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Objectives To provide a standard for total abdominal muscle mass (TAM) quantification on computed tomography (CT) and investigate its association with cardiovascular risk in a primary prevention setting. Methods We included 3016 Framingham Heart Study participants free of cardiovascular disease (CVD) who underwent abdominal CT between 2002 and 2005. On a single CT slice at the level of L3/L4, we segmented (1) TAM-Area, (2) TAM-Index (= TAM-Area/height) and, (3) TAM-Fraction (= TAM-Area/total cross-sectional CT-area). We tested the association of these muscle mass measures with prevalent and incident cardiometabolic risk factors and incident CVD events during a follow-up of 11.0 ± 2.7 years. Results In this community-based sample (49% women, mean age: 50.0 ± 10.0 years), all muscle quantity measures were significantly associated with prevalent and incident cardiometabolic risk factors and CVD events. However, only TAM-Fraction remained significantly associated with key outcomes (e.g., adj. OR 0.68 [0.55, 0.84] and HR 0.73 [0.57, 0.92] for incident hypertension and CVD events, respectively) after adjustment for age, sex, body mass index, and waist circumference. Moreover, only higher TAM-Fraction was associated with a lower risk (e.g., adj. OR: 0.56 [0.36–0.89] for incident diabetes versus TAM-Area: adj. OR 1.26 [0.79–2.01] and TAM-Index: 1.09 [0.75–1.58]). Conclusion TAM-Fraction on a single CT slice at L3/L4 is a novel body composition marker of cardiometabolic risk in a primary prevention setting that has the potential to improve risk stratification beyond traditional measures of obesity. Key Points • In this analysis of the Framingham Heart Study (n = 3016), TAM-F on a single slice CT was more closely associated with prevalent and incident cardiometabolic risk factors as compared to TAM alone or TAM indexed to body surface area. • TAM-F on a single abdominal CT slice at the level of L3/L4 could serve as a standard measure of muscle mass and improve risk prediction

BACKGROUND: Hutchinson-Gilford progeria syndrome (HGPS) is an ultrarare, fatal, premature aging disease caused by a toxic protein called progerin. Circulating progerin has not been previously detected, precluding research using readily available biological samples. This study aimed to develop a plasma progerin assay to evaluate progerin’s quantity, response to progerin-targeted therapy, and relationship to patient survival. METHODS: Biological samples were collected by The Progeria Research Foundation Cell and Tissue Bank from a non-HGPS cohort cross-sectionally and a HGPS cohort longitudinally. HGPS donations occurred at baseline and intermittently while treated with farnesylation inhibitors lonafarnib±pravastatin and zoledronate, within 3 sequential open-label clinical trials at Boston Children’s Hospital totaling >10 years of treatment. An ultrasensitive single-molecule counting progerin immunoassay was developed with prespecified performance parameters. Intra- and interpatient group statistics were descriptive. The relationship between progerin and survival was assessed by using joint modeling with time-dependent slopes parameterization. RESULTS: The assay’s dynamic detection range was 59 to 30 000 pg/mL ( R 2 =0.9987). There was no lamin A cross-reactivity. Mean plasma progerin in non-HGPS participants (n=69; 39 male, 30 female; age, 0.2–71.3 years) was 351±251 pg/mL, and in drug-naive participants with HGPS (n=74; 37 female, 37 male; age, 2.1–17.5 years) was 33 261±12 346 pg/mL, reflecting a 95-fold increase in affected children ( P P =0.99). Lonafarnib treatment resulted in an average per-visit progerin decrease from baseline of between 35% to 62% (all P P CONCLUSIONS: A sensitive, quantitative immunoassay for progerin was developed and used to demonstrate high progerin levels in HGPS plasma that decreased with lonafarnib therapy. The extent of improved survival was associated with both the magnitude of progerin decrease and duration at lower levels. Thus, plasma progerin is a biomarker for HGPS whose reduction enables short- and long-term assessment of progerin-targeted treatment efficacy. REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifiers: NCT00879034 and NCT00916747

PURPOSE OF REVIEW: To provide the current state of the development and application of cardiovascular disease (CVD) prediction tools in people living with HIV (PLWH). RECENT FINDINGS: Several risk prediction models developed on the general population are available to predict CVD risk, the most notable being the US-based pooled cohort equations (PCE), the Framingham risk functions, and the Europe-based SCORE (Systematic COronary Risk Evaluation). In validation studies in cohorts of PLWH, these models generally underestimate CVD risk, especially in individuals who are younger, women, Black race or predicted to be at low/intermediate risk. An HIV-specific CVD prediction model, the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) model, is available, but its performance is modest, especially in US-based cohorts. Enhancing CVD prediction with novel biomarkers of inflammation or coronary artery calcification is of interest but has not yet been evaluated in PLWH. Finally, studies on CVD risk prediction are lacking in diverse PLWH globally. SUMMARY: While available risk models for CVD prediction in PLWH remain suboptimal, clinicians should remain vigilant of higher CVD risk in this population and should use any of these risk scores for risk-stratification to guide preventive interventions. Focus on established traditional risk factors such as smoking remains critical in PLWH. Risk prediction functions tailored to PLWH in diverse settings will enhance clinicians’ ability to deliver optimal preventive care.

BACKGROUND: Older adults may have difficulty meeting the Physical Activity (PA) Guidelines. A favorable balance between PA and sedentary time (SED) is an important determinant of physical performance in older adults. Our objective was to explore associations of PA/SED with physical performance across mid-older age in adults without overt mobility disability. METHODS: Framingham Offspring Study participants free of mobility disability with accelerometry and physical performance data (gait speed, chair stand time, and handgrip strength), were studied in cross-sectional analysis (n = 1352). We regressed physical performance on PA level, measured using steps, moderate to vigorous (MV) PA and SED. We stratified by age groups, adjusted for covariates, and modelled MVPA and SED separately and together as predictors. RESULTS: Only 38% of adults 50–64 years and 15% of adults ≥75 years met the PA Guidelines (i.e., 150 min MVPA per week). Individuals achieving at least 5 min/day of MVPA had 0.062 ± 0.013 m/s greater gait speed and better chair stands and handgrip strength (in women) than those with < 5 min/day of MVPA (p < 0.01) across mid-older age. SED was associated with poorer performance on gait speed and chair stand tests, but results were not significant after adjusting for MVPA (p > 0.05). For adults ≥75 years, every 5000 more steps/day related to ~0.045 m/s greater gait speed (p = 0.006). CONCLUSION: Our cross-sectional study demonstrated that, across mid-older adulthood, MVPA related to better physical performance, but in adults ≥75 years, total steps walked associated with better gait speed. These data warrant future research on the impact of PA on physical performance and health outcomes in older age.

Background Men and women are labeled as obese on the basis of a body mass index (BMI) using the same criterion despite known differences in their fat distributions. Subcutaneous adipose tissue and visceral adipose tissue (VAT), as measured by computed tomography, are advanced measures of obesity that closely correlate with cardiometabolic risk independent of BMI. However, it remains unknown whether prognostic significance of anthropometric measures of adiposity versus VAT varies in men versus women. Methods and Results In 3482 FHS (Framingham Heart Study) participants (48.1% women; mean age, 50.8±10.3 years), we tested the associations of computed tomography–based versus anthropometric measures of fat with cardiometabolic and cardiovascular disease (CVD) risk. Mean follow‐up was 12.7±2.1 years. In men, VAT, as compared with BMI, had a similar strength of association with incident cardiometabolic risk factors (eg, adjusted odds ratio [OR], 2.36 [95% CI, 1.84–3.04] versus 2.66 [95% CI, 2.04–3.47] for diabetes mellitus) and CVD events (eg, adjusted hazard ratio [HR], 1.32 [95% CI, 0.97–1.80] versus 1.74 [95% CI, 1.14–2.65] for CVD death). In women, however, VAT, when compared with BMI, conferred a markedly greater association with incident cardiometabolic risk factors (eg, adjusted OR, 4.51 [95% CI, 3.13–6.50] versus 2.33 [95% CI, 1.88–3.04] for diabetes mellitus) as well as CVD events (eg, adjusted HR, 1.85 [95% CI, 1.26–2.71] versus 1.19 [95% CI, 1.01–1.40] for CVD death). Conclusions Anthropometric measures of obesity, including waist circumference and BMI, adequately capture VAT‐associated cardiometabolic and cardiovascular risk in men but not in women. In women, abdominal computed tomography–based VAT measures permit more precise assessment of obesity‐associated cardiometabolic and cardiovascular risk.

Introduction: Although type 2 diabetes (T2DM) is one of the strongest risk factors for heart failure (HF), there is limited data on contemporary lifetime risk estimates in this segment. Incident HF appears to be decreasing in the general population, but little is known how the risk has changed over time in patients with T2DM. The increasing prevalence and rapidly evolving management of T2DM has furthered interest in the epidemiological relationship between HF and T2DM. We therefore sought to investigate the lifetime risk of HF in people with T2DM and how the long term risk of HF has changed over time in patients with T2DM. Hypothesis: We assessed the hypothesis that there would be a statistically significant reduction in the ten- year risk of HF among patients with T2DM over time in all age groups except the youngest ( Methods: We employed the Danish nationwide databases which included information on all Danish citizens’ hospitalizations, outpatient visits, and medication use since 1978 (diagnoses) and 1995 (medications). Using this data, we calculated the cumulative incidence of HF among patients with T2DM who were free from HF at age 30, 40, 50, 60, and 70 years, respectively. We censored people at time of emigration or at Dec 31, 2017 and we used Aalen-Johnsen estimators to adjust for the competing risk of death. Results: A total of 473,685 patients (47% women) had a diagnosis of T2DM between Jan 1, 1995 and Dec 31, 2017. Of those who were free from HF before T2DM onset, 21,030 were diagnosed before the age of 30; 33,786 before age 40; 55,537 before 50 years of age; 85,108 before age 60; and 98,631 before age 70. During follow-up, 48,026 (10%) were diagnosed with HF and 133,561 were censored for death. The cumulative life-time risk of developing HF among people with diabetes at age 50 was 24% (95% CI 21-27%) in females and 27% (25-29%) in men, p for difference Conclusion: The lifetime risk of HF among patients with T2DM exceeds 1 in 4 for both men and women. There was, however, a decrease in ten-year cumulative incidence of HF over time among patients with T2DM in all age groups.

Coronary artery calcium is an accurate predictor of cardiovascular events. While it is visible on all computed tomography (CT) scans of the chest, this information is not routinely quantified as it requires expertise, time, and specialized equipment. Here, we show a robust and time-efficient deep learning system to automatically quantify coronary calcium on routine cardiac-gated and non-gated CT. As we evaluate in 20,084 individuals from distinct asymptomatic (Framingham Heart Study, NLST) and stable and acute chest pain (PROMISE, ROMICAT-II) cohorts, the automated score is a strong predictor of cardiovascular events, independent of risk factors (multivariable-adjusted hazard ratios up to 4.3), shows high correlation with manual quantification, and robust test-retest reliability. Our results demonstrate the clinical value of a deep learning system for the automated prediction of cardiovascular events. Implementation into clinical practice would address the unmet need of automating proven imaging biomarkers to guide management and improve population health., Coronary artery calcium is an accurate predictor of cardiovascular events but this information is not routinely quantified. Here the authors show a robust and time-efficient deep learning system to automatically quantify coronary calcium on CT scans and predict cardiovascular events in a large, multicentre study.

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.

Background: The current clinical practice of defining obesity based on body mass index (BMI) does not capture differences in fat distribution between men and women. Visceral adipose tissue (VAT) as measured by computed tomography (CT), is an advanced measure of obesity that closely correlates with cardiometabolic risk independent of BMI. However, it remains unknown whether VAT adds additional prognostic significance over BMI in men or women. Methods: In participants of the Framingham Heart Study, we tested the associations of BMI and VAT with incident cardiometabolic events (diabetes, hypertension, low HDL, hypertriglyceridemia), and incident cardiovascular events and death. Mean follow-up was 12.7±2.1 years. Logistic and Cox-regression models were adjusted for age and smoking and adjusted odds and hazard ratios (adj. OR, adj. HR), are presented per 1-SD increase of each measure of body fat. Results: The study cohort comprised 3,482 participants (48.1% women, 50.8±10.3 years old). In men, VAT, as compared to BMI, had a similar strength of association with all cardiometabolic outcomes and incident cardiovascular disease (Figure). In women, however, VAT conferred a markedly greater association with incident cardiometabolic and cardiovascular disease compared to BMI (Figure). Conclusion and Relevance: BMI adequately captures VAT-associated cardiometabolic and cardiovascular risk in men but not in women. In women, abdominal CT-based VAT measures permit more precise assessment of obesity-associated cardiometabolic and cardiovascular risk.

Introduction: Peripartum cardiomyopathy (PPCM) is a form of systolic heart failure that occurs during pregnancy or in the early post-partum period. Obesity is known to be associated with other forms of heart failure in young adults, however it is unclear if it is also a risk factor for the development of PPCM. Objectives: To investigate the association of body mass index (BMI) with PPCM and heart failure in the years following childbirth. Methods: We conducted a retrospective review of pregnant women in the Danish National Patient Registry between 2004 - 2017. Baseline characteristics and other risk factors were obtained at the first prenatal visit (occurring at 8-11 weeks post-conception). Women were followed until the end of the study period, emigration, or death. Logistic regression was performed, adjusting for age as well as other known risk factors for PPCM. Cox proportional hazards analysis was used to assess the long-term risk of development of heart failure. Results: There were 403,820 pregnancies evaluated in 300,892 women, with an average age of 29 years. The average BMI was 24.4 kg/m2, with 21.6% classified as overweight (BMI 25 - 30 kg/m2) and 12.8% as obese (BMI > 30 kg/m2). The rate of PPCM was 0.1 per 1,000 in normal weight and overweight groups, and 0.3 per 1,000 in the obese women. After adjustment for age, ethnicity, smoking status, gestational diabetes, and presence of preeclampsia, there was a statistically significant increased risk of the development of PPCM up to 6 months after childbirth in patients who had class I (odds ratio [OR] 2.25, 95% CI 1.08-4.68) but not class II/III obesity (OR 1.63, 95% CI 0.60-4.43). This elevated risk persisted during long term follow up, with hazard ratios of 2.43 (95% CI 1.55 - 3.80) in women with class I obesity and 3.20 (95% CI 1.93 - 5.30) in women with class II/III obesity. Conclusions: High early pregnancy BMI is associated with elevated risk of development of peripartum cardiomyopathy even after adjustment for traditional risk factors. This risk of heart failure persists for several years after childbirth.

OBJECTIVES Cardiovascular risk is increased in people living with HIV (PLWH). In HIV-uninfected populations, total absolute monocyte count (AMC) has been shown to be predictive of future cardiovascular events (CVEs). We sought to determine whether AMC predicts CVEs in PLWH independent of established and HIV-related cardiovascular risk factors. METHODS We identified all PLWH within the Partners HIV Cohort without factors that could confound the monocyte count. CVE was defined as fatal or non-fatal acute myocardial infarction or ischaemic stroke. Baseline-measured AMC was defined as the average of all outpatient AMC counts a year before and after the baseline date. Multivariable Cox proportional hazards models were used to assess the association of baseline AMC with CVEs. RESULTS Our cohort consisted of 1980 patients, with median follow-up of 10.9 years and 182 CVEs. Mean (± SD) age was 41.9 ± 9.3 years; 73.0% were male. Mean CD4 count was 506.3 ± 307.1 cells/µL, 48% had HIV viral load (VL)

Background The meaning of high‐sensitivity troponin I (hsTnI) concentrations in patients without acute myocardial infarction ( MI ) requires clarity. We hypothesized that among patients referred for diagnostic coronary angiography without acute MI , hsTnI concentrations would correlate with prevalent coronary artery disease ( CAD ) and predict incident cardiovascular events and mortality. Methods and Results We measured hsTnI using a single‐molecule counting assay (99th percentile, 6 ng/L) in samples from 991 patients obtained at the time of angiography. Concentrations of hsTnI were assessed relative to the severity of CAD and prognosis during mean follow‐up of 3.7 years. Median hsTnI concentration was 4.19 ng/L; 38% of patients had hsTnI concentrations ≥99th percentile. Across increasing hsTnI quartiles, patients had higher prevalence of angiographic CAD ; in multivariate models, hsTnI ≥99th percentile independently predicted obstructive CAD (odds ratio: 2.57; P MI (hazard ratio [ HR ]: 2.68; P HR: 2.29; P =0.001), and all‐cause death ( HR: 1.84; P =0.004). In those with >70% coronary stenosis, hsTnI ≥99th percentile independently predicted incident MI ( HR: 1.87; P =0.01), cardiovascular mortality ( HR: 2.74; P =0.001), and the composite end point of MI and all‐cause death ( HR: 2.06; P MI ( HR : 8.41; P HR : 3.60; P =0.03), and the composite end point of MI and all‐cause death ( HR: 3.62; P Conclusions In a large prospective cohort of patients who were free of prevalent MI and undergoing diagnostic coronary angiography, hsTnI concentrations were associated with higher prevalence of CAD and predicted incident MI , cardiovascular death, and all‐cause death. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 00842868.

AIMS Methods to identify patients at risk for incident HF would be welcome as such patients might benefit from earlier interventions. METHODS AND RESULTS From a registry of 1251 patients referred for coronary and/or peripheral angiography, we sought to identify independent predictors of incident HF during follow-up and develop a clinical and biomarker strategy to predict this outcome. There were 991 patients free of prevalent HF at baseline. Cox proportional hazard models were developed to predict adjudicated diagnosis of incident HF. Model discrimination and reclassification were evaluated. At follow-up, 177 (18%) developed new-onset HF. Independent predictors of new-onset HF included five clinical variables (age, male sex, heart rate, history of atrial fibrillation/flutter, and history of hypertension) and two biomarkers (amino-terminal pro-B type natriuretic peptide and ST2). The c-statistic for the model without biomarkers was 0.69; including biomarkers increased the c-statistic to 0.76 (P

Objectives The purpose of this study was to describe the temporal trends in prevalence of left ventricular systolic dysfunction (LVSD) in individuals without and with heart failure (HF) in the community over a 3-decade period of observation. Background Temporal trends in the prevalence and management of major risk factors may affect the epidemiology of HF. Methods We compared the frequency, correlates, and prognosis of LVSD (left ventricular ejection fraction [LVEF] Results Among participants without HF (12,857 person-observations, mean age 53 years, 56% women), the prevalence of LVSD on echocardiography decreased (3.38% in 1985 to 1994 vs. 2.2% in 2005 to 2014; p Conclusions The profile of HF in the community has changed in recent decades, with a lower prevalence of LVSD and an increased frequency of HFpEF, presumably due to concomitant risk factor trends.

BACKGROUND Endothelin-1 (ET-1) is a vasoconstrictor produced by vascular endothelial cells and may play a role in risk for development of coronary artery disease (CAD) and heart failure (HF). In a cohort of 1084 patients referred for coronary angiography, we investigated cross-sectional associations between ET-1 concentrations and prevalent CAD, as well as value of ET-1 for prognostication of future cardiovascular events. METHODS Associations between ET-1 and presence/severity of CAD were assessed. Patients were followed for a median of 4 years for outcomes including incident HF, myocardial infarction (MI), cardiovascular mortality, and all-cause mortality. RESULTS The median concentration of ET-1 was 2.57 ng/L. Patients with ET-1 concentrations above the median were more likely to have higher risk clinical features. Among those without prevalent MI at presentation, ET-1 concentrations were not associated with presence or severity of CAD. In adjusted Cox proportional hazards analyses, log-transformed ET-1 concentrations predicted incident HF [hazard ratio (HR) = 1.51 per increase in log-SD; 95% CI, 1.06–2.15; P = 0.02] and all-cause mortality (HR = 1.61 per increase in log-SD; 95% CI, 1.03–2.53; P = 0.04). Concentrations of ET-1 above the median were associated with shorter time to incident HF, MI, cardiovascular mortality, all-cause mortality, and the composite of incident HF/MI/cardiovascular mortality (all log-rank P < 0.001). CONCLUSIONS Despite epidemiologic links to CAD, we found no cross-sectional association between biologically active ET-1 and prevalent coronary atherosclerosis in an at-risk population referred for coronary angiography. Increased ET-1 concentrations independently predict incident HF and death and are associated with more near-term cardiovascular events.

Hypertension and increased vascular stiffness are viewed as inevitable parts of aging. To elucidate whether the age-related decrease in vascular function is avoidable, we assessed the prevalence, correlates, and prognosis of healthy vascular aging (HVA) in 3196 Framingham Study participants aged ≥50 years. We defined HVA as absence of hypertension and pulse wave velocity P

Differences in proteomic profiles between men and women may provide insights into the biological pathways that contribute to known sex differences in cardiovascular disease (CVD).This study sought to investigate sex differences in circulating biomarkers representative of biological pathways implicated in the development of CVD among Framingham Heart Study participants.The authors measured 71 circulating CVD protein biomarkers in 7,184 participants (54% women, mean age 49 years). Multivariable models were used to evaluate the associations of sex, menopause, and hormone status with biomarkers. Cox models were used to examine whether sex modified the association of biomarkers with incident CVD.Of 71 biomarkers examined, 61 (86%) differed significantly between men and women, of which 37 were higher in women (including adipokines and inflammatory markers such as leptin and C-reactive protein), and 24 were higher in men (including fibrosis and platelet markers such as MMP-8 (matrix metalloproteinase-8) and TIMP-1 (tissue inhibitor of metalloproteinases 1); false discovery rate q 0.05 for all). Sex differences in biomarker profiles were most pronounced between pre-menopausal women versus men, with attenuated sex differences among post-menopausal women not taking hormone replacement therapy. Sex modified the association of specific biomarkers with incident CVD, including CD14 and apolipoprotein B (pIn a predominantly Caucasian population, the authors identified widespread sex differences in circulating biomarkers that reflect distinct pathways implicated in CVD, including inflammation, adiposity, fibrosis, and platelet homeostasis. Menopause and hormone status accounted for some, but not all, of the observed sex differences. Further investigation into factors underlying sex-based differences may provide mechanistic insight into CVD development.

Kidney injury is common in patients with cardiovascular disease.We determined whether blood measurement of kidney injury molecule-1 (KIM-1), would predict kidney outcomes in patients undergoing angiographic procedures for various indications.One thousand two hundred eight patients undergoing coronary and/or peripheral angiography were prospectively enrolled; blood was collected for KIM-1 measurement. Peri-procedural acute kidney injury (AKI) was defined as AKI within 48 hours of contrast exposure. Non-procedural AKI was defined as AKI beyond 48 hours. Development of chronic kidney disease (CKD) was defined as progression to an estimated glomerular filtration rate (eGFR)60 milliliters/minute/1.73 mDuring mean follow up of 4 years, peri-procedural AKI occurred in 5.0%, non-procedural AKI in 27.3%, and 12.4% developed new reduction in eGFR60 mL/min/1.73 m2. Higher KIM-1 concentrations were associated with prevalent comorbidities associated with risk in cardiovascular disease and worse left ventricular function. In adjusted analyses, elevated pre- and post-procedural KIM-1 concentrations predicted not only peri-procedural AKI (odds ratio [OR] 1.54, 95% confidence interval [CI] 1.09-2·18, P = .01 and OR 1.54, 95% CI 1.10-2.15, P = .01, respectively) and non-procedural AKI (hazard ratio [HR] 1·49, 95% CI 1·24-1·78, P .001 and HR 1.46, 95% CI 1.23-1.74, P .001, respectively), but also progression to CKD (OR 1.99, 95% CI 1.32-2.99, P = .001 and OR 2·02, 95% CI 1·35-3·03, P = .001, respectively).In a typical at-risk population undergoing coronary and/or peripheral angiography, blood concentrations of KIM-1 may predict incident peri-procedural and non-procedural AKI, as well as progression to CKD.

Objectives This study sought to examine the association of a borderline left ventricular ejection fraction (LVEF) of 50% to 55% with cardiovascular morbidity and mortality in a community-based cohort. Background Guidelines stipulate a LVEF >55% as normal, but the optimal threshold, if any, remains uncertain. The prognosis of a “borderline” LVEF, 50% to 55%, is unknown. Methods This study evaluated Framingham Heart Study participants who underwent echocardiography between 1979 and 2008 (n = 10,270 person-observations, mean age 60 years, 57% women). Using pooled data with up to 12 years of follow-up and multivariable Cox regression, we evaluated the associations of borderline LVEF and continuous LVEF with the risk of developing a composite outcome (heart failure [HF] or death; primary outcome) and incident HF (secondary outcome). Results During follow-up (median 7.9 years), HF developed in 355 participants, and 1,070 died. Among participants with an LVEF of 50% to 55% (prevalence 3.5%), rates of the composite outcome and HF were 0.24 and 0.13 per 10 years of follow-up, respectively, versus 0.16 and 0.05 in participants having a normal LVEF. In multivariable-adjusted analyses, LVEF of 50% to 55% was associated with increased risk of the composite outcome (hazard ratio [HR]: 1.37; 95% confidence interval [CI]: 1.05 to 1.80) and HF (HR: 2.15; 95% CI: 1.41 to 3.28). There was a linear inverse relationship of continuous LVEF with the composite outcome (HR per 5 LVEF% decrement: 1.12; 95% CI: 1.07 to 1.16) and HF (HR per 5 LVEF% decrement: 1.23; 95% CI: 1.15 to 1.32). Conclusions Persons with an LVEF of 50% to 55% in the community have greater risk for morbidity and mortality relative to persons with an LVEF >55%. Additional studies are warranted to elucidate the optimal management of these individuals.

The 2018 multisociety guidelines on cholesterol management suggest coronary artery calcium (CAC) scoring to guide statin therapy in individuals at intermediate (7.5%

OBJECTIVE: To determine the relation of maternal pre-pregnancy weight with offspring body mass index across adulthood from almost 40 years of follow-up. METHODS: Body mass index (BMI) was measured in Framingham Heart Study Offspring cohort participants between 1971 and 2008. We tested the association of maternal pre-pregnancy weight category (ascertained via direct measure and questionnaire) with serial offspring BMI, overweight, obesity, and change in BMI over time, adjusted for age, sex, and a BMI genetic risk score; secondary models additionally adjusted for physical activity, dietary factors, smoking, education, and familial relatedness. RESULTS: Among 863 participants at initial assessment (83 exposed and 780 controls), mean (SD) age was 33 (10) years, 53% were female, and mean BMI was 24.5 (4.1) kg/m(2). Exposed offspring BMI was higher at every examination cycle; ranging from 1.5 (0.5) to 3.0 (0.5) kg/m(2) (p

Concentrations of circulating apolipoproteins are strongly linked to risk for coronary artery disease (CAD). The relative importance of the additional knowledge of apolipoprotein concentrations within specific lipoprotein species for CAD risk prediction is limited.This study sought to evaluate the performance of a high-density lipoprotein (HDL) apolipoproteomic score, based on targeted mass spectrometry of HDL-associated apolipoproteins, for the detection of angiographic CAD and outcomes.HDL-associated apolipoprotein (apo) A-1, apoC-1, apoC-2, apoC-3, and apoC-4 were measured in 943 participants without prevalent myocardial infarction (MI) referred for coronary angiography in the CASABLANCA (Catheter Sampled Blood Archive in Cardiovascular Diseases) study. A composite HDL apolipoproteomic score (pCAD) was associated with likelihood of obstructive CAD (≥70% lesion in ≥1 vessel) and with incident cardiovascular outcomes over 4-year follow-up.There were 587 (62.2%) patients with coronary stenosis. The pCAD score was associated with the presence of obstructive CAD (odds ratio: 1.39; 95% confidence interval [CI]: 1.14 to 1.69; p 0.001), independently of conventional cardiovascular risk factors including circulating plasma apoA-1 and apoB. The C-index for pCAD was 0.63 (95% CI: 0.59 to 0.67) for the presence of obstructive CAD. Although pCAD was not associated with cardiovascular mortality among all individuals (hazard ratio: 1.24; 95% CI: 0.93 to 1.66; p = 0.15), there was evidence of association for individuals with obstructive CAD (hazard ratio: 1.48; 95% CI: 1.07 to 2.05; p = 0.019).An HDL apolipoproteomic score is associated with the presence of CAD, independent of circulating apoA-1 and apoB concentrations and other conventional cardiovascular risk factors. Among individuals with CAD, this score may be independently associated cardiovascular death. (The CASABLANCA Study: Catheter Sampled Blood Archive in Cardiovascular Diseases [CASABLANCA]; NCT00842868).

This study aimed to determine temporal trends in the incidence of and mortality associated with heart failure (HF) and its subtypes (heart failure with reduced ejection fraction [HFrEF] and heart rate with preserved ejection fraction [HFpEF]) in the community.Major shifts in cardiovascular disease risk factor prevalence and advances in therapies may have influenced HF incidence and mortality.In the FHS (Framingham Heart Study) and CHS (Cardiovascular Health Study), for participants who were ≥60 years of age and free of HF (n = 15,217; 60% women; 2,524 incident HF cases; 115,703 person-years of follow-up), we estimated adjusted incidence rate ratios of HF, HFrEF, and HFpEF from 1990 to 1999 and 2000 to 2009. We compared the cumulative incidence of and mortality associated with HFrEF versus HFpEF within and between decades.Across the 2 decades, HF incidence rate ratio was similar (p = 0.13). The incidence rate ratio of HFrEF declined (p = 0.0029), whereas HFpEF increased (p 0.001). Although HFrEF incidence declined more in men than in women, men had a higher incidence of HFrEF than women in each decade (p 0.001). The incidence of HFpEF significantly increased over time in both men and women (p 0.001 and p = 0.02, respectively). During follow-up after HF, 1,701 individuals died (67.4%; HFrEF, n = 557 [33%]; HFpEF, n = 474 [29%]). There were no significant differences in mortality rates (overall, cardiovascular disease, and noncardiovascular disease) across decades within HF subtypes or between HFrEF and HFpEF within decade.In several U.S. community-based samples from 1990 to 2009, we observed divergent trends of decreasing HFrEF and increasing HFpEF incidence, with stable overall HF incidence and high risk for mortality. Our findings highlight the need to elucidate factors contributing to these observations.

Beta-2-microglobulin (β 2 M), a multifunctional protein involved in immune function, is a filtration marker that has been reported to predict renal failure, cancer, cardiovascular disease (CVD), and all-cause mortality. Previous studies of β 2 M and mortality were limited to select study samples (elderly or patient-based) lacking information on cancer or kidney function. We examined plasma β 2 M as a predictor of all-cause and cause-specific mortality in those with and without chronic kidney disease (CKD). The study sample consisted of Framingham Heart Study participants from the 2 nd (n=3196) and 3 rd (n=3911) generations who attended an on-site examination (2001-2007). Plasma β 2 M concentration was measured using a Luminex bead-based immunoassay. Mortality events were adjudicated by a physician committee. Proportional hazard models were conducted based on standardized values of β 2 M, adjusted for CVD risk factors, prevalent CVD, cancer, and family structure. We additionally analyzed subgroups stratified for CKD (defined as GFR ckdepi < 60 mL/min/1.73 m 2 ). The study sample included 7107 individuals [mean age 50 years, 54% female, 4% with prevalent CKD, mean length of follow-up: 13 years]. In the overall sample, β 2 M concentrations were associated with increased risk of CVD death (HR=1.42 [CI=1.17-1.72]), cancer death (HR=1.27 [CI=1.07-1.5]), and all-cause mortality (HR=1.27 [CI=1.16-1.4]). β 2 M performed better in participants with prevalent CKD than in those free of CKD. Adjusting for cystatin C, a filtration biomarker, did not affect the results. For all-cause mortality, including plasma β 2 M yielded a relative integrated discrimination improvement of 3% (p-value 0.03) beyond the covariate-only model. The net reclassification improvements (NRI) for all-cause mortality was 4% that was not statistically significant (p-value 0.26). We conclude that among middle-aged adults, plasma β 2 M is a predictor of all-cause and cause-specific mortality. Much of the risk associated with β 2 M is concentrated in those with CKD.

Heart failure (HF) with preserved ejection fraction (HFPEF) is a common syndrome of increasing prevalence. The observation of the co-occurrence of fluid overload and overt HF in the presence of a normal left ventricular ejection fraction was made >3 decades ago, yet the pathophysiology behind HFPEF is incompletely understood. Currently, the incidence and the hospitalization rates of HF with reduced ejection fraction (HFREF) are declining in the Western world, in part because of better management of coronary artery disease (CAD) and its risk factors.1 In contrast, the prevalence of HFPEF is increasing, but it is unknown if a changing presentation of CAD may contribute to this trend.1 Indeed, individuals with HFPEF have a high burden of CAD (as assessed by autopsy and angiographic studies), and CAD may adversely affect the clinical course of HFPEF, but a causal role of CAD in HFPEF development is uncertain.2 We used the community-based sample of the Framingham Heart Study to test whether a genetic risk score (GRS) associated with CAD was also associated with HFREF versus HFPEF risk. We further investigated the prognostic importance of a CAD-related GRS in survival after HFPEF and HFREF. We followed attendees from the Original and Offspring cohorts, who had blood drawn for DNA extraction, from the date of blood draw until the occurrence of HF, death, or the end of …

The purpose of this study was to describe the temporal trends in prevalence of left ventricular systolic dysfunction (LVSD) in individuals without and with heart failure (HF) in the community over a 3-decade period of observation.Temporal trends in the prevalence and management of major risk factors may affect the epidemiology of HF.We compared the frequency, correlates, and prognosis of LVSD (left ventricular ejection fraction [LVEF] 50%) among Framingham Study participants without and with clinical HF in 3 decades (1985 to 1994, 1995 to 2004, and 2005 to 2014).Among participants without HF (12,857 person-observations, mean age 53 years, 56% women), the prevalence of LVSD on echocardiography decreased (3.38% in 1985 to 1994 vs. 2.2% in 2005 to 2014; p 0.0001), whereas mean LVEF increased (65% vs. 68%; p 0.001). The elevated risk associated with LVSD (∼2- to 4-fold risk of HF or death) remained unchanged over time. Among participants with new-onset HF (n = 894, mean age 75 years, 52% women), the frequency of heart failure with preserved ejection fraction (HFpEF) increased (preserved LVEF ≥50%: 41.0% in 1985 to 1994 vs. 56.17% in 2005 to 2014; p 0.001) and heart failure with reduced ejection fraction (HFrEF) decreased (reduced LVEF 40%: 44.10% vs. 31.06%; p = 0.002), whereas heart failure with midrange LVEF remained unchanged (LVEF 40% to 50%: 14.90% vs. 12.77%; p = 0.66). Cardiovascular mortality associated with HFrEF declined across decades (hazard ratio: 0.61; 95% confidence interval: 0.39 to 0.97), but remained unchanged for heart failure with midrange LVEF and HFpEF. Approximately 47% of the observed increase in LVEF among those without HF and 75% of the rising proportion of HFpEF across decades was attributable to trends in risk factors, especially a decline in the prevalence of coronary heart disease among those with HF.The profile of HF in the community has changed in recent decades, with a lower prevalence of LVSD and an increased frequency of HFpEF, presumably due to concomitant risk factor trends.

SummaryIdentifying genetic variants associated with circulating protein concentrations (pQTLs) and integrating them with variants from genome-wide association studies (GWAS) may illuminate the proteome’s causal role in disease and bridge a GWAS knowledge gap for hitherto unexplained SNP-disease associations. We conducted GWAS of 71 high-value proteins for cardiovascular disease in 6,861 Framingham Heart Study participants followed by external replication. We comprehensively mapped thousands of pQTLs, including functional annotations and clinical-trait associations, and created an integrated plasma-protein-QTL searchable database. We next identified 15 proteins with pQTLs coinciding with coronary heart disease (CHD)-related variants from GWAS or tested causal for CHD by Mendelian randomization; most of these proteins were associated with new-onset cardiovascular disease events in Framingham participants with long-term follow-up. Identifying pQTLs and integrating them with GWAS results yields insights into genes, proteins, and pathways that may be causally associated with disease and can serve as therapeutic targets for treatment and prevention.

Introduction: Although hypertension in the elderly is no longer considered harmless, increasing arterial stiffness and blood pressure (BP) are still widely seen as inevitable parts of the aging process. However, these phenomena may not be unavoidable as they are nearly absent in populations leading traditional hunter-gatherer lifestyles. Our study had 3 aims: 1) to define a new concept - healthy vascular aging (HVA); 2) to assess prevalence and correlates of HVA in a sample acculturated to a western life-style; and 3) to estimate the magnitude of cardiovascular (CVD) risk associated with HVA vs. absence of HVA. Methods: We studied 3197 Framingham Heart Study participants aged ≥50 years (62±9 years, 56% women) who underwent physical examination, interviews, and measurement of carotid-femoral pulse wave velocity (PWV) in 1999-2008. We defined HVA as no hypertension (BP Results: In our sample, only 566 (17.7%) had HVA. Lower age (OR per 1-SD increase 0.18, 95% confidence interval [CI] 0.14-0.23), female sex (OR 2.03; 95% CI 1.54-2.68), lower BMI (OR per 1-SD increase 0.54; 95% CI 0.47-0.63) and no diabetes (OR 0.09; 95% CI 0.02-0.36) were significantly associated with HVA. A 1-unit increase in the cardiovascular health score conferred 1.55-fold (95% CI 1.38-1.74) odds of HVA. During follow-up (median 9.6 years), 391 participants had CVD events. HVA was associated with an age- and sex-adjusted hazard ratio (HR) of 0.36 (95% CI, 0.22-0.60) and a multivariable-adjusted HR of 0.45 (95% CI, 0.26-0.77) for CVD relative to absence of HVA. Conclusions: One in 6 individuals experiences HVA in our sample. Individuals with HVA are at a considerably low risk of CVD. Prevention strategies targeting modifiable factors and behaviors included in Life’s Simple 7 are important for preventing or delaying vascular aging and the associated risk of CVD.

Background: Despite growing recognition of type 2 myocardial infarction (T2MI; related to supply/demand mismatch), little is known about its risk factors or its association with outcome. Methods: A single-center cohort of patients undergoing coronary or peripheral angiography with or without intervention was prospectively enrolled and followed for incident type 1 and T2MI, and major adverse cardiovascular events (MACE, a composite of all-cause death, nonfatal myocardial infarction [MI], heart failure, stroke, transient ischemic attack, peripheral arterial complication, and cardiac arrhythmia), as well. T2MI was adjudicated using criteria from the Third Universal Definition of MI. Baseline characteristics, blood samples, and angiography information were obtained. Major end points subsequent to first MI were assessed using landmark analyses to compare the rates of first events only where everyone with a prior history of any MACE before MI were censored and adjusted for follow-up times. Cox proportional hazard models were used for time-to-event analyses with age and sex forced into all models and additional covariates evaluated by using the stepwise option for the selection. Results: One thousand two hundred fifty-one patients were enrolled and followed for a median of 3.4 years. Of these patients, 152 (12.2%) had T2MI during follow-up; T2MI was frequently recurrent. Multivariable predictors of T2MI were older age, lower systolic blood pressure, history of coronary artery disease, heart failure, chronic obstructive pulmonary disease, diabetes mellitus, nitrate use, and elevated concentrations of glucose, N-terminal pro-B type natriuretic peptide, and cystatin C. Patients with T2MI had higher rates of subsequent adverse events than those without T2MI (per 100 person-years: MACE, 53.7 versus 21.1, P P P P P P P =0.001). Conclusions: T2MI is common and associated with poor prognosis. Studies evaluating treatment strategies for management of T2MI are needed. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT00842868.

Hyperthyroidism has a well-described association with atrial fibrillation (AF). However, the relation of hypothyroidism to AF has had limited investigation. Hypothyroidism is associated with cardiovascular risk factors, subclinical cardiovascular disease, and overt cardiovascular disease, all of which predispose to AF. We investigated 10-year incidence of AF in a community-dwelling cohort.Among 6,653 Framingham heart Study participants, 5,069 participants, 52% female, with mean age of 57 ± 12 years, were eligible after excluding those with missing thyroid-stimulating hormone (TSH), TSH0.45 μU/L (hyperthyroid), TSH19.9 μU/L, or prevalent AF. Thyroid-stimulating hormone was categorized by range (≥0.45 to4.5, 4.5 to10.0, 10.0 to ≤19.9 μU/L) and by quartiles. We examined the associations between TSH and 10-year risk of AF using multivariable-adjusted Cox proportional hazards analysis.Over 10-year follow-up, we observed 277 cases of incident AF. A 1-SD increase in TSH was not associated with increased risk of AF (hazard ratio 1.01, 95% CI 0.90-1.14, P = .83). In categorical analysis, using TSH ≥0.45 to4.5 μU/L as the referent (equivalent to euthyroid state), we found no significant association between hypothyroidism and 10-year AF risk. Comparing the highest (2.6TSH19.9 μU/L) to lowest (0.45TSH1.3 μU/L) quartiles of TSH further did not identify a significant association between TSH levels and 10-year risk of AF.In conclusion, we did not identify a significant association between hypothyroidism and 10-year risk of incident AF in a community-based study.

Although the idea of people with psychiatric disabilities determining their own treatment and rehabilitation goals is increasingly accepted, its relationship to service outcomes has rarely been evaluated programmatically. A statewide, Medicaid-funded psychiatric rehabilitation program incorporated a systematic goal setting procedure conducted by practitioners trained in helping people set their own individual rehabilitation goals. Individuals who successfully set either residential or employment goals were followed for up to 18 months to assess progress on these goals. Participants were grouped by type of goal (residential or employment) and by level of participation in the intervention (enrolled, completed 18 months, or graduated). Residential functioning for those who set residential goals increased significantly, independent of level of participation. For people who had set employment goals, only graduates of the intervention showed significant employment gains. Furthermore, employment functioning changed significantly when a goal was set in the residential area; in contrast, residential functioning did not change significantly when goals were set in the employment area. This study suggests that the programmatic effect of goal setting procedures can be evaluated, even when the person’s goals are tailored to an individual’s unique preference. Implications for rehabilitation counseling will be discussed.

Background— About one half of patients with heart failure (HF) have preserved ejection fraction (HFPEF) rather than reduced ejection fraction (HFREF). The differences in risk factors predisposing to the 2 subtypes of HF are poorly understood. We sought to identify clinical predictors of new-onset HF and to explore differences in HFPEF versus HFREF. Methods and Results— We studied new-onset HF cases between 1981 and 2008 in Framingham Heart Study participants, classified into HFPEF and HFREF (ejection fraction >45% versus ≤45%). We used Cox multivariable regression to examine predictors of 8-year risk of incident HF and competing-risks analysis to identify predictors that differed between HFPEF and HFREF. Among 6340 participants (60±12 years) with 97 808 person-years of follow-up, 512 developed incident HF. Of 457 participants with left ventricular ejection fraction evaluation at the time of HF diagnosis, 196 (43%) were classified as HFPEF and 261 (56%) as HFREF. Fourteen predictors of overall HF were identified. Older age, diabetes mellitus, and a history of valvular disease predicted both types of HF ( P ≤0.0025 for all). Higher body mass index, smoking, and atrial fibrillation predicted HFPEF only, whereas male sex, higher total cholesterol, higher heart rate, hypertension, cardiovascular disease, left ventricular hypertrophy, and left bundle-branch block predicted risk of HFREF. Conclusions— Although multiple risk factors preceded overall HF, distinct clusters of risk factors determine risk for new-onset HFPEF versus HFREF. This knowledge may enable the design of clinical trials of targeted prevention and the introduction of therapeutic strategies for prevention of HF and its 2 major subtypes.

Evidence for cardioprotective effects of lycopene is inconsistent. Studies of circulating lycopene generally report inverse associations with CVD risk, but studies based on lycopene intake do not. The failure of dietary studies to support the findings based on biomarkers may be due in part to misclassification of lycopene intakes. To address this potential misclassification, we used repeated measures of intake obtained over 10 years to characterise the relationship between lycopene intake and the incidence of CVD (n314), CHD (n171) and stroke (n99) in the Framingham Offspring Study. Hazard ratios (HR) for incident outcomes were derived from Cox proportional hazards regression models using logarithmically transformed lycopene intake adjusted for CVD risk factors and correlates of lycopene intake. HR were interpreted as the increased risk for a 2·7-fold difference in lycopene intake, a difference approximately equal to its interquartile range. Using an average of three intake measures with a 9-year follow-up, lycopene intake was inversely associated with CVD incidence (HR 0·83, 95 % CI 0·70, 0·98). Using an average of two intake measures and 11 years of follow-up, lycopene intake was inversely associated with CHD incidence (HR 0·74, 95 % CI 0·58, 0·94). Lycopene intake was unrelated to stroke incidence. The present study of lycopene intake and CVD provides supporting evidence for an inverse association between lycopene and CVD risk; however, additional research is needed to determine whether lycopene or other components of tomatoes, the major dietary source of lycopene, are responsible for the observed association.

Objective— Neurotensin is a peptide whose receptor (sortilin receptor 1) is linked to cardiovascular disease (CVD) development. We hypothesized concentrations of proneurotensin (stable profragment of neurotensin) would predict incident cardiovascular events in community-based subjects. Approach and Results— Blood samples from 3439 participants in the Framingham Heart Study (FHS) Offspring cohort (mean age 59.2 years, 47.1% male) were tested for proneurotensin. Primary outcome of interest was incident hard CVD (myocardial infarction, stroke, and cardiovascular death); interaction between proneurotensin concentration with sex, low-density lipoprotein concentrations, and sortilin receptor 1 single-nucleotide polymorphisms was sought. At baseline, those in the highest log-proneurotensin quartile were younger and heavier ( P P P P P =0.03). Elevated log-proneurotensin concentrations were associated with shorter time to first event ( P =0.02). We found no effect modification by sex, low-density lipoprotein concentration, or sortilin receptor 1 single-nucleotide polymorphisms. Concentrations of proneurotensin were modestly associated with left ventricular mass and coronary artery calcium in these subjects. Conclusions— Higher concentrations of proneurotensin are associated with a greater risk of incident cardiovascular events in the community. This association did not vary according to sex, baseline low-density lipoprotein, or sortilin receptor 1 genotype.

Background Beyond their resting values, exercise responses in blood pressure ( BP ) and heart rate ( HR ) may add prognostic information for cardiovascular disease ( CVD ). In cross‐sectional studies, exercise BP and HR responses correlate with CVD risk factors; however, it is unclear which factors influence longitudinal changes in exercise responses over time, which is important for our understanding of the development of CVD . Methods and Results We assessed BP and HR responses to low‐level exercise tests (6‐minute Bruce protocol) in 1231 Framingham Offspring participants (55% women) who underwent a routine treadmill test in 1979–1983 (baseline; mean age 39±8 years) that was repeated in 1998–2001 (follow‐up; mean age 58±8 years). Adjusting for baseline exercise responses, we related the follow‐up exercise responses to baseline CVD risk factors and to their changes between examinations. Compared with men, women had greater rise in exercise systolic (S) BP and HR at 20‐year follow‐up (both P SBP and HR , and smoking status were associated with greater exercise SBP at follow‐up (all P SBP and HR at follow‐up (both P SBP (≥180 mm Hg) at follow‐up ( P Conclusion An adverse CVD risk factor profile in young adults and its worsening over time were associated with higher SBP and HR responses to low‐level exercise in midlife. Maintaining or adopting a healthy risk factor profile may favorably impact the exercise responses over time.