Individual and Joint Associations of High-Sensitivity Troponin I and High-Sensitivity Troponin T with Cardiac Phenotypes and Outcomes in the General Population: An Analysis From the Dallas Heart Study.

BACKGROUND: High-sensitivity troponin I (hs-cTnI) and T (hs-cTnT) provide complementary information regarding cardiovascular disease risk. The explanation for their distinct risk profiles is incompletely understood. METHODS AND RESULTS: hs-cTnI and hs-cTnT were measured in Dallas Heart Study participants. Associations of hs-cTnI and hs-cTnT with demographics and phenotypes were assessed using linear regression. Associations with incident heart failure, atherosclerotic cardiovascular disease, global cardiovascular disease, and cardiovascular and all-cause mortality were assessed using Cox models. Among 3276 participants (56% women, 50% Black persons, median age 43 years), the correlation between hs-cTnI and hs-cTnT was modest (Spearman rho=0.35). Variables associated with hs-cTnI but not hs-cTnT included hypertension, higher body mass index and total cholesterol, and lower high-density lipoprotein and cholesterol efflux capacity. Older age, male sex, and diabetes were positively associated, and smoking was negatively associated, with hs-cTnT but not hs-cTnI. Hs-cTnI and hs-cTnT were associated with heart failure (hazard ratio [HR] per SD log hs-cTnI 1.53 [95% CI, 1.30-1.81] and HR per SD log hs-cTnT 1.65 [95% CI, 1.40-1.95]), global cardiovascular disease (HR, 1.22 [95% CI, 1.10-1.34] and HR, 1.27 [95% CI, 1.15-1.32]), and all-cause mortality (HR, 1.12 [95% CI, 1.01-1.25], and HR, 1.17 [95% CI, 1.06-1.29]). After adjustment for N-terminal pro-B-type natriuretic peptide and the alternative troponin, both remained associated with heart failure (HR per SD log hs-cTnI 1.32 [95% CI, 1.1-1.58] and HR per log hs-cTnT 1.27 [95% CI, 1.06-1.51]). CONCLUSIONS: Hs-cTnI and hs-cTnT are modestly correlated, demonstrate differential associations with cardiac and metabolic phenotypes, and provide complementary information regarding heart failure risk.

Effect of liraglutide on thigh muscle fat and muscle composition in adults with overweight or obesity: Results from a randomized clinical trial.

BACKGROUND: Excess muscle fat is observed in obesity and associated with greater burden of cardiovascular risk factors and higher risk of mortality. Liraglutide reduces total body weight and visceral fat but its effect on muscle fat and adverse muscle composition is unknown. METHODS: This is a pre-specified secondary analysis of a randomized, double-blind, placebo-controlled trial that examined the effects of liraglutide plus a lifestyle intervention on visceral adipose tissue and ectopic fat among adults without diabetes with body mass index ≥30 kg/m2 or ≥27 kg/m2 and metabolic syndrome. Participants were randomly assigned to a once-daily subcutaneous injection of liraglutide (target dose 3.0 mg) or matching placebo for 40 weeks. Body fat distribution and muscle composition was assessed by magnetic resonance imaging at baseline and 40-week follow-up. Muscle composition was described by the combination of thigh muscle fat and muscle volume. Treatment difference (95% confidence intervals [CI]) was calculated by least-square means adjusted for baseline thigh muscle fat. The association between changes in thigh muscle fat and changes in body weight were assessed using Spearman correlation coefficients. The effect of liraglutide versus placebo on adverse muscle composition, denoted by high thigh muscle fat and low thigh muscle volume, was explored. RESULTS: Among the 128 participants with follow-up imaging (92.2% women, 36.7% Black), median muscle fat at baseline was 7.8%. The mean percent change in thigh muscle fat over median follow-up of 36 weeks was -2.87% among participants randomized to liraglutide (n = 73) and 0.05% in the placebo group (absolute change: -0.23% vs. 0.01%). The estimated treatment difference adjusted for baseline thigh muscle fat was -0.24% (95% CI, -0.41 to -0.06, P-value 0.009). Longitudinal change in thigh muscle fat was significantly associated with change in body weight in the placebo group but not the liraglutide group. The proportion of participants with adverse muscle composition decreased from 11.0% to 8.2% over follow-up with liraglutide, but there was no change with placebo. CONCLUSIONS: In a cohort of predominantly women with overweight or obesity in the absence of diabetes, once-daily subcutaneous liraglutide was associated with a reduction in thigh muscle fat and adverse muscle composition compared with placebo. The contribution of muscle fat improvement to the cardiometabolic benefits of liraglutide requires further study.

Trimethylamine-N-Oxide and Related Metabolites: Assessing Cardiovascular Risk in the Dallas Heart Study.

OBJECTIVE: To evaluate the association between trimethylamine N-oxide (TMAO) and related metabolites with adverse cardiovascular events in a multiethnic urban primary prevention population. METHODS: We performed a case-control study of 361 participants of the Dallas Heart Study, including 88 participants with an incident atherosclerotic cardiovascular disease (ASCVD) event and 273 controls matched for age, sex, and body mass index without an ASCVD event during 12 years of follow-up (January 1, 2000, through December 31, 2015). Plasma levels of TMAO, choline, carnitine, betaine, and butyrobetaine were measured by mass spectrometry. The differential odds for incident ASCVD by metabolite levels between cases and controls were compared by a conditional logistic regression model adjusted for cardiovascular risk factors. RESULTS: Participants with incident ASCVD had higher levels of TMAO and related metabolites compared with those without ASCVD (P<.05 for all). Those with plasma TMAO concentrations in quartile 4 had a more than 2-fold higher odds of ASCVD compared with those in quartile 1 (odds ratio, 2.77 [95% CI, 1.05 to 7.7; P=.04] for hard ASCVD and 2.41 [95% CI, 1.049 to 5.709; P=.04]). Similar trends were seen with the related metabolites choline, betaine, carnitine, and butyrobetaine. CONCLUSION: Our results suggest that TMAO and related metabolites are independently associated with ASCVD events. Although further studies are needed, measurement of TMAO and related metabolites may have a role in ASCVD risk stratification for primary prevention.

Health and Economic Value of Eliminating Socioeconomic Disparities in US Youth Physical Activity.

Importance: There are considerable socioeconomic status (SES) disparities in youth physical activity (PA) levels. For example, studies show that lower-SES youth are less active, have lower participation in organized sports and physical education classes, and have more limited access to PA equipment. Objective: To determine the potential public health and economic effects of eliminating disparities in PA levels among US youth SES groups. Design and Setting: An agent-based model representing all 6- to 17-year-old children in the US was used to simulate the epidemiological, clinical, and economic effects of disparities in PA levels among different SES groups and the effect of reducing these disparities. Main Outcomes and Measures: Anthropometric measures (eg, body mass index) and the presence and severity of risk factors associated with weight (stroke, coronary heart disease, type 2 diabetes, or cancer), as well as direct and indirect cost savings. Results: This model, representing all 50 million US children and adolescents 6 to 17 years old, found that if the US eliminates the disparity in youth PA levels across SES groups, absolute overweight and obesity prevalence would decrease by 0.826% (95% CI, 0.821%-0.832%), resulting in approximately 383 000 (95% CI, 368 000-399 000) fewer cases of overweight and obesity and 101 000 (95% CI, 98 000-105 000) fewer cases of weight-related diseases (stroke and coronary heart disease events, type 2 diabetes, or cancer). This would result in more than $15.60 (95% CI, $15.01-$16.10) billion in cost savings over the youth cohort's lifetime. There are meaningful benefits even when reducing the disparity by just 25%, which would result in $1.85 (95% CI, $1.70-$2.00) billion in direct medical costs averted and $2.48 (95% CI, $2.04-$2.92) billion in productivity losses averted. For every 1% in disparity reduction, total productivity losses would decrease by about $83.8 million, and total direct medical costs would decrease by about $68.7 million. Conclusions and Relevance: This study quantified the potential savings from eliminating or reducing PA disparities, which can help policymakers, health care systems, schools, funders, sports organizations, and other businesses better prioritize investments toward addressing these disparities.

Lifetime healthcare expenses across demographic and cardiovascular risk groups: The application of a novel modeling strategy in a large multiethnic cohort study.

Objective: To understand the burden of healthcare expenses over the lifetime of individuals and evaluate differences among those with cardiovascular risk factors and among disadvantaged groups based on race/ethnicity and sex. Methods: We linked data from the longitudinal multiethnic Dallas Heart Study, which recruited participants between 2000 and 2002, with inpatient and outpatient claims from all hospitals in the Dallas-Fort Worth metroplex through December 2018, capturing encounter expenses. Race/ethnicity and sex, as well as five risk factors, hypertension, diabetes, hyperlipidemia, smoking, and overweight/obesity, were defined at cohort enrollment. For each individual, expenses were indexed to age and cumulated between 40 and 80 years of age. Lifetime expenses across exposures were evaluated as interactions in generalized additive models. Results: A total of 2184 individuals (mean age, 45±10 years; 61% women, 53% Black) were followed between 2000 and 2018. The mean modeled lifetime cumulative healthcare expenses were $442,629 (IQR, $423,850 to $461,408). In models that included 5 risk factors, Black individuals had $21,306 higher lifetime healthcare spending compared with non-Black individuals (P < .001), and men had modestly higher expenses than women ($5987, P < .001). Across demographic groups, the presence of risk factors was associated with progressively higher lifetime expenses, with significant independent association of diabetes ($28,075, P < .001), overweight/obesity ($8816, P < .001), smoking ($3980, P = .009), and hypertension ($528, P = .02) with excess spending. Conclusion: Our study suggests Black individuals have higher lifetime healthcare expenses, exaggerated by the substantially higher prevalence of risk factors, with differences emerging in older age.

Associations of Cumulative Perceived Stress with Cardiovascular Risk Factors and Outcomes: Findings from The Dallas Heart Study.

Background: Data remain sparse regarding the impact of chronic stress on cardiovascular disease (CVD) risk factors and outcomes. Prior work has been limited by incomplete assessments of perceived stress and focus on single stress domains. We evaluated the association between a composite measure of perceived stress and CVD risk factors and outcomes. Methods: Participants from the Dallas Heart Study phase 2 (2007-2009) without prevalent CVD who completed questionnaire assessments of perceived stress were included (n=2685). Individual perceived stress subcomponents (generalized stress, psychosocial, financial, and neighborhood stress) were standardized and integrated into a single cumulative stress score (CSS) with equal weighting for each component. Associations between CSS and demographics, psychosocial variables and cardiac risk factors were assessed in univariable and multivariable analyses. Cox proportional hazards models were used to determine associations of the CSS with atherosclerotic CVD (ASCVD) and Global CVD (ASCVD, heart failure, and atrial fibrillation) after adjustment for demographics and traditional risk factors. Results: Median age of the study population was 48 years, 55% were female, 49% Black and 15% Hispanic/Latinx. CSS was higher among participants who were younger, female, Black or Hispanic, and those with lower income and educational attainment (p<.0001 for each). Higher CSS was associated with self-report of racial/ethnic discrimination, lack of health insurance and last medical contact > one year previously (p<.0001 for each). In multivariable regression models adjusting for age, gender, race/ethnicity, income and education, higher CSS associated with hypertension, smoking, and higher body mass index, waist circumference Hemoglobin A1C, hs-CRP and sedentary time (p< 0.01 for each). Over a median follow-up of 12.4 years, higher CSS associated with ASCVD (adjusted HR 1.22 per SD, 95% CI 1.01-1.47) and Global CVD (HR 1.20, 95% CI 1.03-1.40). No interactions were seen between CSS, demographic factors, and outcomes. Conclusion: Composite multidimensional assessments of perceived stress may help to identify individuals at risk for CVD who may be targeted for stress mitigation or enhanced prevention strategies. These approaches may be best focused on vulnerable populations, given the higher burden of stress in women, Black and Hispanic individuals, and those with lower income and education. WHAT IS NEW?: A novel measure of cumulative stress was created that integrates generalized, psychosocial, financial, and neighborhood perceived stress.Cumulative stress was higher among women, Black and Hispanic participants, younger individuals and persons with lower income and educational attainment and was associated with adverse health behaviors and increased burden of cardiovascular disease (CVD) risk factors.In a diverse cohort, higher cumulative stress associated with incident CVD after adjustment for demographics and traditional risk factors. No interactions were seen based on demographic factors. CLINICAL IMPLICATIONS: Although associations of chronic stress with CVD were similar across demographic subgroups, the higher burden of stress among younger individuals, women, Black and Hispanic participants, and those with lower SES suggests that CVD risk associated with higher stress affects marginalized groups disproportionately.Cumulative Stress is associated with modifiable risk factors and health behaviors. Future studies should explore targeting behavioral modification and risk factor reduction programs, as well as stress reduction strategies, to individuals with high cumulative stress.Additional research is needed to uncover mechanisms that underly the association between chronic stress and cardiovascular disease.

ICD Knowledge and Attitudes at End of Life in a Diverse and Vulnerable Patient Population.

BACKGROUND: Studies thus far lacking diversity show many patients with implantable cardioverter defibrillators (ICDs) have poor understanding of ICD functioning, preventing informed decision-making near end of life (EOL). OBJECTIVE: To describe knowledge, perceptions, and preferences regarding ICDs among patients nearing EOL in a diverse, safety-net hospital population. METHODS: A cross sectional phone survey of patients with ICDs nearing EOL from a safety-net hospital was performed. The survey assessed knowledge, perceptions, and preferences regarding their ICD. RESULTS: Nearly half (46%) of patients falsely believed turning off shocking function would stop the heart, 69% were unaware that disabling ICDs does not require surgery, and 88% said no doctor had ever discussed the option of deactivation of shocking therapy with them. CONCLUSION: Challenges in health care delivery in a safety-net hospital patient population may result in patients being poorly equipped to align ICD settings with goals of care when nearing EOL.

Coronary Artery Calcium Score to Refine the Use of PCSK9i in Asymptomatic Individuals: A Multicohort Study.

Background The value of coronary artery calcium (CAC) in the allocation of PCSK9i (proprotein convertase subtilisin/kexin type 9 inhibitors) among individuals without clinically evident atherosclerotic cardiovascular disease (ASCVD) is unknown for indications that do not require confirmed familial hypercholesterolemia. We aimed to assess the ability of CAC to stratify ASCVD risk under 3 non-familial hypercholesterolemia PCSK9i allocation paradigms. Methods and Results We included participants without clinically evident ASCVD from MESA (Multi-Ethnic Study of Atherosclerosis), CARDIA (Coronary Artery Risk Development in Young Adults) study, DHS (Dallas Heart Study), and HNR (Heinz Nixdorf Recall) study. Three PCSK9i eligibility scenarios were defined: a broad scenario informed only by high low-density lipoprotein cholesterol levels (N=567), a restrictive one combining higher low-density lipoprotein cholesterol levels and presence of ≥2 additional risk factors (N=127), and a high-risk scenario where individuals with subclinical organ damage or high estimated risk would be treated to achieve low-density lipoprotein cholesterol <55 mg/dL (N=471). The high-risk scenario had the highest ASCVD event rates (27.8% at 10 years). CAC=0 was observed in 35% participants in the broad scenario, 25% in the restrictive scenario, and 16% in the high-risk scenario. In all, CAC=0 was associated with the lowest incident ASCVD rates at 5 and 10 years, and CAC burden was independently associated with ASCVD events adjusting for traditional risk factors. Conclusions CAC may be used to refine the allocation of PCSK9i, potentially leading to a more conservative use if CAC=0. The value of CAC testing is greater in scenarios that use low-density lipoprotein cholesterol levels and/or traditional risk factors to define PCSK9i eligibility (CAC=0 present in 1 of 3-4 patients), whereas its prevalence is lower when allocation is informed by presence of noncoronary subclinical organ damage.

Association Between Thigh Muscle Fat Infiltration and Incident Heart Failure: The Health ABC Study.

BACKGROUND: Excess adiposity is a well-known risk factor for heart failure (HF). Fat accumulation in and around the peripheral skeletal muscle may further inform risk for HF. OBJECTIVES: The purpose of this study was to evaluate the association between intramuscular and intermuscular fat deposition and incident HF in a longitudinal cohort of community-dwelling older adults. METHODS: The associations of intramuscular and intermuscular fat with incident HF were assessed using Cox models among 2,399 participants from the Health ABC (Health, Aging and Body Composition) study (70-79 years of age, 48% male, 40.2% Black) without baseline HF. Intramuscular fat was determined by bilateral thigh muscle density on computed tomography and intermuscular fat area was determined with computed tomography. RESULTS: After a median follow-up of 12.2 years, there were 485 incident HF events. Higher sex-specific tertiles of intramuscular and intermuscular fat were each associated with HF risk. After multivariable adjustment for age, sex, race, education, blood pressure, fasting blood sugar, current smoking, prevalent coronary disease, and creatinine, higher intramuscular fat, but not intermuscular fat, was associated with higher risk for HF (HR: 1.34 [95% CI: 1.06-1.69]; P = 0.012, tertile 3 vs tertile 1). This association remained significant after additional adjustment for body mass index (HR: 1.32 [95% CI: 1.03-1.69]), total percent fat (HR: 1.33 [95% CI: 1.03-1.72]), visceral fat (HR: 1.30 [95% CI: 1.01-1.65]), and indexed thigh muscle strength (HR: 1.30 [95% CI: 1.03-1.64]). The association between higher intramuscular fat and HF appeared specific to higher risk of incident HF with reduced ejection fraction (HR: 1.53 [95% CI: 1.03-2.29]), but not with HF with preserved ejection fraction (HR: 1.28 [95% CI: 0.82-1.98]). CONCLUSIONS: Intramuscular, but not intermuscular, thigh muscle fat is independently associated with HF after adjustment for cardiometabolic risk factors and other measurements of adiposity.

Soluble Fms-like tyrosine kinase-1 (sFlt-1) is associated with subclinical and clinical atherosclerotic cardiovascular disease: The Dallas Heart Study.

BACKGROUND AND AIMS: Soluble Fms-like tyrosine kinase-1 (sFlt-1) plays a role in angiogenesis, atherogenesis, and preeclampsia. The relationship of sFlt-1 with markers of subclinical atherosclerosis and future atherosclerotic cardiovascular disease (ASCVD) events in a generally healthy population is unknown. METHODS: Participants in the Dallas Heart Study with sFlt-1 measured were included (n = 3292). Abdominal aortic atherosclerosis was measured by MRI and coronary artery calcium (CAC) by CT. The cohort was also followed for subsequent ASCVD events (CV death, MI, stroke, unstable angina, revascularization). Multivariable linear and logistic regression analyses and Cox regression analyses were performed adjusting for demographics and traditional cardiac risk factors. RESULTS: sFlt-1 levels were higher in older individuals, males, and African Americans, and tracked with most traditional risk factors. sFlt-1 was significantly associated with higher prevalence of aortic plaque [OR 1.33 (95% CI 1.02-1.73)], greater abdominal aortic wall thickness (p<0.01) and aortic plaque area (p<0.02) but no difference in coronary artery calcification. There were 322 ASCVD events over 12 years of follow-up. Higher sFlt-1 levels associated with increased ASCVD events in unadjusted (16.1% vs. 8.9%, p<0.001, quartile 4 vs. quartile 1) and adjusted analyses (HR 1.58 [1.14-2.18], p<0.01, quartile 4 vs. quartile 1). Findings were unchanged when analyzing sFlt-1 as a continuous variable or when excluding those with a history of ASCVD. CONCLUSIONS: In a population-based cohort, sFlt-1 is associated with measures of subclinical aortic atherosclerosis and clinical ASCVD events. Future studies are warranted on the therapeutic potential of targeting sFlt-1 for atherosclerotic disease.

Clinical Implications of the Amyloidogenic V122I Transthyretin Variant in the General Population.

BACKGROUND: The V122I variant in transthyretin (TTR) is the most common amyloidogenic mutation worldwide. The aim of this study is to describe the cardiac phenotype and risk for adverse cardiovascular outcomes of young V122I TTR carriers in the general population. METHODS AND RESULTS: TTR genotypes were extracted from whole-exome sequence data in participants of the Dallas Heart Study. Participants with African ancestry, available V122I TTR genotypes (N = 1818) and either cardiac magnetic resonance imaging (n = 1364) or long-term follow-up (n = 1532) were included. The prevalence of V122I TTR carriers (45 ± 10 years) was 3.2% (n/N = 59/1818). The V122I TTR carriers had higher baseline left ventricular wall thickness (8.52 ± 1.82 vs 8.21 ± 1.62 mm, adjusted P = .038) than noncarriers, but no differences in other cardiac magnetic resonance imaging measures (P > .05 for all). Although carrier status was not associated with amino terminal pro-B-type natriuretic peptide (NT-proBNP) at baseline (P = .79), V122I TTR carriers had a greater increase in NT-proBNP on follow-up than noncarriers (median 28.5 pg/mL, interquartile range 11.4-104.1 pg/mL vs median 15.9 pg/mL, interquartile range 0.0-43.0 pg/mL, adjusted P = .018). V122I TTR carriers were at a higher adjusted risk of heart failure (hazard ratio 3.82, 95% confidence interval 1.80-8.13, P < .001), cardiovascular death (hazard ratio 2.65, 95% confidence interval 1.14-6.15, P = .023), and all-cause mortality (hazard ratio 1.95, 95% confidence interval 1.08-3.51, P = .026) in comparison with noncarriers. CONCLUSIONS: V122I TTR carrier status was associated with a greater increase in NT-proBNP, slightly greater left ventricular wall thickness, and a higher risk for heart failure, cardiovascular death, and all-cause mortality. These findings suggest the need to develop amyloidosis screening strategies for V122I TTR carriers.

Longitudinal Trajectories and Factors Associated With US County-Level Cardiovascular Mortality, 1980 to 2014.

Importance: Cardiovascular (CV) mortality has declined for more than 3 decades in the US. However, differences in declines among residents at a US county level are not well characterized. Objective: To identify unique county-level trajectories of CV mortality in the US during a 35-year study period and explore county-level factors that are associated with CV mortality trajectories. Design, Setting, and Participants: This longitudinal cross-sectional analysis of CV mortality trends used data from 3133 US counties from 1980 to 2014. County-level demographic, socioeconomic, environmental, and health-related risk factors were compiled. Data were analyzed from December 2019 to September 2021. Exposures: County-level characteristics, collected from 5 county-level data sets. Main Outcomes and Measures: Cardiovascular mortality data were obtained for 3133 US counties from 1980 to 2014 using age-standardized county-level mortality rates from the Global Burden of Disease study. The longitudinal K-means approach was used to identify 3 distinct clusters based on underlying mortality trajectory. Multinomial logistic regression models were constructed to evaluate associations between county characteristics and cluster membership. Results: Among 3133 US counties (median, 49.5% [IQR, 48.9%-50.5%] men; 30.7% [IQR, 27.1%-34.4%] older than 55 years; 9.9% [IQR, 4.5%-22.7%] racial minority group [individuals self-identifying as Black or African American, American Indian or Alaska Native, Asian, Native Hawaiian, Pacific Islander, other, or multiple races/ethnicities]), CV mortality declined by 45.5% overall and by 38.4% in high-mortality strata (694 counties), by 45.0% in intermediate-mortality strata (1382 counties), and by 48.3% in low-mortality strata (1057 counties). Counties with the highest mortality in 1980 continued to demonstrate the highest mortality in 2014. Trajectory groups were regionally distributed, with high-mortality trajectory counties focused in the South and in portions of Appalachia. Low- vs high-mortality groups varied significantly in demographic (racial minority group proportion, 7.6% [IQR, 4.1%-14.5%]) vs 23.9% [IQR, 6.5%-40.8%]) and socioeconomic characteristics such as high-school education (9.4% [IQR, 7.3%-12.6%] vs 20.1% [IQR, 16.1%-23.2%]), poverty rates (11.4% [IQR, 8.8%-14.6%] vs 20.6% [IQR, 17.1%-24.4%]), and violent crime rates (161.5 [IQR, 89.0-262.4] vs 272.8 [IQR, 155.3-431.3] per 100 000 population). In multinomial logistic regression, a model incorporating demographic, socioeconomic, environmental, and health characteristics accounted for 60% of the variance in the CV mortality trajectory (R2 = 0.60). Sociodemographic factors such as racial minority group proportion (odds ratio [OR], 1.70 [95% CI, 1.35-2.14]) and educational attainment (OR, 6.17 [95% CI, 4.55-8.36]) and health behaviors such as smoking (OR for high vs low, 2.04 [95% CI, 1.58-2.64]) and physical inactivity (OR, 3.74 [95% CI, 2.83-4.93]) were associated with the high-mortality trajectory. Conclusions and Relevance: Cardiovascular mortality declined in all subgroups during the 35-year study period; however, disparities remained unchanged during that time. Disparate trajectories were associated with social and behavioral risks. Health policy efforts across multiple domains, including structural and public health targets, may be needed to reduce existing county-level cardiovascular mortality disparities.

A Video-Enhanced, Electronic Modality for Preparticipation Examination of Young Athletes.

ABSTRACT: We developed a video-enhanced preparticipation evaluation symptom questionnaire (the V-PPE), intended to help screen athletes for heart disease. We now report results of a pilot quality improvement study evaluating V-PPE's performance. In a prospective before-and-after study, approximately 5700 high-school athletes were prompted to voluntarily fill out the V-PPE questionnaire. We compared symptom frequencies on standard PPE to those on V-PPE. Of 5700 athletes, 46 (0.8%), 117 (2.0%), 33 (0.6%), and 101 (1.8%) reported syncope, angina, palpitations, and dyspnea, respectively on routine screening. Four hundred and ninety-two (8.6%) voluntarily filled out the V-PPE. Athletes were more likely to report palpitations on V-PPE than PPE, but not angina, dyspnea, syncope, or at least one symptom. Symptom frequencies on electronic PPE questionnaires are lower than recent reports suggest. Embedded videos can alter screening yield. More research is necessary to evaluate the predictive value of the V-PPE for clinically relevant cardiac pathology.

Chronic Stress-Related Neural Activity Associates With Subclinical Cardiovascular Disease in a Community-Based Cohort: Data From the Washington, D.C. Cardiovascular Health and Needs Assessment.

Background: Psychosocial stress correlates with cardiovascular (CV) events; however, associations between physiologic measures of stressors and CVD remain incompletely understood, especially in racial/ethnic minority populations in resource-limited neighborhoods. We examined associations between chronic stress-related neural activity, measured by amygdalar 18Fluorodeoxyglucose (18FDG) uptake, and aortic vascular FDG uptake (arterial inflammation measure) in a community-based cohort. Methods: Forty participants from the Washington, DC CV Health and Needs Assessment (DC-CHNA), a study of a predominantly African-American population in resource-limited urban areas and 25 healthy volunteers underwent detailed phenotyping, including 18FDG PET/CT for assessing amygdalar activity (AmygA), vascular FDG uptake, and hematopoietic (leukopoietic) tissue activity. Mediation analysis was used to test whether the link between AmygA and vascular FDG uptake was mediated by hematopoietic activity. Results: AmygA (1.11 ± 0.09 vs. 1.05 ± 0.09, p = 0.004) and vascular FDG uptake (1.63 ± 0.22 vs. 1.55 ± 0.17, p = 0.05) were greater in the DC-CHNA cohort compared to volunteers. Within the DC-CHNA cohort, AmygA associated with vascular FDG uptake after adjustment for Framingham score and body mass index (ß = 0.41, p = 0.015). The AmygA and aortic vascular FDG uptake relationship was in part mediated by splenic (20.2%) and bone marrow (11.8%) activity. Conclusions: AmygA, or chronic stress-related neural activity, associates with subclinical CVD risk in a community-based cohort. This may in part be mediated by the hematopoietic system. Our findings of this hypothesis-generating study are suggestive of a potential relationship between chronic stress-related neural activity and subclinical CVD in an African American community-based population. Taken together, these findings suggest a potential mechanism by which chronic psychosocial stress, such as stressors that can be experienced in adverse social conditions, promotes greater cardiovascular risk amongst resource-limited, community-based populations most impacted by cardiovascular health disparities. However, larger prospective studies examining these findings in other racially and ethnically diverse populations are necessary to confirm and extend these findings.

Consistent use of lipid lowering therapy in HIV infection is associated with low mortality.

BACKGROUND: In people living with HIV (PLWH), statins may be disproportionately effective but remain underutilized. A large prospective trial in patients with low to moderate cardiovascular (ASCVD) risk will reveal whether they should be considered in all PLWH. But its effect size may not apply to real-world PLWH with higher ASCVD and mortality risk. Also, the clinical role of non-statin lipid-lowering therapy (LLT) and LLT adherence in this population is unknown. METHODS: Comparative multi-level marginal structural model for all-cause mortality examining four time-updated exposure levels to LLT, antihypertensives, and aspirin in a virtual cohort of older PLWH. Incident coronary, cerebrovascular, and overall ASCVD events, serious infections, and new cancer diagnoses served as explanatory outcomes. RESULTS: In 23,276 HIV-infected US-veterans who were followed for a median of 5.2 years after virologic suppression overall mortality was 33/1000 patient years: > 3 times higher than in the US population. Use of antihypertensives or aspirin was associated with increased mortality. Past LLT use (> 1 year ago) had no effect on mortality. LLT exposure in the past year was associated with a reduced hazard ratio (HR) of death: 0.59, 95% confidence interval (CI) 0.51-0.69, p < 0.0001 for statin containing LLT and 0.71 (CI: 0.54-0.93), p = 0.03 for statin-free LLT. For consistent LLT use (> 11/12 past months) the HR of death was 0.48 (CI: 0.35-0.66) for statin-only LLT, 0.34 (CI: 0.23-0.52) for combination LLT, and 0.27 (CI: 0.15-0.48) for statin-free LLT (p < 0.0001 for all). The ASCVD risk in these patients was reduced in similar fashion. Use of statin containing LLT was also associated with reduced infection and cancer risk. Multiple contrasting subgroup analyses yielded comparable results. Confounding is unlikely to be a major contributor to our findings. CONCLUSIONS: In PLWH, ongoing LLT use may lead to substantially lower mortality, but consistent long-term adherence may be required to reduce ASCVD risk. Consistent non-statin LLT may be highly effective and should be studied prospectively.

Effect of Anacetrapib on Cholesterol Efflux Capacity: A Substudy of the DEFINE Trial.

Background Anacetrapib is the only cholesteryl ester transfer protein inhibitor proven to reduce coronary heart disease (CHD). However, its effects on reverse cholesterol transport have not been fully elucidated. Macrophage cholesterol efflux (CEC), the initial step of reverse cholesterol transport, is inversely associated with CHD and may be affected by sex as well as haptoglobin copy number variants among patients with diabetes mellitus. We investigated the effect of anacetrapib on CEC and whether this effect is modified by sex, diabetes mellitus, and haptoglobin polymorphism. Methods and Results A total of 574 participants with CHD were included from the DEFINE (Determining the Efficacy and Tolerability of CETP Inhibition With Anacetrapib) trial. CEC was measured at baseline and 24-week follow-up using J774 macrophages, boron dipyrromethene difluoride-labeled cholesterol, and apolipoprotein B-depleted plasma. Haptoglobin copy number variant was determined using an ELISA assay. Anacetrapib increased CEC, adjusted for baseline CEC, risk factors, and changes in lipids/apolipoproteins (standard ß, 0.23; 95% CI, 0.05-0.41). This CEC-raising effect was seen only in men (P interaction=0.002); no effect modification was seen by diabetes mellitus status. Among patients with diabetes mellitus, anacetrapib increased CEC in those with the normal 1-1 haptoglobin genotype (standard ß, 0.42; 95% CI, 0.16-0.69) but not the dysfunctional 2-1/2-2 genotypes (P interaction=0.02). Conclusions Among patients with CHD, anacetrapib at a dose linked to improved CHD outcomes significantly increased CEC independent of changes in high-density lipoprotein cholesterol or other lipids, with effect modification by sex and a novel pharmacogenomic interaction by haptoglobin genotype, suggesting a putative mechanism for reduced risk requiring validation.

The association of lymphotoxin-beta receptor with the subsequent diagnosis of incident gastrointestinal cancer: results from the Dallas Heart Study.

BACKGROUND: Lymphotoxin-beta receptor (LTßR) is an immunological protein associated with inflammation, and from preclinical studies is implicated in tumorigenesis. The epidemiological relationships with cancer are unknown, hence this study investigated their associations. METHODS: From a multiethnic population-based cohort, 3,032 participants without a prevalent cancer (a diagnosis prior to or within one year of enrollment) at baseline underwent measurement of plasma LTßR. These participants were followed for incident cancer using the Texas Cancer Registry (TCR). RESULTS: Over a median follow-up of 12.1 years, 178 participants developed incident cancer, of which 30 participants developed incident gastrointestinal (GI) cancer. Median plasma LTßR (1.10 vs. 1.00 ng/mL, P<0.02) levels were higher in individuals with overall incident cancer compared to those without cancer. After adjustments for age, sex, and race/ethnicity, these relationships were no longer significant. When analyses were stratified by cancer type, LTßR was positively associated with GI cancer after adjustments: HR, 95% CI per 1-standard deviation increase in concentration 2.64 (1.23-5.68), P=0.013. LTßR stratified by quartiles was significantly associated temporally with the risk of incident GI cancer, log-rank: P=0.011. The median interval to incident GI cancer diagnosis was 5.9 years. CONCLUSIONS: Increased plasma levels of LTßR are associated with the development of GI cancer. The antecedent findings years prior to a subsequent diagnosis of incident GI cancer suggest a role for LTßR in the pathogenesis of GI cancer. Further studies are needed to determine if LTßR can serve as an immune biomarker for GI cancer, in particular hepatocellular and colorectal cancers.

Racial Differences in Malignant Left Ventricular Hypertrophy and Incidence of Heart Failure: A Multicohort Study.

BACKGROUND: A malignant subphenotype of left ventricular hypertrophy (LVH) has been described, in which minimal elevations in cardiac biomarkers identify individuals with LVH at high risk for developing heart failure (HF). We tested the hypothesis that a higher prevalence of malignant LVH among blacks may contribute to racial disparities in HF risk. METHODS: Participants (n=15 710) without prevalent cardiovascular disease were pooled from 3 population-based cohort studies, the ARIC Study (Atherosclerosis Risk in Communities), the DHS (Dallas Heart Study), and the MESA (Multi-Ethnic Study of Atherosclerosis). Participants were classified into 3 groups: those without ECG-LVH, those with ECG-LVH and normal biomarkers (hs-cTnT (high sensitivity cardiac troponin-T) <6 ng/L and NT-proBNP (N-terminal pro-B-type natriuretic peptide) <100 pg/mL), and those with ECG-LVH and abnormal levels of either biomarker (malignant LVH). The outcome was incident HF. RESULTS: Over the 10-year follow-up period, HF occurred in 512 (3.3%) participants, with 5.2% in black men, 3.8% in white men, 3.2% in black women, and 2.2% in white women. The prevalence of malignant LVH was 3-fold higher among black men and women versus white men and women. Compared with participants without LVH, the adjusted hazard ratio for HF was 2.8 (95% CI, 2.1-3.5) in those with malignant LVH and 0.9 (95% CI, 0.6-1.5) in those with LVH and normal biomarkers, with similar findings in each race/sex subgroup. Mediation analyses indicated that 33% of excess hazard for HF among black men and 11% of the excess hazard among black women was explained by the higher prevalence of malignant LVH in blacks. Of black men who developed HF, 30.8% had malignant LVH at baseline, with a corresponding population attributable fraction of 0.21. The proportion of HF cases occurring among those with malignant LVH, and the corresponding population attributable fraction, were intermediate and similar among black women and white men and lowest among white women. CONCLUSIONS: A higher prevalence of malignant LVH may in part explain the higher risk of HF among blacks versus whites. Strategies to prevent development or attenuate risk associated with malignant LVH should be investigated as a strategy to lower HF risk and mitigate racial disparities.

Association of Long-Term Risk Factor Levels With Carotid Atherosclerosis: The Chicago Healthy Aging Magnetic Resonance Imaging Plaque Study (CHAMPS).

BACKGROUND: Absence of cardiovascular risk factors (RF) in young adulthood is associated with a lower risk for cardiovascular disease. However, it is unclear if low RF burden in young adulthood decreases the quantitative burden and qualitative features of atherosclerosis. METHODS: Multi-contrast carotid magnetic resonance imaging was performed on 440 Chicago Healthy Aging Study participants in 2009 to 2011, whose RF (total cholesterol, blood pressure, diabetes mellitus, and smoking) were measured in 1967 to 1973. Participants were divided into 4 groups: low-risk (with total cholesterol <200 mg/dL and no treatment, blood pressure <120/80 mm Hg and no treatment, no smoking, and no diabetes mellitus), 0 high RF but some RF unfavorable (≥1 RF above low-risk threshold but below high-risk threshold), 1 high RF (total cholesterol ≥240 mg/dL or treated, blood pressure ≥140/90 or treated, diabetes mellitus, or smoking), and 2 or more high RF. Association of baseline RF status with carotid atherosclerosis (overall mean carotid wall thickness and lipid-rich necrotic core) at follow-up was assessed. RESULTS: Among 424 participants with evaluable carotid magnetic resonance images, the mean age was 32 years at baseline and 73 years at follow-up; 67% were male, 86% white, and 36% were low-risk at baseline. Two or more high RF status was associated with higher carotid wall thickness (0.99±0.11 mm) and lipid-rich necrotic core prevalence (30%), as compared with low-risk group (0.94±0.09 mm and 17%, respectively). Each increment in baseline RF status was associated with higher carotid wall thickness (ß-coefficient, 0.015; 95% CI, 0.004-0.026) and with higher lipid-rich necrotic core prevalence at older age (odds ratio, 1.26; 95% CI, 1.00-1.58) in models adjusted for baseline RF and demographics. CONCLUSIONS: RF status in young adulthood is associated with the burden and quality of carotid atherosclerosis in older age suggesting that the decades-long protective effect of low-risk status might be mediated through a lower burden of quantitative and qualitative features of atherosclerotic plaque.