Cardiovascular Risk Estimation Is Suboptimal in People With HIV.

BACKGROUND: Established cardiovascular disease (CVD) risk prediction functions may not accurately predict CVD risk in people with HIV. We assessed the performance of 3 CVD risk prediction functions in 2 HIV cohorts. METHODS AND RESULTS: CVD risk scores were calculated in the Mass General Brigham and Kaiser Permanente Northern California HIV cohorts, using the American College of Cardiology/American Heart Association atherosclerotic CVD function, the FHS (Framingham Heart Study) hard coronary heart disease function and the Framingham Heart Study hard CVD function. Outcomes were myocardial infarction or coronary death for FHS hard coronary heart disease function; and myocardial infarction, stroke, or coronary death for American College of Cardiology/American Heart Association and FHS hard CVD function. We calculated regression coefficients and assessed discrimination and calibration by sex; predicted to observed risk of outcome was also compared. In the combined cohort of 9412, 158 (1.7%) had a coronary heart disease event, and 309 (3.3%) had a CVD event. Among women, CVD risk was generally underestimated by all 3 risk functions. Among men, CVD risk was underestimated by the American College of Cardiology/American Heart Association and FHS hard CVD function, but overestimated by the FHS hard coronary heart disease function. Calibration was poor for women using the FHS hard CVD function and for men using all functions. Discrimination in all functions was good for women (c-statistics ranging from 0.78 to 0.90) and moderate for men (c-statistics ranging from 0.71 to 0.72). CONCLUSIONS: Established CVD risk prediction functions generally underestimate risk in people with HIV. Differences in model performance by sex underscore the need for both HIV-specific and sex-specific functions. Development of CVD risk prediction models tailored to HIV will enhance care for aging people with HIV.

Pericoronary Adipose Tissue Density, Inflammation, and Subclinical Coronary Artery Disease Among People With HIV in the REPRIEVE Cohort.

BACKGROUND: Pericoronary adipose tissue (PCAT) may influence plaque development through inflammatory mechanisms. We assessed PCAT density, as a measure of pericoronary inflammation, in relationship to coronary plaque among people with human immunodeficiency virus (HIV [PWH]) and to a matched control population. METHODS: In this baseline analysis of 727 participants of the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) Mechanistic Substudy, we related computed tomography-derived PCAT density to presence and extent (Leaman score) of coronary artery disease (CAD), noncalcified plaque, coronary artery calcium (CAC), and vulnerable plaque features using multivariable logistic regression analyses. We further compared the PCAT density between PWH and age, sex, body mass index, CAC score, and statin use-matched controls from the community-based Framingham Heart Study (N = 464), adjusting for relevant clinical covariates. RESULTS: Among 727 REPRIEVE participants (age 50.8 ± 5.8 years; 83.6% [608/727] male), PCAT density was higher in those with (vs without) coronary plaque, noncalcified plaque, CAC >0, vulnerable plaque, and high CAD burden (Leaman score >5) (P < .001 for each comparison). PCAT density related to prevalent coronary plaque (adjusted odds ratio [per 10 HU]: 1.44; 95% confidence interval, 1.22-1.70; P < .001), adjusted for clinical cardiovascular risk factors, body mass index, and systemic immune/inflammatory biomarkers. Similarly, PCAT density related to CAC >0, noncalcified plaque, vulnerable plaque, and Leaman score >5 (all P ≤ .002). PCAT density was greater among REPRIEVE participants versus Framingham Heart Study (-88.2 ± 0.5 HU versus -90.6 ± 0.4 HU; P < .001). CONCLUSIONS: Among PWH in REPRIEVE, a large primary cardiovascular disease prevention cohort, increased PCAT density independently associated with prevalence and severity of coronary plaque, linking increased coronary inflammation to CAD in PWH.

Plasma Progerin in Patients With Hutchinson-Gilford Progeria Syndrome: Immunoassay Development and Clinical Evaluation.

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 (R2=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<0.0001). Progerin levels did not differ by sex (P=0.99). Lonafarnib treatment resulted in an average per-visit progerin decrease from baseline of between 35% to 62% (all P<0.005); effects were not augmented by adding pravastatin and zoledronate. Progerin levels fell within 4 months of therapy and remained lower for up to 10 years. The magnitude of progerin decrease positively associated with patient survival (P<0.0001; ie, 15 000 pg/mL decrease yields a 63.9% decreased risk of death). For any given decrease in progerin, life expectancy incrementally increased with longer treatment duration. 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.

Evaluating the Cardiovascular Risk in an Aging Population of People With HIV: The Impact of Hepatitis C Virus Coinfection.

Background People with HIV (PWH) are at an increased risk of cardiovascular disease (CVD) with an unknown added impact of hepatitis C virus (HCV) coinfection. We aimed to identify whether HCV coinfection increases the risk of type 1 myocardial infarction (T1MI) and if the risk differs by age. Methods and Results We used data from NA-ACCORD (North American AIDS Cohort Collaboration on Research and Design) from January 1, 2000, to December 31, 2017, PWH (aged 40-79 years) who had initiated antiretroviral therapy. The primary outcome was an adjudicated T1MI event. Those who started direct-acting HCV antivirals were censored at the time of initiation. Crude incidence rates per 1000 person-years were calculated for T1MI by calendar time. Discrete time-to-event analyses with complementary log-log models were used to estimate adjusted hazard ratios and 95% CIs for T1MI among those with and without HCV. Among 23 361 PWH, 4677 (20%) had HCV. There were 89 (1.9%) T1MIs among PWH with HCV and 314 (1.7%) among PWH without HCV. HCV was not associated with increased T1MI risk in PWH (adjusted hazard ratio, 0.98 [95% CI, 0.74-1.30]). However, the risk of T1MI increased with age and was amplified in those with HCV (adjusted hazard ratio per 10-year increase in age, 1.85 [95% CI, 1.38-2.48]) compared with those without HCV (adjusted hazard ratio per 10-year increase in age,1.30 [95% CI, 1.13-1.50]; P<0.001, test of interaction). Conclusions HCV coinfection was not significantly associated with increased T1MI risk; however, the risk of T1MI with increasing age was greater in those with HCV compared with those without, and HCV status should be considered when assessing CVD risk in aging PWH.

Standardized measurement of abdominal muscle by computed tomography: association with cardiometabolic risk in the Framingham Heart Study.

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.

Lifetime Risk of Heart Failure and Trends in Incidence Rates Among Individuals With Type 2 Diabetes Between 1995 and 2018.

Background There are limited data on the lifetime risk of heart failure (HF) in people with type 2 diabetes and how incidence has changed over time. We estimated the cumulative incidence and incidence rates of HF among Danish adults with type 2 diabetes between 1995 and 2018 using nationwide data. Methods and Results In total, 398 422 patients (49% women) with type 2 diabetes were identified. During follow-up, 36 400 (9%) were diagnosed with HF and 121 459 (30%) were censored due to death. Using the Aalen-Johansen estimators, accounting for the risk of death, the estimated residual lifetime risk of HF at age 50 years was calculated as 24% (95% CI 22%-27%) in women and 27% (25%-28%) in men. During the observational period, the proportion of patients treated with statins, angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, and metformin increased from <30% to >60%. Similarly, the annual incidence rates of HF decreased significantly, with declines being greater in older versus younger individuals (5% versus 2% in age >50 versus ≤50 years, respectively; P<0.0001) and in women versus men (5% versus 4%, P=0.02), but similar in patients with and without IHD (4% versus 4%, P=0.53). Conclusions The current lifetime risk of HF in type 2 diabetes approximates 1 in 4 for men and women. Paralleled by an increase in use of evidence-based pharmacotherapy over the past decades, the risk of developing HF has declined across several subgroups and regardless of underlying IHD, suggesting that optimal diabetes treatment can mitigate HF risk.

Assessing Cardiovascular Risk in People Living with HIV: Current Tools and Limitations.

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. 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.

Sex Differences in the Associations of Visceral Adipose Tissue and Cardiometabolic and Cardiovascular Disease Risk: The Framingham Heart Study.

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.

Deep convolutional neural networks to predict cardiovascular risk from computed tomography.

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.

Baseline 10-Year Cardiovascular Risk Scores Predict Cognitive Function in Older Persons, and Particularly Women, Living With Human Immunodeficiency Virus Infection.

BACKGROUND: Cardiovascular 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. METHODS: We 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. RESULTS: Among 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. CONCLUSIONS: Baseline 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.

Risk factor-based subphenotyping of heart failure in the community.

BACKGROUND: Heart failure (HF) is a heterogeneous clinical syndrome with varying prognosis. Subphenotyping of HF is a research priority to advance our understanding of the syndrome. We formulated a subphenotyping schema and compared long-term mortality risk among the HF subphenotypes in the community-based Framingham Study. METHODS AND RESULTS: In hierarchical order, we grouped participants with new-onset HF (stratified by HF with reduced [HFrEF] vs. preserved ejection fraction [HFpEF]) according to the presence of: (1) coronary heart disease (CHD), (2) metabolic syndrome (MetS), (3) hypertension, and (4) 'other' causes. Age at HF onset was lowest in people with the MetS (mean 76 vs. 77 years for HFrEF and HFpEF, respectively) and highest in those with hypertension only (mean 82 and 85 years for HFrEF and HFpEF, respectively). For HFrEF, 10-year cumulative mortality and hazards ratios [HR] were 87% for CHD (n = 219; referent group), 88% for MetS (n = 105; HR 0.95 [95% CI 0.73-1.23]), 82% for hypertension (n = 104; HR 0.71 [0.55-0.91]), and 78% for other (n = 37; HR 0.81 [0.55-1.19]). Corresponding 10-year cumulative mortality and HR data for HFpEF were: 85% for CHD (n = 84; referent), 83% for MetS (n = 118; HR 0.98 [0.72-1.33]), 81% for hypertension (n = 127; HR 0.71 [0.52-0.95]), and 76% for other (n = 43; HR 0.76 [0.50-1.14]). In a sample without overt heart failure (n = 5536), several echocardiographic and vascular indices showed graded worsening of age- and sex adjusted-values among those having CHD, MetS, hypertension, or obesity, compared with individuals not having these risk factors. CONCLUSIONS: HF subphenotypes characterized by the presence of CHD or metabolic syndrome present at a younger age and are marked by greater mortality risk. The clinical utility of the proposed subphenotyping schema warrants further research.

Sex Differences in Circulating Biomarkers of Cardiovascular Disease.

BACKGROUND: 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). OBJECTIVES: 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. METHODS: 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. RESULTS: 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 (pinteraction <0.05 for all). CONCLUSIONS: In 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.

Association of an HDL Apolipoproteomic Score With Coronary Atherosclerosis and Cardiovascular Death.

BACKGROUND: 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. OBJECTIVES: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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).

Objective physical activity and physical performance in middle-aged and older adults.

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 ±â€¯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.

Blood kidney injury molecule-1 predicts short and longer term kidney outcomes in patients undergoing diagnostic coronary and/or peripheral angiography-Results from the Catheter Sampled Blood Archive in Cardiovascular Diseases (CASABLANCA) study.

BACKGROUND: Kidney injury is common in patients with cardiovascular disease. OBJECTIVES: We determined whether blood measurement of kidney injury molecule-1 (KIM-1), would predict kidney outcomes in patients undergoing angiographic procedures for various indications. METHODS: 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 m2 by study conclusion. Univariate and multivariable Cox proportional hazards models were used to identify predictors of non-procedural AKI, while univariate and multivariable logistic regression analysis was used to evaluate peri-procedural AKI and predictors of progression to CKD. RESULTS: During 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 eGFR <60 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). CONCLUSIONS: 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.

Association of Maternal Prepregnancy Weight with Offspring Adiposity Throughout Adulthood over 37 Years of Follow-up.

OBJECTIVE: This study aimed to determine the relation of maternal prepregnancy weight with offspring BMI across adulthood from almost 40 years of follow-up. METHODS: BMI was measured in Framingham Heart Study Offspring cohort participants between 1971 and 2008. The association of maternal prepregnancy weight category (ascertained via direct measure and questionnaire) with serial offspring BMI, overweight, obesity, and change in BMI over time was tested, 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/m2 . Exposed offspring BMI was higher at every examination cycle, ranging from 1.5 (0.5) to 3.0 (0.5) kg/m2 (P < 0.001), with larger differences at later assessments. The rate of increase in offspring BMI over time was higher in exposed offspring before the age of 50 years (ß [SE] = 0.07 [0.02] kg/m2 per year; P = 0.004) but not after the age of 50 years (-0.05 [0.04] kg/m2 per year; P = 0.2). CONCLUSIONS: Maternal prepregnancy weight is associated with greater offspring BMI throughout adulthood, with more rapid weight acceleration in early and midadulthood.

Endothelin-1 Measurement in Patients Undergoing Diagnostic Coronary Angiography-Results from the Catheter Sampled Blood Archive in Cardiovascular Diseases (CASABLANCA) Study.

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.

Author Correction: Genome-wide mapping of plasma protein QTLs identifies putatively causal genes and pathways for cardiovascular disease.

In the originally published version of this Article, financial support was not fully acknowledged. The sentence "KS was supported by the 'Biomedical Research Program' funds at Weill Cornell Medicine in Qatar, a program funded by the Qatar Foundation" has been added to the acknowledgement section in both the PDF and HTML versions of the Article.

Genome-wide mapping of plasma protein QTLs identifies putatively causal genes and pathways for cardiovascular disease.

Identifying genetic variants associated with circulating protein concentrations (protein quantitative trait loci; pQTLs) and integrating them with variants from genome-wide association studies (GWAS) may illuminate the proteome's causal role in disease and bridge a knowledge gap regarding SNP-disease associations. We provide the results of GWAS of 71 high-value cardiovascular disease proteins in 6861 Framingham Heart Study participants and independent external replication. We report the mapping of over 16,000 pQTL variants and their functional relevance. We provide an integrated plasma protein-QTL database. Thirteen proteins harbor pQTL variants that match coronary disease-risk variants from GWAS or test causal for coronary disease by Mendelian randomization. Eight of these proteins predict new-onset cardiovascular disease events in Framingham participants. We demonstrate that identifying pQTLs, integrating them with GWAS results, employing Mendelian randomization, and prospectively testing protein-trait associations holds potential for elucidating causal genes, proteins, and pathways for cardiovascular disease and may identify targets for its prevention and treatment.