarkers. We related eGFR categories to CVD incidence and to progression to ≥Stage 3 chronic kidney disease (eGFR <60 mL/min per 1.73 m2) using Cox regression. Individuals with eGFR 60-69 mL/min per 1.73 m2 (n=320) had higher coronary artery calcium score (odds ratio 1.69; 95% CI 1.02-2.80) compared with the referent group. Individuals with eGFR 60-69 and 70-79 mL/min per 1.73 m2 had higher blood growth differentiating factor-15 concentrations (ß=0.131 and 0.058 per unit-increase in log-biomarker, respectively). Participants with eGFR 60-69 and 80-89 mL/min per 1.73 m2 had higher blood B-type natriuretic peptide concentrations (ß=0.119 and 0.116, respectively). On follow-up (median 16 years; 691 incident CVD and 252 chronic kidney disease events), individuals with eGFR 60-69 and 70-79 mL/min per 1.73 m2 experienced higher CVD incidence (hazard ratio [HR], 1.40; 95% CI, 1.02-1.93 and 1.45, 95% CI, 1.05-2.00, respectively, versus referent). Participants with eGFR 60-69 mL/min per 1.73 m2 experienced higher chronic kidney disease incidence (HR, 2.94; 95% CI, 1.80-4.78 versus referent). Conclusions Individuals with mildly reduced eGFR 60-69 mL/min per 1.73 m2 have a higher burden of subclinical atherosclerosis cross-sectionally, and a greater risk of CVD and chronic kidney disease progression prospectively. Additional studies are warranted to confirm our findings.

Phenome-wide association of 1809 phenotypes and COVID-19 disease progression in the Veterans Health Administration Million Veteran Program.

BACKGROUND: The risk factors associated with the stages of Coronavirus Disease-2019 (COVID-19) disease progression are not well known. We aim to identify risk factors specific to each state of COVID-19 progression from SARS-CoV-2 infection through death. METHODS AND RESULTS: We included 648,202 participants from the Veteran Affairs Million Veteran Program (2011-). We identified characteristics and 1,809 ICD code-based phenotypes from the electronic health record. We used logistic regression to examine the association of age, sex, body mass index (BMI), race, and prevalent phenotypes to the stages of COVID-19 disease progression: infection, hospitalization, intensive care unit (ICU) admission, and 30-day mortality (separate models for each). Models were adjusted for age, sex, race, ethnicity, number of visit months and ICD codes, state infection rate and controlled for multiple testing using false discovery rate (≤0.1). As of August 10, 2020, 5,929 individuals were SARS-CoV-2 positive and among those, 1,463 (25%) were hospitalized, 579 (10%) were in ICU, and 398 (7%) died. We observed a lower risk in women vs. men for ICU and mortality (Odds Ratio (95% CI): 0.48 (0.30-0.76) and 0.59 (0.31-1.15), respectively) and a higher risk in Black vs. Other race patients for hospitalization and ICU (OR (95%CI): 1.53 (1.32-1.77) and 1.63 (1.32-2.02), respectively). We observed an increased risk of all COVID-19 disease states with older age and BMI ≥35 vs. 20-24 kg/m2. Renal failure, respiratory failure, morbid obesity, acid-base balance disorder, white blood cell diseases, hydronephrosis and bacterial infections were associated with an increased risk of ICU admissions; sepsis, chronic skin ulcers, acid-base balance disorder and acidosis were associated with mortality. CONCLUSIONS: Older age, higher BMI, males and patients with a history of respiratory, kidney, bacterial or metabolic comorbidities experienced greater COVID-19 severity. Future studies to investigate the underlying mechanisms associated with these phenotype clusters and COVID-19 are warranted.