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BackgroundCardiovascular disease (CVD) and associated comorbidities increase the risk of cognitive impairment in persons living with human immunodeficiency virus (PLWH). Given the potential composite effect of multiple cardiovascular risk factors on cognition, we examined the ability of the Atherosclerotic Cardiovascular Disease (ASCVD) risk score and the Framingham Heart Study Global CVD risk score (FRS) to predict future cognitive function in older PLWH.MethodsWe constructed linear regression models evaluating the association between baseline 10-year cardiovascular risk scores and cognitive function (measured by a summary z-score, the NPZ-4) at a year 4 follow-up visit.ResultsAmong 988 participants (mean age, 52 years; 20% women), mean 10-year ASCVD risk score at entry into the cohort was 6.8% (standard deviation [SD], 7.1%) and FRS was 13.1% (SD, 10.7%). In models adjusted only for cognitive function at entry, the ASCVD risk score significantly predicted year 4 NPZ-4 in the entire cohort and after stratification by sex (for every 1% higher ASCVD risk, year 4 NPZ-4 was lower by 0.84 [SD, 0.28] overall, P = .003; lower by 2.17 [SD, 0.67] in women, P = .001; lower by 0.78 [SD, 0.32] in men, P = .016). A similar relationship was observed between FRS and year 4 NPZ-4. In multivariable models, higher 10-year ASCVD risk and FRS predicted lower NPZ-4 in women.ConclusionsBaseline 10-year ASCVD risk and FRS predicted future cognitive function in older PLWH with well-controlled infection. Cardiovascular risk scores may help to identify PLWH, especially women, who are at risk for worse cognition over time.

AimsClinical studies of vagal nerve stimulation (VNS) for heart failure with reduced ejection fraction have had mixed results to date. We sought to compare VNS delivery and associated changes in symptoms and function in autonomic regulation therapy via left or right cervical vagus nerve stimulation in patients with chronic heart failure (ANTHEM-HF), increase of vagal tone in heart failure (INOVATE-HF), and neural cardiac therapy for heart failure (NECTAR-HF) for hypothesis generation.Methods and resultsDescriptive statistics were used to analyse data from the public domain for differences in proportions using Pearson's chi-square test, differences in mean values using Student's unpaired t-test, and differences in changes of mean values using two-sample t-tests. Guideline-directed medical therapy recommendations were similar across studies. Fewer patients were in New York Heart Association 3, and baseline heart rate (HR) was higher in ANTHEM-HF. In INOVATE-HF, VNS was aimed at peripheral neural targets, using closed-loop delivery that required synchronization of VNS to R-wave sensing by an intracardiac lead. Pulse frequency was low (1-2 Hz) because of a timing schedule allowing ≤3 pulses of VNS following at most 25% of detected R waves. NECTAR-HF and ANTHEM-HF used open-loop VNS delivery (i.e. independent of any external signal) aimed at both central and peripheral targets. In NECTAR-HF, VNS delivery at 20 Hz caused off-target effects that limited VNS up-titration in a majority of patients. In ANTHEM-HF, VNS delivery at 10 Hz allowed up-titration until changes in HR dynamics were confirmed. Six months after VNS titration, significant improvements in both HR and HR variability occurred only in ANTHEM-HF. When ANTHEM-HF and NECTAR-HF were compared, greater improvements from baseline were observed in ANTHEM-HF in standard deviation in normal-to-normal R-R intervals (94 ± 26 to 111 ± 50 vs. 146 ± 48 to 130 ± 52 ms; P < 0.001), left ventricular ejection fraction (32 ± 7 to 37 ± 0.4 vs. 31 ± 6 to 33 ± 6; P < 0.05), and Minnesota Living with Heart Failure mean score (40 ± 14 to 21 ± 10 vs. 44 ± 22 to 36 ± 21; P < 0.002). When compared with INOVATE-HF, greater improvement in 6-min walk distance was observed in ANTHEM-HF (287 ± 66 to 346 ± 78 vs. 304 ± 111 to 334 ± 111 m; P < 0.04).ConclusionsIn this post-hoc analysis, differences in patient demographics were seen and may have caused the differential responses in symptoms and function observed in association with VNS. Major differences in technology platforms, neural targets, VNS delivery, and HR and HR variability responses could have also potentially played a very important role. Further study is underway in a randomized controlled trial with these considerations in mind.

Background & aimsLittle is known regarding the risk of hepatic steatosis (HS) among adult children of affected parents. We examined the association between parental and offspring HS in the multigenerational Framingham Heart Study, which characterized HS using computed tomography.MethodsWe performed multivariable logistic regression models adjusted for age, sex, alcohol use, and body mass index to generate the odds of HS according to parental HS. We determined the proportion of participants with HS according to parental HS and the presence or absence of hypertension, diabetes, or obesity (BMI ≥30 kg/m2 ). After excluding heavy alcohol use (n = 126) and missing covariates (n = 1), 785 offspring with at least one parent were included.ResultsApproximately 23% (183/785) had at least one parent with HS and 1.1% had two affected parents (9/785). In adjusted models, participants with at least one parent with HS had a nearly two-fold increased odds of HS compared to participants without a parental history of HS (OR 1.86, 95% confidence interval 1.15-3.03). Among participants without hypertension, diabetes, or obesity, a higher proportion had HS if they had a parental history of HS compared to those without (16.1% vs 5.2%, P

BackgroundCoronary artery calcium (CAC) is a powerful novel risk indicator for atherosclerotic cardiovascular disease (ASCVD). Currently, there is no available ASCVD risk prediction tool that integrates traditional risk factors and CAC.MethodsTo develop a CAC ASCVD risk tool for younger individuals in the general population, subjects aged 40 to 65 without prior cardiovascular disease from 3 population-based cohorts were included. Cox proportional hazards models were developed incorporating age, sex, systolic blood pressure, total and high-density lipoprotein cholesterol, smoking, diabetes mellitus, hypertension treatment, family history of myocardial infarction, high-sensitivity C-reactive protein, and CAC scores (Astro-CHARM model [Astronaut Cardiovascular Health and Risk Modification]) as dependent variables and ASCVD (nonfatal/fatal myocardial infarction or stroke) as the outcome. Model performance was assessed internally, and validated externally in a fourth cohort.ResultsThe derivation study comprised 7382 individuals with a mean age 51 years, 45% women, and 55% nonwhite. The median CAC was 0 (25th, 75th [0,9]), and 304 ASCVD events occurred in a median 10.9 years of follow-up. The c-statistic was 0.784 for the risk factor model, and 0.817 for Astro-CHARM ( P

Background and aimsThe factors associated with incident hepatic steatosis are not definitively known. We sought to determine factors associated with incident hepatic steatosis, as measured on computed tomography, in the community.MethodsWe studied Framingham Heart Study participants without heavy alcohol use or baseline hepatic steatosis who underwent computed tomography scans between 2002-2005 (baseline) and 2008-2011 (follow-up). We performed a stepwise logistic regression procedure to determine the predictors associated with incident hepatic steatosis.ResultsWe included 685 participants (mean age: 45.0 ± 6.2 years, 46.8% women). The incidence of hepatic steatosis in our sample was 17.1% over a mean 6.3 years of follow-up. Participants who developed hepatic steatosis had more adverse cardiometabolic profiles at baseline compared to those free of hepatic steatosis at follow-up. Multivariable stepwise regression analysis showed that a simple clinical model including age, sex, body mass index, alcohol consumption and triglycerides was predictive of incident hepatic steatosis (C statistic = 0.791, 95% CI: 0.748-0.834). A complex clinical model, which included visceral adipose tissue volume and liver phantom ratio added to the simple clinical model, and had improved discrimination for predicting incident hepatic steatosis (C statistic = 0.826, 95% CI: 0.786-0.866, P

It is unknown if lifelong exposure to increased hemodynamic stress from an elevated resting heart rate (HR) may contribute to aortic valve calcium (AVC). We performed multivariate regression analyses using data from 1,266 Framingham Heart Study (FHS) Offspring cohort participants and 6,764 Multi-Ethnic Study of Atherosclerosis (MESA) participants. We constructed a genetic risk score (GRS) for HR using summary-level data in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) AVC Consortium to investigate if there was evidence in favor of a causal relation. AVC was present in 39% of FHS Offspring cohort participants and in 13% of MESA cohort participants. In multivariate adjusted models, participants in the highest resting HR quartiles had significantly greater prevalence of AVC, with a prevalence ratio of 1.19 (95% confidence interval [CI] 0.99 to 1.44) for the FHS Offspring cohort and 1.32 (95% CI 1.12 to 1.63) for the MESA cohort, compared with those in the lowest quartile. There was a similar increase in the prevalence of AVC per standard deviation increase in resting HR in both FHS Offspring (prevalence ratio 1.08, 95% CI 1.01 to 1.15) and MESA (1.10, 95% CI 1.03 to 1.17). In contrast with these observational findings, a HR associated GRS was not significantly associated with AVC. Although our observational analysis indicates that a higher resting HR is associated with AVC, our genetic results do not support a causal relation. Unmeasured environmental and/or lifestyle factors associated with both increased resting HR and AVC that are not fully explained by covariates in our observational models may account for the association between resting HR and AVC.

Background and aimsAortic atherosclerosis is an aggregate marker of vascular risk factor exposure and has been associated with intracranial atherosclerosis and stroke. We hypothesized that atherosclerosis of the descending aorta (DAo) could be a risk marker for brain aging and injury.MethodsWe evaluated 1527 participants (mean age 59.9 years, 53.5% women) in the Framingham Offspring cohort who underwent both aortic and brain MRI. Participants were free of clinical stroke, dementia, or other neurological illness at the time of axial MRI of the thoracic and abdominal DAo and subsequent brain MRI. We related the prevalence and burden of aortic plaque to total cerebral brain volume (TCBV) and white matter hyperintensity volume (WMHV). An additional analysis compared incidence of stroke or TIA in participants with and without DAo plaques.ResultsPresence of thoracic DAo plaque (8%) was associated with decreased TCBV in sex-pooled analysis (-0.77, SE 0.25, p = 0.002, equivalent to 4.5 years of aging) and with increased WMHV only in men (0.26, SE 0.12, p = 0.032, equivalent to 6.5 years aging). We observed similar associations of DAo plaque burden with TCBV and WMHV. There were 43 strokes and 11 TIAs in prospective follow-up (median 7 years). Presence of DAo plaque was not associated with subsequent stroke or TIA.ConclusionsIn this cross-sectional community-based study, we found DAo plaque is associated with accelerated brain aging. These data underscore the potential implications of incidentally identified subclinical aortic atherosclerosis and question whether targeted intervention in these high risk individuals can modulate cognitive decline.

ImportanceThe role of coronary artery calcium (CAC) testing for guiding preventive strategies among women at low cardiovascular disease (CVD) risk based on the American College of Cardiology and American Heart Association CVD prevention guidelines is unclear.ObjectiveTo assess the potential utility of CAC testing for CVD risk estimation and stratification among low-risk women.Design, setting, and participantsWomen with 10-year atherosclerotic CVD (ASCVD) risk lower than 7.5% from 5 large population-based cohorts: the Dallas Heart Study (United States), the Framingham Heart Study (United States), the Heinz Nixdorf Recall study (Germany), the Multi-Ethnic Study of Atherosclerosis (United States), and the Rotterdam Study (the Netherlands). The 5 cohorts were selected based on the availability of CAC data in a sizable group of low-risk women from the general population together with the long detailed follow-up data. Across the cohorts, events were assessed from the date of CAC scan (performed from 1998 through 2006) until January 1, 2012; January 1, 2014; or March 6, 2015. Fixed-effects meta-analysis was conducted to combine the results of the 5 studies.ExposuresCAC score by computed tomography.Main outcomes and measuresMain outcome was incident ASCVD, including nonfatal myocardial infarction, coronary heart disease (CHD) death, and stroke. Association of CAC with ASCVD was examined using Cox proportional hazards models. To assess whether CAC was associated with improved ASCVD risk predictions beyond the traditional risk factors, the C statistic and the continuous net reclassification improvement (cNRI) index were calculated.ResultsAmong 6739 women with low ASCVD risk from the 5 studies, mean age ranged from 44 to 63 years and CAC was present in 36.1%. Across the cohorts, median follow-up ranged from 7.0 to 11.6 years. A total of 165 ASCVD events occurred (64 nonfatal myocardial infarctions, 29 CHD deaths, and 72 strokes), with the ASCVD incidence rates ranging from 1.5 to 6.0 per 1000 person-years. Compared with the absence of CAC (CAC = 0), presence of CAC (CAC >0) was associated with an increased risk of ASCVD (incidence rates per 1000 person-years, 1.41 for CAC absence vs 4.33 for CAC presence; difference, 2.92 [95% CI, 2.02-3.83]; multivariable-adjusted hazard ratio, 2.04 [95% CI, 1.44-2.90]). The addition of CAC to traditional risk factors improved the C statistic from 0.73 (95% CI, 0.69-0.77) to 0.77 (95% CI, 0.74-0.81) and provided a cNRI of 0.20 (95% CI, 0.09-0.31) for ASCVD prediction.Conclusions and relevanceAmong women at low ASCVD risk, CAC was present in approximately one-third and was associated with an increased risk of ASCVD and modest improvement in prognostic accuracy compared with traditional risk factors. Further research is needed to assess the clinical utility and cost-effectiveness of this additional accuracy.

AimsIn the dual antiplatelet therapy (DAPT) study, continued thienopyridine beyond 12 months after drug-eluting stent placement was associated with increased mortality compared with placebo. We sought to evaluate factors related to mortality in randomized patients receiving either drug-eluting or bare metal stents in the DAPT study.Methods and resultsPatients were enrolled after coronary stenting, given thienopyridine and aspirin for 12 months, randomly assigned to continued thienopyridine or placebo for an additional 18 months (while taking aspirin), and subsequently treated with aspirin alone for another 3 months. A blinded independent adjudication committee evaluated deaths. Among 11 648 randomized patients, rates of all-cause mortality rates were 1.9 vs. 1.5% (continued thienopyridine vs. placebo, P = 0.07), cardiovascular mortality, 1.0 vs. 1.0% (P = 0.97), and non-cardiovascular mortality, 0.9 vs. 0.5% (P = 0.01) over the randomized period (Months 12-30). Rates of fatal bleeding were 0.2 vs. 0.1% (P = 0.81), and deaths related to any prior bleeding were 0.3 vs. 0.2% (P = 0.36), Months 12-33). Cancer incidence did not differ (2.0 vs. 1.6%, P = 0.12). Cancer-related deaths occurred in 0.6 vs. 0.3% (P = 0.02) and were rarely related to bleeding (0.1 vs. 0, P = 0.25). After excluding those occurring in patients with cancer diagnosed before enrolment, rates were 0.4 vs. 0.3% (P = 0.16).ConclusionBleeding accounted for a minority of deaths among patients treated with continued thienopyridine. Cancer-related death in association with thienopyridine therapy was mainly not related to bleeding and may be a chance finding. Caution is warranted when considering extended thienopyridine in patients with advanced cancer.Trial registrationclinicaltrials.gov Identifier: NCT00977938.

Aim: To explore the risk of major adverse cardiovascular events (MACE) associated with exposure to bexagliflozin. Methods: The analysis included 4090 participants with type 2 diabetes (T2D) enrolled in nine phase 2 and 3 double‐blind randomized controlled trials. All potential MACE were adjudicated by a blinded committee. The primary endpoint for the meta‐analysis was the hazard ratio (HR) for the time to first occurrence of non‐fatal stroke, non‐fatal myocardial infarction (MI), cardiovascular (CV) death or hospitalization for unstable angina (MACE+), tested for non‐inferiority to a ratio of 1.8. The secondary endpoints were time to first occurrence of (i) non‐fatal stroke, non‐fatal MI or CV death (MACE), tested for non‐inferiority to a ratio of 1.3; and (ii) CV death or hospitalization for heart failure, tested for superiority. Results: The HR for the primary endpoint of MACE+ was 0.80 (95% confidence interval [CI] 0.58, 1.09), which fulfilled the non‐inferiority objective with a P value of less than 0.0001. Non‐inferiority for the first key secondary endpoint of MACE was also shown (HR = 0.82; 95% CI 0.59, 1.13; P = 0.0023). Superiority for time to CV death or first hospitalization for heart failure was not shown. Conclusions: Bexagliflozin did not increase the risk of MACE in participants with T2D when compared with placebo or active control. Both the preapproval and postapproval thresholds for CV safety were met and bexagliflozin has been approved by the US Food and Drug Administration. [ABSTRACT FROM AUTHOR]

BackgroundDepression is a heritable trait that exists on a continuum of varying severity and duration. Yet, the search for genetic variants associated with depression has had few successes. We exploit the entire continuum of depression to find common variants for depressive symptoms.MethodsIn this genome-wide association study, we combined the results of 17 population-based studies assessing depressive symptoms with the Center for Epidemiological Studies Depression Scale. Replication of the independent top hits (p

Nonalcoholic fatty liver disease (NAFLD) clusters in families, but the only known common genetic variants influencing risk are near PNPLA3. We sought to identify additional genetic variants influencing NAFLD using genome-wide association (GWA) analysis of computed tomography (CT) measured hepatic steatosis, a non-invasive measure of NAFLD, in large population based samples. Using variance components methods, we show that CT hepatic steatosis is heritable (∼26%-27%) in family-based Amish, Family Heart, and Framingham Heart Studies (n = 880 to 3,070). By carrying out a fixed-effects meta-analysis of genome-wide association (GWA) results between CT hepatic steatosis and ∼2.4 million imputed or genotyped SNPs in 7,176 individuals from the Old Order Amish, Age, Gene/Environment Susceptibility-Reykjavik study (AGES), Family Heart, and Framingham Heart Studies, we identify variants associated at genome-wide significant levels (p