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Background: American College of Cardiology/American Heart Association guidelines recommend distinct risk classification systems for primary and secondary cardiovascular disease prevention. However, both systems rely on similar predictors (eg, age and diabetes), indicating the possibility of a universal risk prediction approach for major adverse cardiovascular events (MACEs)., Objectives: The authors examined the performance of predictors in persons with and without atherosclerotic cardiovascular disease (ASCVD) and developed and validated a universal risk prediction model., Methods: Among 9,138 ARIC (Atherosclerosis Risk In Communities) participants with (n = 609) and without (n = 8,529) ASCVD at baseline (1996-1998), we examined established predictors in the risk classification systems and other predictors, such as body mass index and cardiac biomarkers (troponin and natriuretic peptide), using Cox models with MACEs (myocardial infarction, stroke, and heart failure). We also evaluated model performance., Results: Over a follow-up of approximately 20 years, there were 3,209 MACEs (2,797 for no prior ASCVD). Most predictors showed similar associations with MACE regardless of baseline ASCVD status. A universal risk prediction model with the predictors (eg, established predictors, cardiac biomarkers) identified by least absolute shrinkage and selection operator regression and bootstrapping showed good discrimination for both groups (c-statistics of 0.747 and 0.691, respectively), and risk classification and showed excellent calibration, irrespective of ASCVD status. This universal prediction approach identified individuals without ASCVD who had a higher risk than some individuals with ASCVD and was validated externally in 5,322 participants in the MESA (Multi-Ethnic Study of Atherosclerosis)., Conclusions: A universal risk prediction approach performed well in persons with and without ASCVD. This approach could facilitate the transition from primary to secondary prevention by streamlining risk classification and discussion between clinicians and patients., Competing Interests: Funding Support and Author Disclosures The ARIC study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, under Contract nos. (75N92022D00001, 75N92022D00002, 75N92022D00003, 75N92022D00004, 75N92022D00005). The MESA was supported by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169 from the National Heart, Lung, and Blood Institute, and by grants UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420 from the National Center for Advancing Translational Sciences (NCATS). A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Multivariable equations are recommended by primary prevention guidelines to assess absolute risk of cardiovascular disease (CVD). However, current equations have several limitations. Therefore, we developed and validated the American Heart Association Predicting Risk of CVD EVENTs (PREVENT) equations among US adults 30 to 79 years of age without known CVD., Methods: The derivation sample included individual-level participant data from 25 data sets (N=3 281 919) between 1992 and 2017. The primary outcome was CVD (atherosclerotic CVD and heart failure). Predictors included traditional risk factors (smoking status, systolic blood pressure, cholesterol, antihypertensive or statin use, and diabetes) and estimated glomerular filtration rate. Models were sex-specific, race-free, developed on the age scale, and adjusted for competing risk of non-CVD death. Analyses were conducted in each data set and meta-analyzed. Discrimination was assessed using the Harrell C-statistic. Calibration was calculated as the slope of the observed versus predicted risk by decile. Additional equations to predict each CVD subtype (atherosclerotic CVD and heart failure) and include optional predictors (urine albumin-to-creatinine ratio and hemoglobin A1c), and social deprivation index were also developed. External validation was performed in 3 330 085 participants from 21 additional data sets., Results: Among 6 612 004 adults included, mean±SD age was 53±12 years, and 56% were women. Over a mean±SD follow-up of 4.8±3.1 years, there were 211 515 incident total CVD events. The median C-statistics in external validation for CVD were 0.794 (interquartile interval, 0.763-0.809) in female and 0.757 (0.727-0.778) in male participants. The calibration slopes were 1.03 (interquartile interval, 0.81-1.16) and 0.94 (0.81-1.13) among female and male participants, respectively. Similar estimates for discrimination and calibration were observed for atherosclerotic CVD- and heart failure-specific models. The improvement in discrimination was small but statistically significant when urine albumin-to-creatinine ratio, hemoglobin A1c, and social deprivation index were added together to the base model to total CVD (ΔC-statistic [interquartile interval] 0.004 [0.004-0.005] and 0.005 [0.004-0.007] among female and male participants, respectively). Calibration improved significantly when the urine albumin-to-creatinine ratio was added to the base model among those with marked albuminuria (>300 mg/g; 1.05 [0.84-1.20] versus 1.39 [1.14-1.65]; P =0.01)., Conclusions: PREVENT equations accurately and precisely predicted risk for incident CVD and CVD subtypes in a large, diverse, and contemporary sample of US adults by using routinely available clinical variables., Competing Interests: Disclosures Dr Coresh reports grants from the National Institutes of Health (NIH) and from the National Kidney Foundation during the conduct of the study and personal fees and other support from Healthy.io outside the submitted work. Dr Khan reports grants from NIH during the conduct of the study (R21 HL165376). Dr Chang reports consulting fees from Novartis, Reata, and Amgen, and grants from Novartis, Novo Nordisk, NIH, and the National Kidney Foundation. Dr Palaniappan reports grants from NIH during the conduct of the study (K24 HL150476). Dr Tuttle reports unpaid support from the American Heart Association and grant support from NIH (01MD014712, OT2OD032581, U2CDK114886, UL1TR002319, U54DK083912, U01DK100846, OT2HL161847, and UM1AI109568); the Centers for Disease Control and Prevention (75D301-21-P-12254), as well as Bayer and Travere, paid to the institution; consulting fees from Eli Lilly, Boehringer Ingelheim, AstraZeneca, Goldfinch Bio, Novo Nordisk, Bayer, and Travere Therapeutics Inc; honoraria from Eli Lilly, AstraZeneca, Novo Nordisk, and Bayer; unpaid participation as a Data Safety and Monitoring Board chair for National Institute of Diabetes and Digestive and Kidney diseases (NIDDK)/NIH and George Clinical Institute; and unpaid participation as a Diabetic Kidney Disease collaborative chair for the American Society of Nephrology. Dr Neeland reports speaker and consulting fees from Boehringer Ingelheim, Eli Lilly and Co, Nestle Health Science, and Bayer Pharmaceuticals. Dr Virani reports grants from NIH, US Department of Veterans Affairs, Tahir and Jooma Family. The views expressed in this article are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the US Department of Health and Human Services. All other coauthors have nothing to disclose.

Objective: Few studies have comprehensively examined how health and disease risk influence Alzheimer's disease (AD) biomarkers. The present study examined the association of 14 protein-based health indicators with plasma and neuroimaging biomarkers of AD and neurodegeneration., Methods: In 706 cognitively normal adults, we examined whether 14 protein-based health indices (ie, SomaSignal® tests) were associated with concurrently measured plasma-based biomarkers of AD pathology (amyloid-β [Aβ] 42/40 , tau phosphorylated at threonine-181 [pTau-181]), neuronal injury (neurofilament light chain [NfL]), and reactive astrogliosis (glial fibrillary acidic protein [GFAP]), brain volume, and cortical Aβ and tau. In a separate cohort (n = 11,285), we examined whether protein-based health indicators associated with neurodegeneration also predict 25-year dementia risk., Results: Greater protein-based risk for cardiovascular disease, heart failure mortality, and kidney disease was associated with lower Aβ 42/40 and higher pTau-181, NfL, and GFAP levels, even in individuals without cardiovascular or kidney disease. Proteomic indicators of body fat percentage, lean body mass, and visceral fat were associated with pTau-181, NfL, and GFAP, whereas resting energy rate was negatively associated with NfL and GFAP. Together, these health indicators predicted 12, 31, 50, and 33% of plasma Aβ 42/40 , pTau-181, NfL, and GFAP levels, respectively. Only protein-based measures of cardiovascular risk were associated with reduced regional brain volumes; these measures predicted 25-year dementia risk, even among those without clinically defined cardiovascular disease., Interpretation: Subclinical peripheral health may influence AD and neurodegenerative disease processes and relevant biomarker levels, particularly NfL. Cardiovascular health, even in the absence of clinically defined disease, plays a central role in brain aging and dementia. ANN NEUROL 2024;95:260-273., (© 2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Cardiovascular-kidney-metabolic (CKM) syndrome is a novel construct recently defined by the American Heart Association in response to the high prevalence of metabolic and kidney disease. Epidemiological data demonstrate higher absolute risk of both atherosclerotic cardiovascular disease (CVD) and heart failure as an individual progresses from CKM stage 0 to stage 3, but optimal strategies for risk assessment need to be refined. Absolute risk assessment with the goal to match type and intensity of interventions with predicted risk and expected treatment benefit remains the cornerstone of primary prevention. Given the growing number of therapies in our armamentarium that simultaneously address all 3 CKM axes, novel risk prediction equations are needed that incorporate predictors and outcomes relevant to the CKM context. This should also include social determinants of health, which are key upstream drivers of CVD, to more equitably estimate and address risk. This scientific statement summarizes the background, rationale, and clinical implications for the newly developed sex-specific, race-free risk equations: PREVENT (AHA Predicting Risk of CVD Events). The PREVENT equations enable 10- and 30-year risk estimates for total CVD (composite of atherosclerotic CVD and heart failure), include estimated glomerular filtration rate as a predictor, and adjust for competing risk of non-CVD death among adults 30 to 79 years of age. Additional models accommodate enhanced predictive utility with the addition of CKM factors when clinically indicated for measurement (urine albumin-to-creatinine ratio and hemoglobin A1c) or social determinants of health (social deprivation index) when available. Approaches to implement risk-based prevention using PREVENT across various settings are discussed.

A growing appreciation of the pathophysiological interrelatedness of metabolic risk factors such as obesity and diabetes, chronic kidney disease, and cardiovascular disease has led to the conceptualization of cardiovascular-kidney-metabolic syndrome. The confluence of metabolic risk factors and chronic kidney disease within cardiovascular-kidney-metabolic syndrome is strongly linked to risk for adverse cardiovascular and kidney outcomes. In addition, there are unique management considerations for individuals with established cardiovascular disease and coexisting metabolic risk factors, chronic kidney disease, or both. An extensive body of literature supports our scientific understanding of, and approach to, prevention and management for individuals with cardiovascular-kidney-metabolic syndrome. However, there are critical gaps in knowledge related to cardiovascular-kidney-metabolic syndrome in terms of mechanisms of disease development, heterogeneity within clinical phenotypes, interplay between social determinants of health and biological risk factors, and accurate assessments of disease incidence in the context of competing risks. There are also key limitations in the data supporting the clinical care for cardiovascular-kidney-metabolic syndrome, particularly in terms of early-life prevention, screening for risk factors, interdisciplinary care models, optimal strategies for supporting lifestyle modification and weight loss, targeting of emerging cardioprotective and kidney-protective therapies, management of patients with both cardiovascular disease and chronic kidney disease, and the impact of systematically assessing and addressing social determinants of health. This scientific statement uses a crosswalk of major guidelines, in addition to a review of the scientific literature, to summarize the evidence and fundamental gaps related to the science, screening, prevention, and management of cardiovascular-kidney-metabolic syndrome.

Cardiovascular-kidney-metabolic health reflects the interplay among metabolic risk factors, chronic kidney disease, and the cardiovascular system and has profound impacts on morbidity and mortality. There are multisystem consequences of poor cardiovascular-kidney-metabolic health, with the most significant clinical impact being the high associated incidence of cardiovascular disease events and cardiovascular mortality. There is a high prevalence of poor cardiovascular-kidney-metabolic health in the population, with a disproportionate burden seen among those with adverse social determinants of health. However, there is also a growing number of therapeutic options that favorably affect metabolic risk factors, kidney function, or both that also have cardioprotective effects. To improve cardiovascular-kidney-metabolic health and related outcomes in the population, there is a critical need for (1) more clarity on the definition of cardiovascular-kidney-metabolic syndrome; (2) an approach to cardiovascular-kidney-metabolic staging that promotes prevention across the life course; (3) prediction algorithms that include the exposures and outcomes most relevant to cardiovascular-kidney-metabolic health; and (4) strategies for the prevention and management of cardiovascular disease in relation to cardiovascular-kidney-metabolic health that reflect harmonization across major subspecialty guidelines and emerging scientific evidence. It is also critical to incorporate considerations of social determinants of health into care models for cardiovascular-kidney-metabolic syndrome and to reduce care fragmentation by facilitating approaches for patient-centered interdisciplinary care. This presidential advisory provides guidance on the definition, staging, prediction paradigms, and holistic approaches to care for patients with cardiovascular-kidney-metabolic syndrome and details a multicomponent vision for effectively and equitably enhancing cardiovascular-kidney-metabolic health in the population.

Aims: Interleukin-6 (IL-6) and interleukin-18 (IL-18), important cytokines implicated in atherosclerosis and inflammaging, were assessed for associations with global cardiovascular disease (CVD), atrial fibrillation (AF), and death in older adults., Methods and Results: Participants from Atherosclerosis Risk in Communities study Visit 5 (mean age 75.4 ± 5.1 years) with IL-6 and IL-18 measurements were included (n = 5672). Cox regression models were used to assess associations of IL-6 and IL-18 with coronary heart disease (CHD), ischaemic stroke, heart failure (HF) hospitalization, global CVD (composite of CHD, stroke, and HF), AF, and all-cause death. Over a median follow-up of 7.2 years, there were 1235 global CVD events, 530 AF events, and 1173 deaths. Higher IL-6 [hazard ratio (HR) 1.57, 95% confidence interval (CI) 1.44-1.72 per log unit increase] and IL-18 (HR 1.13, 95% CI 1.01-1.26) were significantly associated with global CVD after adjustment for cardiovascular risk factors. Association between IL-6 and global CVD remained significant after further adjustment for high-sensitivity C-reactive protein (hs-CRP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and high-sensitivity troponin T (hs-TnT) but was no longer significant for IL-18 after further adjustments. Interleukin-6 was also associated with increased risk for CHD, HF, and AF after adjustment for covariates. Both IL-6 and IL-18 were associated with increased risk for all-cause death independent of cardiovascular risk factors and other biomarkers., Conclusion: Among older adults, both IL-6 and IL-18 were associated with global CVD and death. The association between IL-6 with CVD appears to be more robust and was independent of hs-CRP, NT-proBNP, and hs-TnT., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Management of orthostatic hypotension (OH) prioritizes prevention of standing hypotension, sometimes at the expense of supine hypertension. It is unclear whether supine hypertension is associated with adverse outcomes relative to standing hypotension., Objectives: To compare the long-term clinical consequences of supine hypertension and standing hypotension among middle-aged adults with and without OH., Methods: The ARIC study (Atherosclerosis Risk in Communities) measured supine and standing blood pressure (BP) in adults aged 45 to 64 years, without neurogenic OH, between 1987 and 1989. We defined OH as a positional drop in systolic BP ≥20 mm Hg or diastolic BP ≥10 mm Hg, supine hypertension as supine BP≥140/≥90 mm Hg, and standing hypotension as standing BP≤105/≤65 mm Hg. Participants were followed for >30 years. We used Cox regression models to examine associations with cardiovascular disease events, all-cause mortality, falls, and syncope., Results: Of 12 489 participants (55% female, 26% Black, mean age 54 years, SD 6), 4.4% had OH. Among those without OH (N=11 943), 19% had supine hypertension and 21% had standing hypotension, while among those with OH (N=546), 58% had supine hypertension and 38% had standing hypotension. Associations with outcomes did not differ by OH status ( P -interactions >0.25). Supine hypertension was associated with heart failure (hazard ratio, 1.83 [95% CI, 1.68-1.99]), falls (hazard ratio, 1.12 [95% CI, 1.02-1.22]), and all-cause mortality (hazard ratio, 1.45 [95% CI, 1.37-1.54]), while standing hypotension was only significantly associated with mortality (hazard ratio, 1.06 [95% CI, 1.00-1.14])., Conclusions: Supine hypertension was associated with higher risk of adverse events than standing hypotension, regardless of OH status. This challenges conventional OH management, which prioritizes standing hypotension over supine hypertension., Competing Interests: Disclosures None.

Background: NT-proBNP is an important predictor of mortality but is inversely related to estimated glomerular filtration rate (eGFR). Whether the prognostic value of NT-proBNP is similar at different levels of kidney function is unknown., Aims: We evaluated the association of NT-proBNP with eGFR and its implications for all-cause and cardiovascular mortality risk in the general population., Methods: We included adults without prior cardiovascular disease from the National Health and Nutrition Examination Survey (NHANES) 1999 to 2004. We used linear regression to characterize the cross-sectional associations of NT-proBNP with eGFR. We used Cox regression to assess the prospective associations of NT-proBNP with mortality across categories of eGFR., Results: Among 11,456 participants (mean age 43 years, 48% female, 71% White, 11% Black), there was an inverse association between NT-proBNP and eGFR, which was stronger in those with more impaired kidney function. Per 15-unit decrease in eGFR, NT-proBNP was 4.3-fold higher for eGFR<30; 1.7-fold higher for eGFR 30 to 60, 1.4-fold higher for eGFR 61 to 90, 1.1-fold higher for eGFR 91 to 120 mL/min/1.73 m 2 . Over a median 17.6 years of follow-up, 2,275 deaths (622 cardiovascular) occurred. Higher NT-proBNP was associated with higher all-cause (HR per doubling of NT-proBNP: 1.20, 95% CI: 1.16-1.25) and cardiovascular mortality (HR: 1.34, 95% CI 1.25-1.44). Associations were similar across eGFR categories (P-interaction >.10). Adults with NT-proBNP≥450 pg/mL and eGFR<60 mL/min/1.73m 2 had 3.4-fold higher all-cause mortality and 5.5-fold higher cardiovascular mortality risk, compared to those with NT-proBNP<125 pg/mL and eGFR>90 mL/min/1.73m 2 ., Conclusion: Despite its strong inverse association with eGFR, NT-proBNP has robust associations with mortality across the full range of kidney function in the general US adult population., Competing Interests: Disclosures Dr. Christenson has received grant support from Roche Diagnostics, Fujirebio Diagnostics, Beckman Coulter, Siemens Healthcare Diagnostics, Ortho Clinical Diagnostics, Becton Dickinson, Abbott Diagnostics, Mitsubishi, and Horiba Medical; and has consulting agreements with PixCell, Beckman Coulter, Quidel, Siemens Healthineers, and Roche Diagnostics. All other authors reported that they had no financial interests relevant to this manuscript to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Coronary artery calcium (CAC) is a validated marker of atherosclerotic cardiovascular disease (ASCVD) risk; however, it is not routinely incorporated in ASCVD risk prediction in older adults with diabetes. We sought to assess the CAC distribution among this demographic and its association with "diabetes-specific risk enhancers," which are known to be associated with increased ASCVD risk. We used the ARIC (Atherosclerosis Risk in Communities) study data, including adults aged >75 years with diabetes, who had their CAC measured at ARIC visit 7 (2018 to 2019). The demographic characteristics of participants and their CAC distribution were analyzed using descriptive statistics. Multivariable-adjusted logistic regression models were used to estimate the association between diabetes-specific risk enhancers (duration of diabetes, albuminuria, chronic kidney disease, retinopathy, neuropathy, and ankle-brachial index) and elevated CAC, adjusting for age, gender, race, education level, dyslipidemia, hypertension, physical activity, smoking status, and family history of coronary heart disease. The mean age in our sample was 79.9 (SD 3.97) years, with 56.6% women and 62.1% White. The CAC scores were heterogenous, and the median CAC score was higher in participants with a greater number of diabetes risk enhancers, regardless of gender. In the multivariable-adjusted logistic regression models, participants with ≥2 diabetes-specific risk enhancers had greater odds of elevated CAC than those with <2 (odds ratio 2.31, 95% confidence interval 1.34 to 3.98). In conclusion, the distribution of CAC was heterogeneous among older adults with diabetes, with the CAC burden associated with the number of diabetes risk-enhancing factors present. These data may have implications for prognostication in older patients with diabetes and supports the possible incorporation of CAC in the assessment of cardiovascular disease risk in this population., Competing Interests: Declaration of Competing Interest Dr. Blaha has grants funded by National Institutes of Health, Food and Drug Administration, American Health Association, Bayer (Roche), Novo Nordisk, Amgen. He is on advisory boards for Amgen, Novartis, Novo Nordisk, Bayer, Roche, Inozyme, Kaleido, and 89Bio and consults for emocha Health and Kowa. The remaining authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Aims: Cardiac troponin T and I can be measured using a number of high-sensitivity (hs) assays. This study aimed to characterize correlations between four such assays and test their comparative associations with mortality., Methods and Results: Among adults without cardiovascular disease in the 1999-2004 National Health and Nutrition Examination Survey, hs-troponin T was measured using one assay (Roche) and hs-troponin I using three assays (Abbott, Siemens, and Ortho). Cox regression was used to estimate associations with all-cause and cardiovascular mortality. Pearson's correlation coefficients comparing concentrations from each assay ranged from 0.53 to 0.77. There were 2188 deaths (488 cardiovascular) among 9810 participants. Each hs-troponin assay [log-transformed, per 1 standard deviation (SD)] was independently associated with all-cause mortality: hazard ratio (HR) 1.20 [95% confidence interval (CI) 1.13-1.28] for Abbott hs-troponin I; HR 1.10 (95% CI 1.02-1.18) for Siemens hs-troponin I; HR 1.23 (95% CI 1.14-1.33) for Ortho hs-troponin I; and HR 1.31 (95% CI 1.21-1.42) for Roche hs-troponin T. Each hs-troponin assay was also independently associated with cardiovascular mortality (HR 1.44 to 1.65 per 1 SD). Associations of hs-troponin T and all-cause and cardiovascular mortality remained significant after adjusting for hs-troponin I. Furthermore, associations of hs-troponin I remained significant after mutually adjusting for hs-troponin I from the other individual assays: e.g. cardiovascular mortality HR 1.46 (95% CI 1.19-1.79) for Abbott after adjustment for the Siemens assay and HR 1.29 (95% CI 1.09-1.53) for Abbott after adjustment for the Ortho assay., Conclusion: This study demonstrates only modest correlations between hs-troponin T and three hs-troponin I assays and that hs-troponin I assays can provide distinct risk information for mortality in the general population., Competing Interests: Conflict of interest R.H.C. has received grant support from Roche Diagnostics, Fujirebio Diagnostics, Beckman Coulter, Siemens Healthcare Diagnostics, Ortho Clinical Diagnostics, Becton Dickinson, Abbott Diagnostics, Mitsubishi, and Horiba Medical and has consulting agreements with PixCell, Beckman Coulter, Quidel, Siemens Healthineers, and Roche Diagnostics. The other authors report no conflicts of interest relevant to this article., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Significance Statement: Large discordances between eGFR on the basis of creatinine (eGFR cr ) or cystatin C (eGFR cys ) are common in clinical practice. However, which GFR estimating equation (eGFR cr , eGFR cys , or eGFR cr-cys ) is most accurate in these settings is not known. In this real-world study of 9404 concurrent measurements of creatinine, cystatin C, and iohexol clearance, all three equations performed similarly when eGFR cr and eGFR cys were similar (45% of cases). However, with large discordances (55% of cases), eGFR cr-cys was much more accurate than either alone. These findings were consistent among individuals with cardiovascular disease, heart failure, diabetes mellitus, liver disease, and cancer who have been underrepresented in research cohorts. Thus, when eGFR cr and eGFR cys are largely discordant in clinical practice, eGFR cr-cys is more accurate than eGFR cr or eGFR cys ., Background: Cystatin C is recommended as a confirmatory test to eGFR when more precise estimates are needed for clinical decision making. Although eGFR on the basis of both creatinine and cystatin (eGFR cr-cys ) is the most accurate estimate in research studies, it is uncertain whether this is true in real-world settings, particularly when there are large discordances between eGFR based on creatinine (eGFR cr ) and that based on cystatin C (eGFR cys )., Methods: We included 6185 adults referred for measured GFR (mGFR) using plasma clearance of iohexol in Stockholm, Sweden, who had 9404 concurrent measurements of creatinine, cystatin C, and iohexol clearance. The performance of eGFR cr , eGFR cys , and eGFR cr-cys was assessed against mGFR with median bias, P30 , and correct classification of GFR categories. We stratified analyses within three categories: eGFR cys at least 20% lower than eGFR cr (eGFR cys eGFR cr )., Results: eGFR cr and eGFR cys were similar in 4226 (45%) samples, and among these samples all three estimating equations performed similarly. By contrast, eGFR cr-cys was much more accurate in cases of discordance. For example, when eGFR cys eGFR cr (8% of samples), the median biases were -4.5, 8.4, and 1.4 ml/min per 1.73m 2 . The findings were consistent among individuals with cardiovascular disease, heart failure, diabetes mellitus, liver disease, and cancer., Conclusions: When eGFR cr and eGFR cys are highly discordant in clinical practice, eGFR cr-cys is more accurate than either eGFR cr or eGFR cys ., (Copyright © 2023 by the American Society of Nephrology.)

Aims: Chronic kidney disease (CKD) is widely prevalent and independently increases cardiovascular risk. Cardiovascular risk prediction tools derived in the general population perform poorly in CKD. Through large-scale proteomics discovery, this study aimed to create more accurate cardiovascular risk models., Methods and Results: Elastic net regression was used to derive a proteomic risk model for incident cardiovascular risk in 2182 participants from the Chronic Renal Insufficiency Cohort. The model was then validated in 485 participants from the Atherosclerosis Risk in Communities cohort. All participants had CKD and no history of cardiovascular disease at study baseline when ∼5000 proteins were measured. The proteomic risk model, which consisted of 32 proteins, was superior to both the 2013 ACC/AHA Pooled Cohort Equation and a modified Pooled Cohort Equation that included estimated glomerular filtrate rate. The Chronic Renal Insufficiency Cohort internal validation set demonstrated annualized receiver operating characteristic area under the curve values from 1 to 10 years ranging between 0.84 and 0.89 for the protein and 0.70 and 0.73 for the clinical models. Similar findings were observed in the Atherosclerosis Risk in Communities validation cohort. For nearly half of the individual proteins independently associated with cardiovascular risk, Mendelian randomization suggested a causal link to cardiovascular events or risk factors. Pathway analyses revealed enrichment of proteins involved in immunologic function, vascular and neuronal development, and hepatic fibrosis., Conclusion: In two sizeable populations with CKD, a proteomic risk model for incident cardiovascular disease surpassed clinical risk models recommended in clinical practice, even after including estimated glomerular filtration rate. New biological insights may prioritize the development of therapeutic strategies for cardiovascular risk reduction in the CKD population., Competing Interests: Conflict of interest P.G. serves on a medical advisory board to SomaLogic, Inc. for which he accepts no salary, honoraria, or any other financial incentives. J.C. is a scientific advisor to SomaLogic, Inc. S.L.S. serves as a consultant to Agios, FORMA Therapeutics, Global Blood Therapeutics, NOVARTIS, and ORIC Pharmaceuticals., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background NT-proBNP (N-terminal pro-B-type natriuretic peptide) is strongly associated with mortality in patients with heart failure. Prior studies, primarily in middle-aged and older populations, have suggested that NT-proBNP has prognostic value in ambulatory adults. Methods and Results We conducted a prospective cohort analysis of adults, aged ≥20 years, in the nationally representative 1999 to 2004 National Health and Nutrition Examination Survey, to characterize the association of NT-proBNP with mortality in the general US adult population overall and by age, race and ethnicity, and body mass index. We used Cox regression to characterize associations of NT-proBNP with all-cause and cardiovascular disease (CVD) mortality through 2019, adjusting for demographics and cardiovascular risk factors. We included 10 645 individuals (mean age, 45.7 years; 50.8% women; 72.8% White adults; 8.5% with a self-reported history of CVD). There were 3155 deaths (1009 CVD-related) over a median 17.3 years of follow-up. Among individuals without prior CVD, elevated NT-proBNP (≥75th percentile [81.5 pg/mL] versus <25th percentile [20.5 pg/mL]) was associated with a significantly higher risk of all-cause (hazard ratio [HR], 1.67 [95% CI, 1.39-2.00]) and CVD mortality (HR, 2.87 [95% CI, 1.61-5.11]). Associations of NT-proBNP with all-cause and CVD mortality were generally similar across subgroups defined by age, sex, race and ethnicity, or body mass index (all P interaction >0.05). Conclusions In a representative sample of the US adult population, NT-proBNP was an important independent risk factor for all-cause and CVD mortality. NT-proBNP may be useful for monitoring risk in the general adult population.

Aims: Chronic kidney disease (CKD) increases risk of cardiovascular disease (CVD). Less is known about how CVD associates with future risk of kidney failure with replacement therapy (KFRT)., Methods and Results: The study included 25 903 761 individuals from the CKD Prognosis Consortium with known baseline estimated glomerular filtration rate (eGFR) and evaluated the impact of prevalent and incident coronary heart disease (CHD), stroke, heart failure (HF), and atrial fibrillation (AF) events as time-varying exposures on KFRT outcomes. Mean age was 53 (standard deviation 17) years and mean eGFR was 89 mL/min/1.73 m2, 15% had diabetes and 8.4% had urinary albumin-to-creatinine ratio (ACR) available (median 13 mg/g); 9.5% had prevalent CHD, 3.2% prior stroke, 3.3% HF, and 4.4% prior AF. During follow-up, there were 269 142 CHD, 311 021 stroke, 712 556 HF, and 605 596 AF incident events and 101 044 (0.4%) patients experienced KFRT. Both prevalent and incident CVD were associated with subsequent KFRT with adjusted hazard ratios (HRs) of 3.1 [95% confidence interval (CI): 2.9-3.3], 2.0 (1.9-2.1), 4.5 (4.2-4.9), 2.8 (2.7-3.1) after incident CHD, stroke, HF and AF, respectively. HRs were highest in first 3 months post-CVD incidence declining to baseline after 3 years. Incident HF hospitalizations showed the strongest association with KFRT [HR 46 (95% CI: 43-50) within 3 months] after adjustment for other CVD subtype incidence., Conclusion: Incident CVD events strongly and independently associate with future KFRT risk, most notably after HF, then CHD, stroke, and AF. Optimal strategies for addressing the dramatic risk of KFRT following CVD events are needed., Competing Interests: Conflict of interest: P.B.M. reports grants and personal fees from Boehringer Ingelheim; personal fees and non-financial support from Napp, Astrazeneca; personal fees from GSK, Pharmacosmos, and Astellas, outside the submitted work. J.J.C. is a Statistical Editor for the European Heart Journal. K.M. reports grants from NIDDK, during the conduct of the study; grants and personal fees from Kyowa Kirin, personal fees from Akebia, Kowa, and Fukuda Denshi, outside the submitted work. M.E.G. reports grants from National Kidney Foundation and from Kidney Disease Improving Global Outcomes outside the submitted work. J.C. reports grants from National Institute of Health and National Kidney Foundation during the conduct of the study; consulting at Healthy.io and scientific advisor to SomaLogic outside the submitted work. J.Ch. reports grants from National Health and Medical Research Council of Australia and grants and personal fees from Servier International outside the submitted work. L.C. reports consulting from CSL Vifor, honorarium for giving a talk from Fresenius Medical Care, and grants from NIH-NIDDK outside the submitted work. A.R.C. reports personal fees from Novartis, Amgen, Reata; grants from Novo Nordisk, Bayer, outside the submitted work. D.d.Z. reports personal fees from Merck during the conduct of the study, Bayer, Boehringer Ingelheim, and Travere outside the submitted work. M.E. reports institutional grants from Astellas pharma, AstraZeneca, and Vifor Pharma; honoraria form Astellas pharma, AstraZeneca, Baxter healthcare, and Fresenius Medical Care; support for attending meetings from Baxter healthcare, participation on a DSMB or Advisory Board for Astellas pharma, AstraZeneca, and Vifor pharma, and a leadership or fiduciary role on the Steering Committee of the Swedish Renal Registry, outside the submitted work. O.M.G. reports personal fees from Akebia, Amgen, AstraZeneca, Reata, Ardelyx, and QED, outside the submitted work. H.J.L.H. reports grants and honoraria for steering committee to his institution from Abbvie; grants and honoraria for steering committee and payments for advisory boards to his institution from AstraZeneca; honoraria for steering committee and payments for advisory boards from Bayer; grants and honoraria for steering committee and payments for advisory boards to his institution from Boehringer Ingelheim; honoraria for steering committee to his institution from CSL Behring, Chinook, Dimerix, Gilead; grants and honoraria for steering committee to his institution from Janssen, honoraria for steering committee to his institution from Eli Lilly, Merck, Mitsubishi Tanabe; grants and honoraria for steering committee to his institution from Novo Nordisk; and honoraria for steering committee to his institution from Travere Pharmaceuticals outside the submitted work. W.G.H. reports SHARP was funded by Merck & Co., Inc., Whitehouse Station, NJ USA, during the conduct of the study; he received grants from Boehringer Ingelheim and Eli Lilly; grants and fellowship from MRC UK, and fellowship from Kidney Research UK outside the submitted work. R.W.M. reports grants from NIHR and Kidney Research UK during the conduct of the study. G.N.N. reports personal fees, non-financial support, and other support (Scientific Cofounder, have equity/stock options, royalties and consulting) from Renalytix; personal fees and non-financial support from Pensieve Health; non-financial support and other support (Scientific Cofounder, have equity/stock options) from Nexus I Connect, Sole proprietor of Data2Wisdom LLC; personal fees from Variant Bio, Qiming Capital, Cambridge Consulting, Daiichi Sankyo, and Menarini Health, outside the submitted work. M.R. reports grants from NIH during the conduct of the study. N.S. reports being a current employee of GSK and employed at AMGA at the time of this study. B.S. reports grants from AstraZeneca, GlaxoSmithKline, and Fresenius Medical Care outside the submitted work. D.C.W. reports personal fees from AstraZeneca during the conduct of the study; personal fees from Amgen, Astellas, Bayer, Boehringer Ingelheim, Gilead, GlaxoSmithKline, Janssen, Mundipharma, Merck Sharp and Dohme, Tricida, Vifor and Zydus; and personal fees from AstraZeneca outside the submitted work. J.v.d.B. reports being an employee and stakeholder of Binnovate Digital Health BV outside the submitted work. All other co-authors have nothing to disclose. Some of the data reported here have been supplied by the United States Renal Data System. The interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as an official policy or interpretation of the US Government., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background GDF15 (growth differentiation factor 15) is a potent predictor of bleeding in people with cardiovascular disease. However, whether GDF15 is associated with bleeding in individuals without a history of cardiovascular disease is unknown. Methods and Results The study population was from the ARIC (Atherosclerosis Risk in Communities) study. We studied the association of GDF15 with hospitalized bleeding events among 9205 participants (1993-1995) without prior bleeding and cardiovascular disease (mean age 60 years, 57% women, 21% Black). Plasma levels of GDF15 were measured in relative fluorescence units using DNA-based aptamer technology. Bleeding was ascertained using discharge codes. We examined hazard ratios (HRs) of incident bleeding using Cox models and risk prediction with the addition of GDF15 to clinical predictors of bleeding. There were 1328 hospitalizations with bleeding during a median follow-up of 22.5 years. The majority (76.5%) were because of gastrointestinal bleeding. The absolute incidence rate of bleeding per 1000 person-years was 11.64 in the highest quartile of GDF15 versus 5.22 in the lowest quartile. The highest versus lowest quartile of GDF15 demonstrated an adjusted HR of 2.00 (95% CI, 1.69-2.35) for total bleeding. The findings were consistent when we examined bleeding as the primary discharge diagnosis. The addition of GDF15 to clinical predictors of bleeding improved the C-statistic by 0.006 (0.002-0.011) from 0.684 to 0.690, P =0.008. Conclusions Higher levels of GDF15 were associated with bleeding events and improved the risk prediction beyond clinical predictors in individuals without cardiovascular disease.

Background: While American nephrology societies recommend using the 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) estimated glomerular filtration rate (eGFR) equation without a Black race coefficient, it is unknown how this would impact disease distribution, prognosis and kidney failure risk prediction in predominantly White non-US populations., Methods: We studied 1.6 million Stockholm adults with serum/plasma creatinine measurements between 2007 and 2019. We calculated changes in eGFR and reclassification across KDIGO GFR categories when changing from the 2009 to 2021 CKD-EPI equation; estimated associations between eGFR and the clinical outcomes kidney failure with replacement therapy (KFRT), (cardiovascular) mortality and major adverse cardiovascular events using Cox regression; and investigated prognostic accuracy (discrimination and calibration) of both equations within the Kidney Failure Risk Equation., Results: Compared with the 2009 equation, the 2021 equation yielded a higher eGFR by a median [interquartile range (IQR)] of 3.9 (2.9-4.8) mL/min/1.73 m2, which was larger at older age and for men. Consequently, 9.9% of the total population and 36.2% of the population with CKD G3a-G5 was reclassified to a higher eGFR category. Reclassified individuals exhibited a lower risk of KFRT, but higher risks of all-cause/cardiovascular death and major adverse cardiovascular events, compared with non-reclassified participants of similar eGFR. eGFR by both equations strongly predicted study outcomes, with equal discrimination and calibration for the Kidney Failure Risk Equation., Conclusions: Implementing the 2021 CKD-EPI equation in predominantly White European populations would raise eGFR by a modest amount (larger at older age and in men) and shift a major proportion of CKD patients to a higher eGFR category. eGFR by both equations strongly predicted outcomes., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Aims: The 2021 European Society of Cardiology (ESC) guideline on cardiovascular disease (CVD) prevention categorizes moderate and severe chronic kidney disease (CKD) as high and very-high CVD risk status regardless of other factors like age and does not include estimated glomerular filtration rate (eGFR) and albuminuria in its algorithms, systemic coronary risk estimation 2 (SCORE2) and systemic coronary risk estimation 2 in older persons (SCORE2-OP), to predict CVD risk. We developed and validated an 'Add-on' to incorporate CKD measures into these algorithms, using a validated approach., Methods: In 3,054 840 participants from 34 datasets, we developed three Add-ons [eGFR only, eGFR + urinary albumin-to-creatinine ratio (ACR) (the primary Add-on), and eGFR + dipstick proteinuria] for SCORE2 and SCORE2-OP. We validated C-statistics and net reclassification improvement (NRI), accounting for competing risk of non-CVD death, in 5,997 719 participants from 34 different datasets., Results: In the target population of SCORE2 and SCORE2-OP without diabetes, the CKD Add-on (eGFR only) and CKD Add-on (eGFR + ACR) improved C-statistic by 0.006 (95%CI 0.004-0.008) and 0.016 (0.010-0.023), respectively, for SCORE2 and 0.012 (0.009-0.015) and 0.024 (0.014-0.035), respectively, for SCORE2-OP. Similar results were seen when we included individuals with diabetes and tested the CKD Add-on (eGFR + dipstick). In 57 485 European participants with CKD, SCORE2 or SCORE2-OP with a CKD Add-on showed a significant NRI [e.g. 0.100 (0.062-0.138) for SCORE2] compared to the qualitative approach in the ESC guideline., Conclusion: Our Add-ons with CKD measures improved CVD risk prediction beyond SCORE2 and SCORE2-OP. This approach will help clinicians and patients with CKD refine risk prediction and further personalize preventive therapies for CVD., Competing Interests: Conflict of interest: Ku.M. reports grants from NIDDK; grants and personal fees from Kyowa Kirin, personal fees from Akebia outside the submitted work. M.G. reports grants from NIH and National Kidney Foundation outside the submitted work. J.A. reports personal fees from AstraZeneca, Novartis, and Boerhinger Ingelheim outside the submitted work. A.R.C. reports personal fees from Novartis, Reata, and Amgen; grants from Novo Nordisk outside the submitted work. N.E. reports personal fees from Bayer and AG Leverkusen outside the submitted work. K.E. reports grants from Amgen, Astra Zenceca, Bayer, Evotec, and Vifor; personal fees from Akebia, Astra Zeneca, Bayer, Otsuka, and Retrophin outside the submitted work. S.K.J reports salary support from US Government and Department of Veterans Affairs during the conduct of the study. C.K. reports personal fees from Bayer, Abbott, Astra-Zeneca, Takeda, Tricida, Akebia, Cara Therapeutics, Vifor, Rockwell, CSL Behring, Reata, Boehringer Ingelheim, and GSK outside the submitted work. A.S.L. reports grants and contracts from NIH and NKF for studies in CKD and a contract from AstraZeneca for DSMB for clinical trials of dapagliflozin. Ka.M. reports grants from Ministry of Health, Labor, and Welfare, Japan. G.N.N reports personal fees from Renalytix, Daiichi Sankyo, Menarini Medical, Qiming Capital, and Variant Bio; other fees from Pensieve Health, Nexus I Connect outside the submitted work; patent KidneyIntelX pending to Renalytix. M.G.S. reports grants from NIH- NIA/NIDDK/NHLBI during the conduct of the study; personal fees from Cricket Health, Intercept Pharmaceuticals, Bayer Pharmaceuticals, AztraZeneca, Boeringer Ingelheim; grants from Bayer Pharmaceuticals outside the submitted work. M.D.S reports a honoraria from AstraZeneca outside the submitted work. N.S. is a current employee of GSK and employed at AMGA. M.W. reports personal fees from Amgen and Freeline outside the submitted work. J.C. reports grants from National Institute of Health and National Kidney Foundation, during the conduct of the study; personal fees from Healthy.io and SomaLogic outside the submitted work. No other potential conflicts of interest relevant to this article were reported. All other authors report no potential conflicts., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To characterize and compare glucose-lowering medication use in type 2 diabetes in the U.S., Sweden, and Israel, including adoption of newer medications and prescribing patterns., Research Design and Methods: We used data from the National Health and Nutrition Examination Survey (NHANES) from the U.S., the Stockholm CREAtinine Measurements (SCREAM) project from Sweden, and Maccabi Healthcare Services (Maccabi) from Israel. Specific pharmacotherapy for type 2 diabetes between 2007 and 2018 was examined., Results: Use of glucose-lowering medications among patients with type 2 diabetes was substantially lower in NHANES and SCREAM than in Maccabi (66.0% in NHANES, 68.4% in SCREAM, and 88.1% in Maccabi in 2017-2018). Among patients who took at least one glucose-lowering medication in 2017-2018, metformin use was also lower in NHANES and SCREAM (74.1% in NHANES, 75.9% in SCREAM, and 92.6% in Maccabi) whereas sulfonylureas use was greater in NHANES (31.5% in NHANES, 16.0% in SCREAM, and 14.9% in Maccabi). Adoption of dipeptidyl peptidase 4 inhibitors and sodium-glucose cotransporter 2 inhibitors (SGLT2i) was slower in NHANES and SCREAM than in Maccabi. History of atherosclerotic cardiovascular disease, heart failure, reduced kidney function, or albuminuria was not consistently associated with greater use of SGLT2i or glucagon-like peptide 1 receptor agonists (GLP1RA) across the three countries., Conclusions: There were substantial differences in real-world use of glucose-lowering medications across the U.S., Sweden, and Israel, with more optimal pharmacologic management in Israel. Variation in access to care and medication cost across countries may have contributed to these differences. SGLT2i and GLP1RA use in patients at high risk was limited in all three countries during this time period., (© 2022 by the American Diabetes Association.)

Background: It remains unclear whether elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) can serve as a "risk equivalent" for cardiovascular disease to adults at high cardiovascular risk., Methods: We included 9789 participants (mean age 63.2 years, 55% women, 19.4% Black, 13% with a history of cardiovascular disease) who attended Atherosclerosis Risk in Communities Study Visit 4 (1996-1998). We classified participants as having a history of cardiovascular disease at baseline and, among those without cardiovascular disease, we defined categories of NT-proBNP (<125, 125-449, ≥450 pg/mL). We used Cox regression to estimate associations of NT-proBNP with incident cardiovascular disease and mortality., Results: Over a median 20.5 years of follow-up, there were 4562 deaths (917 cardiovascular deaths). There were 2817 first events and 806 recurrent events (in those with a history of cardiovascular disease at baseline). Among individuals without a history of cardiovascular disease, those adults with NT-proBNP ≥450 pg/mL had significantly higher risks of all-cause death (hazard ratio [HR] 2.12; 95% confidence interval [CI], 1.78-2.53), cardiovascular mortality (HR 2.92; 95% CI, 2.15-3.97), incident total cardiovascular disease (HR 2.59; 95% CI, 2.13-3.16), atherosclerotic cardiovascular disease (HR 2.20; 95% CI, 1.72-2.80), and heart failure (HR 3.81; 95% CI, 3.01-4.81), compared with individuals with NT-proBNP <125 pg/mL. The elevated cardiovascular risk in persons with high NT-proBNP and no history of cardiovascular disease was similar to, or higher than, the risk conferred by a history of cardiovascular disease., Conclusions: Our findings suggest that it might be appropriate to manage adults with NT-proBNP ≥450 pg/mL as if they had a history of clinical cardiovascular disease., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke., Methods: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition-Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank., Results: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values <60 or >105 mL·min -1 ·1.73 m -2 , compared with those with eGFR between 60 and 105 mL·min -1 ·1.73 m -2 . Mendelian randomization analyses for CHD showed an association among participants with eGFR <60 mL·min -1 ·1.73 m -2 , with a 14% (95% CI, 3%-27%) higher CHD risk per 5 mL·min -1 ·1.73 m -2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min -1 ·1.73 m -2 . Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD., Conclusions: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.

Background: Proteins and metabolites are essential for many biological functions and often linked through enzymatic or transport reactions. Individual molecules have been associated with all-cause mortality. Many of these are correlated and might jointly represent pathways or endophenotypes involved in diseases., Results: We present an integrated analysis of proteomics and metabolomics via a local dimensionality reduction clustering method. We identified 224 modules of correlated proteins and metabolites in the Atherosclerosis Risk in Communities (ARIC) study, a general population cohort of older adults (N = 4046, mean age 75.7, mean eGFR 65). Many of the modules displayed strong cross-sectional associations with demographic and clinical characteristics. In comprehensively adjusted analyses, including fasting plasma glucose, history of cardiovascular disease, systolic blood pressure and kidney function among others, 60 modules were associated with mortality. We transferred the network structure to the African American Study of Kidney Disease and Hypertension (AASK) (N = 694, mean age 54.5, mean mGFR 46) and identified mortality associated modules relevant in this disease specific cohort. The four mortality modules relevant in both the general population and CKD were all a combination of proteins and metabolites and were related to diabetes / insulin secretion, cardiovascular disease and kidney function. Key components of these modules included N-terminal (NT)-pro hormone BNP (NT-proBNP), Sushi, Von Willebrand Factor Type A, EGF And Pentraxin (SVEP1), and several kallikrein proteases., Conclusion: Through integrated biomarkers of the proteome and metabolome we identified functions of (patho-) physiologic importance related to diabetes, cardiovascular disease and kidney function., (© 2022. The Author(s).)

Background: More than 80% of adult patients diagnosed with cancer survive long term. Long-term complications of cancer and its therapies may increase the risk of cardiovascular disease (CVD), but prospective studies using adjudicated cancer and CVD events are lacking., Objectives: The aim of this study was to assess the risk of CVD in cancer survivors in a prospective community-based study., Methods: We included 12,414 ARIC (Atherosclerosis Risk In Communities) study participants. Cancer diagnoses were ascertained via linkage with state registries supplemented with medical records. Incident CVD outcomes were coronary heart disease (CHD), heart failure (HF), stroke, and a composite of these. We used multivariable Poisson and Cox regressions to estimate the association of cancer with incident CVD., Results: Mean age was 54 years, 55% were female, and 25% were Black. A total of 3,250 participants (25%) had incident cancer over a median 13.6 years of follow-up. Age-adjusted incidence rates of CVD (per 1,000 person-years) were 23.1 (95% CI: 24.7-29.1) for cancer survivors and 12.0 (95% CI: 11.5-12.4) for subjects without cancer. After adjustment for cardiovascular risk factors, cancer survivors had significantly higher risks of CVD (HR: 1.37; 95% CI: 1.26-1.50), HF (HR: 1.52; 95% CI: 1.38-1.68), and stroke (HR: 1.22; 95% CI: 1.03-1.44), but not CHD (HR: 1.11; 95% CI: 0.97-1.28). Breast, lung, colorectal, and hematologic/lymphatic cancers, but not prostate cancer, were significantly associated with CVD risk., Conclusions: Compared with persons without cancer, adult cancer survivors have significantly higher risk of CVD, especially HF, independent of traditional cardiovascular risk factors. There is an unmet need to define strategies for CVD prevention in this high-risk population., Competing Interests: Funding Support and Author Disclosures The ARIC study has been supported with federal funds from the National Heart, Lung, and Blood Institute (NHLBI), the National Institutes of Health (NIH), and the Department of Health and Human Services under contract numbers 75N92022D00001, 75N92022D00002, 75N92022D00003, 75N92022D00004, and 75N92022D00005. Studies on cancer in the ARIC study are also supported by the National Cancer Institute (grant U01CA164975). This research was additionally supported by a Cancer Center Support Grant from the National Cancer Institute (grant P30 CA006973). Ms Daya was supported by NIH/NHLBI grant T32HL007024. Dr Selvin was supported by NIH/National Institute of Diabetes and Digestive and Kidney Diseases grants K24 HL152440 and R01 DK089174. Dr Ndumele was supported by NIH/NHLBI grant R01 HL146907 and American Heart Association grant 20SFRN35120152. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Stroke is a leading cause of morbidity and mortality among adults in the U.S. Ideal levels of the Life's Simple 7 (LS7) are associated with lower cardiovascular disease (CVD) and all-cause mortality. However, the association of LS7 with CVD, recurrent stroke, and all-cause mortality after incident stroke is unknown., Methods: We used data from the ARIC study, a cohort of 13,508 adults from four US communities, 45-64 years old at baseline (1987-1989). Cardiovascular hospitalizations and mortality were ascertained in follow-up through December 31 st , 2017. We defined cardiovascular health (CVH) based on AHA definitions for LS7 (range 0-14) and categorized CVH into four levels: LS7 0-3, 4-6, 7-9, and ≥10 (ideal LS7), according to prior studies. Outcomes included incident stroke, CVD, recurrent stroke, all-cause mortality, and a composite outcome including all the above. Adjusted hazard ratios (95% CI) were estimated with Cox proportional hazards regression models., Results: Median (25%-75%) follow-up for incident stroke was 28 (18.6-29.2) years. Participants with incident stroke were 55.7 (SD 5.6) years-old at baseline, 53% were women and 35% Black. Individuals with LS7 score ≥10 had 65% lower risk (HR: 0.35; 95% CI: 0.29-0.41) of incident stroke than those with LS7 4-6 (reference group). Of 1,218 participants with incident stroke, 41.2% (n=502) had composite CVD and 68.3% (n=832) died during a median (25%-75%) follow-up of 4.0 (0.76-9.95) years. Adjusted HR (95% CI) for stroke survivors with LS7≥10 at baseline were 0.74 (0.58-0.94) for the composite outcome, 0.38(0.17-0.85) for myocardial infarction, 0.60 (0.40-0.90) for heart failure, 0.63 (0.48-0.84) for all-cause mortality, and 0.65 (0.39-1.08) for recurrent stroke., Conclusions: Good and excellent midlife cardiovascular health are associated with lower risks of incident stroke and CVD after stroke. Clinicians should stress the importance of a healthy lifestyle for primary and secondary CVD prevention., (Copyright © 2022 Elsevier Inc. All rights reserved.)

A reliable, individualized, and dynamic surrogate of cardiovascular risk, synoptic for key biologic mechanisms, could shorten the path for drug development, enhance drug cost-effectiveness and improve patient outcomes. We used highly multiplexed proteomics to address these objectives, measuring about 5000 proteins in each of 32,130 archived plasma samples from 22,849 participants in nine clinical studies. We used machine learning to derive a 27-protein model predicting 4-year likelihood of myocardial infarction, stroke, heart failure, or death. The 27 proteins encompassed 10 biologic systems, and 12 were associated with relevant causal genetic traits. We independently validated results in 11,609 participants. Compared to a clinical model, the ratio of observed events in quintile 5 to quintile 1 was 6.7 for proteins versus 2.9 for the clinical model, AUCs (95% CI) were 0.73 (0.72 to 0.74) versus 0.64 (0.62 to 0.65), c -statistics were 0.71 (0.69 to 0.72) versus 0.62 (0.60 to 0.63), and the net reclassification index was +0.43. Adding the clinical model to the proteins only improved discrimination metrics by 0.01 to 0.02. Event rates in four predefined protein risk categories were 5.6, 11.2, 20.0, and 43.4% within 4 years; median time to event was 1.71 years. Protein predictions were directionally concordant with changed outcomes. Adverse risks were predicted for aging, approaching an event, anthracycline chemotherapy, diabetes, smoking, rheumatoid arthritis, cancer history, cardiovascular disease, high systolic blood pressure, and lipids. Reduced risks were predicted for weight loss and exenatide. The 27-protein model has potential as a "universal" surrogate end point for cardiovascular risk.

Background: Glycated albumin is of growing interest as an alternative biomarker of glycemia. However, the association of glycated albumin with long-term outcomes in the general population is uncharacterized. We evaluated the associations of glycated albumin and hemoglobin A1c (HbA1c) with mortality in US adults., Methods: We conducted a prospective analysis of 12 915 participants in the National Health and Nutrition Examination Survey 1999-2004. We used Cox regression to characterize associations of glycated albumin and HbA1c with all-cause and cardiovascular mortality through 2014. We categorized glycated albumin based on percentiles corresponding to clinical cut-points for HbA1c. No diagnosed diabetes: <5.0% (<12th percentile), 5.0% to 5.6% (12th-82nd percentile, reference), 5.7% to 6.4% (83rd-97th percentile), and ≥6.5% (≥98th percentile). Diagnosed diabetes: <7.0% (<50th percentile), 7.0% to 8.9% (50th-83rd percentile), and ≥9.0% (≥84th percentile)., Results: Among US adults (mean age 46 years), the prevalence of diagnosed diabetes was 6.8%. Glycated albumin and HbA1c were highly correlated (r = 0.76). Over the median 16.8 years follow-up, there were 2818 deaths (652 cardiovascular). Adults with diagnosed diabetes and glycated albumin ≥84th percentile had the highest risk for all-cause mortality [hazard ratio (HR) 3.96, 95% CI 3.06-5.13] and cardiovascular mortality (HR 6.80, 95% CI 4.20-11.03). HbA1c had associations with all-cause and cardiovascular mortality that were similar to those for glycated albumin., Conclusions: Among US adults, increased values of glycated albumin and HbA1c were associated with all-cause and cardiovascular mortality, particularly in persons with diagnosed diabetes. Glycated albumin may be a useful alternative test of glycemia., (© American Association for Clinical Chemistry 2022. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Clinical trials have demonstrated cardiovascular benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA). However, their impact on all-cause and cause-specific hospitalization in real-world practice remains unclear. We identified patients with diabetes who initiated SGLT2i (n = 2,492), GLP-1RA (n = 1,982), or dipeptidyl peptidase-4 inhibitors (DPP4i, n = 2,492) between 2015 and 2018 in Geisinger Health System. We examined all-cause hospitalization (net benefit indicator) and cardiovascular disease (CVD) hospitalization (CV benefit indicator), as well as non-CVD hospitalization (harm indicator), using Cox proportional hazards regression. During a median follow-up of 16 months, SGLT2i and GLP-1RA were associated with lower risk of all-cause hospitalization (hazard ratio [HR] 0.85, 95% CI 0.75 to 0.95 for SGLT2i; HR 0.89, 95% CI 0.78 to 0.98 for GLP-1RA), as well as CVD hospitalization (HR 0.61, 95% CI 0.47 to 0.79) for SGLT2i; HR 0.77, 95% CI 0.60 to 0.99 for GLP-1RA) compared with DPP4i. The risks of all-cause and CVD hospitalization were similar between SGLT2i and GLP-1RA. SGLT2i was associated with substantially lower risk of myocardial infarction and heart failure hospitalization compared with DPP4i and lower risk of heart failure hospitalization compared with GLP-1RA. The risk of non-CVD hospitalization did not differ among the treatment groups. These results from real-world comparison further encourage SGLT2i and GLP-1RA use in routine diabetes care, particularly among patients at high risk of cardiovascular events., Competing Interests: Disclosures The authors have no conflicts of interest to declare., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background/objectives: Traditional cardiovascular risk factors are less predictive in older age. High-sensitivity cardiac troponin I (hs-cTnI) is a marker of subclinical cardiomyocyte damage associated with cardiovascular risk in middle-aged adults. We hypothesized hs-cTnI would be indicative of mortality and cardiovascular risk beyond traditional cardiovascular risk factors in older adults and may be more discriminatory compared to hs-troponin T (hs-cTnT)., Design: Prospective cohort study., Setting: Population-based Atherosclerosis Risk in Communities (ARIC) Study., Participants: We included 5,876 ARIC participants at Visit 5 (2011-2013)., Outcomes and Measures: We used Cox regression for the association of hs-cTnI categories (women: <4, 4-<10, ≥10 ng/ml; men: <6, 6-<12, ≥12 ng/ml, prevalent cardiovascular disease (CVD)) with mortality and incident CVD (atherosclerotic CVD [ASCVD]: coronary heart disease or stroke, or heart failure)., Results: Participants were ages 66 to 90, 23% black, 42% male, and 24% had prevalent CVD. There were 1,053 (321 CVD) deaths (median follow-up 6.3 years). Participants with elevated hs-cTnI and no CVD (7% of participants) had mortality risk similar to those with a history of CVD (55.6 vs 55.7 deaths/1,000 person-years, P = .99). After adjustment, elevated hs-cTnI and no CVD (hazard ratio (HR) = 2.38, 95% confidence interval (CI) = 1.85-3.06) and prevalent CVD (HR = 2.21, 95% CI = 1.90-2.57) remained associated with mortality, compared to low hs-cTnI and no CVD. Elevated hs-cTnI was independently associated with incident CVD (HR = 3.41, 95% CI = 2.58-4.51), ASCVD (HR = 2.02, 95% CI = 1.36-2.98), and heart failure (HR = 6.16, 95% CI = 4.24-8.95). The addition of hs-cTnI significantly improved C-statistics for all outcomes and added greater discrimination than hs-cTnT for cardiovascular mortality and incident heart failure., Conclusions: Hs-cTnI improves mortality and CVD risk stratification in older adults beyond traditional risk factors and improved model discrimination more than hs-cTnT for certain outcomes. Elevated hs-cTnI without CVD identifies a high-risk group with comparable mortality risk as those with a history of clinical CVD., (© 2020 The American Geriatrics Society.)

Cardiovascular diseases (CVDs), principally ischemic heart disease (IHD) and stroke, are the leading cause of global mortality and a major contributor to disability. This paper reviews the magnitude of total CVD burden, including 13 underlying causes of cardiovascular death and 9 related risk factors, using estimates from the Global Burden of Disease (GBD) Study 2019. GBD, an ongoing multinational collaboration to provide comparable and consistent estimates of population health over time, used all available population-level data sources on incidence, prevalence, case fatality, mortality, and health risks to produce estimates for 204 countries and territories from 1990 to 2019. Prevalent cases of total CVD nearly doubled from 271 million (95% uncertainty interval [UI]: 257 to 285 million) in 1990 to 523 million (95% UI: 497 to 550 million) in 2019, and the number of CVD deaths steadily increased from 12.1 million (95% UI:11.4 to 12.6 million) in 1990, reaching 18.6 million (95% UI: 17.1 to 19.7 million) in 2019. The global trends for disability-adjusted life years (DALYs) and years of life lost also increased significantly, and years lived with disability doubled from 17.7 million (95% UI: 12.9 to 22.5 million) to 34.4 million (95% UI:24.9 to 43.6 million) over that period. The total number of DALYs due to IHD has risen steadily since 1990, reaching 182 million (95% UI: 170 to 194 million) DALYs, 9.14 million (95% UI: 8.40 to 9.74 million) deaths in the year 2019, and 197 million (95% UI: 178 to 220 million) prevalent cases of IHD in 2019. The total number of DALYs due to stroke has risen steadily since 1990, reaching 143 million (95% UI: 133 to 153 million) DALYs, 6.55 million (95% UI: 6.00 to 7.02 million) deaths in the year 2019, and 101 million (95% UI: 93.2 to 111 million) prevalent cases of stroke in 2019. Cardiovascular diseases remain the leading cause of disease burden in the world. CVD burden continues its decades-long rise for almost all countries outside high-income countries, and alarmingly, the age-standardized rate of CVD has begun to rise in some locations where it was previously declining in high-income countries. There is an urgent need to focus on implementing existing cost-effective policies and interventions if the world is to meet the targets for Sustainable Development Goal 3 and achieve a 30% reduction in premature mortality due to noncommunicable diseases., Competing Interests: Author Disclosures This study was funded by the Bill and Melinda Gates Foundation. Dr. Benjamin has received funding from the National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI) (R01HL092577, 1R01HL128914) and American Heart Association (18SFRN34110082). Dr. Brauer has received a grant from the Bill and Melinda Gates Foundation. Dr. Catapano has received support from Fondazione Cariplo 2015-0524 and 2015-0564, H2020 REPROGRAM PHC-03-2015/667837-2, ERA NET ER-2017-2364981, GR-2011-02346974, Ministry of Health - Ricerca Corrente Multimedica; has received research grant/support from Sanofi, Sanofi Regeneron, Amgen, Mylan, Menarini, and Eli Lilly; has served on the speakers bureau for Akcea, Amgen, Sanofi, Esperion, Kowa, Novartis, Ionis Pharmaceuticals, Mylan, Menarini, Merck, Recordati, Regeneron, Daiichi-Sankyo, AstraZeneca, Aegerion, Amryt, and Sandoz; has received honoraria from Akcea, Amgen, Sanofi, Esperion, Kowa, Novartis, Ionis Pharmaceuticals, Mylan, Menarini, Merck, Recordati, Regeneron Daiichi-Sankyo, AstraZeneca, Aegerion, Amryt, and Sandoz; and has served as a consultant/on the Advisory Board for Akcea, Amgen, Sanofi, Esperion, Kowa, Novartis, Ionis Pharmaceuticals, Mylan, Menarini, Merck, Recordati, Regeneron Daiichi-Sankyo, Genzyme, Aegerion, and Sandoz. Dr. Coresh has received funding from the NIH and National Kidney Foundation; and has served as an advisor to Healthy.io. Dr. Fowkes has served on the Advisory Board for AstraZeneca. Dr. Muntner has received grants and personal fees from Amgen Inc. Dr. Ribeiro has received partial support by CNPq (310679/2016-8 and 465518/2014-1) and by FAPEMIG (PPM-00428-17). Dr. Zuhlke has received funding by the UK Medical Research Council (MRC) and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement and the National Research Foundation of South Africa. Dr. Rigotti has served as a consultant to Achieve Life Sciences; and has received royalties from UpToDate, Inc. Dr. Rodgers is employed by The George Institute for Global Health (TGI) and seconded part time to George Medicines Pty Ltd (GM); TGI has submitted patent applications with respect to low-fixed-dose combination products for the treatment of cardiovascular or cardiometabolic disease and is listed as one of the inventors; George Health Enterprises Pty. Ltd. (GHE) and its subsidiary, GM, have received investment funds to develop fixed-dose combination products, including combinations of blood pressure-lowering drugs; GHE is the social enterprise arm of TGI (Dr. Rodgers does not have a direct financial interest in these patent applications or investments). Dr. Sundström holds ownership in companies providing services to Itrim, Amgen, Janssen, Novo Nordisk, Eli Lilly, Boehringer Ingelheim, Bayer, Pfizer, and AstraZeneca, outside the submitted work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: The cardiorenal syndrome refers to a bidirectional relationship between the kidney and the heart. However, epidemiological evidence of cardiovascular disease (CVD) as a risk factor for chronic kidney disease (CKD) progression is actually scarce., Methods and Results: We examined the slopes of estimated glomerular filtration rate (eGFR) decline in the 2 years before vs. after an incident hospitalization with heart failure (HF) (n = 20 420), coronary heart disease (CHD) (n = 18 152), or stroke (n = 1808) using data from a complete laboratory data collection in Stockholm, Sweden between 2006 and 2011. eGFR slopes were estimated using mixed-effect models with unstructured residual correlation. Overall, incident hospitalization with HF and CHD, but not stroke, was significantly associated with a subsequent accelerated decline in eGFR, with a faster eGFR decline and greater slope change after HF than CHD. The pre-event vs. post-event eGFR slopes (mL/min/1.73 m 2 per year) were -1.67 (-1.77 to -1.57) vs. -2.76 (-2.82 to -2.71), with a Δslope of -1.09 (-1.16 to -1.02) for HF; -1.09 (-1.20 to -0.98) vs. -1.87 (-1.92 to -1.81), with a Δslope of -0.78 (-0.85 to -0.70) for CHD; and -1.00 (-1.37 to -0.63) vs. -0.99 (-1.19 to -0.78), with a Δslope of 0.02 (-0.24 to 0.27) for stroke. The accelerated declines in eGFR after HF and CHD were consistent across the spectrum of eGFR, although pre-event eGFR slopes were steeper in lower eGFR (e.g. pre-event eGFR slope for HF -0.64 (-0.76 to -0.53) for eGFR ≥60 mL/min/1.73 m 2 , -1.43 (-1.57 to -1.30) for eGFR 30-59 mL/min/1.73 m 2 , and -2.42 (-2.71 to -2.12) for eGFR <30 mL/min/1.73 m 2 )., Conclusions: Incident hospitalization with cardiac diseases (i.e. HF and CHD) was significantly associated with a subsequent acceleration of eGFR decline., (© 2020 European Society of Cardiology.)

Background: Mitochondrial DNA copy number (mtDNA-CN) has been associated with a variety of aging-related diseases, including all-cause mortality. However, the mechanism by which mtDNA-CN influences disease is not currently understood. One such mechanism may be through regulation of nuclear gene expression via the modification of nuclear DNA (nDNA) methylation., Methods: To investigate this hypothesis, we assessed the relationship between mtDNA-CN and nDNA methylation in 2507 African American (AA) and European American (EA) participants from the Atherosclerosis Risk in Communities (ARIC) study. To validate our findings, we assayed an additional 2528 participants from the Cardiovascular Health Study (CHS) (N = 533) and Framingham Heart Study (FHS) (N = 1995). We further assessed the effect of experimental modification of mtDNA-CN through knockout of TFAM, a regulator of mtDNA replication, via CRISPR-Cas9., Results: Thirty-four independent CpGs were associated with mtDNA-CN at genome-wide significance (P < 5 × 10 - 8 ). Meta-analysis across all cohorts identified six mtDNA-CN-associated CpGs at genome-wide significance (P < 5 × 10 - 8 ). Additionally, over half of these CpGs were associated with phenotypes known to be associated with mtDNA-CN, including coronary heart disease, cardiovascular disease, and mortality. Experimental modification of mtDNA-CN demonstrated that modulation of mtDNA-CN results in changes in nDNA methylation and gene expression of specific CpGs and nearby transcripts. Strikingly, the "neuroactive ligand receptor interaction" KEGG pathway was found to be highly overrepresented in the ARIC cohort (P = 5.24 × 10 - 12 ), as well as the TFAM knockout methylation (P = 4.41 × 10 - 4 ) and expression (P = 4.30 × 10 - 4 ) studies., Conclusions: These results demonstrate that changes in mtDNA-CN influence nDNA methylation at specific loci and result in differential expression of specific genes that may impact human health and disease via altered cell signaling.

Background: The Healthy Eating Index-2015 (HEI-2015) score measures adherence to recommendations from the 2015-2020 Dietary Guidelines for Americans. The HEI-2015 was altered from the HEI-2010 by reclassifying sources of dietary protein and replacing the empty calories component with 2 new components: saturated fats and added sugars., Objectives: Our aim was to assess whether the HEI-2015 score, along with 3 other previously defined indices, were associated with incident cardiovascular disease (CVD), CVD mortality, and all-cause mortality., Methods: We conducted a prospective analysis of 12,413 participants aged 45-64 y (56% women) from the Atherosclerosis Risk in Communities (ARIC) Study. The HEI-2015, Alternative Healthy Eating Index-2010 (AHEI-2010), alternate Mediterranean (aMed) diet, and Dietary Approaches to Stop Hypertension Trial (DASH) scores were computed using the average dietary intakes of Visits 1 (1987-1989) and 3 (1993-1995). Incident CVD, CVD mortality, and all-cause mortality data were ascertained from baseline through 31 December, 2017. We used Cox proportional hazards models to estimate HRs and 95% CIs., Results: There were 4509 cases of incident CVD, 1722 cases of CVD mortality, and 5747 cases of all-cause mortality over a median of 24-25 y of follow-up. Compared with participants in the lowest quintile of HEI-2015, participants in the highest quintile had a 16% lower risk of incident CVD (HR: 0.84; 95% CI: 0.76-0.93; P-trend < 0.001), 32% lower risk of CVD mortality (HR: 0.68; 95% CI: 0.58-0.80; P-trend < 0.001), and 18% lower risk of all-cause mortality (HR: 0.82; 95% CI: 0.75-0.89; P-trend < 0.001) after adjusting for demographic and lifestyle covariates. There were similar protective associations for AHEI-2010, aMed, and DASH scores, and no significant interactions by race., Conclusions: Higher adherence to the 2015-2020 Dietary Guidelines for Americans was associated with lower risks of incident CVD, CVD mortality, and all-cause mortality among US adults., (Copyright © American Society for Nutrition 2019.)

Background: Cardiorenal syndrome is a well known concept, bolstered by extensive investigations of CKD as a risk factor of cardiovascular disease. However, data on whether cardiovascular disease increases long-term risk of ESKD are sparse., Methods: We assessed the association of incident hospitalization with major cardiovascular diseases (heart failure, atrial fibrillation, coronary heart disease, and stroke) with subsequent risk of ESKD among individuals enrolled in the Atherosclerosis Risk in Communities study; the analysis included 9047 individuals without prevalent cardiovascular disease at their fourth study visit. Each relevant incident cardiovascular disease event was entered into multivariable Cox proportional hazard models as a time-varying exposure to estimate hazard ratios., Results: During a median follow-up of 17.5 years, there were 2598 cases of hospitalization with cardiovascular disease (heart failure, n =1269; atrial fibrillation, n =1337; coronary heart disease, n =696; and stroke, n =559) and 210 cases of incident ESKD. The incidence of major cardiovascular disease was associated with increased risk of ESKD, with the highest risk for heart failure (hazard ratio, 11.40; 95% confidence interval, 8.38 to 15.50), followed by coronary heart disease, atrial fibrillation, and stroke. When we analyzed heart failure with preserved ejection fraction and heart failure with reduced ejection fraction separately, the risk was nominally higher for heart failure with preserved ejection fraction., Conclusions: Major incident cardiovascular disease events were associated with ESKD, independent of kidney risk factors. In particular, heart failure showed a very strong association with ESKD. Our findings highlight the importance of monitoring and managing kidney disease in patients with cardiovascular disease. The potentially distinct contribution to ESKD of heart failure with preserved versus reduced ejection fraction deserves future investigation., (Copyright © 2020 by the American Society of Nephrology.)

Importance: In the 2017 American College of Cardiology (ACC)/American Heart Association (AHA) guideline, the definition of hypertension was lowered from a blood pressure (BP) of greater than or equal to 140/90 to greater than or equal to 130/80 mm Hg. The new diastolic BP threshold of 80 mm Hg was recommended based on expert opinion and changes the definition of isolated diastolic hypertension (IDH)., Objective: To compare the prevalence of IDH in the United States, by 2017 ACC/AHA and 2003 Joint National Committee (JNC7) definitions, and to characterize cross-sectional and longitudinal associations of IDH with outcomes., Design, Setting, and Participants: Cross-sectional analyses of the National Health and Nutrition Examination Survey (NHANES 2013-2016) and longitudinal analyses of the Atherosclerosis Risk in Communities (ARIC) Study (baseline 1990-1992, with follow-up through December 31, 2017). Longitudinal results were validated in 2 external cohorts: (1) the NHANES III (1988-1994) and NHANES 1999-2014 and (2) the Give Us a Clue to Cancer and Heart Disease (CLUE) II cohort (baseline 1989)., Exposures: IDH, by 2017 ACC/AHA (systolic BP <130 mm Hg, diastolic BP ≥80 mm Hg) and by JNC7 (systolic BP <140 mm Hg, diastolic BP ≥90 mm Hg) definitions., Main Outcomes and Measures: Weighted estimates for prevalence of IDH in US adults and prevalence of US adults recommended BP pharmacotherapy by the 2017 ACC/AHA guideline based solely on the presence of IDH. Risk of incident atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), and chronic kidney disease (CKD) in the ARIC Study., Results: The study population included 9590 adults from the NHANES (mean [SD] baseline age, 49.6 [17.6] years; 5016 women [52.3%]) and 8703 adults from the ARIC Study (mean [SD] baseline age, 56.0 [5.6] years; 4977 women [57.2%]). The estimated prevalence of IDH in the NHANES was 6.5% by the 2017 ACC/AHA definition and 1.3% by the JNC7 definition (absolute difference, 5.2% [95% CI, 4.7%-5.7%]). Among those newly classified as having IDH, an estimated 0.6% (95% CI, 0.5%-0.6%) also met the guideline threshold for antihypertensive therapy. Compared with normotensive ARIC participants, IDH by the 2017 ACC/AHA definition was not significantly associated with incident ASCVD (n = 1386 events; median follow-up, 25.2 years; hazard ratio [HR], 1.06 [95% CI, 0.89-1.26]), HF (n = 1396 events; HR, 0.91 [95% CI, 0.76-1.09]), or CKD (n = 2433 events; HR, 0.98 [95% CI, 0.65-1.11]). Results were also null for cardiovascular mortality in the 2 external cohorts (eg, HRs of IDH by the 2017 ACC/AHA definition were 1.17 [95% CI, 0.87-1.56] in the NHANES [n = 1012 events] and 1.02 [95% CI, 0.92-1.14] in CLUE II [n = 1497 events])., Conclusions and Relevance: In this analysis of US adults, the estimated prevalence of IDH was more common when defined by the 2017 ACC/AHA BP guideline compared with the JNC7 guideline. However, IDH was not significantly associated with increased risk for cardiovascular outcomes.

Whether persons without prevalent cardiovascular disease (CVD) but elevated levels of high-sensitivity cardiac troponin T (hs-cTnT) or N-terminal pro-B-type natriuretic peptide (NT-proBNP) are at high risk of infection is unknown. Using 1996-2013 data from the Atherosclerosis Risk in Communities Study, we estimated hazard ratios for incident hospitalization with infection in relation to plasma hs-cTnT and NT-proBNP concentrations among participants without prevalent CVD and contrasted them with hazard ratios for persons with prevalent CVD (coronary heart disease, heart failure, or stroke). In a multivariable Cox model, prevalent CVD was significantly associated with risk of hospitalization with infection (hazard ratio (HR) = 1.31, 95% confidence interval (CI): 1.19, 1.45). Among participants without prevalent CVD, hs-cTnT and NT-proBNP were independently associated with infection risk in a graded fashion (e.g., HR = 1.44 (95% CI: 1.24, 1.69) for hs-cTnT ≥14 ng/L and HR = 1.28 (95% CI: 1.14, 1.44) for hs-cTnT 9-13 ng/L vs. <3 ng/L; HR = 1.57 (95% CI: 1.35, 1.81) for NT-proBNP ≥248.1 pg/mL and HR = 1.19 (95% CI: 1.06, 1.34) for NT-proBNP 137.2-248.0 pg/mL vs. <48.1 pg/mL). The 15-year cumulative incidences of hospitalization with infection were similar for participants with prevalent CVD and participants who did not have prevalent CVD but had hs-cTnT ≥14 ng/L or NT-proBNP ≥248.1 pg/mL. Thus, hs-cTnT and NT-proBNP were independently associated with infection risk. Persons without CVD but with elevated hs-cTnT or NT-proBNP levels should be recognized to have similar infection risks as persons with prevalent CVD., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.

Background: Two coding variants in the apo L1 gene ( APOL1 ) are strongly associated with kidney disease in blacks. Kidney disease itself increases the risk of cardiovascular disease, but whether these variants have an independent direct effect on the risk of cardiovascular disease is unclear. Previous studies have had inconsistent results., Methods: We conducted a two-stage individual participant data meta-analysis to assess the association of APOL1 kidney-risk variants with adjudicated cardiovascular disease events and death, independent of kidney measures. The analysis included 21,305 blacks from eight large cohorts., Results: Over 8.9±5.0 years of follow-up, 2076 incident cardiovascular disease events occurred in the 16,216 participants who did not have cardiovascular disease at study enrollment. In fully-adjusted analyses, individuals possessing two APOL1 kidney-risk variants had similar risk of incident cardiovascular disease (coronary heart disease, myocardial infarction, stroke and heart failure; hazard ratio 1.11, 95% confidence interval, 0.96 to 1.28) compared to individuals with zero or one kidney-risk variant. The risk of coronary heart disease, myocardial infarction, stroke and heart failure considered individually was also comparable by APOL1 genotype. APOL1 genotype was also not associated with death. There was no difference in adjusted associations by level of kidney function, age, diabetes status, or body-mass index., Conclusions: In this large, two-stage individual participant data meta-analysis, APOL1 kidney-risk variants were not associated with incident cardiovascular disease or death independent of kidney measures., (Copyright © 2019 by the American Society of Nephrology.)

Background: Cardiovascular guidelines include risk prediction models for decision making that lack the capacity to include novel predictors.Methods and Results:We explored a new "predictor patch" approach to calibrating the predicted risk from a base model according to 2 components from outside datasets: (1) the difference in observed vs. expected values of novel predictors and (2) the hazard ratios (HRs) for novel predictors, in a scenario of adding kidney measures for cardiovascular mortality. Using 4 US cohorts (n=54,425) we alternately chose 1 as the base dataset and constructed a base prediction model with traditional predictors for cross-validation. In the 3 other "outside" datasets, we developed a linear regression model with traditional predictors for estimating expected values of glomerular filtration rate and albuminuria and obtained their adjusted HRs of cardiovascular mortality, together constituting a "patch" for adding kidney measures to the base model. The base model predicted cardiovascular mortality well in each cohort (c-statistic 0.78-0.91). The addition of kidney measures using a patch significantly improved discrimination (cross-validated ∆c-statistic 0.006 [0.004-0.008]) to a similar degree as refitting these kidney measures in each base dataset., Conclusions: The addition of kidney measures using our new "predictor patch" approach based on estimates from outside datasets improved cardiovascular mortality prediction based on traditional predictors, providing an option to incorporate novel predictors to an existing prediction model.

Background Previous studies have documented the cardiometabolic health benefits of plant-based diets; however, these studies were conducted in selected study populations that had narrow generalizability. Methods and Results We used data from a community-based cohort of middle-aged adults (n=12 168) in the ARIC (Atherosclerosis Risk in Communities) study who were followed up from 1987 through 2016. Participants' diet was classified using 4 diet indexes. In the overall plant-based diet index and provegetarian diet index, higher intakes of all or selected plant foods received higher scores; in the healthy plant-based diet index, higher intakes of only the healthy plant foods received higher scores; in the less healthy plant-based diet index, higher intakes of only the less healthy plant foods received higher scores. In all indexes, higher intakes of animal foods received lower scores. Results from Cox proportional hazards models showed that participants in the highest versus lowest quintile for adherence to overall plant-based diet index or provegetarian diet had a 16%, 31% to 32%, and 18% to 25% lower risk of cardiovascular disease, cardiovascular disease mortality, and all-cause mortality, respectively, after adjusting for important confounders (all P<0.05 for trend). Higher adherence to a healthy plant-based diet index was associated with a 19% and 11% lower risk of cardiovascular disease mortality and all-cause mortality, respectively, but not incident cardiovascular disease (P<0.05 for trend). No associations were observed between the less healthy plant-based diet index and the outcomes. Conclusions Diets higher in plant foods and lower in animal foods were associated with a lower risk of cardiovascular morbidity and mortality in a general population.

Background In patients with myocardial infarction ( MI ), reduced kidney function is recognized as an important predictor of poor prognosis, but the impact of albuminuria, a representative measure of kidney damage, has not been extensively evaluated. Methods and Results In the SCREAM (Stockholm Creatinine Measurements) project (2006-2012), we identified 2469 patients with incident MI with dipstick proteinuria measured within a year before MI (427 patients also had urine albumin to creatinine ratio [ ACR ] measured concurrently) and obtained estimates for ACR with multiple imputation in participants with data solely on dipstick proteinuria. We quantified the association of ACR with the post- MI composite and individual outcomes of all-cause mortality, cardiovascular mortality, recurrent MI , ischemic stroke, or heart failure using Cox models and then evaluated the improvement in C statistic. During a median follow-up of 1.0 year after MI , 1607 participants (65.1%) developed the post- MI composite outcome. Higher ACR levels were independently associated with all outcomes except for ischemic stroke. Per 8-fold higher ACR (eg, 40 versus 5 mg/g), the hazard ratio of composite outcome was 1.21 (95% CI , 1.08-1.35). The addition of the ACR improved the C statistic of the post- MI composite by 0.040 (95% CI, 0.030-0.051). Largely similar results were obtained regardless of diabetic status and when ACR or dipstick was separately analyzed without imputation. Conclusions In patients with MI , albuminuria was a potent predictor of subsequent outcomes, suggesting the importance of paying attention to the information on albuminuria, in addition to kidney function, in this high-risk population.

Background and Aims: Diabetes increases risk for atherosclerotic cardiovascular disease (ASCVD). Current guidelines do not recommend measuring lipoprotein(a), another ASCVD risk factor, in these individuals. We examined the association of lipoprotein(a) levels with incident ASCVD events in persons with and without diabetes or prediabetes., Methods: Lipoprotein(a) and other ASCVD risk factors were measured at baseline (1996-1998) in the biracial Atherosclerosis Risk in Communities study; participants without prevalent ASCVD (coronary heart disease or stroke) were monitored ∼15 years for incident ASCVD events., Results: Of 9871 eligible participants (mean age 63 years; 5816 women; 2155 African Americans), 1543 had diabetes and 3615 had prediabetes. Cumulative ASCVD incidence rates (event/1000-person years) were higher in participants with diabetes (26%) or prediabetes (13%) than in nondiabetic individuals (10%, p < 0.001). When comparing highest to lowest lipoprotein(a) categories (≥50 mg/dL vs. ≤10 mg/dL), increasing lipoprotein(a) levels were significantly associated with increasing incident ASCVD events in Caucasian participants with prediabetes (hazard ratio [HR] = 1.35; 95% confidence interval [CI] 1.07-1.69); p = 0.03) and diabetes (HR = 1.42; 95% CI 1.10-1.84; p < 0.01), but not those with normal fasting blood glucose. Adding lipoprotein(a) to Pooled Cohort Equation variables improved risk prediction in persons with diabetes (Δ in area under the receiver operating characteristic curve [AUC] 0.0087, net reclassification index [NRI] 0.1761) and prediabetes (ΔAUC 0.0025, NRI 0.0938)., Conclusions: In this biracial cohort, elevated lipoprotein(a) levels in Caucasian individuals with diabetes or prediabetes were associated with further increased ASCVD risk. Adding lipoprotein(a) to traditional risk factors improved ASCVD risk prediction., (Copyright © 2018. Published by Elsevier B.V.)

Rationale & Objective: Arterial stiffness is suggested as a mediator of cardiorenal interaction. However, previous studies reported inconsistent associations between chronic kidney disease (CKD) and arterial stiffness and were limited by using either estimated glomerular filtration rate (eGFR) or albumin-creatinine ratio (ACR) and examining arterial stiffness at limited segments., Study Design: Cross-sectional., Setting & Participants: 3,424 Atherosclerosis in Communities (ARIC) Study participants aged 66 to 90 years during 2011 to 2013., Predictors: eGFR and ACR., Outcome: Pulse wave velocity (PWV) at 6 segments: carotid-femoral (cfPWV), heart-carotid (hcPWV), and heart-femoral (hfPWV), reflecting central stiffness; heart-ankle (haPWV) and brachial-ankle (baPWV), representing both central and peripheral stiffness; and femoral-ankle (faPWV), indicating peripheral stiffness., Analytical Approach: Multiple linear and logistic regression models to quantify the associations of eGFR and ACR with continuous PWV and elevated PWV (in the highest quartile), respectively., Results: After adjusting for age, sex, and race, higher cfPWV and hfPWV were consistently associated with lower eGFR and higher ACR. Higher haPWV and baPWV were also observed with higher ACR. The independent association of both CKD measures with elevated cfPWV remained consistent after adjusting for additional confounders (ORs of elevated cfPWV were 1.09 [95% CI, 1.01-1.18] per 15-mL/min/1.73m 2 lower eGFR and 1.20 [95% CI, 1.07-1.33] per 4-fold higher ACR). Higher ACR was also associated with elevated hfPWV and haPWV (ORs per 4-fold higher ACR were 1.25 [95% CI, 1.12-1.39] for elevated hfPWV and 1.19 [95% CI, 1.06-1.33] for elevated haPWV). Lower eGFR was associated with lower odds of elevated baPWV and faPWV (ORs per 15-mL/min/1.73m 2 lower eGFR were 0.92 [95% CI, 0.84-0.99] and 0.91 [95% CI, 0.85-0.99], respectively)., Limitation: Unable to address temporality between CKD measures and arterial stiffness., Conclusions: Both lower eGFR and higher ACR are independently associated with measures of central arterial stiffness, with stronger associations for ACR over eGFR. Our findings suggest that central arterial stiffness may be an important pathophysiologic phenotype of vascular disease in CKD., (Copyright © 2018 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Introduction: The interplay between midlife vascular risk factors and midlife cognitive function with later life mild cognitive impairment (MCI) and dementia (DEM) is not well understood., Methods: In the Atherosclerosis Risk in Communities Study, cardiovascular risk factors and cognition were assessed in midlife, ages 45-64 years. In 2011-2013, 20-25 years later, all consenting Atherosclerosis Risk in Communities participants underwent a cognitive and neurological evaluation and were given adjudicated diagnoses of cognitively normal, MCI, or DEM., Results: In 5995 participants with complete covariate data, midlife diabetes, hypertension, obesity, and hypercholesterolemia were associated with late-life MCI and DEM. Low midlife cognition function was also associated with greater likelihood of late-life MCI or DEM. Both midlife vascular risk factors and midlife cognitive function remained associated with later life MCI or DEM when both were in the model., Discussion: Later life MCI and DEM were independently associated with midlife vascular risk factors and midlife cognition., (Copyright © 2018 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Background: Loss-of-function mutations in the SGLT1 (sodium/glucose co-transporter-1) gene result in a rare glucose/galactose malabsorption disorder and neonatal death if untreated. In the general population, variants related to intestinal glucose absorption remain uncharacterized., Objectives: The goal of this study was to identify functional SGLT1 gene variants and characterize their clinical consequences., Methods: Whole exome sequencing was performed in the ARIC (Atherosclerosis Risk in Communities) study participants enrolled from 4 U.S. communities. The association of functional, nonsynonymous substitutions in SGLT1 with 2-h oral glucose tolerance test results was determined. Variants related to impaired glucose tolerance were studied, and Mendelian randomization analysis of cardiometabolic outcomes was performed., Results: Among 5,687 European-American subjects (mean age 54 ± 6 years; 47% male), those who carried a haplotype of 3 missense mutations (frequency of 6.7%)-Asn51Ser, Ala411Thr, and His615Gln-had lower 2-h glucose and odds of impaired glucose tolerance than noncarriers (β-coefficient: -8.0; 95% confidence interval [CI]: -12.7 to -3.3; OR: 0.71; 95% CI: 0.59 to 0.86, respectively). The association of the haplotype with oral glucose tolerance test results was consistent in a replication sample of 2,791 African-American subjects (β = -16.3; 95% CI: -36.6 to 4.1; OR: 0.39; 95% CI: 0.17 to 0.91) and an external European-Finnish population sample of 6,784 subjects (β = -3.2; 95% CI: -6.4 to -0.02; OR: 0.81; 95% CI: 0.68 to 0.98). Using a Mendelian randomization approach in the index cohort, the estimated 25-year effect of a reduction of 20 mg/dl in 2-h glucose via SGLT1 inhibition would be reduced prevalent obesity (OR: 0.43; 95% CI: 0.23 to 0.63), incident diabetes (hazard ratio [HR]: 0.58; 95% CI: 0.35 to 0.81), heart failure (HR: 0.53; 95% CI: 0.24 to 0.83), and death (HR: 0.66; 95% CI: 0.42 to 0.90)., Conclusions: Functionally damaging missense variants in SGLT1 protect from diet-induced hyperglycemia in multiple populations. Reduced intestinal glucose uptake may protect from long-term cardiometabolic outcomes, providing support for therapies that target SGLT1 function to prevent and treat metabolic conditions., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Hypertriglyceridemia is associated with increased remnant-like particle cholesterol (RLP-C) and triglycerides in low-density lipoprotein (LDL-TG). Recent studies have focused on atherogenicity of RLP-C, with few data on LDL-TG., Objectives: The aim of this study was to examine associations of RLP-C and LDL-TG with incident cardiovascular disease (CVD) events and genetic variants in the ARIC (Atherosclerosis Risk In Communities) study., Methods: Fasting plasma RLP-C and LDL-TG levels were measured in 9,334 men and women without prevalent CVD. Participants were followed for incident CVD events (coronary heart disease and ischemic stroke) for up to 16 years. Associations between LDL-TG and RLP-C levels and genetic variants were assessed by whole-exome sequencing using single-variant analysis for common variants and gene-based burden tests for rare variants; both an unbiased and a candidate gene approach were explored., Results: RLP-C and LDL-TG levels were correlated with triglyceride levels (r = 0.85 and r = 0.64, p < 0.0001). In minimally adjusted analyses, RLP-C and LDL-TG were associated with CVD risk, but in models adjusted for traditional risk factors including lipids, only LDL-TG was associated with incident CHD (hazard ratio: 1.28; 95% confidence interval: 1.10 to 1.50) and stroke (hazard ratio: 1.47; 95% confidence interval: 1.13 to 1.92). A common APOE variant, rs7412, had the strongest association with LDL-TG and RLP-C (p < 5 × 10 -8 )., Conclusions: RLP-C and LDL-TG levels were predictive of CVD and associated with APOE variants. LDL-TG may represent a marker of dysfunctional remnant lipoprotein metabolism associated with increased CVD risk. Further research is needed to determine whether LDL-TG plays a causal role in CVD and may be a target for therapy., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The Thrombolysis in Myocardial Infarction (TIMI) Risk Score for Secondary Prevention (TRS2°P), a 0-to-9-point system based on the presence/absence of 9 clinical factors, was developed to classify the risk of major adverse cardiovascular events (MACE) (a composite of cardiovascular death, recurrent myocardial infarction, or ischemic stroke) among patients with a recent myocardial infarction. Its performance has not been examined internationally outside of a clinical trial setting., Methods and Results: We evaluated the performance of TRS2°P for predicting MACE in 53 599 patients with recent myocardial infarction in 5 international cohorts from New Zealand, South Korea, Sweden, and the United States participating in the Chronic Kidney Disease Prognosis Consortium. Overall, there were 19 444 cases of MACE across 5 cohorts over a mean follow-up of 5 years, and the overall MACE rate ranged from 5.0 to 18.4 (per 100 person-years). The TRS2°P showed modest calibration (Brier score ranged from 0.144 to 0.173) and discrimination (C-statistics >0.61 in all studies except 1 from Korea with 0.55) across cohorts relative to its original Brier score of 0.098 and C-statistic of 0.67 in the derived data set. Although there was some heterogeneity across cohorts, the 9 predictors in the TRS2°P were generally associated with higher MACE risk, with strongest associations observed (meta-analyzed adjusted hazard ratio 1.6-1.7) for history of heart failure, age ≥75 years, and prior stroke, followed by peripheral artery disease, kidney dysfunction, diabetes mellitus, and hypertension (hazard ratio 1.3-1.4). Prior coronary bypass graft surgery and smoking did not reach statistical significance (hazard ratio ≈1.1)., Conclusions: TRS2°P, a simple scoring system with 9 routine clinical factors, was modestly predictive of secondary events when applied in patients with recent myocardial infarction from diverse clinical and geographic settings., (© 2018 The Authors and Merck Sharpe & Dohme Corp. Published on behalf of the American Heart Association, Inc., by Wiley.)