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Nicotinamide adenine dinucleotide (NAD + ) is an essential co-factor in metabolic reactions and co-substrate for signaling enzymes. Failing human hearts display decreased expression of the major NAD + biosynthetic enzyme nicotinamide phosphoribosyltransferase (Nampt) and lower NAD + levels, and supplementation with NAD + precursors is protective in preclinical models. Here we show that Nampt loss in adult cardiomyocytes caused depletion of NAD + along with marked metabolic derangements, hypertrophic remodeling and sudden cardiac deaths, despite unchanged ejection fraction, endurance and mitochondrial respiratory capacity. These effects were directly attributable to NAD + loss as all were ameliorated by restoring cardiac NAD + levels with the NAD + precursor nicotinamide riboside (NR). Electrocardiograms revealed that loss of myocardial Nampt caused a shortening of QT intervals with spontaneous lethal arrhythmias causing sudden cardiac death. Thus, changes in NAD + concentration can have a profound influence on cardiac physiology even at levels sufficient to maintain energetics., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: The role of cellular senescence in human heart failure (HF) remains unclear. The senescence-associated secretory phenotype (SASP) is composed of proteins released by senescent cells. We assessed the prognostic significance and biologic pathways associated with the SASP in human HF using a plasma proteomics approach., Methods and Results: We measured 25 known SASP proteins among 2248 PHFS (Penn HF Study) participants using the SOMAScan V4 assay. We extracted the common variance in these proteins to generate SASP factor scores and assessed the relationship between these SASP factor scores and (1) all-cause death and (2) the composite of death or HF hospital admission. We also assessed the relationship of each SASP factor to 4746 other proteins, correcting for multiple comparisons, followed by pathway analyses. Two SASP factors were identified. Both factors were associated with older age, lower estimated glomerular filtration rate, and more advanced New York Heart Association class, among other clinical variables. Both SASP factors exhibited a significant positive association with the risk of death independent of the Meta-Analysis of Global-Group in Chronic HF score and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels. The 2 identified SASP factors were associated with 1201 and 1554 proteins, respectively, belonging to various pathways including the coagulation system, complement system, acute phase response signaling, and retinoid X receptor-related pathways that regulate cell metabolism., Conclusions: Increased SASP components are independently associated with adverse outcomes in HF. Biologic pathways associated with SASP are predominantly related to coagulation, inflammation, and cell metabolism.

Background: Kidney disease is common in heart failure with preserved ejection fraction (HFpEF). However, the biologic correlates and prognostic significance of kidney injury (KI), in HFpEF, beyond the estimated glomerular filtration rate (eGFR), are unclear., Methods and Results: Using baseline plasma samples from the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial, we measured the following KI biomarkers: cystatin-C, fatty acid-binding protein-3, Beta-2 microglobulin, neutrophil gelatinase-associated lipocalin, and kidney-injury molecule-1. Factor analysis was used to extract the common variability underlying these biomarkers. We assessed the relationship between the KI-factor score and the risk of death or HF-related hospital admission in models adjusted for the Meta-Analysis Global Group in Chronic Heart Failure risk score and eGFR. We also assessed the relationship between the KI factor score and ~5000 plasma proteins, followed by pathway analysis. We validated our findings among HFpEF participants in the Penn Heart Failure Study. KI was associated with the risk of death or HF-related hospital admission independent of the Meta-Analysis Global Group in Chronic Heart Failure risk score and eGFR. Both the risk score and eGFR were no longer associated with death or HF-related hospital admission after adjusting for the KI factor score. KI was predominantly associated with proteins and biologic pathways related to complement activation, inflammation, fibrosis, and cholesterol homeostasis. KI was associated with 140 proteins, which reproduced across cohorts. Findings regarding biologic associations and the prognostic significance of KI were also reproduced in the validation cohort., Conclusions: KI is associated with adverse outcomes in HFpEF independent of baseline eGFR. Patients with HFpEF and KI exhibit a plasma proteomic signature indicative of complement activation, inflammation, fibrosis, and impaired cholesterol homeostasis.

Heart failure (HF) is one of the most common, complex, heterogeneous diseases in the world, with over 1-3% of the global population living with the condition. Progression of HF can be tracked via MRI measures of structural and functional changes to the heart, namely left ventricle (LV), including ejection fraction, mass, end-diastolic volume, and LV end-systolic volume. Moreover, while genome-wide association studies (GWAS) have been a useful tool to identify candidate variants involved in HF risk, they lack crucial tissue-specific and mechanistic information which can be gained from incorporating additional data modalities. This study addresses this gap by incorporating transcriptome-wide and proteome-wide association studies (TWAS and PWAS) to gain insights into genetically-regulated changes in gene expression and protein abundance in precursors to HF measured using MRI-derived cardiac measures as well as full-stage all-cause HF. We identified several gene and protein overlaps between LV ejection fraction and end-systolic volume measures. Many of the overlaps identified in MRI-derived measurements through TWAS and PWAS appear to be shared with all-cause HF. We implicate many putative pathways relevant in HF associated with these genes and proteins via gene-set enrichment and protein-protein interaction network approaches. The results of this study (1) highlight the benefit of using multi-omics to better understand genetics and (2) provide novel insights as to how changes in heart structure and function may relate to HF.

Background: Although several studies have addressed plasma proteomics in heart failure with preserved ejection fraction, limited data are available on the prognostic value of urinary proteomics. The objective of our study was to identify urinary proteins/peptides associated with death and heart failure admission in patients with heart failure with preserved ejection fraction., Methods and Results: The study population included participants enrolled in TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial). The relationship between urine protein levels and the risk of death or heart failure admission was assessed using Cox regression, in both nonadjusted analyses and adjusting for urine creatinine levels, and the MAGGIC (Meta-Analysis Global Group in Chronic Heart Failure) score. A total of 426 (12.4%) TOPCAT participants had urinary protein data and were included. There were 40 urinary proteins/peptides significantly associated with death or heart failure admission in nonadjusted analyses, 21 of which were also significant adjusted analyses. Top proteins in the adjusted analysis included ANGPTL2 (angiopoietin-like protein 2) (hazard ratio [HR], 0.5731 [95% CI, 0.47-0.7]; P =3.13E-05), AMY2A (α amylase 2A) (HR, 0.5496 [95% CI, 0.44-0.69]; P =0.0001), and DNASE1 (deoxyribonuclease-1) (HR, 0.5704 [95% CI, 0.46-0.71]; P =0.0002). Higher urinary levels of proteins involved in fibrosis (collagen VI α-1, collagen XV α-1), metabolism (pancreatic α-amylase 2A/B, mannosidase α class 1A member 1), and inflammation (heat shock protein family D member 1, inducible T cell costimulatory ligand) were associated with a lower risk of death or heart failure admission., Conclusions: Our study identifies several novel associations between urinary proteins/peptides and outcomes in heart failure with preserved ejection fraction. Many of these associations are independent of clinical risk scores and may aid in risk stratification in this patient population.

Background: Identifying novel molecular drivers of disease progression in heart failure (HF) is a high-priority goal that may provide new therapeutic targets to improve patient outcomes. The authors investigated the relationship between plasma proteins and adverse outcomes in HF and their putative causal role using Mendelian randomization., Methods and Results: The authors measured 4776 plasma proteins among 1964 participants with HF with a reduced left ventricular ejection fraction enrolled in PHFS (Penn Heart Failure Study). Assessed were the observational relationship between plasma proteins and (1) all-cause death or (2) death or HF-related hospital admission (DHFA). The authors replicated nominally significant associations in the Washington University HF registry (N=1080). Proteins significantly associated with outcomes were the subject of 2-sample Mendelian randomization and colocalization analyses. After correction for multiple testing, 243 and 126 proteins were found to be significantly associated with death and DHFA, respectively. These included small ubiquitin-like modifier 2 (standardized hazard ratio [sHR], 1.56; P <0.0001), growth differentiation factor-15 (sHR, 1.68; P <0.0001) for death, A disintegrin and metalloproteinase with thrombospondin motifs-like protein (sHR, 1.40; P <0.0001), and pulmonary-associated surfactant protein C (sHR, 1.24; P <0.0001) for DHFA. In pathway analyses, top canonical pathways associated with death and DHFA included fibrotic, inflammatory, and coagulation pathways. Genomic analyses provided evidence of nominally significant associations between levels of 6 genetically predicted proteins with DHFA and 11 genetically predicted proteins with death., Conclusions: This study implicates multiple novel proteins in HF and provides preliminary evidence of associations between genetically predicted plasma levels of 17 candidate proteins and the risk for adverse outcomes in human HF.

Background: NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels are variably elevated in heart failure with preserved ejection fraction (HFpEF), even in the presence of increased left ventricular filling pressures. NT-proBNP levels are prognostic in HFpEF and have been used as an inclusion criterion for several recent randomized clinical trials. However, the underlying biologic differences between HFpEF participants with high and low NT-proBNP levels remain to be fully understood., Methods: We measured 4928 proteins using an aptamer-based proteomic assay (SOMAScan) in available plasma samples from 2 cohorts: (1) Participants with HFpEF enrolled in the PHFS (Penn Heart Failure Study; n=253); (2) TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial) participants in the Americas (n=218). We assessed the relationship between SOMAScan-derived plasma NT-proBNP and levels of other proteins available in the SOMAScan assay version 4 using robust linear regression, with correction for multiple comparisons, followed by pathway analysis., Results: NT-proBNP levels exhibited prominent proteome-wide associations in PHFS and TOPCAT cohorts. Proteins most strongly associated with NT-proBNP in both cohorts included SVEP1 (sushi, von Willebrand factor type-A, epidermal growth factor, and pentraxin domain containing 1; β TOPCAT =0.539; P <0.0001; β PHFS =0.516; P <0.0001) and ANGPT2 (angiopoietin 2; β TOPCAT =0.571; P <0.0001; β PHFS =0.459; P <0.0001). Canonical pathway analysis demonstrated consistent associations with multiple pathways related to fibrosis and inflammation. These included hepatic fibrosis and inhibition of matrix metalloproteases. Analyses using cut points corresponding to estimated quantitative concentrations of 360 pg/mL (and 480 pg/mL in atrial fibrillation) revealed similar proteomic associations., Conclusions: Circulating NT-proBNP levels exhibit prominent proteomic associations in HFpEF. Our findings suggest that higher NT-proBNP levels in HFpEF are a marker of fibrosis and inflammation. These findings will aid the interpretation of NT-proBNP levels in HFpEF and may guide the selection of participants in future HFpEF clinical trials., Competing Interests: Disclosures Dr Chirinos has recently consulted for Bayer, Sanifit, Fukuda-Denshi, Bristol Myers Squibb, Johnson & Johnson, Edwards Life Sciences, Merck, and the Galway-Mayo Institute of Technology. He received University of Pennsylvania research grants from the National Institutes of Health, Fukuda-Denshi, Bristol Myers Squibb, and Microsoft. He is named as an inventor in a University of Pennsylvania patent for the use of inorganic nitrates/nitrites in Heart Failure With Preserved Ejection Fraction. He has received research device loans from Atcor Medical, Fukuda-Denshi, Uscom, NDD Medical Technologies, Microsoft, and MicroVision Medical. Dr Zamani receives research support from Amgen. He has consulted for Pfizer and Vyaire. Dr Rietzschel has received unrestricted educational grants from Amgen, Merck Sharp & Dohme, AstraZeneca, Sanofi, and Unilever and speakers’ or consultancy fees from Daiichi Sankyo, Novo Nordisk, Boehringer Ingelheim, Servier, Amgen, Sanofi, Novartis, and Teva, all paid directly to Ghent University. He is named as inventor on patent applications for the use of plasma and urine protein biomarkers in heart failure. Dr Richards is supported by grants from Singapore National Medical Research Council and the Health Research Council of New Zealand. He holds the New Zealand Heart Foundation Chair in Cardiovascular Studies. In kind support and research grants are received from Roche Diagnostics, Abbott Laboratories, and Novo Nordisk. He is named on ≈30 cardiovascular biomarker patents. Dr Gill acknowledges support by the British Heart Foundation Centre of Research Excellence at Imperial College London (RE/18/4/34215). The other authors report no conflicts.

Proteinuria is common in heart failure with preserved ejection fraction (HFpEF), but its biologic correlates are poorly understood. We assessed the relation between 49 plasma proteins and the urinary protein/creatinine ratio (UPCR) in 365 participants in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial. Linear regression and network analysis were used to represent relations between protein biomarkers and UPCR. Higher UPCR was associated with older age, a greater proportion of female gender, smaller prevalence of previous myocardial infarction, and greater prevalence of diabetes, insulin use, smoking, and statin use, in addition to a lower estimated glomerular filtration rate, hematocrit, and diastolic blood pressure. Growth differentiation factor 15 (GDF-15; β = 0.15, p <0.0001), followed by N-terminal proatrial natriuretic peptide (NT-proANP; β = 0.774, p <0.0001), adiponectin (β = 0.0005, p <0.0001), fibroblast growth factor 23 (FGF-23, β = 0.177; p <0.0001), and soluble tumor necrosis factor receptors I (β = 0.002, p <0.0001) and II (β = 0.093, p <0.0001) revealed the strongest associations with UPCR. Network analysis showed that UPCR is linked to various proteins primarily through FGF-23, which, along with GDF-15, indicated node characteristics with strong connectivity, whereas UPCR did not. In a model that included FGF-23 and UPCR, the former was predictive of the risk of death or heart-failure hospital admission (standardized hazard ratio 1.83, 95% confidence interval 1.49 to 2.26, p <0.0001) and/or all-cause death (standardized hazard ratio 1.59, 95% confidence interval 1.22 to 2.07, p = 0.0005), whereas UPCR was not prognostic. Proteinuria in HFpEF exhibits distinct proteomic correlates, primarily through its association with FGF-23, a well-known prognostic marker in HFpEF. However, in contrast to FGF-23, UPCR does not hold independent prognostic value., Competing Interests: Declaration of Competing Interest Dr. Chirinos is supported by National Institutes of Health grants R01-HL 121510, U01-TR003734, 3U01TR003734-01W1, U01-HL160277, R33-HL-146390, R01-HL153646, K24-AG070459, R01-AG058969, R01-HL104106, P01-HL094307, R03-HL146874, R56-HL136730, R01 HL155599, R01 HL157264, R01HL155, and 1R01HL153646-01. He has recently consulted for Bayer, Sanifit, Fukuda-Denshi, Bristol-Myers Squibb, Johnson & Johnson, Edwards Life Sciences, Merck, NGM Biopharmaceuticals, and the Galway-Mayo Institute of Technology. He received University of Pennsylvania research grants from National Institutes of Health, Fukuda-Denshi, Bristol-Myers Squibb, Microsoft, and Abbott. He is named as inventor in a University of Pennsylvania patent for the use of inorganic nitrates/nitrites for the treatment of heart failure and on a patent application for the use of a novel biomarker (endotrophin) in heart failure with preserved ejection fraction. He has received payments for editorial roles from the American Heart Association, the American College of Cardiology, and Wiley. He has received research device loans from Atcor Medical, Fukuda-Denshi, Uscom, NDD Medical Technologies, Microsoft, and MicroVision Medical. The remaining authors have no competing interests to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Apolipoprotein M (ApoM) binds sphingosine-1-phosphate (S1P) and is inversely associated with mortality in human heart failure (HF). Here, we show that anthracyclines such as doxorubicin (Dox) reduce circulating ApoM in mice and humans, that ApoM is inversely associated with mortality in patients with anthracycline-induced heart failure, and ApoM heterozygosity in mice increases Dox-induced mortality. In the setting of Dox stress, our studies suggest ApoM can help sustain myocardial autophagic flux in a post-transcriptional manner, attenuate Dox cardiotoxicity, and prevent lysosomal injury., Competing Interests: Dr Javaheri was supported by R01HL155344 and K08HL138262 from the National Heart, Lung, and Blood Institute and by the Diabetes Research Center at Washington University in St Louis of the National Institutes of Health (NIH) under award number P30DK020579, as well as NIH grant P30DK056341 (Nutrition Obesity Research Center), and by the Children’s Discovery Institute of Washington University (MC-FR-2020-919) and St Louis Children’s Hospital. Dr Guo was supported by an American Heart Association Postdoctoral Fellowship (898679). Dr Diwan was supported by grants from the Department of Veterans Affairs (I01BX004235) and the NIH (HL107594, HL43431, and NS094692). Dr Scherrer-Crosbie is supported by R01HL130539 and R01HL131613. Dr Rawnsley was supported by training grant support from the NIH (T32007081). Dr Desai was supported by R01HL136603. Dr Bergom was supported by R01HL147884. Research reported in this publication was also supported by the National Cancer Institute of the NIH under award numbers R50CA211466 (Dr Rettig), R35CA210084 (Dr DiPersio), P01CA101937 (Dr DiPersio), and R01HL119962 (Dr Parks). Human heart tissue procurement was supported by the National Heart, Lung, and Blood Institute via R01HL105993 (Drs Margulies and Cappola). Drs Christoffersen and Hajny were supported by the Novo Nordisk Foundation (0053008 and NNF13OC0003898). Dr Stitziel was supported in part by R01HL131961, R01HL159171, P01HL151328, and UM1HG008853 and by the Foundation for Barnes-Jewish Hospital. We acknowledge support from the NIH Shared Instrumentation Grant (S10RR027552) for support through the Hope Center Neuroimaging Core, the Molecular Microbiology Imaging Facility, and the Advanced Imaging and Tissue Analysis Core of the Digestive Disease Research Core Center (DDRCC NIH P30DK052574) at Washington University School of Medicine. Dr Stitziel has received consulting fees from Sension Therapeutics and investigator-initiated research funding from Regeneron Pharmaceuticals unrelated to the content of this study. Dr Javaheri has a pending patent for fusion protein nanodiscs for the treatment of heart failure and eye diseases, receives research funding from AstraZeneca, and is on the Scientific Advisory Board of Mobius Scientific. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

Heart failure is a leading cause of cardiovascular morbidity and mortality. However, the contribution of common genetic variation to heart failure risk has not been fully elucidated, particularly in comparison to other common cardiometabolic traits. We report a multi-ancestry genome-wide association study meta-analysis of all-cause heart failure including up to 115,150 cases and 1,550,331 controls of diverse genetic ancestry, identifying 47 risk loci. We also perform multivariate genome-wide association studies that integrate heart failure with related cardiac magnetic resonance imaging endophenotypes, identifying 61 risk loci. Gene-prioritization analyses including colocalization and transcriptome-wide association studies identify known and previously unreported candidate cardiomyopathy genes and cellular processes, which we validate in gene-expression profiling of failing and healthy human hearts. Colocalization, gene expression profiling, and Mendelian randomization provide convergent evidence for the roles of BCKDHA and circulating branch-chain amino acids in heart failure and cardiac structure. Finally, proteome-wide Mendelian randomization identifies 9 circulating proteins associated with heart failure or quantitative imaging traits. These analyses highlight similarities and differences among heart failure and associated cardiovascular imaging endophenotypes, implicate common genetic variation in the pathogenesis of heart failure, and identify circulating proteins that may represent cardiomyopathy treatment targets., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Endotrophin, a collagen type VI-derived peptide, mediates metabolic dysregulation, inflammation, and fibrosis in animal models, but has not been studied in human heart failure (HF)., Methods: We examined the association between circulating endotrophin and outcomes in participants suffering from HF with preserved ejection fraction (HFpEF) enrolled in the TOPCAT trial (n=205). Associations were validated in a participant-level meta-analysis (n=810) that included participants with HFpEF from the PHFS study (United States; n=174), PEOPLE cohort (New Zealand; n=168), a randomized trial of vasodilator therapy (United States; n=45), a cohort from Donostia University Hospital and University of Navarra (Spain; n=171), and the TRAINING-HF trial (Spain; n=47). We also assessed associations in HF with reduced ejection fraction in PHFS (n=1,642)., Results: Plasma endotrophin levels at baseline were associated with risk of future death (standardized hazard ratio [HR] = 1.74; 95% confidence interval [CI]=1.36-2.24; P<0.001) and death or HF-related hospital admission (DHFA; standardized HR=2.11; 95% CI= 1.67-2.67; P<0.001) in TOPCAT. Endotrophin improved reclassification and discrimination for these outcomes beyond the MAGGIC risk score and NT-proBNP (N-terminal pro b-type natriuretic peptide). Findings were confirmed in the participant-level meta-analysis. In participants with HF with reduced ejection fraction in PHFS, endotrophin levels were associated with death (standardized HR=1.82; 95% CI=1.66-2.00; P<0.001) and DHFA (standardized HR=1.40; 95% CI=1.31-1.50; P<0.001), but the strength of the latter association was substantially lower than for the MAGGIC risk score (standardized HR=1.93; 95% CI=1.76-2.12) and BNP (standardized HR=1.78; 95% CI=1.66-1.92)., Conclusions: Circulating endotrophin levels are independently associated with future poor outcomes in patients with HF, particularly in HFpEF. (Funded by Bristol Myers Squibb; Instituto de Salud Carlos III [Spain] and European Regional Development Fund; European Commission CRUCIAL project; and the U.S. National Institutes of Health National Heart, Lung, and Blood Institute.).

Heart disease is associated with re-expression of key transcription factors normally active only during prenatal development of the heart. However, the impact of this reactivation on the regulatory landscape in heart disease is unclear. Here, we use RNA-seq and ChIP-seq targeting a histone modification associated with active transcriptional enhancers to generate genome-wide enhancer maps from left ventricle tissue from up to 26 healthy controls, 18 individuals with idiopathic dilated cardiomyopathy (DCM), and five fetal hearts. Healthy individuals have a highly reproducible epigenomic landscape, consisting of more than 33,000 predicted heart enhancers. In contrast, we observe reproducible disease-associated changes in activity at 6,850 predicted heart enhancers. Combined analysis of adult and fetal samples reveals that the heart disease epigenome and transcriptome both acquire fetal-like characteristics, with 3,400 individual enhancers sharing fetal regulatory properties. We also provide a comprehensive data resource (http://heart.lbl.gov) for the mechanistic exploration of DCM etiology., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: There is a paucity of data regarding sex differences in the profiles and outcomes of ambulatory patients on left ventricular assist device (LVAD) support who present to the emergency department (ED)., Methods and Results: We performed a retrospective analysis of 57,200 LVAD-related ED patient encounters from the 2010 to 2018 Nationwide Emergency Department Sample. International Classification of Diseases Clinical Modification, Ninth Revision and Tenth Revision, codes identified patients aged 18 years or older with LVADs and associated primary and comorbidity diagnoses. Clinical characteristics and outcomes were stratified by sex and compared. Multivariable logistic regression was used to evaluate predictors of hospital admission and death. Female patient encounters comprised 27.2% of ED visits and occurred at younger ages and more frequently with obesity and depression (all P < .01). There were no sex differences in presentation for device complication, stroke, infection, or heart failure (all P > .05); however, female patient encounters were more often respiratory- and genitourinary or gynecological related (both P < .01). After adjustment for age group, diabetes, depression, and hypertension, male patient encounters had a 38% increased odds of hospital admission (95% confidence interval 1.20-1.58), but there was no sex difference in the adjusted odds of death (odds ratio 1.11, 95% confidence interval 0.86-1.45)., Conclusions: Patient encounters of females on LVAD support have significantly different comorbidities and outcomes compared with males. Further inquiry into these sex differences is imperative to improve long-term outcomes., Competing Interests: Declaration of Competing Interest A.T.O. reports consulting for Cytokinetics and Myokardia/Bristol Myers Squibb and has received research support from Cytokinetics, Myokardia/Bristol Myers Squibb, and Pfizer. J.W.R. has received paid consulting fees from Abiomed, Amgen, Myokardia/Bristol Myers Squibb, Cytokinetics, Bayer, and Novartis. E.Y.B. reports research support paid to the University of Pennsylvania by Medtronic Inc. and Impulse Dynamics Ltd. The remaining authors report no disclosures., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: The TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial) suggested clinical benefits of spironolactone treatment among patients with heart failure with preserved ejection fraction enrolled in the Americas. However, a comprehensive assessment of biologic pathways impacted by spironolactone therapy in heart failure with preserved ejection fraction has not been performed., Methods: We conducted aptamer-based proteomic analysis utilizing 5284 modified aptamers to 4928 unique proteins on plasma samples from TOPCAT participants from the Americas (n=164 subjects with paired samples at baseline and 1 year) to identify proteins and pathways impacted by spironolactone therapy in heart failure with preserved ejection fraction. Mean percentage change from baseline was calculated for each protein. Additionally, we conducted pathway analysis of proteins altered by spironolactone., Results: Spironolactone therapy was associated with proteome-wide significant changes in 7 proteins. Among these, CARD18 (caspase recruitment domain-containing protein 18), PKD2 (polycystin 2), and PSG2 (pregnancy-specific glycoprotein 2) were upregulated, whereas HGF (hepatic growth factor), PLTP (phospholipid transfer protein), IGF2R (insulin growth factor 2 receptor), and SWP70 (switch-associated protein 70) were downregulated. CARD18, a caspase-1 inhibitor, was the most upregulated protein by spironolactone (-0.5% with placebo versus +66.5% with spironolactone, P <0.0001). The top canonical pathways that were significantly associated with spironolactone were apelin signaling, stellate cell activation, glycoprotein 6 signaling, atherosclerosis signaling, liver X receptor activation, and farnesoid X receptor activation. Among the top pathways, collagens were a consistent theme that increased in patients receiving placebo but decreased in patients randomized to spironolactone., Conclusions: Proteomic analysis in the TOPCAT trial revealed proteins and pathways altered by spironolactone, including the caspase inhibitor CARD18 and multiple pathways that involved collagens. In addition to effects on fibrosis, our studies suggest potential antiapoptotic effects of spironolactone in heart failure with preserved ejection fraction, a hypothesis that merits further exploration.

Aims: The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure., Methods and Results: The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 × 10 -8 under an additive genetic model., Conclusions: HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Truncating variants in TTN (TTNtvs) are the most common known cause of nonischemic dilated cardiomyopathy (DCM), but how TTNtvs cause disease has remained controversial. Efforts to detect truncated titin proteins in affected human DCM hearts have failed, suggesting that disease is caused by haploinsufficiency, but reduced amounts of titin protein have not yet been demonstrated. Here, we leveraged a collection of 184 explanted posttransplant DCM hearts to show, using specialized electrophoretic gels, Western blotting, allelic phasing, and unbiased proteomics, that truncated titin proteins can quantitatively be detected in human DCM hearts. The sizes of truncated proteins corresponded to that predicted by their respective TTNtvs; the truncated proteins were encoded by the TTNtv-bearing allele; and no degradation fragments from protein encoded by either allele were detectable. In parallel, full-length titin was less abundant in TTNtv + than in TTNtv − DCM hearts. Disease severity or need for transplantation did not correlate with TTNtv location. Transcriptomic profiling revealed few differences in splicing or allelic imbalance of the TTN transcript between TTNtv + and TTNtv − DCM hearts. Studies with isolated human adult cardiomyocytes revealed no defects in contractility in cells from TTNtv + compared to TTNtv − DCM hearts. Together, these data demonstrate the presence of truncated titin protein in human TTNtv + DCM, show reduced amounts of full-length titin protein in TTNtv + DCM hearts, and support combined dominant-negative and haploinsufficiency contributions to disease.

Aims: Our objective was to better understand the genetic bases of dilated cardiomyopathy (DCM), a leading cause of systolic heart failure., Methods and Results: We conducted the largest genome-wide association study performed so far in DCM, with 2719 cases and 4440 controls in the discovery population. We identified and replicated two new DCM-associated loci on chromosome 3p25.1 [lead single-nucleotide polymorphism (SNP) rs62232870, P = 8.7 × 10-11 and 7.7 × 10-4 in the discovery and replication steps, respectively] and chromosome 22q11.23 (lead SNP rs7284877, P = 3.3 × 10-8 and 1.4 × 10-3 in the discovery and replication steps, respectively), while confirming two previously identified DCM loci on chromosomes 10 and 1, BAG3 and HSPB7. A genetic risk score constructed from the number of risk alleles at these four DCM loci revealed a 3-fold increased risk of DCM for individuals with 8 risk alleles compared to individuals with 5 risk alleles (median of the referral population). In silico annotation and functional 4C-sequencing analyses on iPSC-derived cardiomyocytes identify SLC6A6 as the most likely DCM gene at the 3p25.1 locus. This gene encodes a taurine transporter whose involvement in myocardial dysfunction and DCM is supported by numerous observations in humans and animals. At the 22q11.23 locus, in silico and data mining annotations, and to a lesser extent functional analysis, strongly suggest SMARCB1 as the candidate culprit gene., Conclusion: This study provides a better understanding of the genetic architecture of DCM and sheds light on novel biological pathways underlying heart failure., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Background: Diurnal variation of natriuretic peptide (NP) levels and its relationship with 24-h blood pressure (BP) rhythm has not been established. Obese individuals have a relative NP deficiency and disturbed BP rhythmicity., Objectives: This clinical trial evaluated the diurnal rhythmicity of NPs (B-type natriuretic peptide [BNP], mid-regional pro-atrial natriuretic peptide [MR-proANP], N-terminal pro-B-type natriuretic peptide [NT-proBNP]) and the relationship of NP rhythm with 24-h BP rhythm in healthy lean and obese individuals., Methods: On the background of a standardized diet, healthy, normotensive, lean (body mass index 18.5 to 25 kg/m 2 ) and obese (body mass index 30 to 45 kg/m 2 ) individuals, age 18 to 40 years, underwent 24-h inpatient protocol involving ambulatory BP monitoring starting 24 h prior to the visit, controlled light intensity, and repeated blood draws for assessment of analytes. Cosinor analysis of normalized NP levels (normalized to 24-h mean value) was conducted to assess the diurnal NP rhythm and its relationship with systolic BP., Results: Among 52 participants screened, 40 participants (18 lean, 22 obese; 50% women; 65% Black) completed the study. The median range spread (percentage difference between the minimum and maximum values) over 24 h for MR-proANP, BNP, and NT-proBNP levels was 72.0% (interquartile range [IQR]: 50.9% to 119.6%), 75.5% (IQR: 50.7% to 106.8%), and 135.0% (IQR: 66.3% to 270.4%), respectively. A cosine wave-shaped 24-h oscillation of normalized NP levels (BNP, MR-proANP, and NT-proBNP) was noted both in lean and obese individuals (p rhythmicity  <0.05 for all). A larger phase difference between MR-proANP BP rhythm (-4.9 h vs. -0.7 h) and BNP BP rhythm (-3.3 h vs. -0.9 h) was seen in obese compared with lean individuals., Conclusions: This human physiological trial elucidates evidence of diurnal NP rhythmicity and the presence of an NP-BP rhythm axis. There exists a misalignment of the NP-BP diurnal rhythm in the obese, which may contribute to the disturbed diurnal BP pattern observed among obese individuals. (The Diurnal Rhythm in Natriuretic Peptide Levels; NCT03834168)., Competing Interests: Funding Support and Author Disclosures This research was partly supported by the National Center for Advancing Translational Research of the National Institutes of Health under award number UL1TR001417 to the University of Alabama at Birmingham Center for Clinical and Translational Science. Dr. Margulies has received research grant support from Sanofi-Aventis, Merck, Sharp, and Dohme, and GlaxoSmithKline; and has consulted for MyoKardia, Pfizer, and Luitpold Pharmaceuticals. Drs. Wang and P. Arora are named as coinventors on a patent application relating to the use of miRNAs for the treatment of hypertension and other disorders. Dr. P. Arora is supported by the National Institutes of Health Mentored Patient-Oriented Research Award 5K23HL146887-02. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Peripartum cardiomyopathy (PPCM) occurs in ≈1:2000 deliveries in the United States and worldwide. The genetic underpinnings of PPCM remain poorly defined. Approximately 10% of women with PPCM harbor truncating variants in TTN (TTNtvs). Whether mutations in other genes can predispose to PPCM is not known. It is also not known if the presence of TTNtvs predicts clinical presentation or outcomes. Nor is it known if the prevalence of TTNtvs differs in women with PPCM and preeclampsia, the strongest risk factor for PPCM., Methods: Women with PPCM were retrospectively identified from several US and international academic centers, and clinical information and DNA samples were acquired. Next-generation sequencing was performed on 67 genes, including TTN , and evaluated for burden of truncating and missense variants. The impact of TTNtvs on the severity of clinical presentation, and on clinical outcomes, was evaluated., Results: Four hundred sixty-nine women met inclusion criteria. Of the women with PPCM, 10.4% bore TTNtvs (odds ratio=9.4 compared with 1.2% in the reference population; Bonferroni-corrected P [ P *]=1.2×10 -46 ). We additionally identified overrepresentation of truncating variants in FLNC (odds ratio=24.8, P *=7.0×10 -8 ), DSP (odds ratio=14.9, P *=1.0×10 -8 ), and BAG3 (odds ratio=53.1, P *=0.02), genes not previously associated with PPCM. This profile is highly similar to that found in nonischemic dilated cardiomyopathy. Women with TTNtvs had lower left ventricular ejection fraction on presentation than did women without TTNtvs (23.5% versus 29%, P =2.5×10 -4 ), but did not differ significantly in timing of presentation after delivery, in prevalence of preeclampsia, or in rates of clinical recovery., Conclusions: This study provides the first extensive genetic and phenotypic landscape of PPCM and demonstrates that predisposition to heart failure is an important risk factor for PPCM. The work reveals a degree of genetic similarity between PPCM and dilated cardiomyopathy, suggesting that gene-specific therapeutic approaches being developed for dilated cardiomyopathy may also apply to PPCM, and that approaches to genetic testing in PPCM should mirror those taken in dilated cardiomyopathy. Last, the clarification of genotype/phenotype associations has important implications for genetic counseling.

Pathogenic mutations in LAMIN A/C (LMNA) cause abnormal nuclear structure and laminopathies. These diseases have myriad tissue-specific phenotypes, including dilated cardiomyopathy (DCM), but how LMNA mutations result in tissue-restricted disease phenotypes remains unclear. We introduced LMNA mutations from individuals with DCM into human induced pluripotent stem cells (hiPSCs) and found that hiPSC-derived cardiomyocytes, in contrast to hepatocytes or adipocytes, exhibit aberrant nuclear morphology and specific disruptions in peripheral chromatin. Disrupted regions were enriched for transcriptionally active genes and regions with lower LAMIN B1 contact frequency. The lamina-chromatin interactions disrupted in mutant cardiomyocytes were enriched for genes associated with non-myocyte lineages and correlated with higher expression of those genes. Myocardium from individuals with LMNA variants similarly showed aberrant expression of non-myocyte pathways. We propose that the lamina network safeguards cellular identity and that pathogenic LMNA variants disrupt peripheral chromatin with specific epigenetic and molecular characteristics, causing misexpression of genes normally expressed in other cell types., Competing Interests: Declaration of interests K.M. is an advisor to and holds equity in Variant Bio and Verve Therapeutics., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Diabetes mellitus (DM) is associated with a higher risk of heart failure hospitalization and mortality in patients with heart failure with preserved ejection fraction (HFpEF). Using SomaScan assays and proteomics analysis of plasma from participants in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial and the Penn Heart Failure Study, this study identified 10 proteins with significantly different expression in patients with HFpEF and DM. Of these, apolipoprotein M was found to mediate 72% (95% CI: 36% to 100%; p < 0.001) of the association between DM and the risk of cardiovascular death, aborted cardiac arrest, and heart failure hospitalization., Competing Interests: Dr. Hanff is supported by the National Institutes of Health (grant HL-00789). Dr. Cohen is supported by K23-HL133843. Dr. Javaheri is supported by K08-HL138262. Dr. Zamani is supported by grant K23-HL-13055. Dr. Chirinos is supported by a research grant from Bristol-Myers Squibb and by grants R01-HL 121510- 01A1, R61-HL-146390, R01-AG058969, 1R01-HL104106, P01-HL094307, R03-HL146874-01, and R56-HL136730. Dr. Javaheri has been named co-inventor on the patent application for the use of fusion protein nanodiscs for the treatment of heart failure. Drs. Zhao, Walsh, Maranville, Wang, Adam, Ramirez-Valle, Schafer, Seiffert, Gordon, and Cvijic own stock in Bristol-Myers Squibb. Dr. Cappola has received research funding from Bristol-Myers Squibb. Dr. Zamani has consulted for Vyaire. Dr. Chirinos has been a consultant for Sanifit, Microsoft, Fukuda-Denshi, Bristol-Myers Squibb, OPKO Healthcare, Ironwood Pharmaceuticals, Pfizer, Akros Pharma, Merck, Bayer, JNJ, and Edwards Life Sciences; and received research grants from National Institutes of Health, American College of Radiology Network, Fukuda Denshi, Bristol-Myers Squibb, and Microsoft, and has been named as inventor in a University of Pennsylvania patent for the use of inorganic nitrates/nitrites for the treatment of heart failure and preserved ejection fraction. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2021 The Authors.)

Importance: The coronavirus disease 2019 (COVID-19) pandemic has required a shift in health care delivery platforms, necessitating a new reliance on telemedicine., Objective: To evaluate whether inequities are present in telemedicine use and video visit use for telemedicine visits during the COVID-19 pandemic., Design, Setting, and Participants: In this cohort study, a retrospective medical record review was conducted from March 16 to May 11, 2020, of all patients scheduled for telemedicine visits in primary care and specialty ambulatory clinics at a large academic health system. Age, race/ethnicity, sex, language, median household income, and insurance type were all identified from the electronic medical record., Main Outcomes and Measures: A successfully completed telemedicine visit and video (vs telephone) visit for a telemedicine encounter. Multivariable models were used to assess the association between sociodemographic factors, including sex, race/ethnicity, socioeconomic status, and language, and the use of telemedicine visits, as well as video use specifically., Results: A total of 148 402 unique patients (86 055 women [58.0%]; mean [SD] age, 56.5 [17.7] years) had scheduled telemedicine visits during the study period; 80 780 patients (54.4%) completed visits. Of 78 539 patients with completed visits in which visit modality was specified, 35 824 (45.6%) were conducted via video, whereas 24 025 (56.9%) had a telephone visit. In multivariable models, older age (adjusted odds ratio [aOR], 0.85 [95% CI, 0.83-0.88] for those aged 55-64 years; aOR, 0.75 [95% CI, 0.72-0.78] for those aged 65-74 years; aOR, 0.67 [95% CI, 0.64-0.70] for those aged ≥75 years), Asian race (aOR, 0.69 [95% CI, 0.66-0.73]), non-English language as the patient's preferred language (aOR, 0.84 [95% CI, 0.78-0.90]), and Medicaid insurance (aOR, 0.93 [95% CI, 0.89-0.97]) were independently associated with fewer completed telemedicine visits. Older age (aOR, 0.79 [95% CI, 0.76-0.82] for those aged 55-64 years; aOR, 0.78 [95% CI, 0.74-0.83] for those aged 65-74 years; aOR, 0.49 [95% CI, 0.46-0.53] for those aged ≥75 years), female sex (aOR, 0.92 [95% CI, 0.90-0.95]), Black race (aOR, 0.65 [95% CI, 0.62-0.68]), Latinx ethnicity (aOR, 0.90 [95% CI, 0.83-0.97]), and lower household income (aOR, 0.57 [95% CI, 0.54-0.60] for income <$50 000; aOR, 0.89 [95% CI, 0.85-0.92], for $50 000-$100 000) were associated with less video use for telemedicine visits. These results were similar across medical specialties., Conclusions and Relevance: In this cohort study of patients scheduled for primary care and medical specialty ambulatory telemedicine visits at a large academic health system during the early phase of the COVID-19 pandemic, older patients, Asian patients, and non-English-speaking patients had lower rates of telemedicine use, while older patients, female patients, Black, Latinx, and poorer patients had less video use. Inequities in accessing telemedicine care are present, which warrant further attention.

The electrocardiogram (ECG) is one of the most useful non-invasive diagnostic tests for a wide array of cardiac disorders. Traditional approaches to analyzing ECGs focus on individual segments. Here, we performed comprehensive deep phenotyping of 77,190 ECGs in the UK Biobank across the complete cycle of cardiac conduction, resulting in 500 spatial-temporal datapoints, across 10 million genetic variants. In addition to characterizing polygenic risk scores for the traditional ECG segments, we identified over 300 genetic loci that are statistically associated with the high-dimensional representation of the ECG. We established the genetic ECG signature for dilated cardiomyopathy, associated the BAG3, HSPB7/CLCNKA, PRKCA, TMEM43, and OBSCN loci with disease risk and confirmed this association in an independent cohort. In total, our work demonstrates that a high-dimensional analysis of the entire ECG provides unique opportunities for studying cardiac biology and disease and furthering drug development. A record of this paper's transparent peer review process is included in the Supplemental Information., Competing Interests: Declaration of Interests N.V. is a paid consultant for Regeneron Pharmaceuticals. The other authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Rationale: Identifying genetic markers for heterogeneous complex diseases such as heart failure is challenging and requires prohibitively large cohort sizes in genome-wide association studies to meet the stringent threshold of genome-wide statistical significance. On the other hand, chromatin quantitative trait loci, elucidated by direct epigenetic profiling of specific human tissues, may contribute toward prioritizing subthreshold variants for disease association., Objective: Here, we captured noncoding genetic variants by performing epigenetic profiling for enhancer H3K27ac chromatin immunoprecipitation followed by sequencing in 70 human control and end-stage failing hearts., Methods and Results: We have mapped a comprehensive catalog of 47 321 putative human heart enhancers and promoters. Three thousand eight hundred ninety-seven differential acetylation peaks (FDR [false discovery rate], 5%) pointed to pathways altered in heart failure. To identify cardiac histone acetylation quantitative trait loci (haQTLs), we regressed out confounding factors including heart failure disease status and used the G-SCI (Genotype-independent Signal Correlation and Imbalance) test 1 to call out 1680 haQTLs (FDR, 10%). RNA sequencing performed on the same heart samples proved a subset of haQTLs to have significant association also to gene expression (expression quantitative trait loci), either in cis (180) or through long-range interactions (81), identified by Hi-C (high-throughput chromatin conformation assay) and HiChIP (high-throughput protein centric chromatin) performed on a subset of hearts. Furthermore, a concordant relationship between the gain or disruption of TF (transcription factor)-binding motifs, inferred from alternative alleles at the haQTLs, implied a surprising direct association between these specific TF and local histone acetylation in human hearts. Finally, 62 unique loci were identified by colocalization of haQTLs with the subthreshold loci of heart-related genome-wide association studies datasets., Conclusions: Disease and phenotype association for 62 unique loci are now implicated. These loci may indeed mediate their effect through modification of enhancer H3K27 acetylation enrichment and their corresponding gene expression differences (bioRxiv: https://doi.org/10.1101/536763). Graphical Abstract: A graphical abstract is available for this article.

Background: Apo (apolipoprotein) M mediates the physical interaction between high-density lipoprotein (HDL) particles and sphingosine-1-phosphate (S1P). Apo M exerts anti-inflammatory and cardioprotective effects in animal models., Methods: In a subset of PHFS (Penn Heart Failure Study) participants (n=297), we measured apo M by Enzyme-Linked ImmunoSorbent Assay (ELISA). We also measured total S1P by liquid chromatography-mass spectrometry and isolated HDL particles to test the association between apo M and HDL-associated S1P. We confirmed the relationship between apo M and outcomes using modified aptamer-based apo M measurements among 2170 adults in the PHFS and 2 independent cohorts: the Washington University Heart Failure Registry (n=173) and a subset of TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial; n=218). Last, we examined the relationship between apo M and ≈5000 other proteins (SomaScan assay) to identify biological pathways associated with apo M in heart failure., Results: In the PHFS, apo M was inversely associated with the risk of death (standardized hazard ratio, 0.56 [95% CI, 0.51-0.61]; P <0.0001) and the composite of death/ventricular assist device implantation/heart transplantation (standardized hazard ratio, 0.62 [95% CI, 0.58-0.67]; P <0.0001). This relationship was independent of HDL cholesterol or apo AI levels. Apo M remained associated with death (hazard ratio, 0.78 [95% CI, 0.69-0.88]; P <0.0001) and the composite of death/ventricular assist device/heart transplantation (hazard ratio, 0.85 [95% CI, 0.76-0.94]; P =0.001) in models that adjusted for multiple confounders. This association was present in both heart failure with reduced and preserved ejection fraction and was replicated in the Washington University cohort and a cohort with heart failure with preserved ejection fraction only (TOPCAT). The S1P and apo M content of isolated HDL particles strongly correlated ( R =0.81, P <0.0001). The top canonical pathways associated with apo M were inflammation (negative association), the coagulation system (negative association), and liver X receptor/retinoid X receptor activation (positive association). The relationship with inflammation was validated with multiple inflammatory markers measured with independent assays., Conclusions: Reduced circulating apo M is independently associated with adverse outcomes across the spectrum of human heart failure. Further research is needed to assess whether the apo M/S1P axis is a suitable therapeutic target in heart failure.

Background: We used a large-scale, high-throughput DNA aptamer-based discovery proteomic platform to identify circulating biomarkers of cardiac remodeling and incident heart failure (HF) in community-dwelling individuals., Methods: We evaluated 1895 FHS (Framingham Heart Study) participants (age 55±10 years, 54% women) who underwent proteomic profiling and echocardiography. Plasma levels of 1305 proteins were related to echocardiographic traits and to incident HF using multivariable regression. Statistically significant protein-HF associations were replicated in the HUNT (Nord-Trøndelag Health) study (n=2497, age 63±10 years, 43% women), and results were meta-analyzed. Genetic variants associated with circulating protein levels (pQTLs) were related to echocardiographic traits in the EchoGen (n=30 201) and to incident HF in the CHARGE (n=20 926) consortia., Results: Seventeen proteins associated with echocardiographic traits in cross-sectional analyses (false discovery rate <0.10), and 8 of these proteins had pQTLs associated with echocardiographic traits in EchoGen ( P <0.0007). In Cox models adjusted for clinical risk factors, 29 proteins demonstrated associations with incident HF in FHS (174 HF events, mean follow-up 19 [limits, 0.2-23.7] years). In meta-analyses of FHS and HUNT, 6 of these proteins were associated with incident HF ( P <3.8×10 - 5 ; 3 with higher risk: NT-proBNP [N-terminal proB-type natriuretic peptide], TSP2 [thrombospondin-2], MBL [mannose-binding lectin]; and 3 with lower risk: ErbB1 [epidermal growth factor receptor], GDF-11/8 [growth differentiation factor-11/8], and RGMC [hemojuvelin]). For 5 of the 6 proteins, pQTLs were associated with echocardiographic traits ( P <0.0006) in EchoGen, and for RGMC, a protein quantitative trait loci was associated with incident HF ( P =0.001)., Conclusions: A large-scale proteomics approach identified new predictors of cardiac remodeling and incident HF. Future studies are warranted to elucidate how biological pathways represented by these proteins may mediate cardiac remodeling and HF risk and to assess if these proteins can improve HF risk prediction.

Background: Better risk stratification strategies are needed to enhance clinical care and trial design in heart failure with preserved ejection fraction (HFpEF)., Objectives: The purpose of this study was to assess the value of a targeted plasma multi-marker approach to enhance our phenotypic characterization and risk prediction in HFpEF., Methods: In this study, the authors measured 49 plasma biomarkers from TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial participants (n = 379) using a Multiplex assay. The relationship between biomarkers and the risk of all-cause death or heart failure-related hospital admission (DHFA) was assessed. A tree-based pipeline optimizer platform was used to generate a multimarker predictive model for DHFA. We validated the model in an independent cohort of HFpEF patients enrolled in the PHFS (Penn Heart Failure Study) (n = 156)., Results: Two large, tightly related dominant biomarker clusters were found, which included biomarkers of fibrosis/tissue remodeling, inflammation, renal injury/dysfunction, and liver fibrosis. Other clusters were composed of neurohormonal regulators of mineral metabolism, intermediary metabolism, and biomarkers of myocardial injury. Multiple biomarkers predicted incident DHFA, including 2 biomarkers related to mineral metabolism/calcification (fibroblast growth factor-23 and OPG [osteoprotegerin]), 3 inflammatory biomarkers (tumor necrosis factor-alpha, sTNFRI [soluble tumor necrosis factor-receptor I], and interleukin-6), YKL-40 (related to liver injury and inflammation), 2 biomarkers related to intermediary metabolism and adipocyte biology (fatty acid binding protein-4 and growth differentiation factor-15), angiopoietin-2 (related to angiogenesis), matrix metalloproteinase-7 (related to extracellular matrix turnover), ST-2, and N-terminal pro-B-type natriuretic peptide. A machine-learning-derived model using a combination of biomarkers was strongly predictive of the risk of DHFA (standardized hazard ratio: 2.85; 95% confidence interval: 2.03 to 4.02; p < 0.0001) and markedly improved the risk prediction when added to the MAGGIC (Meta-Analysis Global Group in Chronic Heart Failure Risk Score) risk score. In an independent cohort (PHFS), the model strongly predicted the risk of DHFA (standardized hazard ratio: 2.74; 95% confidence interval: 1.93 to 3.90; p < 0.0001), which was also independent of the MAGGIC risk score., Conclusions: Various novel circulating biomarkers in key pathophysiological domains are predictive of outcomes in HFpEF, and a multimarker approach coupled with machine-learning represents a promising strategy for enhancing risk stratification in HFpEF., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)