We derived and validated proteomic risk scores (PRSs) for heart failure (HF) prognosis that provide absolute risk estimates for all-cause mortality within 1 year. Plasma samples from individuals with HF with reduced ejection fraction (HFrEF; ejection fraction <40%; training/validation n=1247/762) and preserved ejection fraction (HFpEF; ejection fraction ≥50%; training/validation n=725/785) from 3 independent studies were run on the SomaScan Assay measuring ≈5000 proteins. Machine learning techniques resulted in unique 17- and 14-protein models for HFrEF and HFpEF that predict 1-year mortality. Discrimination was assessed via C-index and 1-year area under the curve (AUC), and survival curves were visualized. PRSs were also compared with Meta-Analysis Global Group in Chronic HF (MAGGIC) score and NT-proBNP (N-terminal pro-B-type natriuretic peptide) measurements and further assessed for sensitivity to disease progression in longitudinal samples (HFrEF: n=396; 1107 samples; HFpEF: n=175; 350 samples). In validation, the HFpEF PRS performed significantly better (P≤0.1) for mortality prediction (C-index, 0.79; AUC, 0.82) than MAGGIC (C-index, 0.71; AUC, 0.74) and NT-proBNP (PRS C-index, 0.76 and AUC, 0.81 versus NT-proBNP C-index, 0.72 and AUC, 0.76). The HFrEF PRS performed comparably to MAGGIC (PRS C-index, 0.76 and AUC, 0.83 versus MAGGIC C-index, 0.75 and AUC, 0.84) but had a significantly better C-Index (P=0.026) than NT-proBNP (PRS C-index, 0.75 and AUC, 0.78 versus NT-proBNP C-index, 0.73 and AUC, 0.77). PRS included known HF pathophysiology biomarkers (93%) and novel proteins (7%). Longitudinal assessment revealed that HFrEF and HFpEF PRSs were higher and increased more over time in individuals who experienced a fatal event during follow-up. PRSs can provide valid, accurate, and dynamic prognostic estimates for patients with HF. This approach has the potential to improve longitudinal monitoring of patients and facilitate personalized care.

ABSTRACT Previous pharmacogenetic findings for beta‐blocker pharmacodynamic candidate genes (ADRB1, ADRB2, ADRA2C, GRK4, and GRK5) have been inconsistent. Therefore, the purpose of this study was to determine whether interactions of pharmacodynamic variants with beta‐blocker exposure significantly associated with survival in patients with heart failure with reduced ejection (HFrEF). The 893 patients were 51% self‐reported African American and 49% self‐reported White race, 36% female, and 240 died (27%) over a median follow‐up of 2.8 years. The primary outcome was all‐cause mortality. Using Cox proportional hazards models with time‐varying beta‐blocker exposure and adjusted for clinical risk factors and ancestry, interactions of ADRB1 Arg389Gly, ADRB1 Ser49‐Arg389Gly haplotype, ADRA2C Del322‐325, and GRK4 Ala486Val with beta‐blocker exposure were significant before correction for multiple comparisons (p < 0.1), but only GRK4 Ala486Val remained significant in African Americans after correction for multiple comparisons using the adaptive Hochberg method (p = 0.022). Beta‐blocker exposure only associated with a significant reduction in the risk of mortality in the African American HFrEF patients with the GRK4 Ala486/Ala486 genotype (HR = 0.44; 95% CI = 0.20–0.96; p = 0.04). In conclusion, the interaction of GRK4 Ala486Val with beta‐blocker exposure significantly associated with survival in African American HFrEF patients. Larger sample sizes or meta‐analyses are needed to have more statistical power to better assess beta‐blocker pharmacogenetic interactions for ADRB1 Arg389Gly, ADRB1 Ser49‐Arg389Gly haplotype, and ADRA2C Del322‐325 in the future.

Background: Cytosolic Connexin-43 (Cx43) plays a crucial role in the formation of gap junctions. Proper levels, localization, function, and interactions of Cx43 with other proteins are vital for maintaining electrical coupling between cardiomyocytes. A reduction in Cx43 protein levels in heart failure (HF) can lead to ventricular arrhythmias and sudden death. In the failing heart, β3 adrenergic receptors (ARs) are upregulated, a maladaptation that can lead to downregulation of Cx43. We previously showed that treatment of HF dogs with a β3-AR antagonist (APD418) improves LV systolic function. Hypothesis: The present study tested the hypothesis that 1) Cx43 protein levels are decreased in LV myocardium of dogs with HF and 2) treatment with a β3-AR antagonist (APD418) restores Cx43 protein levels. Studies were performed in LV myocardium of dogs with coronary microembolization-induced HF. In addition to marked LV dysfunction, the model, as in humans with HF, manifests spontaneous ventricular arrhythmias and sudden death. Methods: Studies were performed in LV tissue from 14 dogs with HF (LV EF ~35%) that were randomized to receive a 6-hour intravenous infusion of APD418 (4.224 mg/kg, n=7) or vehicle (0.9% NaCl, n=7). LV tissue from 7 normal healthy (NL) dogs served as controls. Cytosolic fractions were isolated from LV myocardium, and Cx43 protein levels were quantified with Western blotting using a dog specific monoclonal antibody. Housekeeping protein (cytosolic GAPDH) was used as a loading control. Band intensities were expressed in densitometric units (du). Results: Cytosolic GAPDH were unchanged between NL and HF dogs. Compared to NL dogs, vehicle treated HF dogs showed significantly reduced Cx43 levels (0.97 ± 0.05 vs. 2.98 ± 0.46 du, p<0.05). Treatment with APD418 significantly increased Cx43 levels compared to vehicle controls (1.82 ± 0.49 vs. 0.97 ± 0.05 du, p < 0.05). Conclusion: Cytosolic Cx43 levels are reduced in LV myocardium of dogs with HF; an abnormality that can trigger ventricular arrhythmias. Treatment with the β3-AR antagonist APD418 improves Cx43 protein levels. In addition to improving LV systolic function in HF, APD418 may potentially act to limit the development of life-threatening ventricular arrhythmias.

Increased acetylation or “hyperacetylation” of mitochondrial (MITO) proteins can lead to abnormalities of the electron transport chain (ETC) and oxidative phosphorylation. In this study we examined the levels of proteins that regulate acetylation. Studies were performed in isolated MITO fractions from left ventricular (LV) myocardium of seven healthy normal (NL) dogs and seven dogs with coronary microembolization-induced heart failure (HF, LV ejection fraction ~35%). Protein levels of drivers of hyperacetylation, namely sirtuin-3 (Sirt-3), a MITO deacetylase, and CD38, a regulator of nicotinamide adenine dinucleotide (NAD+), were measured by Western blotting, and the bands were quantified in densitometric units (du). To assess MITO function, MITO components directly influenced by a hyperacetylation state, namely the protein level of cytophillin-D (CyPD), a regulator of MITO permeability transition pore and MITO Complex-I activity, were also measured. Protein level of Sirt-3 and amount of NAD+ were decreased in HF compared to NL dogs. Protein levels of CD38 and CyPD were increased in HF compared to NL dogs. Complex-I activity was decreased in HF compared to NL dogs. The results support the existence of a protein hyperacetylation state in mitochondria of failing LV myocardium compared to NL. This abnormality can contribute to MITO dysfunction as evidenced by reduced Complex-I activity and opening of MITO permeability pores.

The rapid advancement of genomic and precision medicine has expanded the role of genetics and genomics in the diagnosis, risk stratification, and management of cardiovascular diseases. With the decreasing cost and increasing accessibility of genetic testing, its clinical utility continues to expand, necessitating updated policies to ensure equitable access, appropriate regulatory oversight, and ethical data stewardship. This policy statement by the American Heart Association provides a framework addressing key policy areas, including equitable implementation of genetic testing, the impact of federal regulations, data privacy concerns, reimbursement for genetic counseling services, and the integration of emerging technologies such as artificial intelligence in cardiovascular genomics into clinical practice. This policy statement underscores the importance of strategic investments in biobanking and genomic research across all populations to enhance variant interpretation and to improve risk prediction models. In addition, it highlights the evolving landscape of pharmacogenomics, polygenic risk scores, and precision public health approaches to cardiovascular disease prevention. By advocating for a multidisciplinary approach that bridges scientific innovation, clinical application, and policy development, this policy statement aims to optimize the benefits of genetic and genomic testing while mitigating disparities and ethical challenges in its implementation.

Background To improve prediction of individual responses to beta-blocker (BB) therapy in Heart failure with reduced ejection fraction (HFrEF) patients, various novel approaches such as proteomics are being used. Aim Our goal was to derive and validate a proteomic response predictor (PRP) for BB survival benefit in HFrEF patients. Methods A total of 930 patients with Heart Failure (HF) and low ejection fraction (EF<50%) from the Heart Failure Pharmacogenomic Registry (HFPGR) were studied. Plasma was profiled using SOMAscan v4 (approximately 5k proteins). The cohort was randomly divided into a derivation subset of 623 patients and a validation set in the remaining n=307. The component proteins of PRP were selected using Lasso-penalized Cox regression of all-cause mortality focusing on protein-by-BB interaction, and adjusted for MAGGIC score, BB propensity score, and race. The PRP score was generated using the coefficients from the Cox model results. The PRP was then tested in the validation group as both a continuous variable and a dichotomized variable. Results Ten proteins (Table 1) were selected for the optimal PRP in the derivation subset. In validation testing, the interaction of BB with PRP on mortality was significant (P=0.000635). To dichotomize the PRP, various cutoffs were compared across deciles within the derivation group. When PRP is dichotomized at the median, the HR associated with BB treatment in the in favorable response PRP group was 0.41 while in the PRP non-responder group and was 1.78 (95%CI = 1.08-2.93) which was statistically significant (Pinteraction=0.016). Conclusions Using proteomic profiling of plasma, a 10 protein predictor of BB response in HFrEF was created and validated.

Background: Hexokinase II (HKII) binds to the mitochondrial (MITO) outer membrane, directing glucose for energy production. Cyclophilin D (CypD) regulates the MITO permeability transition pore (MPTP) and interacts with HKII. Increased CypD in failing hearts of obese patients exacerbates MITO dysfunction, contributing to heart failure. CypD regulation involves post-translational modifications. We previously showed that failing hearts show reduced MITO function and increased protein acetylation. Purpose: This study investigates the differential expression of HKII and CypD in the mitochondria of left ventricular (LV) myocardium in dogs with chronic heart failure (CHF). Methods: Frozen LV tissues from 7 normal (NL) dogs and 7 dogs with CHF (LV ejection fraction≤35%) induced by intracoronary microembolization were used. Protein levels of HXII (102 kDa), CypD (37 kDa), and porin (33 kDa, unchanged in failing hearts) were determined by Western blotting with chemiluminescence, using commercially available antibodies. The MITO fraction lysate was analyzed, and band intensities were quantified in densitometric units (du) and normalized to porin. Results: Porin protein levels were similar in the MITO fractions of NL and HF dogs (2.12 ± 0.15 vs. 2.16 ± 0.12 du). HXII levels remained unchanged (0.47 ± 0.07 vs. 0.48 ± 0.08 du), while CypD levels were upregulated (2.95 ± 0.49 vs. 0.47 ± 0.05 du) in HF dogs compared to NL dogs. In HF dogs, HXII levels normalized to porin remained unchanged (0.22 ± 0.03 vs. 0.24 ± 0.05), but CypD levels were significantly upregulated (1.40 ± 0.23 vs. 0.23 ± 0.04, p<0.05) compared to NL dogs. Conclusions: Unchanged HXII but upregulated CypD protein levels in LV mitochondria from HF dogs may contribute to MITO dysfunction via enhanced MPTP opening, triggering cardiomyocyte apoptosis. Pharmacologic interventions modulating CypD levels could help prevent or slow MITO dysfunction and cardiomyocyte loss in failing hearts.

AIMS:Plasma metabolites are prognostic in heart failure with reduced ejection fraction (HFrEF), with citric acid cycle metabolites linked to ejection fraction (EF) changes. We investigated these mechanisms in a canine chronic HFrEF model. We tested associations between changes in plasma metabolites, left ventricular (LV) end-diastolic volume and cardiomyocyte mitochondrial function. METHODS:Eighteen dogs underwent microembolization to induce moderate HFrEF (target LVEF 35%-40%). Plasma metabolites, LV size and mitochondrial function were assessed over 12 months. RESULTS:Plasma metabolite heatmap showed acylcarnitine changes, with early alterations in organic acids and amino acids predicting later adverse LV remodelling. Using either baseline or change over time, 13 metabolites correlated with 12 month LV enlargement. This is mostly often at 3 months (11 of 13), notably C18:2 (r = -0.58, P = 0.003) and cardiac anaplerotic substrates like glutamine (r = -0.52, P = 0.009) and 3-HBA (r = -0.43, P = 0.035). Impaired cardiomyocyte mitochondrial function correlated with LV enlargement (max ATP synthesis 12.7 vs. 19.9 nmol/min/mg, P = 0.0036; ADP-stimulated respiration 224 vs. 308 nAtom O/min/mg protein; P = 0.0064). Plasma metabolites correlated with mitochondrial parameters at 12 month, particularly with MAX ATP: malate (r = -0.75, P < 0.001), fumarate (r = -0.6, P = 0.008) and glutamine (r = 0.51, P = 0.031). CONCLUSIONS:In canine HFrEF, plasma acylcarnitines, citric acid cycle or anaplerotic metabolites predicted adverse LV remodelling. LV enlargement correlated with reduced cardiomyocyte mitochondrial function, which in turn was also associated with increased citric acid cycle metabolites. Together, these data suggest impaired cardiac energetic function drives plasma metabolite associations in HFrEF progression.

Importance: Evaluation for myocardial infarction (MI) in emergency departments (EDs) is a common, resource-intensive process. High-sensitivity cardiac troponin I (hs-cTnI) assays have become a key tool in rapidly ruling out MI, with the potential to reduce health care resource utilization. Objective: To determine whether a 0-hour and 1-hour (hereafter referred to as 0/1-hour) hs-cTnI accelerated protocol reduces health care resource utilization compared with a traditional 0/3-hour standard care protocol for MI exclusion in the ED. Design, setting, and participants: This is a prespecified secondary analysis of the RACE-IT trial, a stepped-wedge randomized clinical implementation trial conducted across 9 EDs in Michigan. The trial enrolled 32 608 consecutive ED patients evaluated for suspected MI between July 8, 2020, and April 3, 2021. Statistical analysis was conducted from July 10 to September 5, 2024. Interventions: The 0/1-hour hs-cTnI accelerated protocol for MI exclusion was compared with the traditional 0/3-hour standard care protocol. Main outcomes and measures: Main outcomes were ED discharge to home, ED length of stay, rates of cardiac stress testing, cardiology consultation, left heart catheterization, and cardiac revascularization within 30 days. Results: A total of 32 608 patients (median age, 59 years [IQR, 45-71 years]; 18 705 women [57.4%]) were included in the analysis. The rate of ED discharge to home was 58.0% for the accelerated protocol group (11 082 of 19 103) and 59.8% for the standard care group (8070 of 13 505) (adjusted odds ratio [AOR], 1.05; 95% CI, 0.95-1.15). The accelerated protocol group showed significant reductions in the odds of cardiac stress testing (3.3% [623 of 19 103] vs 3.9% [526 of 13 505]; AOR, 0.62; 95% CI, 0.49-0.78), cardiology consultations (8.6% [1640 of 19 103] vs 12.2% [1651 of 13 505]; AOR, 0.57; 95% CI, 0.49-0.67), and left heart catheterization rates (1.0% [198 of 19 103] vs 1.2% [167 of 13 505]; AOR, 0.65; 95% CI, 0.43-0.99) compared with the standard protocol group. The median ED length of stay decreased by 20 minutes (IQR, 18-24 minutes) in the accelerated protocol group, with no significant change in revascularization rates. Conclusions and relevance: This secondary analysis of a randomized clinical trial of a 0/1-hour hs-cTnI protocol to rule out MI in the ED found that there was a reduction in cardiac evaluations and ED length of stay without increasing revascularization rates compared with the standard 0/3-hour hs-cTnI protocol. This approach could optimize health care resources in EDs.

Introduction Even though premature ventricular contractions (PVCs) are often viewed as harmless, recent studies show that a πρεχεδινγ PVC beat might be inefficient. It suggests that even a moderate number of PVCs could reduce contractile efficiency and elevate event risk. Yet, the prevalence of moderate to high PVCs (>5%) in stable heart failure (HF) patients and the association between PVC percentage and cardiac event risk in stable HF patients are still unclear. Aim This study aimed to quantify HF patients with >5% PVCs and to evaluate the predictive power of PVCs for cardiac events. Methods Our study retrospectively reviewed 651 HF patients from Amsterdam UMC (AUMC) with LVEF < 40% or NTproBNP > 600 pg/ml, and 180 HF patients from Henry Ford Hospital (HFH) with LVEF < 40%. We employed a multivariable Cox regression model to evaluate predictors of cardiac events, such as all-cause mortality, VT/VF and/or ICD shocks, and cardiac arrest, selecting variables with p < 0.05 from univariable analysis. For survival models, numeric variables not fitting a normal distribution were transformed into categorical variables using ROC-derived thresholds. Results In AUMC and HFH cohorts, the median age was 64 years, with 43.5% and 50% females, respectively. Approximately, 9-11% of patients in both cohorts had more than 5% PVCs. In AUMC cohort, individuals in the top three PVC deciles faced significantly higher event risk than lower deciles (Figure 1). Based on univariable analysis, four predictors, including PVC %, NT-proBNP, occurrences of bi/trigeminy, and NSVT were selected for inclusion in the multivariable survival model. Thresholds of 0.5% for PVCs and 6000 pg/ml for NTproBNP were used. PVCs greater than 0.5% were significantly linked to an increased risk of cardiac events, exhibiting hazard ratios (HR) greater than two across all models with significant p-values, and slightly outperforming NSVT in predictive strength. (Table 1) Conclusions Our analysis across two independent cohorts reveals that 9-11% of stable HF patients exhibit a notable PVC burden (>5% of total beats), even with adequate treatment. In AUMC cohort, PVC burden exceeding 0.5%, equal to about 3-4 beats per minute, is significantly associated with increased cardiac event risk, suggesting PVC's predictive power may rival that of NSVTs.

Introduction/Background: Cardiovascular disease (CVD) is the leading cause of death for American adults and has a multifactorial onset including genetic factors. However, there is poor uptake of guideline-directed genetic testing, and the clinical utility of more routine genetic testing in the setting of CVD is uncertain. Research Questions/Hypothesis: Determine the diagnostic yield and clinical impact of a comprehensive clinical genome sequencing (cGS) test applied in a broad sample of typical CVD patients. Methods: A prospective, open-label, single arm, single-center clinical trial was conducted. Inclusion required a diagnosis of at least one among: cardiomyopathy/heart failure, aortopathy, arrhythmia, coronary or peripheral artery disease, or dyslipidemia. Participants (n=1000) received a CLIA/CAP certified genetic sequencing test that included: pathogenic and likely pathogenic variants from 215 CVD-associated genes, 4 common risk alleles for CVD, and 35 non-CVD ACMG secondary finding genes, as well as 65 functional pharmacogenetic alleles from 10 genes. The rate of new genetic diagnoses and changes in clinical management (medication changes, diagnostic tests, or new specialty consultation) occurring within 6 months of genetic test results were collected. Results: Of the 1000 participants, 50% were female, 39% self-identified as Black, and average age was 68 years (Table). A total of 167 participants received a monogenic or risk-allele finding (16.7%). Among these, 74 had CVD gene findings, roughly half of which were within three genes: TTR (n = 16), TTN (n = 14), and LDLR (n = 8). Non-CVD ACMG secondary findings occurred in 14 patients. Risk allele findings were reported in 100 participants. Among those with vs. without (n=833) a monogenic or risk allele finding, a change in management occurred in 27 (16.2%) compared to 16 (1.9%, p<0.0001). The most common changes made were: a radiologic test (n=16), a referral a specialist (n=13), a new genetic diagnosis (n=11), a medication change (n=8), or a lab test (n=4)[DL1] [K2] . Pharmacogenetic findings were present in >99% of patients and led to medication change recommendations in 30 patients. Conclusion(s): In this study utilization of routine genetic testing in CVD patients found functional genetic variants in ~1 in 6 patients, among whom a new genetic diagnosis or a change in management occurred in 16.2% within 6 months. Longer follow up is needed to capture the full potential impact of genetic testing.

Evaluation for myocardial infarction (MI) in emergency departments (EDs) is a common, resource-intensive process. High-sensitivity cardiac troponin I (hs-cTnI) assays have become a key tool in rapidly ruling out MI, with the potential to reduce health care resource utilization. To determine whether a 0-hour and 1-hour (hereafter referred to as 0/1-hour) hs-cTnI accelerated protocol reduces health care resource utilization compared with a traditional 0/3-hour standard care protocol for MI exclusion in the ED. This is a prespecified secondary analysis of the RACE-IT trial, a stepped-wedge randomized clinical implementation trial conducted across 9 EDs in Michigan. The trial enrolled 32 608 consecutive ED patients evaluated for suspected MI between July 8, 2020, and April 3, 2021. Statistical analysis was conducted from July 10 to September 5, 2024. The 0/1-hour hs-cTnI accelerated protocol for MI exclusion was compared with the traditional 0/3-hour standard care protocol. Main outcomes were ED discharge to home, ED length of stay, rates of cardiac stress testing, cardiology consultation, left heart catheterization, and cardiac revascularization within 30 days. A total of 32 608 patients (median age, 59 years [IQR, 45-71 years]; 18 705 women [57.4%]) were included in the analysis. The rate of ED discharge to home was 58.0% for the accelerated protocol group (11 082 of 19 103) and 59.8% for the standard care group (8070 of 13 505) (adjusted odds ratio [AOR], 1.05; 95% CI, 0.95-1.15). The accelerated protocol group showed significant reductions in the odds of cardiac stress testing (3.3% [623 of 19 103] vs 3.9% [526 of 13 505]; AOR, 0.62; 95% CI, 0.49-0.78), cardiology consultations (8.6% [1640 of 19 103] vs 12.2% [1651 of 13 505]; AOR, 0.57; 95% CI, 0.49-0.67), and left heart catheterization rates (1.0% [198 of 19 103] vs 1.2% [167 of 13 505]; AOR, 0.65; 95% CI, 0.43-0.99) compared with the standard protocol group. The median ED length of stay decreased by 20 minutes (IQR, 18-24 minutes) in the accelerated protocol group, with no significant change in revascularization rates. This secondary analysis of a randomized clinical trial of a 0/1-hour hs-cTnI protocol to rule out MI in the ED found that there was a reduction in cardiac evaluations and ED length of stay without increasing revascularization rates compared with the standard 0/3-hour hs-cTnI protocol. This approach could optimize health care resources in EDs. ClinicalTrials.gov Identifier: NCT04488913

Background: Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a key glycolytic enzyme traditionally considered a housekeeping protein. Recent studies, however, suggest that GAPDH plays a role in cellular processes such as apoptosis and more importantly, in mitochondrial (MITO) function through regulation of mitophagy, a process of selective degradation and clearance of damaged mitochondria by lysosomes. We previously showed that accumulation of damaged mitochondria is a characteristic feature of constituent cardiomyocytes of the failing left ventricular (LV) myocardium. This abnormality points to dysregulation of mitophagy in heart failure (HF) that can lead to overall MITO dysfunction in HF with subsequent energy deprivation. Purpose: In this study, we tested the hypothesis that GAPDH protein levels are selectively reduced in MITO fractions isolated from LV tissue of dogs with chronic HF compared to healthy normal (NL) dogs. Methods: Studies were performed using LV tissue from 7 healthy NL dogs and 7 HF dogs (LV ejection fraction≤35%) produced by multiple intracoronary microembolizations. GAPDH (37 kDa) protein levels were measured in lithium dodecyl sulfate (LDS) lysate of 1) LV homogenate, 2) cytosolic fraction, 3) MITO fractions and 4) sarcolemmal fractions by Western blotting coupled with chemiluminescence using a canine-specific commercially available antibody. Band intensities were expressed in densitometric units (du). Results: Results are shown in the table. A significant reduction in GAPDH levels was observed in the MITO fractions of HF dogs compared to NL dogs (p< 0.05). In contrast, GAPDH levels in the homogenate, cytosol, and sarcolemma fractions showed no significant differences between HF and NL groups. Conclusion: GAPDH protein levels are selectively reduced in mitochondria of LV myocardium of dogs with chronic HF. This observation is consistent with abnormal mitophagy in HF evidenced by accumulation of damaged mitochondria in cardiomyocytes. Given the importance of mitochondria in heart function, targeting MITO dysfunction remains a promising therapeutic approach for the treatment of HF.

Heart failure (HF) is a major contributor to global morbidity and mortality. While distinct clinical subtypes, defined by etiology and left ventricular ejection fraction, are well recognized, their genetic determinants remain inadequately understood. In this study, we report a genome-wide association study of HF and its subtypes in a sample of 1.9 million individuals. A total of 153,174 individuals had HF, of whom 44,012 had a nonischemic etiology (ni-HF). A subset of patients with ni-HF were stratified based on left ventricular systolic function, where data were available, identifying 5,406 individuals with reduced ejection fraction and 3,841 with preserved ejection fraction. We identify 66 genetic loci associated with HF and its subtypes, 37 of which have not previously been reported. Using functionally informed gene prioritization methods, we predict effector genes for each identified locus, and map these to etiologic disease clusters through phenome-wide association analysis, network analysis and colocalization. Through heritability enrichment analysis, we highlight the role of extracardiac tissues in disease etiology. We then examine the differential associations of upstream risk factors with HF subtypes using Mendelian randomization. These findings extend our understanding of the mechanisms underlying HF etiology and may inform future approaches to prevention and treatment.

Background Chronic heart failure (HF) is often accompanied by abnormalities of kidney function that contribute to progressive worsening of the HF state. Cardiorenal syndrome (CRS) in humans with HF is sometimes attributed to kidney underperfusion secondary to low cardiac output and/or low renal perfusion pressure, but the cellular mechanism(s) is not fully understood. We previously showed that mitochondrial (MITO) function is abnormal in cardiomyocytes of the failing heart, and it is possible that similar energetic dysfunction in the kidneys contributes to renal dysfunction in HF. In the present study, we tested the hypothesis that MITO function is abnormal in kidneys of dogs with chronic HF and dogs with CRS compared to normal (NL) dogs. Methods MITO functional studies were performed in fresh renal epithelial cells isolated from the left kidney of 6 NL dogs, 6 HF dogs (LV ejection fraction 34±1 %) and 6 CRS dogs (LV ejection fraction 33±2%), for a total n=18 animals. HF was produced using coronary microembolizations. CRS was produced in HF dogs by unilateral nephrectomy of the right kidney and creation of a stenosis of the left renal vein sufficient to result in renal venous congestion (increasing venous pressure by 20-30 mmHg). MITO function was assessed as follows: 1) Mitochondrial ADP-stimulated state-3 respiration (ADPresp) was measured using a Strathkelvin respirometer, 2) mitochondrial complex-IV (COX-IV) activity was measured polarographically, 3) mitochondrial membrane potential (Δψm) was measured using the fluorescent cationic JC-1 dye, and 4) mitochondrial maximum rate of ATP synthesis (ATPsyn) was measured using the bioluminescent ApoSENSOR assay kit. Results The table summarizes all MITO function measurements. ADPresp, COV-IV activity, Δψm, and ATPsyn were significantly lower in renal epithelial cells from HF dogs compared to NL dogs. Moreover, all MITO parameters were significantly lower in cells from CRS dogs when compared to NL dogs as well as to HF dogs. Conclusions MITO function of renal epithelial cells is abnormal in HF dogs and markedly compromised in CRS dogs. MITO abnormalities likely contribute to renal dysfunction that accompanies HF. Additional investigations are needed to test if interventions that improve MITO function in the setting of HF can protect renal function or treat CRS.

STUDY OBJECTIVES:Significant variability exists in patient populations and diagnostic capabilities among hospital-based emergency departments (HBEDs) and freestanding emergency departments (FSEDs). While high sensitivity cardiac troponin (hs-cTn) research has focused on HBEDs, its application in FSEDs remains unexplored. This study assesses the comparative, real-world effectiveness of a 0/1-h accelerated protocol (AP) using hs-cTn between HBEDs and FSEDs. METHODS:We conducted a pre-planned, secondary analysis of a stepped-wedge cluster randomized trial involving nine EDs within an integrated health system, from July 2020 to March 2021, comprised of five HBEDs and four FSEDs. The trial implemented a 0/1-h AP utilizing hs-cTnI to evaluate acute myocardial infarction (AMI). Adult ED patients with an ECG and cardiac troponin ordered were eligible, excluding those with STEMI, hs-cTnI > 18 ng/L, or trauma-related symptoms. The primary outcome was safe ED discharge, defined as discharge without death or AMI within 30 days. RESULTS:The trial included 32,609 patients, 26,957 in HBEDs and 5652 in FSEDs. Safe discharge from HBED occurred 53.7% (5935/11,062) of the time in the standard care arm and 50.3% (7991/15895) under the AP (aOR 1.04, 95% CI 0.94-1.15, p = 0.50). Safe discharge from a FSED occurred 86.0% (2102/2443) of the time in the standard care arm and increased to 95.0% (3049/3209) under the AP (aOR 1.48, 95% CI 1.03-2.13, p = 0.033). Overall, the observed association between the AP and safe discharge was stronger in FSEDs than in HBEDs ( Δ $$ \Delta $$ log(aOdds) 1.05, 95% CI (0.82, 1.29), p < 0.001). CONCLUSION:Implementing a 0/1-h AP using hs-cTnI to evaluate for AMI was associated with higher rates of safe discharge in FSEDs compared to HBEDs.

The improving ATTENDance (iATTEND) to cardiac rehabilitation (CR) trial tested the hypotheses that hybrid CR (HYCR) (combination of virtual and in-facility CR sessions) would result in greater attendance compared with traditional, facility-based only CR (FBCR) and yield equivalent improvements in exercise capacity and health status. Patients were randomized to HYCR (n = 142) or FBCR (n = 140), stratified by gender and race. Attendance was assessed as number of CR sessions completed within 6 months (primary end point) and the percentage of patients completing 36 CR sessions. Other end points (tested for equivalency) included exercise capacity and self-reported health status. HYCR patients completed 1 to 12 sessions in-facility, with the balance completed virtually using synchronized, 2-way audiovisual technology. Neither total number of CR sessions completed within 6 months (29 ± 12 vs 28 ± 12 visits, adjusted p = 0.94) nor percentage of patients completing 36 sessions (59 ± 4% vs 51 ± 4%, adjusted p = 0.32) were significantly different between HYCR and FBCR, respectively. The between-group changes for exercise capacity (peak oxygen uptake, 6-minute walk distance) and health status were equivalent. Regarding safety, no sessions required physician involvement, there was 1 major adverse event after a virtual session, and no falls required medical attention. In conclusion, although we rejected our primary hypothesis that attendance would be greater with HYCR versus FBCR, we showed that FBCR and HYCR resulted in similar patient attendance patterns and equivalent improvements in exercise capacity and health status. HYCR which incorporates virtually supervised exercise should be considered an acceptable alternative to FBCR. NCT Identifier: 03646760; The Improving ATTENDance to Cardiac Rehabilitation Trial - Full-Text View - ClinicalTrials. gov; https://classic.clinicaltrials.gov/ct2/show/NCT03646760.

BACKGROUND: Mechanisms of benefit with SGLT2is (sodium-glucose cotransporter-2 inhibitors) in heart failure (HF) remain incompletely characterized. Dapagliflozin alters ketone and fatty acid metabolism in HF with reduced ejection fraction though similar effects have not been observed in HF with preserved ejection fraction. We explore whether metabolic effects of SGLT2is vary across the left ventricular ejection fraction spectrum and their relationship with cardiometabolic end points in 2 randomized trials of dapagliflozin in HF. METHODS: Metabolomic profiling of 61 metabolites was performed in 527 participants from DEFINE-HF (Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients With HF With Reduced Ejection Fraction) and PRESERVED-HF (Dapagliflozin in PRESERVED Ejection Fraction HF; 12-week, placebo-controlled trials of dapagliflozin in HF with reduced ejection fraction and HF with preserved ejection fraction, respectively). Linear regression was used to assess changes in principal components analysis-defined metabolite factors with treatment from baseline to 12 weeks, as well as the relationship between changes in metabolite clusters and HF-related end points. RESULTS: The mean age was 66 +/- 11 years, 43% were female, and 33% were self-identified as Black. Two principal components analysis-derived metabolite factors (which were comprised of ketone and short-/medium-chain acylcarnitines) increased with dapagliflozin compared with placebo. Ketosis (defined as 3-hydroxybutyrate >500 mu M) was achieved in 4.5% with dapagliflozin versus 1.2% with placebo (P=0.03). There were no appreciable treatment effects on amino acids, including branched-chain amino acids. Increases in several acylcarnitines were consistent across LVEF (P-interaction>0.10), whereas the ketogenic effect diminished at higher LVEF (P-interaction=0.01 for 3-hydroxybutyrate). Increases in metabolites reflecting mitochondrial dysfunction (particularly long-chain acylcarnitines) and aromatic amino acids and decreases in branched-chain amino acids were associated with worse HF-related outcomes in the overall cohort, with consistency across treatment and LVEF. CONCLUSIONS: SGLT2is demonstrate common (fatty acid) and distinct (ketogenic) metabolic signatures across the LVEF spectrum. Changes in key pathways related to fatty acid and amino acid metabolism are associated with HF-related end points and may serve as therapeutic targets across HF subtypes.