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Background: Dietary intake of fruit and vegetables (FV) in the US falls well below recommended guidelines with only 12.2% of adults consuming at least 1.5-2 cup equivalents of fruit and 9.3% consuming at least 2-3 cup equivalents of vegetables each day. The Dietary Approaches to Stop Hypertension (DASH) trial demonstrated that consuming a “Mediterranean diet” with increased average daily FV intake resulted in reductions of systolic blood pressure of 0.8mmHg in those without hypertension and 7.2mmHg in those with hypertension. We used simulation modeling to estimate the impact of increasing FV intake in the population who currently are low FV consumers on subsequent incident cardiovascular disease (CVD) and death. Methods: We used the CVD Policy Model, a dynamic state-transition model of CVD risk factors, events, and outcomes to simulate the impact of increasing FV intake by one cup equivalent per day in US adults aged 35-94 years with no prior CVD who consume less than cup equivalent of FV per day; based on the National Health and Nutrition Examination Survey (NHANES) years 2015-2018. We used estimates of FV intake on blood pressure reductions based on DASH and ran 10 year simulations, focusing on the population with uncontrolled hypertension (baseline systolic BP ≥140mmHg). Results: Based on NHANES, 40.5M US adults age 35-94 years without a history of CVD consume less than 1 cup equivalent of FV per day. Increasing FV intake by cup equivalents per day in this population is estimated to prevent 98,000 incident CVD and 16,000 CVD deaths over 10 years, of which 82,000 (84%) and 13,000 (81%) respectively occur in 8.9M of this population with uncontrolled hypertension. Women would be expected to realize the greatest population improvements with increase in FV consumption. Conclusion: Increasing fruit and vegetable consumption among US adults could yield considerable population health benefits in prevention of cardiovascular disease and death, particularly for those with existing hypertension.

Background: Hypertension is a leading preventable cause of CHD, stroke, and heart failure (HF). WHO hypertension guidelines recommend initiating first dose medication in hypertensive adults with access to healthcare, yet many US adults with a usual source of care are not receiving treatment. We estimate the population impact of initiating hypertensive therapy in untreated US adults with uncontrolled blood pressure (BP) and access to usual healthcare on incident CVD. Methods: We used the CVD Policy Model, a dynamic state-transition model of CVD risk factors, events, and outcomes to simulate the impact over 10 years of treating uncontrolled BP in our target population of US adults 35-94 years of age with no prior CVD, baseline systolic BP ≥140mmHg, and no current hypertensive medication use, estimated from National Health and Nutrition Examination Survey years 2015-2018. We initiated first dose medication in the target population reporting access to a usual source of healthcare and at least two visits per year. We used the Law, Morris and Wald equation to estimate the systolic BP effect size for a standard first dose of medication. Results: Initiating hypertension medications in those with currently untreated but with regular healthcare access would prevent 214,000 incident CVD events in the US, a quarter of which (52,000) are incident heart failure (Table 1). First dose treatment (and maintenance) would be expected to reduce incident CHD by 9.1%, HF by 6.1%, ischemic stroke by 8.1%, and hemorrhagic stroke by 11.3% over the decade, compared to no treatment. Treatment of hypertension would have the greatest relative benefit in the prevention on incident CVD events in those younger than 65, compared with those over 65 years of age. Conclusion: In the US population with regular access to healthcare, initiating first dose medications for hypertension in those with elevated blood pressure but currently untreated would reduce incident CVD in both sexes and all age groups, with particular benefit for prevention in those less than 65 years of age.

Introduction: Non-statin therapies may improve long-term outcomes in patients with atherosclerotic cardiovascular disease (ASCVD) who experience statin-associated side effects (SASE). Objective: To examine the cost-effectiveness of a newly approved combination of bempedoic acid and ezetimibe (BAEze) in patients with ASCVD from a U.S. healthcare sector perspective. Methods: State-transition Markov model of US adults with ASCVD and low-density lipoprotein cholesterol (LDL-C) ≥70mg/dL on maximally tolerated statin and ezetimibe. The study cohort was stratified by concurrent statin use: high-intensity (group1), moderate-/low-intensity (group 2), or no statin due to severe SASE (group 3). The intervention group received BAEze (annual cost $2,447) instead of ezetimibe. We estimated baseline LDL-C from NHANES; relative LDL-C lowering and rate of adverse events from randomized trials; and the relationship between LDL-C lowering and cardiovascular events from meta-analyses of statin trials. The main outcome was lifetime incremental cost-effectiveness ratio (ICER), with a threshold of $100,000 per quality-adjusted-life-year (QALY) gained. Results: BAEze had an ICER of $188,000/QALY in group 1 (95% UI: 141,500-284,600; cost-effective in 0% of 10,000 probabilistic simulations) and $175,600/QALY (132,700-264,700; cost-effective in 0% simulations) in group 2. In group 3, BAEze produced 0.28 incremental QALYs at a lifetime cost of $25,600, yielding an ICER of $92,600/QALY (66,000-152,100; cost-effective in 59% simulations). Conclusions: Among US adults with ASCVD, cost-effectiveness of BAEze varies substantially by concurrent statin use, and only meets conventional cost-effectiveness thresholds among patients unable to take a statin due to severe SASE. Our findings argue for the selective use of BAEze among patients with ASCVD and severe SASE but should be updated when more data on long-term effectiveness and safety become available.

Introduction: Studies suggest that greater physical activity (PA) may be associated with favorable carotid artery characteristics, while greater time spent in sedentary behavior (SB) may be a potential risk factor for atherosclerosis development and progression. We evaluated the association between leisure-time PA and SB in midlife and their temporal patterns with carotid atherosclerotic morphology measured by MRI. Methods: ARIC Carotid-MRI participants (n=1582, mean age: 53 years, 43% male, 18% Black) with self-reported assessments of PA and SB at visits 1 (1987-1989) and 3 (1993-1995), who participated in the Carotid MRI substudy in 2004-2006 were included. Self-reported leisure-time PA was categorized based on the American Heart Association’s Life Simple 7 categorization of ideal, intermediate, or poor PA. SB was ascertained based on participant report of how often they watched television during leisure-time, and categorized as low [“never”/ “seldom”], medium [“sometimes”], or high [“often”/“very often”]. To measure persistent PA and SB, we examined participants who reported the same level of PA (n=849) or SB (n=954) at both visits 1 and 3. Carotid MRI using a 1.5T scanner quantified internal carotid artery wall thickness, lipid core, and calcification measures. Weighted analyses accounted for the sampling design allowing for generalizability to the visit 1 ARIC population. Multivariable linear and logistic regression were used for continuous and categorical outcomes, respectively. All models were adjusted for demographic, behavioral, and lifestyle factors. Results: Though no clear trends were observed for PA, higher levels of SB were associated with a greater odds of lipid core presence and lower odds of calcification (Table). Similar trends were observed for the persistence analyses, though none were statistically significant. Conclusions: PA and SB may influence atherosclerotic plaque characteristics. SB and lack of PA may have different measurable effects on plaque morphology.

Background: Both high sugar intake and low fruit and vegetable (FV) consumption increase the risk of coronary heart disease (CHD). Sugar-sweetened beverage (SSB) taxes can reduce sugar intake, whereas FV subsidies increase FV consumption. Several cities in the US have proposed an innovative policy that used the SSB tax revenue towards FV subsidies. It is unclear what the long-term health and economic impact this innovative policy could have in large cities such as New York City (NYC). Objective: To project lifetime CHDs averted and costs if a penny-per-ounce SSB tax were used to subsidize FV incentives in NYC using a validated microsimulation model of cardiovascular disease. Methods: We used the SHINE CVD model to compare the cost and CHD outcomes of a combination of SSB tax and FV subsidy policy with only SSB tax, only FV subsidy, and no policy from a healthcare sector perspective, respectively. Population demographics and health profiles were estimated using data from the 2013-2014 NYC Health and Nutrition Examination Survey. We simulated 10,000 adults starting at age 40. CHD risk factor trajectories and risk of incident CHD events were derived from six pooled prospective U.S. cohorts. Policy effects and price elasticity were derived from recent meta-analyses. SSB tax (penny-per-ounce) and FV subsidy were modeled to directly affect incidence rates of CHD events. Medical costs were included and discounted at 3%. Results: Compared to the non-policy scenario over the simulated lifetime, the SHINE CVD model projected that the policy intervention with SSB taxes only would prevent 62 per 10,000 (95% CI: 57 - 67) CHD events at a penny-per-ounce rate, the intervention with FV subsidies only would prevent 28 per 10,000 (95% CI: 24-34), and the combined policy would prevent 91 CHD events (95% CI: 87 - 96). Total medical cost savings over the simulation period ranged from $22.5 million (95% CI: $21.5 - $23.6 million), $13.1 million (95% CI: $12.3 - $13.8million), and $37.9 million (95% CI: $36.5 - $39.4million), or $0.45 million/year, $0.27 million/year, $0.75 million/year for SSB taxes only, FV subsidies only, and the combined policy, respectively. Conclusion: Using a computer simulation model, we showed how converting SSB tax revenues into FV subsidies could result in substantial benefits within the NYC population in terms of CHD outcomes and overall healthcare cost savings. Results from the SHINE CVD model may inform the ongoing policy-making efforts.

Introduction: The Predicting Out-of-Office Blood Pressure in the Clinic (PROOF-BP) algorithm accurately estimates out-of-office BP to guide ambulatory BP monitoring (ABPM) among adults in the UK and Canada with suspected high BP. We tested the validity of PROOF-BP in a diverse US population and developed a US-specific algorithm. Methods: We pooled data from four US studies (CARDIA, JHS, Masked Hypertension Study, and Improving Detection of Hypertension Study) that assessed both office BP and 24-hour ABPM. We included participants with >=2 office and >=10 daytime ambulatory BP readings. PROOF-BP estimates the difference between office systolic BP (SBP) and diastolic BP (DBP) and daytime ambulatory SBP and DBP using clinic BP measurements and patient characteristics. We examined the performance of PROOF-BP in US data and then used multivariable linear regression to develop a new algorithm optimized for the US population. We tested the ability of PROOF-BP to discriminate high awake ambulatory SBP and DBP (SBP/DBP >=130/80 mm Hg) using the area under the receiver-operator curve (AUROC). Models were developed in a 70% randomly selected derivation set and tested in a 30% validation set. The optimal predicted ambulatory BP thresholds were defined as those that resulted in the smallest proportion of individuals recommended for ABPM with an overall classification error Results: We analyzed 3,080 individuals with a mean (SD) age of 52.0 (11.9) years, 38% were male, and 54% were black. Mean (SD) office SBP/DBP was 121.8 (16.6)/75.3 (9.8) mm Hg, mean (SD) awake ambulatory SBP/DBP was 127.3 (13.5)/78.6 (8.8) mm Hg, and 51% had awake ABPM >=130/80 mm Hg. The discrimination for high awake ABPM was similar between the existing (AUROC SBP = 0.77, DBP = 0.73) and US-specific models (AUROC SBP = 0.77, DBP = 0.72). Optimal predicted ambulatory BP thresholds with the US-specific algorithm were 125-134/75-84 mm Hg, resulting in 55% of the pooled cohort recommended for ABPM; compared to 66% recommended by the 2017 ACC/AHA guidelines. Conclusions: Both the original and US-specific PROOF-BP algorithms predicted high out-of-office BP among US adults. PROOF-BP may be used to guide clinical decisions and resource allocation among individuals considered for ABPM.

Introduction: Intensive systolic blood pressure (SBP) treatment ( Methods: We projected life expectancy after SPRINT using six US cohort studies in the National Heart, Lung, and Blood Institute Pooled Cohorts Study (NHLBI-PCS). We included SPRINT-eligible NHLBI-PCS participants as those aged >=50 years with SBP 130-180 mm Hg and increased cardiovascular disease (CVD) risk without diabetes or history of stroke. We used propensity scores to weight NHLBI-PCS participants to resemble SPRINT participants. In SPRINT participants, we estimated in-trial survival (=4 years) using an age-based FPSM and applied the formula to SPRINT participants to predict post-trial survival. We combined in- and post-trial survival to project overall life expectancy for each SPRINT participant and compared it to commonly used Gompertz methods. Results: We included 8,584 SPRINT and 10,610 SPRINT-eligible NHLBI-PCS participants. After propensity weighting, mean (SD) age was 67.9 (9.4) and 68.7 (8.8) years, 35.5% and 38.3% were female in SPRINT and NHLBI-PCS, respectively. Predicted in-trial survival was similar to that observed in SPRINT with both FPSM and Gompertz models (Figure). Assuming constant treatment effects, projected mean life expectancy using the NHLBI-PCS method was 21.1 (7.4) years with intensive and 19.3 (7.2) years with standard treatment; compared to 11.2 (2.3) and 10.5 (2.2) years, respectively, using the Gompertz method. Conclusions: Combining SPRINT and NHLBI-PCS observed data may offer a more realistic estimate of life expectancy than by parametrically extrapolating SPRINT data.

Introduction: Home blood pressure monitoring (HBPM) is an option recommended by the 2017 ACC/AHA guidelines to confirm a hypertension diagnosis or identify masked hypertension. Using clinic BP and patient characteristics, the Predicting Out-of-Office BP in the Clinic (PROOF-BP) algorithm can be used to guide HBPM decisions. It is unknown how existing patient use and physician recommendations for HBPM align with current screening recommendations. Methods: We used the 2009-2014 National Health and Nutrition Examination Survey (NHANES) to identify US adults aged ≥20 years without hypertension or antihypertensive medication use. We identified those who would have been recommended to undergo HBPM by ACC/AHA guidelines as those with a mean BP 120-159/ Results: We included 7,185 NHANES adults without hypertension; weighted mean (SE) age was 41.5 (0.3) years, 48% female, and mean BP 117.0 (0.3)/70.4 (0.3) mm Hg. Overall, 50.3% of adults without hypertension would have been recommended to undergo HBPM by ACC/AHA guidelines and 29.7% by PROOF-BP ( Table ). Only 13.3% of those recommended HBPM by ACC/AHA guidelines used or were told to use HBPM, compared to 11.5% of those not recommended screening. Similar results were seen among those recommended HBPM by PROOF-BP ( Table ). Conclusions: Our analysis shows that prior to 2017 guidelines, a substantial proportion of US adults may have had their hypertensive status misclassified due to a lack of HBPM or undergo unnecessary monitoring. These findings suggest an opportunity for clinicians and health systems to more clearly target HBPM to those who need it given guidelines currently in use.

Background: Low fruit and vegetable (FV) consumption is considered one of the leading causes of deteriorating health outcomes, and has been linked to obesity, diabetes, and cardiovascular disease. Yet, few adults in New York City (NYC) consume the daily recommended amounts. In order to address the need for fresh and affordable fruits and vegetables, the NYC Department of Health and Mental Hygiene has implemented the “Health Bucks” program, which provides low-income population with coupons that can be used to purchase fruits and vegetetabls. Previous studies have shown the impact of the Health Bucks program on fruit and vegetable consumption; however, it is unclear how the program would influence cardiovascular health and the associated health care costs in the long term. Objective: To estimate the health and economic impact of the Health Bucks program using a validated microsimulation model of cardiovascular disease (CVD) in NYC. Methods: We used the Simulations for Health Improvement and Equity (SHINE) CVD Model to estimate the impact of the Health Bucks program on lifetime CVD events and direct medical costs (2019 USD). We considered different program strengths by assuming the program can reduce the cost of fruits and vegetables by 20%, 30%, and 40%. Population characteristics were estimated based on data from the 2013-2014 NYC Health and Nutrition Examination Survey. CVD risk factor trajectories and risk of incident CVD events were derived from six pooled longitudinal US cohorts. Policy effects were derived from the literature. We run 1,000 simulations to account for uncertainties in the parameter. We discounted costs by 3% and reported health care costs in 2019 dollars. Results: A Health Bucks program that can reduce the cost of fruits and vegetables by 20%, 30%, and 40% would prevent 2,690 (95% CI: -14,793, 20,173), 27,386 (95% CI: 9,967, 44,805), and 50,014 (95% CI: 15,227, 50,014) coronary heart disease events, respectively, over the simulated lifetimes of the NYC population. The program would also prevent 47,469 (95% CI: 35,008, 59,931), 59,127 (95% CI: 46,676, 71,579), and 85,359 (95% CI: 72,902, 97,815) stroke events based on the price reduction level. The program would result in savings in health care costs, ranged from $937 million to $1.8 billion based on the price reduction level over the lifetime or from $19 million to $37 million annually. Conclusions: We projected that the Health Bucks program could prevent a significant number of CVD events among adults in NYC and yield substantial health care cost savings. Public health practitioners and policymakers may consider adopting this program in other locations.

Background: Sugar-sweetened beverages (SSB) are currently the single largest source of added sugar in the US diet, and consumption in New York City (NYC) remains high. Evidence suggests that a high sugar consumption increases the risk of coronary heart disease. To date, excise taxes on SSB have been implemented in several US jurisdictions. While reductions in SSB consumption have been reported in several places where the SSB tax was implemented, it is unclear what the long term health and economic impact an SSB tax could have within the demographically and socioeconomically diverse NYC. In addition, the impact of varying tax structures remains unknown. Objective: To project the cardiovascular health outcomes and cost-savings of variations on the penny-per-ounce SSB tax structure (simulating a half-penny to two-penny range) using a validated microsimulation model of cardiovascular disease. Methods: The Simulations for Health Improvement and Equity (SHINE) CVD Model was used to estimate the lifetime direct medical costs (2019 USD) and effectiveness of SSB tax from a healthcare sector perspective. Population demographics and health profiles were estimated using data from the 2013-2014 NYC Health and Nutrition Examination Survey. CVD risk factor trajectories and risk of incident CVD events were derived from six pooled prospective U.S. cohorts. Policy effects and price elasticity were derived from recent meta-analyses. SSB tax was modeled to directly affect incidence rates of CVD events and was derived from variations of the penny-per-ounce tax scheme. Costs were discounted at 3%. Results: Compared to the non-policy situation, the SHINE CVD model projected that an SSB tax would prevent 29,341 (95% CI: 11,747-46,935) coronary heart disease (CHD) events at a half penny-per-ounce rate, 37,034 (95% CI: 19,336-54,732), at one penny-per-ounce, and 68,846 CHD events (95% CI: 51,306- 86,386) at a two-pennies-per-ounce rate over the simulated lifetimes of the NYC population. Total cost savings over this time period ranged from $662 million (95% CI $584-$741 million), $714 million (95% CI: $620-$808 million), and $1.03 billion (95% CI $0.92 - $1.16 billion), or $13.5 million/year, $14.6 million/year, $21.0 million/year for half-penny, one-penny, and two-pennies-per-ounce taxes respectively. Conclusion: Using a computer simulation model, we showed how different increments of the penny-per-ounce SSB tax could result in substantial benefits within the NYC population in terms of CVD outcomes and overall health care cost savings. Results from the SHINE CVD model may inform the ongoing policymaking efforts.

Introduction: Individuals with no established cardiovascular disease (CVD) are currently recommended preventive statin therapy based on 10-year absolute risk (AR) of CVD, and individuals with a 10-year AR ≥7.5% are recommended statins. However, individuals with elevated LDL cholesterol experience greater absolute CVD absolute risk reduction (ARR) from statin therapy compared with those with the same 10-year AR but with lower LDL. A previous study showed that ARR-based statin treatment would prevent more CVD events than AR-based treatment in the 10 years following treatment initiation. Objective: This study aimed to quantify the long-term benefits of treating patients based on ARR rather than AR. Methods: A microsimulation version of the CVD Policy Model, a decision-analytic state transition model, simulated intermediate-strength statin therapy in 40,000 CVD-free US adults (50% female) under a variety of treatment strategies. The model predicts health outcomes for individuals based on their age, sex, and risk factor profile, accounting for the competing risk of non-CVD mortality. Individuals entered the model aged 40 years, and a time horizon of 40 years was employed. Life year gains and CVD events prevented compared to no treatment were estimated for a range of 10-year ARR and AR treatment initiation thresholds. Results: At the same numbers of patient-years of treatment (PYoT), ARR consistently produced more life year gains than AR (Figure). A 10-year ARR threshold of ≥2.62% would lead to approximately the same PYoT as standard of care (10-year AR ≥7.5%) while preventing 60 additional CVD events and producing 421 additional life year gains in the cohort. Conclusion: Treating patients with statins based on ARR would yield significant health gains in the U.S. population compared to standard AR-based treatment strategies. The ARR strategy may also achieve greater adherence and uptake as it focuses on individuals with elevated levels of a modifiable risk factor.

Introduction: Cumulative exposure to cardiovascular disease (CVD) risk factors during young adulthood is associated with later life CVD risk. Few prospective cohort studies measured exposures in young adulthood. We sought to develop and validate a method to impute trajectories of CVD risk factors across the life course. Methods: 36,546 participants (55% women, 25% black, average exams 5.1/participant) from 6 studies (ARIC, CARDIA, CHS, Framingham Offspring, Health ABC, and MESA) were included. Demographics and CVD risk factors (BMI, smoking, BP, lipids, glucose, medications for BP, lipids and glucose) were collected at each exam and harmonized across cohorts. We multiply imputed complete risk factor trajectories from age 18 to 99 years for each participant using an extension of linear mixed modeling (for continuous variables) and interval-censored survival modeling (for categorical variables), taking into account the multilevel structure of data. For validation, we randomly selected 25% of all participants and deleted their observed data for exam age 20-35, 50-65, or 80-95 years. We then imputed risk factor values for deleted age periods and compared imputed values with directly observed values. Results: Imputed values were relatively consistent with observed values for BMI, SBP, LDL, and glucose, particularly in young and middle ages ( Figure ). The mean (standard deviation) of the difference between imputed vs. observed values for BMI, SBP, LDL, and glucose were 0.1 (2.7) kg/m 2 , 0.9 (16.3) mm Hg, -1.1 (30.2) mg/dL, and -0.6 (23.0) mg/dL. The prevalence of imputed smoking, diabetes, and medications were also consistent with observed data. Conclusions: We demonstrated a validated method for estimating CVD risk factor trajectories across the life course. This approach may advance understanding of potential impact of cumulative early risk factor exposures on later life CVD risk, and inform primary prevention strategies over the life course. Figure. Mean and prevalence of observed vs. imputed risk factors by age periods 2

Introduction: Prehypertension defined as blood pressure (BP) 120-139/80-89 mmHg, has a prevalence of 23% in U.S. young adults (age 20-39 years). Young adult high diastolic blood pressure (DBP) has been associated with later life coronary heart disease (CHD), but it is unclear if lifelong benefits of early blood pressure control outweigh costs and side-effect risks. Objective: We estimated CHD events and life-long cost-effectiveness of U.S. Preventive Service Task Force recommended lifestyle modification (LM) or pharmacotherapy in young adults with DBP ≥80mmHg, incremental to later life hypertension treatment. Methods: A microsimulation model simulated CHD events from age 20 until death for 20-year olds selected from 1999-2014 NHANES. Individual risk factor trajectories were assigned, and risk functions predicted CHD based on Framingham Offspring Study data, accounting for both age 20-39 time-weighted average DBP and later life systolic blood pressure (SBP). Simulated interventions lowered DBP ≥80mmHg for age 20-39 years, and SBP ≥140mmHg for age ≥40 years. Cost-effectiveness was measured as incremental cost-effectiveness ratios (ICERs) and net health benefit (NHB) at willingness to pay (WTP) threshold $50,000/quality adjusted life year (QALY). Results: In 40,000 young adults with DBP ≥80 mmHg (50% women), pharmacologic BP control in young adulthood and later life prevented the most CHD events (Table). The strategy that yielded highest NHB in women was pharmacologic control after age 40 (ICER $26,536/QALY). In men, lifestyle modification to control DBP in young adulthood plus pharmacotherapy for later life hypertension (ICER $42,481/QALY) yielded highest NHB. Conclusion: Early DBP control in young adults could achieve substantial health benefits over the life course but standard interventions to achieve this goal are costly. Innovative strategies to reduce pharmacotherapy costs and improve sustainability of lifestyle modification could make early BP control a higher-value prevention strategy in young adults.

Introduction: Uncertainty remains regarding the most efficient and cost-effective 10-year atherosclerotic cardiovascular disease (ASCVD) risk prediction tool for identifying moderate to high-risk patients for primary prevention statin treatment. Methods: We utilized the CVD Policy Model, a computer microsimulation model of ASCVD incidence, prevalence, mortality, and costs, to compare cost-effectiveness of statin treatment at varying 10-year predicted ASCVD risk thresholds for Framingham CVD (FRS-CVD), Reynolds Risk Score (RRS), and Pooled Cohorts Risk Equations over a 10-year time horizon in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort. Cost effectiveness was assessed at predicted 10-year risk ≥ 20.0%, 15.0%, 10.0%, 7.5%, 5.0%, and 2.5%. We restricted the simulation cohort to participants aged 50 to 74 years who were not taking statins at baseline (n = 2,871). Moderate intensity statin treatment effectiveness was parameterized in the model as a 29% low-density lipoprotein cholesterol reduction. Total cost comprised statins ($100/year), side effect costs, and ASCVD event costs. Disability from treatment side effects and ASCVD events were included. Results: Average FRS-CVD, RRS, and Pooled Cohorts 10-year predicted ASCVD risks were 18.8%, 11.3%, 12.2%, for men and 8.9%, 4.3%, 6.6%, for women, respectively. At the same predicted risk, FRS-CVD consistently selected the most patients for treatment, and RRS the fewest ( Figure ). Compared with no treatment, treating patients with RRS ≥ 20% was cost saving in men. Subsequent risk threshold strategies with incremental cost effectiveness Conclusions: At cost-effectiveness thresholds less than $75,000/QALY, RRS was the highest value tool for men while the Pooled Cohorts Risk Equations performed best for women.

Introduction: In the United States, the rising number of adults with type 2 diabetes (T2D) is thought to be associated with the rise in obesity. Obesity may be associated with T2D through biologic pathways where excess weight strains the body’s metabolic machinery, such as mitochondria. Mitochondria are dynamic organelles whose regulation and function respond to cell stress, such as insulin resistance. Previous research reveals that insulin resistance is associated with obesity prior to hyperglycemia. Mitochondrial DNA copy number is a measure of mitochondrial DNA content, and correlates with both the number and size of mitochondria. We assessed the hypothesis that mitochondrial DNA copy number is associated with T2D in a community-based, prospective cohort study. A lower mitochondrial DNA copy number in these analyses represents worse mitochondrial function. Methods: We included 6,633 white ARIC participants without coronary heart disease who had mitochondrial DNA copy number measured from visit 2 (1990-1992). Our sample had a mean age of 57 ± 5.6 years, was 43% male, average BMI of 27 ± 4.9 kg/m2, and 27% with hypertension. Those with diabetes had an average hemoglobin A 1c of 7.2 ± 1.8 (n=681). The mitochondrial DNA copy number value used in analyses represents a sample’s standard deviation (SD) from a mean of zero for age- and sex-adjusted distributions. The mitochondrial DNA copy number data was then divided into quintiles, with the most negative mitochondrial DNA copy number in quintile 1 (Q1), the mean of zero in Q3, and the most positive in Q5. We defined T2D as self-report of doctor diagnosis, current use of glucose-lowering medication, or fasting blood glucose ≥ 126 mg/dL or non-fasting blood glucose ≥ 200 mg/dL measured at study visits. We used logistic regression to estimate the odds of prevalent T2D for each quintile group compared to Q3. Confounders considered in the base model included age at sample collection, sex, education level, and medication use (thyroid and estrogen). All analyses were done in Stata 14.1. Results: The prevalence of T2D was higher in the lower mitochondrial DNA copy number quintiles: 15% in Q1 (mean copy number: -1.40 SD) 11% in Q2 (-0.46 SD), and 9% in Q3-Q5 (0.04 SD, 0.52 SD, 1.33 SD). There was increased odds of T2D in lower mitochondrial DNA copy number quintiles, but with no additional benefit of copy number above the mean. The odds of T2D in each quintile compared to Q3 was 1.9 in Q1 (95% CI 1.49, 2.46), 1.36 in Q2 (95% CI 1.05, 1.77), 0.99 in Q4 (95% CI 0.76, 1.30) and 0.96 in Q5 (95% CI 0.74, 1.26). Conclusion: Examining the association of mitochondrial dysfunction and diabetes in a large community-based cohort connects results from experimental studies to epidemiologic studies and provides the opportunity to characterize the complex pathogenesis of diabetes using cohort data.

Introduction: Intracranial atherosclerotic stenosis (ICAS) is a common cause of stroke. Determinants of ICAS include conventional cardiovascular (CV) risk factors such as hypertension and dyslipidemia. The association of diabetes mellitus (DM) and/or hyperglycemia with ICAS, however, is less well documented. Hypothesis: In a community-based population, biomarkers of hyperglycemia will be cross-sectionally associated with prevalent ICAS independent of CV risk factors. Methods: Our analyses were conducted in a subsample of participants of the Atherosclerosis Risk in Communities (ARIC) Study who participated in the ARIC-Neurocognitive Study in 2011-13 with cerebrovascular magnetic resonance angiography and no history of stroke. For the present analyses, we grouped the participants into 3 categories based on the highest ICAS category among any of the intracranial arteries we assessed: “no stenosis”, “ Results (Table): There were 1,658 individuals included in our study (age 67-90 years, women 58%, Black 29%), 31% (514/1658) had diagnosed diabetes, 10% (165/1658) had ≥50 % stenosis at any of the intracerebral arteries. In crude analyses, those with higher glucose and HbA1c were more likely to have ICAS among the non-diabetes and the diabetes. In logistic regression, highest quintile of glucose, relative to the lowest, had odds ratio of 2.26 (95% confidence interval 1.48, 3.45) for being in each successive ICAS category after adjustment for CV risk factors. Conclusion: Higher glucose and HbA1c were associated with higher odds of ICAS independent of CV risk factors. The finding suggests that hyperglycemia plays a role in pathogenesis of ICAS.

Background: Heart failure patients are at increased risk of ventricular arrhythmias and all-cause mortality. However, existing clinical and serum markers only modestly predict these adverse events. Objective: We sought to use metabolic profiling to identify novel biomarkers in two independent prospective cohorts of patients with implantable cardioverter defibrillators (ICDs) for primary prevention of sudden cardiac death (SCD). Methods and Results: Baseline serum was quantitatively profiled for 42 known biologically-relevant amine-based metabolites among 402 patients from the PROSE-ICD Study (derivation group) and 240 patients from the GRADE Study (validation group) for ventricular arrhythmia-induced ICD shocks and all-cause mortality. In multivariate Cox models adjusted for traditional cardiovascular risk factors, 3 amines (N-methyl-L-histidine, symmetric dimethylarginine [SDMA], and L-kynurenine) were associated with all-cause mortality in both derivation and validation cohorts (Figure 1). Additionally, L-histidine, SDMA, L-kynurenine, L-4-hydroxyproline, and L-glutamine were associated with ventricular arrhythmia-induced ICD shocks in one of the cohorts, suggesting their potential to be novel markers of ventricular arrhythmia (Figure 2). Conclusions: Utilizing metabolic profiling, we identified several novel amine markers that were associated with appropriate shock and mortality in primary prevention ICD patients. These findings shed insight into the potential biologic pathways leading to adverse events in these patients, which will in turn aid the development of newer therapeutics for reducing SCD and mortality.

Introduction: Diet is a complex exposure of unquestionable relevance for cardiovascular disease (CVD) risk. South Korea, a population with traditionally low rates of CVD, has changed in recent decades from a traditional diet to more Western and modern dietary patterns. The impact of these changes are uncertain. Hypothesis: We aimed to evaluate the hypothesis that non-traditional dietary patterns were associated with an increased prevalence of hypertension in a large sample of young and middle-aged Korean adults. Methods: We conducted a cross sectional study of 220,979 adult men and women who underwent a screening health examination between January 2011 and December 2013 at the Kangbuk Samsung Total Healthcare Center in Seoul and Suwon, South Korea who did not have any history of cardiovascular disease, cancer, diabetes, hypertension, or dyslipidemia. Diet was assessed using a validated 103-item food frequency questionnaire and principal component analysis was used to derive three major dietary patterns: Western Korean, characterized by higher intakes of noodles, red meat, processed meat, raw or salted fish, shellfish, poultry, soda, and alcohol; Traditional Korean, characterized by higher intakes of vegetables, mushrooms, preserved vegetables, soya and other beans, fruits, fish, and seaweed; and Modern Korean, characterized by higher intakes of bread and cereals, milk and dairy products, snacks, and pizza, and lower intakes of alcohol, rice, and preserved vegetables. Hypertension was defined as having a systolic blood pressure ≥140 mmHg and/or a diastolic blood pressure ≥ 90 mmHg. Systolic hypertension was defined as having a systolic blood pressure ≥140 mmHg. Results: The prevalence of hypertension was 2.9%. In fully adjusted multivariable models, the odds ratios for hypertension comparing the 90th to the 10th percentile of dietary scores were 1.58 (95%CI 1.42, 1.75), 1.11 (95%CI 1.01, 1.21), 0.73 (95%CI 0.66, 0.81) for Western, Traditional, and Modern Korean dietary patterns, respectively. The corresponding odds ratios for systolic hypertension were 1.50 (95%CI 1.28, 1.76), 1.17 (95%CI 1.01, 1.36), and 0.68 (95%CI 0.58, 0.79), respectively. Conclusion: In this large cross-sectional study of young and middle-aged Korean men and women, diet transition to a more Western pattern, characterized by higher intake of meats and alcohol, was associated with a higher prevalence of hypertension and may be associated with increased CVD risk.

Introduction: Few studies have evaluated the association between type and amount of dietary protein intake and clinically evident cardiovascular disease, with inconsistent findings, and no study has investigated the association between type and amount of dietary protein intake and subclinical coronary atherosclerosis. Hypothesis: We examined the associations of total, animal, and vegetable protein intakes with coronary artery calcium (CAC) in a large population of asymptomatic adults. Methods: We performed a cross-sectional study of 29,034 asymptomatic young and middle-aged adults (mean age 41.6 years; males 80.3%) who are free of clinically evident cancer or cardiovascular disease. All participants underwent a health screening examination including cardiac computed tomography for CAC scoring and completed a food frequency questionnaire at the Kangbuk Samsung Hospital Total Healthcare Centers in Seoul and Suwon, South Korea from March, 2011 to April, 2013. Protein intake and other nutrient intake were adjusted for total energy intake using the residual method. Multivariable-adjusted CAC score ratios and 95% confidence intervals (CIs) were estimated by robust Tobit regression models for natural logarithm (CAC score + 1). Results: The proportion of study participants with detectable CAC (CAC score > 0) was 13.4 %. After adjustment for total energy intake, other nutrient intake, and potential confounding factors, we found an increased prevalence of CAC with higher animal protein intake, but not with total and vegetable protein intakes. In multivariable-adjusted models, CAC ratios (95% CIs) comparing the highest with the lowest quintiles were 1.82 (1.09-3.04; P for trend = 0.01) for animal protein intake, 1.25 (0.87-1.81; P for trend = 0.13) for vegetable protein intake, and 1.19 (0.74-1.93; P for trend = 0.59) for total protein intake. Conclusion: High animal protein intake, but not total or vegetable protein, was associated with an increased prevalence of subclinical coronary atherosclerosis and with a greater degree of coronary calcification.

Introduction: The role of pulse wave velocity (PWV) in assessing cardiovascular disease (CVD) risk in asymptomatic non-elderly adults is unclear. PWV assessment, however, is readily available, non-invasive, cheap, and does not involve radiation exposure. Hypothesis: The aim of our study was to evaluate the hypothesis that brachial-ankle PWV was associated with coronary artery calcium (CAC) in a large sample of young and middle-aged asymptomatic adults, and that PWV increases the predictive value of traditional CVD risk factors for predicting the presence of CAC. Methods: Cross-sectional study of 15,009 asymptomatic men and women without a history of cardiovascular disease who underwent a health screening program that included both PWV and CAC measurements. Brachial-ankle PWV was obtained from bilateral brachial and posterior tibial artery pressure waveforms using the oscillometric method. Robust tobit regression was used to assess the association between PWV and natural log(CAC+1) and logistic regression was used to model the presence of detectable CAC (CAC>0) and CAC>100 adjusting for multiple CVD risk factors. Measures of calibration and discrimination were calculated to test the incremental value of adding PWV to traditional risk factors in predicting prevalent CAC. Results: The mean age of the study participants was 41.6 years (SD 7.2) and 83% (12,452) were men. Subjects with higher PWV had generally less favorable CVD risk profiles. The multivariable-adjusted CAC score ratios (95% confidence interval) comparing quintiles 2 - 5 of PWV to the first quintile were 1.21 (0.78, 1.86), 1.54 (1.01, 2.33), 1.98 (1.30, 3.01), and 2.83 (1.84, 4.37), respectively (P trend 100 were consistent with the results for CAC ratios. The addition of PWV to traditional risk factors significantly improved the discrimination and calibration of models for predicting the prevalence of detectable CAC (net reclassification index [NRI] for predicting detectable CAC and CAC score > 100 of 0.167 and 0.252, respectively; both p Conclusions: In this large sample of young and middle-aged asymptomatic adults, brachial-ankle PWV was independently associated with the presence and the extent of CAC. PWV measurements improve the prediction of detectable CAC compared to traditional CVD risk factors and may help identify young and middle-age subjects with increased risk of subclinical disease.

Objective: Nonalcoholic fatty liver disease (NAFLD) is associated with insulin resistance (IR) and with other metabolic abnormalities, but the association of NAFLD with the risk of clinical cardiovascular disease (CVD) is controversial. Furthermore, the risk associated with the combination of NAFLD and IR has not been evaluated in prospective studies. The aim of this study was to evaluate the association of NAFLD with or without IR on the incidence of coronary heart disease (CHD) and stroke. Methods: We performed a cohort study in 166,126 adults without CVD at baseline who underwent a health checkup exam during 2008 - 2011 and were followed-up through December 31, 2012 (average follow-up of 3.2 years). NAFLD was defined as hepatic steatosis on ultrasonography in the absence of excessive alcohol use or other identifiable causes. IR was defined as a homeostasis model assessment of IR (HOMA-IR) value ≥ 2.5. Incident hospitalizations for CHD events and strokes were ascertained through data linkage with the Korean Health Insurance Review and Assessment Service (HIRA) database. Results: At baseline, the prevalence of NAFLD and of IR were 25.1 and 6.3%, respectively. During follow-up, 831 participants developed CHD and 582 subjects developed stroke. After adjusting for age, sex, center, year of screening exam, BMI, smoking, alcohol intake, physical activity, family history of CVD, and education, the hazard ratios (95 % confidence intervals) for CHD comparing NAFLD without IR, IR without NAFLD, and NAFLD with IR vs. no NAFLD without IR were 1.07 (0.91 - 1.27), 1.19 (0.74 - 1.91) and 1.55 (1.18 - 2.03), respectively. The corresponding hazard ratios for stroke were 0.93 (0.75 - 1.16), 1.40 (0.83 - 2.35) and 1.82 (1.32 - 2.52), respectively. The P-values for the interaction of NAFLD and IR for CHD and stroke were 0.48 and 0.28, respectively. These associations did not differ by clinically relevant subgroups. Conclusions: The combination of NAFLD and IR was associated with an increased incidence of CHD and of stroke, but this was not observed in those with either NAFLD or IR alone. The combination of NAFLD and IR may identify individuals at high cardiometabolic risk who may need to receive more intensive preventive intervention.

Introduction: Prior studies have raised the question of whether an association exists between physical activity (PA) and atrial fibrillation (AF), with mixed results. We sought to use the Multi-Ethnic Study of Atherosclerosis (MESA) database to examine the association between PA and AF in a diverse population without clinically recognized prevalent cardiovascular disease (CVD). Hypothesis: Increased exercise will have a protective influence on AF incidence. Methods: MESA participants (N=5793) with a completed baseline PA survey and complete covariate data were included. Incident AF events were determined based on hospital discharge ICD-9 codes and Medicare inpatient claims. Total intentional exercise (TIE), defined as a sum of walking for exercise, dance/sport, and conditioning, was used as our independent variable of interest. The MESA population was stratified based on whether they reported participation in any vigorous physical activity (VPA), which was defined as “heavy effort” expended in household chores, lawn/yard/garden/farm work, conditioning activities, and occupational/volunteering work. Cox models, adjusted for demographics and CVD risk factors, were used to determine hazard ratios (HR) for incident AF based on total intentional exercise (TIE) for the subgroups. We performed similar analyses using TIE as a categorical variable stratified into tertiles. Results: During a mean follow-up of 7.7±1.9 years, 199 AF cases occurred. In the overall MESA population, TIE alone was not associated with incident AF. However, within the group that reported any VPA (N=1866), there was a statistically significant protective influence of increasing TIE on incident AF (HR=0.658, p=0.014). Additionally, among the same group, the top tertile of TIE was associated with a significantly lower risk of incident AF compared with the group with no TIE (HR=0.48, p=0.048). Conclusions: TIE was associated with a lower risk of incident AF among those that participated in any VPA, and this protective influence was most notable among those that performed the most TIE. Perhaps as importantly, no subgroup of participants demonstrated an increased risk of incident AF with TIE. These results re-emphasize the beneficial role of exercise for cardiovascular health.

Background: Deep terminal negativity of the P wave in V1 (P prime in V1, PPV1) defined as PPV1 ≤ -0.1mV in amplitude and ≥40 ms in duration (one small box on ECG grid) is sign of a left atrium enlargement, and a component in the Romhilt-Estes score of left ventricular hypertrophy (LVH). LVH is known to be associated with the risk of sudden cardiac death (SCD). Deep PPV1 negativity is also associated with atrial fibrillation (AF) and stroke; both have been linked to SCD as well. However, it is unknown whether or not PPV1 negativity is independently associated with SCD. Method: Baseline resting digital 12-lead ECGs of 13232 ARIC cohort participants (mean age 53.9±5.7 y; 5760 [43.5%] men; 9747 [73.7%] white) were analyzed. Individuals with prevalent baseline coronary heart disease (CHD), heart failure (HF), or QRS ≥ 120 ms were excluded. The ECGs were analyzed using a 12SL TM algorithm (GE Healthcare, Wauwatosa, WI, USA). Amplitude and duration of PPV1 was automatically measured. Results: Deep PPV1 negativity was observed in 97 (0.73%) participants. During a median follow-up of 14 years, 182 participants had SCD. In multivariable competing risks regression analysis, deep PPV1 negativity was significantly associated with SCD after adjustment for baseline risk factors of CHD and SCD (age, sex, race, diabetes, smoking, alcohol consumption, cholesterol, triglycerides, body mass index, serum creatinine, albumin, systolic blood pressure, use of antihypertensive, QT-prolonging medications, level of physical activity, mean heart rate, QTc, QRS duration, ECG-LVH by Cornell product), and incident HF, AF, stroke [subHR 3.8 (95%CI 1.88-7.69); P Conclusion: In apparently CV healthy, middle-aged individuals, deep terminal negativity of P-wave in V1 is associated with about 4-times higher risk of SCD during 14 years of follow-up. Further studies should explore the cardiac substrate underlying presence of this marker and its use for risk stratification.