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Quinn S Wells,1,2 Eric Farber-Eger,1,2 Loren Lipworth,2,3 Paul Dluzniewski,4 Ricardo Dent,4 John Umeijiego,4 Sarah S Cohen3,5 1Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; 2Vanderbilt Translational and Clinical Cardiovascular Research Center (VTRACC), Vanderbilt University Medical Center, Nashville, TN, USA; 3Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; 4Center for Observational Research, Amgen, Inc., Thousand Oaks, CA, USA; 5Epidstrategies, A Division of Toxstrategies, Inc., Cary, NC, USACorrespondence: Sarah S Cohen Tel +1 919-885-0548Email scohen@epidstrategies.comPurpose: Given known differences between real-world and clinical trial populations, we characterized demographics, clinical characteristics, and outcomes using real-world (RW) data for patients with heart failure with reduced ejection fraction (HFrEF), including those similar to subjects enrolled in an HFrEF clinical trial to better understand patient populations that could benefit from novel therapies.Patients and Methods: Using Vanderbilt University Medical Center electronic health records (2006– 2019), two RW cohorts of HFrEF patients were identified. The “Clinical Cohort” was based on a validated HFrEF algorithm and left ventricular ejection fraction (LVEF) ≤ 40%. The “GALACTIC-HF-like Cohort” mirrored enrollment requirements of the GALACTIC-HF clinical trial including hospitalizations, medications, laboratory values, and LVEF ≤ 35%.Results: Median age at index for the Clinical Cohort (N = 3954) and GALACTIC-HF-like Cohort (N = 1541) were 65 and 61 years, respectively; both were 67% male and 80% white. Over half had coronary artery disease (55% Clinical vs 64% GALACTIC-HF-like); hypercholesterolemia was common (69% Clinical vs 74% GALACTIC-HF-like). Chronic kidney disease (31 vs 21%), atrial fibrillation (32 vs 29%), and cardiac resynchronization or implantable cardioverter defibrillator (26 vs 23%) were higher in the GALACTIC-HF-like Cohort. ACE inhibitor use was high in both groups but more common in the GALACTIC-HF-like Cohort (71% and 82%, respectively). Beta-blockers or loop diuretics were used by > 90% of both cohorts. HF hospitalization rates were 261 (95% CI 224, 297) per 1000 person-years in Clinical versus 523 (484, 562) in GALACTIC-HF-like Cohort (median follow-up of 2.9 and 4.2 years, respectively).Conclusion: Approximately 40% of RW HFrEF patients met criteria for the GALACTIC-HF trial. While findings of ongoing clinical trials may be directly generalizable to this sizable proportion of patients, future trials should examine whether the majority of patients with lower prevalence of comorbidities and rate of HF hospitalization could benefit from emerging HF treatments.Keywords: heart failure, reduced ejection fraction, real-world evidence, electronic health record

ObjectiveBody mass index (BMI) is commonly used to assess obesity, which is associated with numerous diseases and negative health outcomes. BMI has been shown to be a heritable, polygenic trait, with close to 100 loci previously identified and replicated in multiple populations. We aim to replicate known BMI loci and identify novel associations in a trans-ethnic study population.SubjectsUsing eligible participants from the Population Architecture using Genomics and Epidemiology consortium, we conducted a trans-ethnic meta-analysis of 102 514 African Americans, Hispanics, Asian/Native Hawaiian, Native Americans and European Americans. Participants were genotyped on over 200 000 SNPs on the Illumina Metabochip custom array, or imputed into the 1000 Genomes Project (Phase I). Linear regression of the natural log of BMI, adjusting for age, sex, study site (if applicable), and ancestry principal components, was conducted for each race/ethnicity within each study cohort. Race/ethnicity-specific, and combined meta-analyses used fixed-effects models.ResultsWe replicated 15 of 21 BMI loci included on the Metabochip, and identified two novel BMI loci at 1q41 (rs2820436) and 2q31.1 (rs10930502) at the Metabochip-wide significance threshold (P

Hepatic steatosis is a central phenotype in multi-system metabolic dysfunction and is increasing in parallel with the obesity pandemic. We use a translational approach integrating clinical phenotyping and outcomes, circulating proteomics, and tissue transcriptomics to identify dynamic, functional biomarkers of hepatic steatosis. Using multi-modality imaging and broad proteomic profiling, we identify proteins implicated in the progression of hepatic steatosis that are largely encoded by genes enriched at the transcriptional level in the human liver. These transcripts are differentially expressed across areas of steatosis in spatial transcriptomics, and several are dynamic during stages of steatosis. Circulating multi-protein signatures of steatosis strongly associate with fatty liver disease and multi-system metabolic outcomes. Using a humanized "liver-on-a-chip" model, we induce hepatic steatosis, confirming cell-specific expression of prioritized targets. These results underscore the utility of this approach to identify a prognostic, functional, dynamic "liquid biopsy" of human liver, relevant to biomarker discovery and mechanistic research applications., Competing Interests: Declaration of interests R.S., J.E.B., and A.S.P. have filed for a patent relevant to the findings in this manuscript. R.S. is supported in part by grants from the National Institutes of Health (NIH) and the American Heart Association (AHA). R.S. has equity ownership in Thryv Therapeutics and has served as a consultant for Amgen and Cytokinetics. R.S. is a co-inventor on a patent for ex-RNA signatures of cardiac remodeling (not relevant to the current work), and other patents on proteomic signatures of fitness and lung disease. A.S.P. and E.C. are supported by the AHA Strategically Focused Research Network in Cardiometabolic Disease. J.F.K.S. and G.M. are employees of Emulate, Inc. (a maker of the liver-on-a-chip) and may hold equity interest in Emulate, Inc. S.D. holds a research grant from Bristol Myers Squibb, is a founder and holds equity in Switch Therapeutics, and is a founder and consultant and holds equity for Thryv Therapeutics. J.K. has served as a consultant to Gilead, Merck, ViiV Healthcare, and Janssen and also received research support from Gilead Sciences and Merck. R.K. is supported in part by grants from the NIH; has received grants from AstraZeneca, PneumRx/BTG, and Spiration; has received consulting fees from CVS Caremark, AstraZeneca, GlaxoSmithKline, and CSA Medical; and has received speaking fees from GlaxoSmithKline, AstraZeneca, and Boehringer Ingelheim. K.A. is supported by an AHA Career Development Award (#929347). J.A.F. serves as a consultant or advisory board member for Kynos Therapeutics, Resolution Therapeutics, Ipsen, River 2 Renal Corp., Stimuliver, Global Clinical Trial Partners, and Guidepoint and has received speaker’s fees from HistoIndex and research grant funding from GlaxoSmithKline, Intercept Pharmaceuticals, and Genentech. T.J.K. undertakes consultancy work for Perspectum, Clinnovate Health, Kynos Therapeutics, Fibrofind, HistoIndex, Concept Life Sciences, and Resolution Therapeutics and has received speaker’s fees from Incyte Corporation and Servier Laboratories. K.V.K.-J. is a member of the scientific advisory board at Dyrnamix. J.J.C. receives project funding from GE Healthcare, Siemens Healthineers, TheraTech, and the NIH. M.N. has received speaking honoraria from Cytokinetics., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Obesity and metabolic dysregulation (MetD) have increasing prevalence and adversely affect asthma morbidity and therapeutic response., Objective: To determine the role of weight and MetD on incident asthma in adulthood., Methods: In a retrospective, longitudinal cohort of patients, we performed a time-to-asthma diagnosis analysis after a 3-year landmark period (t 0 -t 3 ) during which weight and MetD components were evaluated. We assessed incident asthma risk with MetD components and weight., Results: In total, 90,081 patients met the inclusion criteria, with 836 cases (0.93%) of incident asthma in our primary cohort. Diabetes present at t 0 , but no other MetD components, was associated with increased risk of asthma (adjusted hazard ratio = 1.85, 95% CI: 1.27-2.71, P = .0002). The effect of weight on asthma risk, independent of other MetD components, identified individuals with overweight or obesity as having a 10-year attributable risk of 15.4%. Metformin was prescribed more frequently, and hemoglobin A1c levels were lower in patients with diabetes in whom asthma did not develop (P < .0001)., Conclusion: Weight and diabetes prevention and management represent modifiable risk factors for adult asthma development., Competing Interests: Disclosures Dr Bacharier reports personal fees from GlaxoSmithKline, Genentech/Novartis, Merck, DBV Technologies, Teva, Boehringer Ingelheim, AstraZeneca, Avillion, WebMD/Medscape, Sanofi/Regeneron, Vectura, Circassia, OM Pharma, Elsevier, Kinaset, and Vertex outside the submitted work. Dr Cahill served on scientific advisory boards for AstraZeneca, Sanofi, Genentech, Regeneron, Novartis, and GlaxoSmithKline; served as a consultant for Ribon Therapeutics, Third Harmonic Bio, and Verantos; reports royalties from UpToDate; and reports research support from Novo Nordisk. The remaining authors have no conflicts of interest to report., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The objective of this study was to determine the unique clinical and cardiometabolic risk characteristics of weight-cyclers and identify differences between weight-cyclers and individuals with other weight-change trajectories., Methods: A deidentified database of 1,428,204 Vanderbilt University Medical Center patients from 1997 to 2020 was included based on having ≥5 years of recorded weights. Patients with a history of malignant neoplasm, bariatric surgery, implausible BMI (e.g., <15 or >80 kg/m 2 ), or missing documented height were excluded, yielding 83,261 participants categorized by weight trajectory, i.e., weight-stable, weight-gainer, weight-loser, or weight-cycler, based on criteria of ≥5% weight-change thresholds. Additionally, quartiles of average successive weight variability were evaluated to determine the effect of absolute differences among successive weight values., Results: Over half (55%) of participants were weight-cyclers, 23% were weight-gainers, 12% were weight-losers, and 10% were weight-stable over 5 years. Although baseline BMI did not differ among groups, weight-cyclers were more likely to have lower high-density lipoprotein cholesterol and higher blood glucose and triglyceride levels and to have been prescribed antihypertensive, dyslipidemia, and/or antidiabetic therapies. They were also younger and more likely to be smokers. Participants with the greatest weight variability (i.e., highest quartile of average successive weight variability) had higher cardiometabolic risk scores., Conclusions: Weight cycling was highly prevalent but yielded no meaningful overall change in body weight after 5 years. These findings support a paradigm shift in weight management in individuals with overweight/obesity toward reducing cardiometabolic risk with or without weight loss., (© 2024 The Author(s). Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.)

Given expanding studies in epidemiology and disease-oriented human studies offering hundreds of associations between the human "ome" and disease, prioritizing molecules relevant to disease mechanisms among this growing breadth is important. Here, we link the circulating proteome to human heart failure (HF) propensity (via echocardiographic phenotyping and clinical outcomes) across the lifespan, demonstrating key pathways of fibrosis, inflammation, metabolism, and hypertrophy. We observe a broad array of genes encoding proteins linked to HF phenotypes and outcomes in clinical populations dynamically expressed at a transcriptional level in human myocardium during HF and cardiac recovery (several in a cell-specific fashion). Many identified targets do not have wide precedent in large-scale genomic discovery or human studies, highlighting the complementary roles for proteomic and tissue transcriptomic discovery to focus epidemiological targets to those relevant in human myocardium for further interrogation., Competing Interests: Declaration of interests S.G.D. is a consultant for Abbott, and S.G.D. and K.J.L. have industry research support from Novartis. R.V.S. has served as a consultant for Amgen, Cytokinetics, and Thryv Therapeutics (with options ownership in Thryv). R.V.S. is a co-inventor on a patent for ex-RNA signatures of cardiac remodeling and a pending patent on proteomic signatures of fitness and lung and liver diseases. R.V.S. also has stock options with Thryv Therapeutics. A.S.P. is a co-inventor on a pending patent for proteomic signatures of fitness, lung, and liver diseases. K.A. does ad hoc consulting for Tegus and Guidepoint and serves on a DSMB for Fortrea. M.N. has received speaking honoraria from Cytokinetics. K.J.L. serves as a consultant for Medtronic, Implicit Biosciences, Kiniksa Pharmaceuticals, and Cytokinetics. K.J.L. receives grant support from Amgen, Novartis, Kiniksa Pharmaceuticals, and Implicit Biosciences. S.D. is a co-founder and has equity in Thryv therapeutics and Switch Therapeutics. S.D. has received grant support from Abbot Laboratories and Bristol Myers Squib. S.D. is a co-inventor on a patent on tissue-specific EV-RNAs. R.K. has received personal fees from GSK, Astrazeneca, Boehringer Ingelheim, and CVS Caremark. S.J.S. has received consulting fees from 35Pharma, Abbott, Alleviant, AstraZeneca, Amgen, Aria CV, Axon Therapies, BaroPace, Bayer, Boehringer-Ingelheim, Boston Scientific, BridgeBio, Bristol Myers Squibb, Corvia, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, eMyosound, Imara, Impulse Dynamics, Intellia, Ionis, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, ReCor, Regeneron, Rivus, SalubriusBio, Sardocor, Shifamed, Tectonic, Tenax, Tenaya, Ulink, and Ultromics. J.M.A. was employed by Amgen. J.W. reports consulting/scientific advisory board for Abiomed, Abbott, Astra Zeneca, Boehringer Ingelheim, and Cytokinetics within the last 24 months., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Rationale: Accelerated decline in lung function is associated with incident COPD, hospitalizations and death. However, identifying this trajectory with longitudinal spirometry measurements is challenging in clinical practice., Objective: To determine whether a proteomic risk score trained on accelerated decline in lung function can assess risk of future respiratory disease and mortality., Methods: In CARDIA, a population-based cohort starting in young adulthood, longitudinal measurements of FEV1 percent predicted (up to six timepoints over 30 years) were used to identify accelerated and normal decline trajectories. Protein aptamers associated with an accelerated decline trajectory were identified with multivariable logistic regression followed by LASSO regression. The proteomic respiratory susceptibility score was derived based on these circulating proteins and applied to the UK Biobank and COPDGene studies to examine associations with future respiratory morbidity and mortality., Measurements and Results: Higher susceptibility score was independently associated with all-cause mortality (UKBB: HR 1.56, 95%CI 1.50-1.61; COPDGene: HR 1.75, 95%CI 1.63-1.88), respiratory mortality (UKBB: HR 2.39, 95% CI 2.16-2.64; COPDGene: HR 1.83, 95%CI 1.33-2.51), incident COPD (UKBB: HR 1.84, 95%CI 1.71-1.98), incident respiratory exacerbation (COPDGene: OR 1.11, 95%CI 1.03-1.20), and incident exacerbation requiring hospitalization (COPDGene: OR 1.18, 95%CI 1.08-1.28)., Conclusions: A proteomic signature of increased respiratory susceptibility identifies people at risk of respiratory death, incident COPD, and respiratory exacerbations. This susceptibility score is comprised of proteins with well-known and novel associations with lung health and holds promise for the early detection of lung disease without requiring years of spirometry measurements.

Heart failure (HF) is a significant health burden, with two major clinical subtypes: HF with reduced (HFrEF) and preserved ejection fraction (HFpEF). Blood pressure and lipid profile are established risk factors of HF. We performed univariable and multivariable Mendelian randomization (MR) analyses to assess potential causal effects of blood pressures and lipids on HF subtypes. Genetic instruments for blood pressures and lipids were derived from genome-wide association studies (GWASs) among the European participants of the UK Biobank. GWAS summaries of HFrEF and HFpEF were obtained from the meta-analysis of the European participants from the Million Veteran Program and the Vanderbilt University DNA Databank. Systolic blood pressure exhibited a supportive MR association primarily with HFpEF (odds ratio [OR], 1.14; 95% confidence interval [CI], 1.04-1.23), while diastolic blood pressure had an independent MR association with HFrEF (OR, 1.43; 95% CI, 1.13-1.77). MR associations also supported the observation that higher levels of low-density lipoprotein cholesterol increase the risk for both subtypes (HFrEF OR, 1.10 and 95% CI, 1.05-1.17; HFpEF OR, 1.05 and 95% CI, 1.02-1.09). These findings underscore differences in HF subtype-specific risk profiles and mechanisms, which may lead to different interventional strategies for different HF subtypes.

Aims: The lymphocyte adaptor protein (LNK) is a negative regulator of cytokine and growth factor signalling. The rs3184504 variant in SH2B3 reduces LNK function and is linked to cardiovascular, inflammatory, and haematologic disorders, including stroke. In mice, deletion of Lnk causes inflammation and oxidative stress. We hypothesized that Lnk-/- mice are susceptible to atrial fibrillation (AF) and that rs3184504 is associated with AF and AF-related stroke in humans. During inflammation, reactive lipid dicarbonyls are the major components of oxidative injury, and we further hypothesized that these mediators are critical drivers of the AF substrate in Lnk-/- mice., Methods and Results: Lnk-/- or wild-type (WT) mice were treated with vehicle or 2-hydroxybenzylamine (2-HOBA), a dicarbonyl scavenger, for 3 months. Compared with WT, Lnk-/- mice displayed increased AF duration that was prevented by 2-HOBA. In the Lnk-/- atria, action potentials were prolonged with reduced transient outward K+ current, increased late Na+ current, and reduced peak Na+ current, pro-arrhythmic effects that were inhibited by 2-HOBA. Mitochondrial dysfunction, especially for Complex I, was evident in Lnk-/- atria, while scavenging lipid dicarbonyls prevented this abnormality. Tumour necrosis factor-α (TNF-α) and interleukin-1 beta (IL-1β) were elevated in Lnk-/- plasma and atrial tissue, respectively, both of which caused electrical and bioenergetic remodelling in vitro. Inhibition of soluble TNF-α prevented electrical remodelling and AF susceptibility, while IL-1β inhibition improved mitochondrial respiration but had no effect on AF susceptibility. In a large database of genotyped patients, rs3184504 was associated with AF, as well as AF-related stroke., Conclusion: These findings identify a novel role for LNK in the pathophysiology of AF in both experimental mice and humans. Moreover, reactive lipid dicarbonyls are critical to the inflammatory AF substrate in Lnk-/- mice and mediate the pro-arrhythmic effects of pro-inflammatory cytokines, primarily through electrical remodelling., Competing Interests: Conflict of interest: K.T.M. has a pending patent application, and A.K. is a co-inventor on US Patent # 14/232,615, both with Metabolic Technologies, Inc. and Vanderbilt University., (© The Author(s) 2024. 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.)

Despite the wide effects of cardiorespiratory fitness (CRF) on metabolic, cardiovascular, pulmonary and neurological health, challenges in the feasibility and reproducibility of CRF measurements have impeded its use for clinical decision-making. Here we link proteomic profiles to CRF in 14,145 individuals across four international cohorts with diverse CRF ascertainment methods to establish, validate and characterize a proteomic CRF score. In a cohort of around 22,000 individuals in the UK Biobank, a proteomic CRF score was associated with a reduced risk of all-cause mortality (unadjusted hazard ratio 0.50 (95% confidence interval 0.48-0.52) per 1 s.d. increase). The proteomic CRF score was also associated with multisystem disease risk and provided risk reclassification and discrimination beyond clinical risk factors, as well as modulating high polygenic risk of certain diseases. Finally, we observed dynamicity of the proteomic CRF score in individuals who undertook a 20-week exercise training program and an association of the score with the degree of the effect of training on CRF, suggesting potential use of the score for personalization of exercise recommendations. These results indicate that population-based proteomics provides biologically relevant molecular readouts of CRF that are additive to genetic risk, potentially modifiable and clinically translatable., (© 2024. The Author(s).)

Background: Atrial Fibrillation (AF) is a common and clinically heterogeneous arrythmia. Machine learning (ML) algorithms can define data-driven disease subtypes in an unbiased fashion, but whether the AF subgroups defined in this way align with underlying mechanisms, such as high polygenic liability to AF or inflammation, and associate with clinical outcomes is unclear., Methods: We identified individuals with AF in a large biobank linked to electronic health records (EHR) and genome-wide genotyping. The phenotypic architecture in the AF cohort was defined using principal component analysis of 35 expertly curated and uncorrelated clinical features. We applied an unsupervised co-clustering machine learning algorithm to the 35 features to identify distinct phenotypic AF clusters. The clinical inflammatory status of the clusters was defined using measured biomarkers (CRP, ESR, WBC, Neutrophil %, Platelet count, RDW) within 6 months of first AF mention in the EHR. Polygenic risk scores (PRS) for AF and cytokine levels were used to assess genetic liability of clusters to AF and inflammation, respectively. Clinical outcomes were collected from EHR up to the last medical contact., Results: The analysis included 23,271 subjects with AF, of which 6,023 had available genome-wide genotyping. The machine learning algorithm identified 3 phenotypic clusters that were distinguished by increasing prevalence of comorbidities, particularly renal dysfunction, and coronary artery disease. Polygenic liability to AF across clusters was highest in the low comorbidity cluster. Clinically measured inflammatory biomarkers were highest in the high comorbid cluster, while there was no difference between groups in genetically predicted levels of inflammatory biomarkers. Subgroup assignment was associated with multiple clinical outcomes including mortality, stroke, bleeding, and use of cardiac implantable electronic devices after AF diagnosis., Conclusion: Patient subgroups identified by unsupervised clustering were distinguished by comorbidity burden and associated with risk of clinically important outcomes. Polygenic liability to AF across clusters was greatest in the low comorbidity subgroup. Clinical inflammation, as reflected by measured biomarkers, was lowest in the subgroup with lowest comorbidities. However, there were no differences in genetically predicted levels of inflammatory biomarkers, suggesting associations between AF and inflammation is driven by acquired comorbidities rather than genetic predisposition.

Background: Heart transplantation using donation after circulatory death (DCD) allografts is increasingly common, expanding the donor pool and reducing transplant wait times. However, data remain limited on clinical outcomes., Objectives: We sought to compare 6-month and 1-year clinical outcomes between recipients of DCD hearts, most of them recovered with the use of normothermic regional perfusion (NRP), and recipients of donation after brain death (DBD) hearts., Methods: We conducted a single-center retrospective observational study of all adult heart-only transplants from January 2020 to January 2023. Recipient and donor data were abstracted from medical records and the United Network for Organ Sharing registry, respectively. Survival analysis and Cox regression were used to compare the groups., Results: During the study period, 385 adults (median age 57.4 years [IQR: 48.0-63.7 years]) underwent heart-only transplantation, including 122 (32%) from DCD donors, 83% of which were recovered with the use of NRP. DCD donors were younger and had fewer comorbidities than DBD donors. DCD recipients were less often hospitalized before transplantation and less likely to require pretransplantation temporary mechanical circulatory support compared with DBD recipients. There were no significant differences between groups in 1-year survival, incidence of severe primary graft dysfunction, treated rejection during the first year, or likelihood of cardiac allograft vasculopathy at 1 year after transplantation., Conclusions: In the largest single-center comparison of DCD and DBD heart transplantations to date, outcomes among DCD recipients are noninferior to those of DBD recipients. This study adds to the published data supporting DCD donors as a safe means to expand the heart donor pool., Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. All rights reserved.)

Background: Peripheral artery disease (PAD) is underdiagnosed due to poor patient and clinician awareness. Despite this, no widely accepted PAD screening is recommended., Objectives: The authors used machine learning to develop an automated risk stratification tool for identifying patients with a high likelihood of PAD., Methods: Using data from the electronic health record (EHR), ankle-brachial indices (ABIs) were extracted for 3,298 patients. In addition to ABI, we extracted 60 other patient characteristics and used a random forest model to rank the features by association with ABI. The model identified several features independently correlated with PAD. We then built a logistic regression model to predict PAD status on a validation set of patients (n = 1,089), an external cohort of patients (n = 2,922), and a national database (n = 2,488). The model was compared to an age-based and random forest model., Results: The model had an area under the curve (AUC) of 0.68 in the validation set. When evaluated on an external population using EHR data, it performed similarly with an AUC of 0.68. When evaluated on a national database, it had an AUC of 0.72. The model outperformed an age-based model (AUC: 0.62; P < 0.001). A random forest model with inclusion of all 60 features did not perform significantly better (AUC: 0.71; P = 0.31)., Conclusions: Statistical techniques can be used to build models which identify individuals at high risk for PAD using information accessible from the EHR. Models such as this may allow large health care systems to efficiently identify patients that would benefit from aggressive preventive strategies or targeted-ABI screening.

Conventional measurements of fasting and postprandial blood glucose levels investigated in genome-wide association studies (GWAS) cannot capture the effects of DNA variability on 'around the clock' glucoregulatory processes. Here we show that GWAS meta-analysis of glucose measurements under nonstandardized conditions (random glucose (RG)) in 476,326 individuals of diverse ancestries and without diabetes enables locus discovery and innovative pathophysiological observations. We discovered 120 RG loci represented by 150 distinct signals, including 13 with sex-dimorphic effects, two cross-ancestry and seven rare frequency signals. Of these, 44 loci are new for glycemic traits. Regulatory, glycosylation and metagenomic annotations highlight ileum and colon tissues, indicating an underappreciated role of the gastrointestinal tract in controlling blood glucose. Functional follow-up and molecular dynamics simulations of lower frequency coding variants in glucagon-like peptide-1 receptor (GLP1R), a type 2 diabetes treatment target, reveal that optimal selection of GLP-1R agonist therapy will benefit from tailored genetic stratification. We also provide evidence from Mendelian randomization that lung function is modulated by blood glucose and that pulmonary dysfunction is a diabetes complication. Our investigation yields new insights into the biology of glucose regulation, diabetes complications and pathways for treatment stratification., (© 2023. The Author(s).)

Background and Objectives: Elevated fibroblast growth factor-23 (FGF23) has been consistently associated with heart failure, particularly heart failure with preserved ejection fraction, among patients with CKD and in the general population. FGF23 may directly induce cardiac remodeling and heart failure. However, biases affecting observational studies impede robust causal inferences. Mendelian randomization leverages genetic determinants of a risk factor to examine causality. We performed a two-sample Mendelian randomization to assess causal associations between FGF23 and heart failure., Design, Setting, Participants, & Measurements: Genetic instruments were genome-wide significant genetic variants associated with FGF23, including variants near PIP5K1B , RGS14 , LINC01229 , and CYP24A1. We analyzed data from the Heart Failure Molecular Epidemiology for Therapeutic Targets and BioVU biobanks to examine associations of the four variants with overall heart failure, heart failure with preserved ejection fraction, and heart failure with reduced and mid-range ejection fraction. We developed an eGFR polygenic risk score using summary statistics from the Chronic Kidney Disease Genetics Consortium (CKDGen) genome-wide association study of eGFR in >1 million individuals and performed stratified analyses across eGFR polygenic risk score strata., Results: Genetically determined FGF23 was not associated with overall heart failure in the Heart Failure Molecular Epidemiology for Therapeutic Targets consortium (odds ratio, 1.13; 95% confidence interval, 0.89 to 1.42 per unit higher genetically predicted log FGF23) and the full BioVU sample (odds ratio, 1.32; 95% confidence interval, 0.95 to 1.84). In stratified analyses in BioVU, higher FGF23 was associated with overall heart failure (odds ratio, 3.09; 95% confidence interval, 1.38 to 6.91) among individuals with low eGFR-polygenic risk score (<1 SD below the mean), but not those with high eGFR-polygenic risk score ( P interaction = 0.02). Higher FGF23 was also associated with heart failure with preserved ejection fraction among all BioVU participants (odds ratio, 1.47; 95% confidence interval, 1.01 to 2.14) and individuals with low eGFR-polygenic risk score (odds ratio, 7.20; 95% confidence interval, 2.80 to 18.49), but not those high eGFR-polygenic risk score ( P interaction = 2.25 × 10 -4 ). No significant associations were observed with heart failure with reduced and midrange ejection fraction., Conclusion: We found no association between genetically predicted FGF23 and heart failure in the Heart Failure Molecular Epidemiology for Therapeutic Targets consortium. In BioVU, genetically elevated FGF23 was associated with higher heart failure risk, specifically heart failure with preserved ejection fraction, particularly among individuals with low genetically predicted eGFR., Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022&#95;07&#95;28&#95;CJN00960122.mp3., (Copyright © 2022 by the American Society of Nephrology.)

Background Early (grade 1) cardiac left ventricular diastolic dysfunction (G1DD) increases the risk for heart failure with preserved ejection fraction and may improve with aggressive risk factor modification. Type 2 diabetes, obesity, hypertension, and coronary heart disease are associated with increased incidence of diastolic dysfunction. The genetic drivers of G1DD are not defined. Methods and Results We curated genotyped European ancestry G1DD cases (n=668) and controls with normal diastolic function (n=1772) from Vanderbilt's biobank. G1DD status was explored through (1) an additive model genome-wide association study, (2) shared polygenic risk through logistic regression, and (3) instrumental variable analysis using 2-sample Mendelian randomization (the inverse-variance weighted method, Mendelian randomization-Egger, and median) to determine potential modifiable risk factors. There were no common single nucleotide polymorphisms significantly associated with G1DD status. A polygenic risk score for BMI was significantly associated with increased G1DD risk (odds ratio [OR], 1.20 for 1-SD increase in BMI [95% CI, 1.08-1.32]; P =0.0003). The association was confirmed by the inverse-variance weighted method (OR, 1.89 [95% CI, 1.37-2.61]). Among the candidate mediators for BMI, only fasting glucose was significantly associated with G1DD status by the inverse-variance weighted method (OR, 4.14 for 1-SD increase in fasting glucose [95% CI, 1.55-11.02]; P =0.005). Multivariable Mendelian randomization showed a modest attenuation of the BMI association (OR, 1.84 [95% CI, 1.35-2.52]) when adjusting for fasting glucose. Conclusions These data suggest that a genetic predisposition to elevated BMI increases the risk for G1DD. Part of this effect may be mediated through altered glucose homeostasis.

Background: Study of pulmonary arterial hypertension (PAH) in claims-based (CB) cohorts may facilitate understanding of disease epidemiology, however previous CB algorithms to identify PAH have had limited test characteristics. We hypothesized that machine learning algorithms (MLA) could accurately identify PAH in an CB cohort., Methods: ICD-9/10 codes, CPT codes or PAH medications were used to screen an electronic medical record (EMR) for possible PAH. A subset (Development Cohort) was manually reviewed and adjudicated as PAH or "not PAH" and used to train and test MLAs. A second subset (Refinement Cohort) was manually reviewed and combined with the Development Cohort to make The Final Cohort, again divided into training and testing sets, with MLA characteristics defined on test set. The MLA was validated using an independent EMR cohort., Results: 194 PAH and 786 "not PAH" in the Development Cohort trained and tested the initial MLA. In the Final Cohort test set, the final MLA sensitivity was 0.88, specificity was 0.93, positive predictive value was 0.89, and negative predictive value was 0.92. Persistence and strength of PAH medication use and CPT code for right heart catheterization were principal MLA features. Applying the MLA to the EMR cohort using a split cohort internal validation approach, we found 265 additional non-confirmed cases of suspected PAH that exhibited typical PAH demographics, comorbidities, hemodynamics., Conclusions: We developed and validated a MLA using only CB features that identified PAH in the EMR with strong test characteristics. When deployed across an entire EMR, the MLA identified cases with known features of PAH., (© 2022. The Author(s).)

Aims: Mitral valve prolapse (MVP) is a common valvular heart disease with a prevalence of >2% in the general adult population. Despite this high incidence, there is a limited understanding of the molecular mechanism of this disease, and no medical therapy is available for this disease. We aimed to elucidate the genetic basis of MVP in order to better understand this complex disorder., Methods and Results: We performed a meta-analysis of six genome-wide association studies that included 4884 cases and 434 649 controls. We identified 14 loci associated with MVP in our primary analysis and 2 additional loci associated with a subset of the samples that additionally underwent mitral valve surgery. Integration of epigenetic, transcriptional, and proteomic data identified candidate MVP genes including LMCD1, SPTBN1, LTBP2, TGFB2, NMB, and ALPK3. We created a polygenic risk score (PRS) for MVP and showed an improved MVP risk prediction beyond age, sex, and clinical risk factors., Conclusion: We identified 14 genetic loci that are associated with MVP. Multiple analyses identified candidate genes including two transforming growth factor-β signalling molecules and spectrin β. We present the first PRS for MVP that could eventually aid risk stratification of patients for MVP screening in a clinical setting. These findings advance our understanding of this common valvular heart disease and may reveal novel therapeutic targets for intervention., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Heart failure (HF) has no cure and, for HF with preserved ejection fraction (HFpEF), no life-extending treatments. Defining the clinical epidemiology of HF could facilitate earlier identification of high-risk individuals. We define the clinical epidemiology of HF subtypes (HFpEF and HF with reduced ejection fraction [HFrEF]), identified among 2.7 million individuals receiving routine clinical care. Differences in patterns and rates of accumulation of comorbidities, frequency of hospitalization, use of specialty care, were defined for each HF subtype. Among 28,156 HF cases, 8322 (30%) were HFpEF and 11,677 (42%) were HFrEF. HFpEF was the more prevalent subtype among older women. 177 Phenotypes differentially associated with HFpEF versus HFrEF. HFrEF was more frequently associated with diagnoses related to ischemic cardiac injury while HFpEF was associated more with non-cardiac comorbidities and HF symptoms. These comorbidity patterns were frequently present 3 years prior to a HFpEF diagnosis. HF subtypes demonstrated distinct patterns of clinical co-morbidities and disease progression. For HFpEF, these comorbidities were often non-cardiac and manifested prior to the onset of a HF diagnosis. Recognizing these comorbidity patterns, along the care continuum, may present a window of opportunity to identify individuals at risk for developing incident HFpEF., (© 2021. The Author(s).)

Objective: Red cell distribution width (RDW) is an enigmatic biomarker associated with the presence and severity of multiple cardiovascular diseases (CVDs). It is unclear whether elevated RDW contributes to, results from, or is pleiotropically related to CVDs. We used contemporary genetic techniques to probe for evidence of aetiological associations between RDW, CVDs, and CVD risk factors., Methods: Using an electronic health record (EHR)-based cohort, we built and deployed a genetic risk score (GRS) for RDW to test for shared genetic architecture between RDW and the cardiovascular phenome. We also created GRSs for common CVDs (coronary artery disease, heart failure, atrial fibrillation, peripheral arterial disease, venous thromboembolism) and CVD risk factors (body mass index (BMI), low-density lipoprotein, high-density lipoprotein, systolic blood pressure, diastolic blood pressure, serum triglycerides, estimated glomerular filtration rate, diabetes mellitus) to test each for association with RDW. Significant GRS associations were further interrogated by two-sample Mendelian randomisation (MR). In a separate EHR-based cohort, RDW values from 1-year pre-gastric bypass surgery and 1-2 years post-gastric bypass surgery were compared., Results: In a cohort of 17 937 subjects, there were no significant associations between the RDW GRS and CVDs. Of the CVDs and CVD risk factors, only genetically predicted BMI was associated with RDW. In subsequent analyses, BMI was associated with RDW by multiple MR methods. In subjects undergoing bariatric surgery, RDW decreased postsurgery and followed a linear relationship with BMI change., Conclusions: RDW is unlikely to be aetiologically upstream or downstream of CVDs or CVD risk factors except for BMI. Genetic and clinical association analyses support an aetiological relationship between BMI and RDW., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Body mass index (BMI) is the most commonly used predictor of weight-related comorbidities and outcomes. However, the presumed relationship between height and weight intrinsic to BMI may introduce bias with respect to prediction of clinical outcomes. A series of analyses comparing the performance of models representing weight and height as separate interacting variables to models using BMI were performed using Vanderbilt University Medical Center's deidentified electronic health records and landmark methodology., Methods: Use of BMI or height-weight interaction in prediction models for established weight-related cardiometabolic traits and metabolic syndrome was evaluated. Specifically, prediction models for hypertension, diabetes mellitus, low high-density lipoprotein, and elevated triglycerides, atrial fibrillation, coronary artery disease, heart failure, and peripheral artery disease were developed. Model performance was evaluated using likelihood ratio, R 2 , and Somers' Dxy rank correlation. Differences in model predictions were visualized using heat maps., Results: Compared to BMI, the maximally flexible height-weight interaction model demonstrated improved prediction, higher likelihood ratio, R 2 , and Somers' Dxy rank correlation, for event-free probability for all outcomes. The degree of improvement to the prediction model differed based on the outcome and across the height and weight range., Conclusions: Because alternative measures of body composition such as waist-to-hip ratio are not routinely collected in the clinic clinical risk models quantifying risk based on height and weight measurements alone are essential to improve practice. Compared to BMI, modeling height and weight as independent, interacting variables results in less bias and improved predictive accuracy for all tested traits. Considering an individual's height and weight opposed to BMI is a better method for quantifying individual disease risk., Competing Interests: J. Beckman declares potential conflicts with Amgen, Bayer, Glaxo Smith Kline, Janssen, Novartis, and Sanofi in the past 12months. All other authors declare no conflicts of interest., (© 2021 The Authors. Obesity Science & Practice published by World Obesity and The Obesity Society and John Wiley & Sons Ltd.)

Major depressive disorder (MDD) and loneliness are phenotypically and genetically correlated with coronary artery disease (CAD), but whether these associations are explained by pleiotropic genetic variants or shared comorbidities is unclear. To tease apart these scenarios, we first assessed the medical morbidity pattern associated with genetic risk factors for MDD and loneliness by conducting a phenome-wide association study in 18,385 European-ancestry individuals in the Vanderbilt University Medical Center biobank, BioVU. Polygenic scores for MDD and loneliness were developed for each person using previously published meta-GWAS summary statistics, and were tested for association with 882 clinical diagnoses ascertained via billing codes in electronic health records. We discovered strong associations with heart disease diagnoses, and next embarked on targeted analyses of CAD in 3893 cases and 4197 controls. We found odds ratios of 1.11 (95% CI, 1.04-1.18; P 8.43 × 10 -4 ) and 1.13 (95% CI, 1.07-1.20; P 4.51 × 10 -6 ) per 1-SD increase in the polygenic scores for MDD and loneliness, respectively. Results were similar in patients without psychiatric symptoms, and the increased risk persisted in females even after adjusting for multiple conventional risk factors and a polygenic score for CAD. In a final sensitivity analysis, we statistically adjusted for the genetic correlation between MDD and loneliness and re-computed polygenic scores. The polygenic score unique to loneliness remained associated with CAD (OR 1.09, 95% CI 1.03-1.15; P 0.002), while the polygenic score unique to MDD did not (OR 1.00, 95% CI 0.95-1.06; P 0.97). Our replication sample was the Atherosclerosis Risk in Communities (ARIC) cohort of 7197 European-ancestry participants (1598 incident CAD cases). In ARIC, polygenic scores for MDD and loneliness were associated with hazard ratios of 1.07 (95% CI, 0.99-1.14; P = 0.07) and 1.07 (1.01-1.15; P = 0.03), respectively, and we replicated findings from the BioVU sensitivity analyses. We conclude that genetic risk factors for MDD and loneliness act pleiotropically to increase CAD risk in females., (© 2019. The Author(s).)

From the start of the coronavirus disease 2019 (COVID-19) pandemic, researchers have looked to electronic health record (EHR) data as a way to study possible risk factors and outcomes. To ensure the validity and accuracy of research using these data, investigators need to be confident that the phenotypes they construct are reliable and accurate, reflecting the healthcare settings from which they are ascertained. We developed a COVID-19 registry at a single academic medical center and used data from March 1 to June 5, 2020 to assess differences in population-level characteristics in pandemic and non-pandemic years respectively. Median EHR length, previously shown to impact phenotype performance in type 2 diabetes, was significantly shorter in the SARS-CoV-2 positive group relative to a 2019 influenza tested group (median 3.1 years vs 8.7; Wilcoxon rank sum P = 1.3e-52). Using three phenotyping methods of increasing complexity (billing codes alone and domain-specific algorithms provided by an EHR vendor and clinical experts), common medical comorbidities were abstracted from COVID-19 EHRs, defined by the presence of a positive laboratory test (positive predictive value 100%, recall 93%). After combining performance data across phenotyping methods, we observed significantly lower false negative rates for those records billed for a comprehensive care visit (p = 4e-11) and those with complete demographics data recorded (p = 7e-5). In an early COVID-19 cohort, we found that phenotyping performance of nine common comorbidities was influenced by median EHR length, consistent with previous studies, as well as by data density, which can be measured using portable metrics including CPT codes. Here we present those challenges and potential solutions to creating deeply phenotyped, acute COVID-19 cohorts., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: The purpose of this study was to determine the frequency of unexpectedly low natriuretic peptide (NP) levels in a clinical population., Background: Higher NP concentrations are typically observed as a compensatory response to elevated cardiac wall stress. Under these conditions, low NP levels may be indicative of a "NP deficiency.", Methods: We identified 3 clinical scenarios in which high B-type natriuretic peptide (BNP) levels would be expected: 1) hospitalization for heart failure (HF); 2) abnormal cardiac structure or function; or 3) abnormal hemodynamics. In Vanderbilt's electronic health record, 47,970 adult patients had BNP measurements. A total of 13,613 patients had at least 1 of the 3 conditions (hospitalized HF, n = 9,153; abnormal cardiac structure/function, n = 7,041; abnormal hemodynamics, n = 363). We quantified the frequency of low BNP levels. We performed whole exome sequencing of the NPPB gene in a subset of 9 patients., Results: Very low BNP levels (<50 pg/ml) were observed in 4.9%, 14.0%, and 16.3% of patients with hospitalized HF, abnormal cardiac structure/function, or abnormal hemodynamics, respectively. A small proportion (0.1% to 1.1%) in each group had BNP levels below detection limits. Higher body mass index was the strongest predictor of unexpectedly low BNP. Exome sequencing did not reveal coding variation predicted to alter detection of BNP by clinical assays., Conclusions: A subset of patients with confirmed HF or cardiac dysfunction have unexpectedly low BNP levels. Obesity is the strongest correlate of unexpectedly low BNP levels. Our findings support the possible existence of NP deficiency, which may render some individuals more susceptible to volume or pressure overload., Competing Interests: Funding Support and Author Disclosures This research was supported by Career Development Award #IK2 CX001678 from the U.S. Department of Veterans Affairs Clinical Sciences Research and Development (CSR&D) Program, Vanderbilt University Medical Center Faculty Research Scholars award, and National Institute of Health Awards: National Heart, Lung, and Blood Institute grants K12 HL109019, 1K23HL128928-01A1, 1K23HL146887-01, R01 HL131532, 1 R01 HL146588, 3 R01 HL146588-01S1, 1 U01 HL125212-01, and R01HL140074; National Institute of Diabetes and Digestive and Kidney Diseases T32DK007061; and the National Center for Advancing Translational Sciences of the National Institutes of Health UL1TR000445 (Vanderbilt). The authors report they have no relationships relevant to the content of this paper to disclose., (Published by Elsevier Inc.)

Background: There is an unclear relationship of obesity to the pathogenesis and severity of pulmonary arterial hypertension (PAH) and pulmonary venous hypertension (PVH)., Research Question: Is BMI casually associated with pulmonary artery pressure (PAP) and/or markers of pulmonary vascular remodeling?, Study Design and Methods: The study design was a two-sample inverse-variance weighted Mendelian randomization. We constructed two BMI genetic risk scores from genome-wide association study summary data and deployed them in nonoverlapping cohorts of subjects referred for right heart catheterization (RHC) or echocardiography. A BMI highly polygenic risk score (hpGRS) optimally powered to detect shared genetic architecture of obesity with other traits was tested for association with RHC parameters including markers of pulmonary vascular remodeling. A BMI strict genetic risk score (sGRS) composed of high-confidence genetic variants was used for Mendelian randomization analyses to assess if higher BMI causes higher PAP., Results: Among all subjects, both directly measured BMI and hpGRS were positively associated with pulmonary arterial pressures but not markers of pulmonary vascular remodeling. Categorical analyses revealed BMI and hpGRS were associated with PVH but not PAH. Mendelian randomization of the sGRS supported that higher BMI is causal of higher systolic pulmonary artery pressure (sPAP). Sensitivity analyses showed sPAP-BMI sGRS relationship was preserved when either individuals with PAH or PVH were excluded. In the echocardiographic cohort, BMI and hpGRS were positively associated with estimated PAP and markers of left heart remodeling., Interpretation: BMI is a modifier of pulmonary hypertension severity in both PAH and PVH but is only involved in the pathogenesis of PVH., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Objective: Type 2 diabetes mellitus (T2DM) reduces exercise capacity, but the mechanisms are incompletely understood. We probed the impact of ischemic stress on skeletal muscle metabolite signatures and T2DM-related vascular dysfunction., Methods: we recruited 38 subjects (18 healthy, 20 T2DM), placed an antecubital intravenous catheter, and performed ipsilateral brachial artery reactivity testing. Blood samples for plasma metabolite profiling were obtained at baseline and immediately upon cuff release after 5 min of ischemia. Brachial artery diameter was measured at baseline and 1 min after cuff release., Results: as expected, flow-mediated vasodilation was attenuated in subjects with T2DM (P<0.01). We confirmed known T2DM-associated baseline differences in plasma metabolites, including homocysteine, dimethylguanidino valeric acid and β-alanine (all P<0.05). Ischemia-induced metabolite changes that differed between groups included 5-hydroxyindoleacetic acid (healthy: -27%; DM +14%), orotic acid (healthy: +5%; DM -7%), trimethylamine-N-oxide (healthy: -51%; DM +0.2%), and glyoxylic acid (healthy: +19%; DM -6%) (all P<0.05). Levels of serine, betaine, β-aminoisobutyric acid and anthranilic acid were associated with vessel diameter at baseline, but only in T2DM (all P<0.05). Metabolite responses to ischemia were significantly associated with vasodilation extent, but primarily observed in T2DM, and included enrichment in phospholipid metabolism (P<0.05)., Conclusions: our study highlights impairments in muscle and vascular signaling at rest and during ischemic stress in T2DM. While metabolites change in both healthy and T2DM subjects in response to ischemia, the relationship between muscle metabolism and vascular function is modified in T2DM, suggesting that dysregulated muscle metabolism in T2DM may have direct effects on vascular function., (© 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Objective: To evaluate how common echocardiographic metrics of aortic stenosis (AS) influence the proportion of patients who may be categorised as having severe stenosis and therefore considered for valve replacement., Methods: Retrospective analysis was performed of all echocardiograms with aortic valve area (AVA) ≤1.2 cm 2 and peak jet velocity (V max ) ≥3 m/s from 1 December 2014 through 30 October 2017 at a single academic medical centre. Echocardiographic indices collected include AVA, V max , left ventricular ejection fraction, stroke volume and annotated aortic stenosis severity., Results: Among 807 patients with AVA ≤1.2 cm 2 and V max ≥3 m/s (44.0% female, median age 74 years (IQR: 66-81)), 45.6% had V max ≥4 m/s, while 75.8% had AVA ≤1 cm 2 . 40.0% of patients had concordant indices (V max ≥4 m/s and AVA ≤1 cm 2 ), and 35.8% had discordant indices (V max <4 m/s and AVA ≤1 cm 2 ) of severe AS. Compared with those with concordant indices, patients with discordant indices were more commonly female (54.0% vs 44.3%, p<0.05) and less commonly characterised as severe (42.6% vs 93.8%, p<0.001). Patients with paradoxical low-flow, low-gradient severe AS by echocardiography were disproportionately female (61.5% vs 41.8%, p<0.001), and their disease was characterised as severe only 49.5% of the time., Conclusions: Patients with discordant indices, who are disproportionately female, are commonly described in clinical echocardiography reports as having less than severe AS. Given the potential benefit of AVR in patients with AVA ≤1 cm 2 regardless of V max , this could have important clinical implications., Competing Interests: Competing interests: BRL has received research grants from Edwards Lifesciences and Roche Diagnostics; served on scientific advisory boards for Roche Diagnostics and has been a consultant to Medtronic and Roche Diagnostics., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: There is significant interindividual variability in the rate of aortic stenosis (AS) progression that is not accounted for in the current surveillance algorithms. We sought to examine the association between changes in peak aortic jet velocity (Vmax) and mean gradient (MG) among patients with mild or moderate AS and risk of progression to severe disease., Methods: Adult subjects referred for echocardiography at a single academic referral center with a diagnosis of mild or moderate AS and ≥2 additional surveillance echocardiograms were included in the study. Changes in Vmax and MG between the first two echocardiograms were indexed to time and tested for association with future progression to severe AS., Results: Among three hundred and sixty-four subjects, the median time between first and second echocardiograms was 1.3 years and initial changes in Vmax and MG indexed to time were +0.16 m/s per year and +1.44 mmHg per year, respectively. Fifty-three (15%) and fifty-six (15%) subjects progressed to severe AS defined by Vmax and MG, respectively. In multivariable logistic regression, initial increase in Vmax (OR = 4.19, 95% CI 1.93-9.10, p < 0.001) and initial increase in MG (OR = 1.12, 95% CI 1.06-1.18, p < 0.001) were associated with progression to severe AS., Conclusions: Initial changes in Vmax and MG among patients with mild or moderate AS are strongly associated with risk of progression to severe AS and may help guide individualized surveillance strategies., (© 2020 The Authors.)

Non-alcoholic fatty liver disease (NAFLD) affects over 30% of adults in the United States. Bone morphogenetic protein (BMP) signaling is known to contribute to hepatic fibrosis, but the role of BMP signaling in the development of NAFLD is unclear. In this study, treatment with either of two BMP inhibitors reduced hepatic triglyceride content in diabetic (db/db) mice. BMP inhibitor-induced decrease in hepatic triglyceride levels was associated with decreased mRNA encoding Dgat2, an enzyme integral to triglyceride synthesis. Treatment of hepatoma cells with BMP2 induced DGAT2 expression and activity via intracellular SMAD signaling. In humans we identified a rare missense single nucleotide polymorphism in the BMP type 1 receptor ALK6 (rs34970181;R371Q) associated with a 2.1-fold increase in the prevalence of NAFLD. In vitro analyses revealed R371Q:ALK6 is a previously unknown constitutively active receptor. These data show that BMP signaling is an important determinant of NAFLD in a murine model and is associated with NAFLD in humans.

Background Inflammation may contribute to incident heart failure (HF). Rheumatoid arthritis (RA), a prototypic inflammatory condition, may serve as a model for understanding inflammation-related HF risk. Methods and Results Using the Vanderbilt University Medical Center electronic health record, we retrospectively identified 9889 patients with RA and 9889 control patients without autoimmune disease matched for age, sex, and race. Prevalent HF at entry into the electronic health record or preceding RA diagnosis was excluded. Incident HF was ascertained using International Classification of Diseases, Ninth Revision (ICD-9), codes and medications. Over 177 566 person-years of follow-up, patients with RA were at 21% greater risk of HF (95% CI, 3-42%) independent of traditional cardiovascular risk factors. Among patients with RA, higher CRP (C-reactive protein) was associated with greater HF risk ( P <0.001), while the anti-inflammatory drug methotrexate was associated with ≈25% lower HF risk ( P =0.021). In a second cohort (n=115) of prospectively enrolled patients with and without RA, we performed proteomics and cardiac magnetic resonance imaging to discover circulating markers of inflammation associated with cardiac structure and function. Artemin levels were higher in patients with RA compared with controls ( P =0.009), and higher artemin levels were associated with worse ventricular end-systolic elastance and ventricular-vascular coupling ratio ( P =0.044 and P =0.031, respectively). Conclusions RA, a prototypic chronic inflammatory condition, is associated with increased risk of HF. Among patients with RA, higher levels of CRP were associated with greater HF risk, while methotrexate was associated with lower risk.

Left ventricular (LV) mass is a prognostic biomarker for incident heart disease and all-cause mortality. Large-scale genome-wide association studies have identified few SNPs associated with LV mass. We hypothesized that a polygenic discovery approach using LV mass measurements made in a clinical population would identify risk factors and diseases associated with adverse LV remodeling. We developed a polygenic single nucleotide polymorphism-based predictor of LV mass in 7,601 individuals with LV mass measurements made during routine clinical care. We tested for associations between this predictor and 894 clinical diagnoses measured in 58,838 unrelated genotyped individuals. There were 29 clinical phenotypes associated with the LV mass genetic predictor at FDR q < 0.05. Genetically predicted higher LV mass was associated with modifiable cardiac risk factors, diagnoses related to organ dysfunction and conditions associated with abnormal cardiac structure including heart failure and atrial fibrillation. Secondary analyses using polygenic predictors confirmed a significant association between higher LV mass and body mass index and, in men, associations with coronary atherosclerosis and systolic blood pressure. In summary, these analyses show that LV mass-associated genetic variability associates with diagnoses of cardiac diseases and with modifiable risk factors which contribute to these diseases.

Background The value of thrombophilia test acquisition in improving risk prediction beyond clinical presentation remains unknown. We investigated the effect of thrombophilia test acquisition on venous thromboembolism (VTE) outcomes. Methods and Results We performed a retrospective cohort study of adult patients over a 15-year period (September 2001 and May 2016) with first diagnosis of VTE in a single academic medical center. Participants were identified by International Classification of Diseases, Ninth Revision ( ICD-9 ), Current Procedural Terminology ( CPT ) codes and medication history. Participants with thrombophilia testing were matched to control participants without thrombophilia testing using a propensity model. Primary outcomes included recurrent VTE, anticoagulant use 12 months after the index VTE event, bleeding-related hospitalization, and death. From 3590 unique patients who met the inclusion criteria, 747 participants with VTE who underwent thrombophilia testing were matched to a control participant without testing. Tested participants were more likely to have a recurrent event (46.1% versus 28.5%; P <0.001) and an anticoagulant prescription 12 months from the index event (53.9% versus 37.1%; P <0.001) but had no significant difference in bleeding-related hospitalization (11.4% versus 11.8%; P =0.81) compared with untested participants. An abnormal thrombophilia test result, per se, did not predict recurrent VTE (47.8% versus 44.1%; P =0.13), longer duration anticoagulation (53.2% versus 54.8%; P =0.51), bleeding (11.5% versus 11.3%; P =0.70), or mortality (12.2% versus 16.1%; P =0.18) compared with participants who had normal test results. Conclusions The decision to perform thrombophilia testing, but not the test result, is associated with a high risk of recurrent VTE despite a greater likelihood of long-duration anticoagulation.

African Americans experience the highest burden of hypertension in the United States compared with other groups. Genetic contributions to this complex condition are now emerging in this as well as other populations through large-scale genome-wide association studies (GWAS) and meta-analyses. Despite these recent discovery efforts, relatively few large-scale studies of blood pressure have considered the joint influence of genetics and social determinants of health despite extensive evidence supporting their impact on hypertension. To identify these expected interactions, we accessed a subset of the Vanderbilt University Medical Center (VUMC) biorepository linked to de-identified electronic health records (EHRs) of adult African Americans genotyped using the Illumina Metabochip ( n = 2,577). To examine potential interactions between education, a recognized social determinant of health, and genetic variants contributing to blood pressure, we used linear regression models to investigate two-way interactions for systolic and diastolic blood pressure (DBP). We identified a two-way interaction between rs6687976 and education affecting DBP ( p = 0.052). Individuals homozygous for the minor allele and having less than a high school education had higher DBP compared with (1) individuals homozygous for the minor allele and high school education or greater and (2) individuals not homozygous for the minor allele and less than a high school education. To our knowledge, this is the first EHR -based study to suggest a gene-environment interaction for blood pressure in African Americans, supporting the hypothesis that genetic contributions to hypertension may be modulated by social factors.

Rationale: Red cell distribution width (RDW) is a prognostic factor in many diseases; however, its clinical utility remains limited because the relative value of RDW as a biomarker across disease states has not been established. Objectives: To establish an unbiased RDW disease hierarchy to guide the clinical use of RDW and to assess its relationship to cardiovascular hemodynamic and structural parameters. Methods: We performed phenome-wide association studies for RDW in discovery and replication cohorts derived from a deidentified electronic health record in nonanemic individuals. RDW values obtained within 30 days of echocardiogram or right heart catheterization were tested for association with structural and hemodynamic variables. Results: RDW was associated with 263 phenotypes in both men and women in the discovery cohort ( n  = 121,530), 48 of which replicated in an independent cohort ( n  = 2,039). The strongest associations were observed with pulmonary arterial hypertension (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.9-2.3), chronic pulmonary heart disease (OR, 2.0; 95% CI, 1.9-2.2), and congestive heart failure (OR, 1.9; 95% CI, 1.8-2.0); P  < 1 × 10 -74 for all. By echocardiography, RDW was higher in the setting of right ventricular dysfunction than left ventricular dysfunction ( P  < 0.001). Measured invasively, mean pulmonary arterial pressure was associated with RDW (21 vs. 33 mm Hg at 25th vs. 75th percentile RDW; P  < 1 × 10 -7 ) and remained strongly significant even when controlling for mean pulmonary capillary wedge pressure (21 vs. 29 mm Hg at 25th vs. 75th percentile RDW; P  < 1 × 10 -7 ). Conclusions: Among 1,364 coded medical conditions, increased RDW was strongly associated with pulmonary hypertension and heart failure. Hemodynamic and echocardiographic phenotyping confirmed these associations and underscored that the most clinically relevant phenotype associated with RDW was pulmonary hypertension. These hypothesis-generating findings highlight the potential shared pathophysiology of pulmonary hypertension and elevated RDW. Elevated RDW in the absence of anemia should alert clinicians to the potential for underlying cardiopulmonary disease.

Background: The measurements used to define pulmonary hypertension (PH) etiology, pulmonary arterial wedge pressure (PAWP), and left ventricular end-diastolic pressure (LVEDP) vary in clinical practice. We aimed to identify clinical features associated with measurement discrepancy between PAWP and LVEDP in patients with PH., Methods: We extracted clinical data and invasive hemodynamics from consecutive patients undergoing concurrent right and left heart catheterization at Vanderbilt University between 1998 and 2014. The primary outcome was discordance between PAWP and LVEDP in patients with PH in a logistic regression model., Results: We identified 2,270 study subjects (median age, 63 years; 53% men). The mean difference between PAWP and LVEDP was -1.6 mm Hg (interquartile range, -15 to 12 mm Hg). The two measurements were moderately correlated by linear regression (R = 0.6, P < .001). Results were similar when restricted to patients with PH. Among patients with PH (n = 1,331), older age (OR, 1.77; 95% CI, 1.23-2.45) was associated with PAWP underestimation in multivariate models, whereas atrial fibrillation (OR, 1.75; 95% CI, 1.08-2.84), a history of rheumatic valve disease (OR, 2.2; 95% CI, 1.36-3.52), and larger left atrial diameter (OR, 1.70; 95% CI, 1.24-2.32) were associated with PAWP overestimation of LVEDP. Results were similar in sensitivity analyses., Conclusions: Clinically meaningful disagreement between PAWP and LVEDP is common. Atrial fibrillation, rheumatic valve disease, and larger left atrial diameter are associated with misclassification of PH etiology when relying on PAWP alone. These findings are important because of the fundamental differences in the treatment of precapillary and postcapillary PH., (Copyright © 2018 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Daptomycin-associated myopathy has been identified in 2%-14% of patients, and rhabdomyolysis is a known adverse effect. Although risk factors for daptomycin-associated myopathy are poorly defined, creatine phosphokinase (CPK) monitoring and temporary discontinuation of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or "statins," has been recommended., Methods: We conducted a single-center, retrospective, matched case-control risk factor analysis in adult and pediatric patients from 2004 to 2015. Patients in whom myopathy (defined as CPK values above the upper limit of normal) developed during daptomycin treatment were matched 1:1 to no-myopathy controls with at least the same duration of therapy. Risk factors independently associated with myopathy were determined using multivariable conditional logistic regression. Secondary analysis was performed in patients with rhabdomyolysis, defined as CPK values ≥10 times the upper limit of normal., Results: Of 3042 patients reviewed, 128 (4.2%) were identified as having daptomycin-associated myopathy, 25 (0.8%) of whom had rhabdomyolysis; 121 (95%) of the 128 were adults, and the mean duration of therapy before CPK elevation was 16.7 days (range, 1-58 days). In multivariate analysis, deep abscess treatment (odds ratio, 2.80; P = .03), antihistamine coadministration (3.50; P = .03), and statin coadministration (2.60; P = .03) were independent risk factors for myopathy. Obesity (odds ratio, 3.28; P = .03) and statin coadministration (4.67; P = .03) were found to be independent risk factors for rhabdomyolysis, and older age was associated with reduced risk (0.97; P = .05)., Conclusions: Statin coadministration with daptomycin was independently associated with myopathy and rhabdomyolysis. This is the first study to provide strong evidence supporting this association. During coadministration, we recommend twice-weekly CPK monitoring and consideration of withholding statins.

Background: Glaucoma is a leading cause of blindness in developed countries. Primary open-angle glaucoma (POAG), the most prevalent clinical subtype of glaucoma in the United States, affects African Americans at a higher rate compared with European Americans. Risk factors identified for POAG include increased age and family history, which coupled with heritability estimates, suggest this complex condition is associated with genetic and environmental factors. To date, several genome-wide studies have identified loci significantly associated with POAG risk, but most of these studies were performed in populations of European-descent., Methods: To identify population-specific and trans-population genetic associations for POAG, we genotyped 11,521 African Americans using the Illumina Metabochip as part of the Epidemiologic Architecture for Genes Linked to Environment (EAGLE) study accessing BioVU, the Vanderbilt University Medical Center's biorepository linked to de-identified electronic health records. Among this study population, we identified 138 cases of POAG and 1376 controls and performed Metabochip-wide tests of association. We also estimated local genetic ancestry at CDKN2B-AS1, a POAG-associated locus established in European-descent populations., Results: Overall, we did not identify significant single SNP-POAG associations after adjusting for multiple testing. We did, however, detect a significant association between POAG risk and local African genetic ancestry at CDKN2B-AS1, where on average cases were of 90% African descent compared with controls at 58% (p = 2 × 10 - 6 )., Conclusions: These data suggest that CDKN2B-AS1 is an important locus for POAG risk among African Americans, warranting further investigation to identify the variants underlying this association.

Background: High levels of triglycerides (TG ≥200 mg/dL) are an emerging risk factor for cardiovascular disease. Conversely, very low levels of TG are associated with decreased risk for cardiovascular disease. Precision medicine aims to capitalize on recent findings that rare variants such as APOC3 R19X (rs76353203) are associated with risk of disease, but it is unclear how population-based associations can be best translated in clinical settings at the individual-patient level., Methods: To explore the potential usefulness of screening for genetic predictors of cardiovascular disease, we surveyed BioVU, the Vanderbilt University Medical Center's biorepository linked to de-identified electronic health records (EHRs), for APOC3 19X mutations among adult European American patients (> 45 and > 55 years of age for men and women, respectively) with the lowest percentile of TG levels. The initial search identified 262 patients with the lowest TG levels in the biorepository; among these, 184 patients with sufficient DNA and the lowest TG levels were chosen for Illumina ExomeChip genotyping., Results: A total of two patients were identified as heterozygotes of APOC3 R19X for a minor allele frequency (MAF) of 0.55% in this patient population. Both heterozygous patients had only a single mention of TG in the EHR (31 and 35 mg/dL, respectively), and one patient had evidence of previous cardiovascular disease., Conclusions: In this patient population, we identified two patients who were carriers of the APOC3 19X null variant, but only one lacked evidence of disease in the EHR highlighting the challenges of inclusion of functional or previously associated genetic variation in clinical risk assessment.

Background: Transthoracic echocardiography (TTE) is used to estimate pulmonary artery systolic pressure, but an adequate tricuspid regurgitation velocity (TRV) needed to calculate pulmonary artery systolic pressure is not always present. It is unknown whether the absence of a measurable TRV signifies normal pulmonary artery pressure., Methods and Results: We extracted hemodynamic, TTE, and clinical data from Vanderbilt's deidentified electronic medical record in all patients referred for right heart catheterization between 1998 and 2014. Pulmonary hypertension (PH) was defined as mean pulmonary artery pressure ≥25 mm Hg. We examined the prevalence and clinical correlates of PH in patients without a reported TRV. We identified 1262 patients with a TTE within 2 days of right heart catheterization. In total, 803/1262 (64%) had a reported TRV, whereas 459 (36%) had no reported TRV. Invasively confirmed PH was present in 47% of patients without a reported TRV versus 68% in those with a reported TRV ( P <0.001). Absence of a TRV yielded a negative predictive value for excluding PH of 53%. Right ventricular dysfunction, left atrial dimension, elevated body mass index, higher brain natriuretic peptide, diabetes mellitus, and heart failure were independently associated with PH among patients without a reported TRV., Conclusions: PH is present in almost half of patients without a measurable TRV who are referred for both TTE and right heart catheterization. Clinical and echocardiographic features of left heart disease are associated with invasively confirmed PH in subjects without a reported TRV. Clinicians should use caution when making assumptions about PH status in the absence of a measurable TRV on TTE., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Diastolic dysfunction (DD), an abnormality in cardiac left ventricular (LV) chamber compliance, is associated with increased morbidity and mortality. Although DD has been extensively studied in older populations, co-morbidity patterns are less well characterized in middle-aged subjects. We screened 156,434 subjects with transthoracic echocardiogram reports available through Vanderbilt's electronic heath record and identified 6,612 subjects 40 to 55 years old with an LV ejection fraction ≥50% and diastolic function staging. We tested 452 incident and prevalent clinical diagnoses for associations with early-stage DD (n = 1,676) versus normal function. There were 44 co-morbid diagnoses associated with grade 1 DD including hypertension (odds ratio [OR] = 2.02, 95% confidence interval [CI] 1.78 to 2.28, p <5.3 × 10-29), type 2 diabetes (OR 1.96, 95% CI 1.68 to 2.29, p = 2.1 × 10-17), tachycardia (OR 1.38, 95% CI 0.53 to 2.19, p = 2.9 × 10-6), obesity (OR 1.76, 95% CI 1.51 to 2.06, p = 1.7 × 10-12), and clinical end points, including end-stage renal disease (OR 3.29, 95% CI 2.19 to 4.96, p = 1.2 × 10-8) and stroke (OR 1.5, 95% CI 1.12 to 2.02, p = 6.9 × 10-3). Among the 60 incident diagnoses associated with DD, heart failure with preserved ejection fraction (OR 4.63, 95% CI 3.39 to 6.32, p = 6.3 × 10-22) had the most significant association. Among subjects with normal diastolic function and blood pressure at baseline, a blood pressure measurement in the hypertensive range at the time of the second echocardiogram was associated with progression to stage 1 DD (p = 0.04). In conclusion, DD was common among subjects 40 to 55 years old and was associated with a heavy burden of co-morbid disease., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Circulating B-type natriuretic peptide (BNP) concentrations strongly predict mortality in patients with heart failure (HF). Both cardiac and extracardiac stimuli influence BNP levels, suggesting that BNP might have similar prognostic value in patients without HF., Objectives: The aim of this study was to compare the prognostic value of BNP between patients with and those without HF., Methods: Using the Vanderbilt University Medical Center electronic health record, 30,487 patients (median age 63 years, 50% men, 17% black, 38% with HF) who had a first plasma BNP measurement between 2002 and 2013, with follow-up through 2015, were studied. The risk for death according to BNP level was quantified using multivariate Cox proportional hazards models., Results: BNP levels were lower in patients without HF (median 89 pg/ml; interquartile range: 34 to 238 pg/ml) compared with those with HF (median 388 pg/ml; interquartile range: 150 to 940 pg/ml) (p < 0.0001). Over 90,898 person-years of follow-up, 5,903 patients without HF (31%) and 6,181 patients with HF (53%) died. In multivariate models including demographic and clinical characteristics, BNP and age were the strongest predictors of death in both patients with and those without HF. In acute care settings and even among outpatients with modestly elevated BNP, the risk for death according to BNP was similar between patients with and those without HF. For instance, a BNP level of 400 pg/ml was associated with a 3-year risk for death of 21% (95% confidence interval: 20% to 23%) and 19% (95% confidence interval: 17% to 20%) in patients with and those without HF, respectively., Conclusions: Among patients without HF, plasma BNP level is a stronger predictor of death than traditional risk factors. The risk for death associated with any given BNP level is similar between patients with and those without HF, particularly in the acute care setting., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Hypokalemia has been consistently reported as a common occurrence during targeted temperature management (TTM) in comatose survivors of cardiac arrest. We sought to better describe changes in serum potassium throughout the different stages of TTM and to assess for any prognostic significance. We analyzed a prospectively collected cohort of 240 patients treated with TTM following cardiac arrest at a tertiary care hospital between 2007 and 2014. The primary outcome was poor neurologic outcome at hospital discharge, defined as a Cerebral Performance Category score >2. Secondary outcomes included death and recurrent ventricular arrhythmia before hospital discharge. Multivariable logistic regression was used to assess for association of hypokalemia and hyperkalemia with the designated outcomes. During all phases of TTM, hypokalemia and hyperkalemia occurred in 207 (86%) and 77 (32%) of patients, respectively. Hypokalemia occurred in 203 (85%) patients at target temperature, and 25 (10%) patients were hyperkalemic following normothermia. In multivariable logistic regression, hypokalemia was not associated with poor neurologic outcomes or recurrent ventricular arrhythmia. Hypokalemia was associated with reduced odds of death before hospital discharge (odds ratio = 0.36, 95% confidence interval 0.13 to 0.97, p = 0.044). Hyperkalemia was not associated with poor neurologic outcomes, death, or recurrent ventricular arrhythmia., (Copyright © 2017 Elsevier Inc. All rights reserved.)