BACKGROUND:Cardiac troponin is increasingly used for cardiovascular risk prediction. While abnormal values often reflect subclinical cardiovascular disease, they can be raised due to interference, where antibodies influence the assay or clearance of troponin from the circulation by forming macrotroponin complexes. The frequency of macrotroponins and its association with future risk are unknown. METHODS:In a general population cohort, participants with both cardiac troponin I and T measurements available (n=19 499, median 49 [25th-75th percentile, 36-58] years of age, 58.3% women) were categorized into 3 groups: no myocardial injury (neither cardiac troponin I or T was elevated), suspected macrotroponin (either cardiac troponin was elevated and discordant with a >3-fold difference in concentration), and myocardial injury (either cardiac troponin was elevated without discordance). Macrotroponin complex formation was verified in a subset of samples (n=203) using immunoglobulin depletion and ultracentrifugation. Associations with future myocardial infarction, ischemic stroke, or cardiovascular death were evaluated using Cox proportional hazards models adjusted for known cardiovascular risk factors. The generalizability of our findings was determined through replication in a second general population cohort study. RESULTS:Elevated cardiac troponin I was present in 1% (193 of 19 499) of participants and elevated cardiac troponin T in 6% (1159 of 19 499). Among those, 48% and 57% were discordant, respectively. Biochemical testing attributed 92.5% of discordant troponin I and 15.4% of discordant troponin T to macrotroponin complexes. Participants with myocardial injury were at increased risk of future cardiovascular events compared with those without (cardiac troponin I: adjusted hazard ratio [HR], 2.90 [95% CI, 1.99-4.22]; cardiac troponin T: adjusted HR, 1.99 [95% CI, 1.63-2.42]), whereas those with suspected macrotroponin had similar risk as those without elevated values for suspected macrotroponin I (adjusted HR, 1.59 [95% CI, 0.94-2.70]) and T (adjusted HR, 1.27 [95% CI, 1.00-1.61]). Findings were similar in the replication cohort. CONCLUSIONS:Assay interference due to macrotroponin complex formation is common in individuals with elevated cardiac troponin concentrations in the general population, particularly for cardiac troponin I. This has important implications for the use of cardiac troponin testing for cardiovascular risk assessment in the general population.
BACKGROUND:Clonal hematopoiesis (CH) arising from mutations in hematopoietic genes has been identified as an important risk factor for atherosclerotic cardiovascular disease. Despite the established role of some CH mutations in promoting atherosclerosis progression, their role in clinically relevant LDL (low-density lipoprotein) lowering-induced plaque remodeling or regression has not been extensively studied. METHODS:To assess the effects of TET2 (tet methylcytosine dioxygenase 2) CH on plaque resolution, we prepared control or chimeric Tet2+/- CH mice with conditional deletion of Tet2 in hematopoietic stem cells during LDL lowering-induced plaque remodeling. After establishing atherosclerosis by Western diet feeding for 12 weeks in Ldlr-/- mice, Tet2 was deleted by tamoxifen injection, and hypercholesterolemia was either normalized to simulate clinical lipid management, or mice were continued on the Western diet. RESULTS:Unlike control mice, Tet2+/- CH mice failed to significantly reduce necrotic core area or increase fibrous cap thickness and showed impaired macrophage efferocytosis during LDL lowering. Single-cell RNA sequencing and gene set enrichment analysis of aortic cell populations revealed that Tet2 deficient monocyte/macrophage populations were defective in glycolysis, phagocytosis, and actin polymerization. Tet2-deficient bone marrow-derived macrophages and Tet2+/- induced pluripotent stem cell-derived human macrophages showed defective ability to sustain continuing rounds of efferocytosis. Bone marrow-derived macrophages displayed reduced apoptotic cell binding and internalization and impaired activity of Wiskott-Aldrich syndrome protein and SCAR (suppressor of cyclic AMP receptor) homolog complex mediated actin polymerization. We linked these defects to reduced anaerobic glycolysis and lactate levels and rescued them by lactate supplementation or by treatment with the HIF-1α (hypoxia-inducible factor 1α) activator molidustat. Molidustat treatment reversed the defects in necrotic core and fibrous cap formation during LDL lowering-induced plaque remodeling in Tet2+/- CH mice. Reduced plasma lactate levels were also shown in TET2 clonal hematopoiesis of indeterminate potential carriers in the UK Biobank. CONCLUSIONS:Our data identify impaired efferocytosis and glycolysis-lactate-actin polymerization pathways in advanced atherosclerosis as potential therapeutic targets to induce proresolving restructuring of the plaque immune cells and to promote beneficial atherosclerosis remodeling in subjects with TET2 CH.
Since the publication of the 2015 American Heart Association scientific statement on infective endocarditis, its incidence has increased, its epidemiology has changed, and novel diagnostic and treatment options have become available. Updated case definitions, non-culture-based pathogen identification methods, and advanced multimodality imaging techniques have emerged. A randomized controlled trial of partial oral therapy published in 2019 may change the treatment landscape for the foreseeable future. Percutaneous mechanical aspiration of right-sided vegetations is being used in select patients with uncontrolled infection despite appropriate antimicrobial therapy. The importance of an endocarditis team has become increasingly recognized in the management of this life-threatening syndrome. Therefore, multidisciplinary experts in cardiovascular infections were commissioned to develop this updated scientific statement on the diagnosis and management of infective endocarditis.
BACKGROUND:Myocardial ischemia/reperfusion injury triggers profound metabolic reprogramming and lactate accumulation. However, how this metabolic stress regulates inflammatory gene expression remains poorly understood. We hypothesized that lactylation, a lactate-derived posttranslational modification, links metabolic stress to aberrant RNA splicing and cardiac inflammation through the RNA-binding protein HNRNPK (heterogeneous nuclear ribonucleoprotein K). METHODS:We analyzed atrial tissues from patients undergoing cardiopulmonary bypass and murine ischemia/reperfusion hearts to assess lactylation dynamics. Lactylation-specific proteomics, RNA sequencing, and crosslinking and immunoprecipitation followed by quantitative polymerase chain reaction were used to identify HNRNPK targets. Mechanisms were defined using site-directed mutagenesis (HNRNPK-K405R), isoform-specific overexpression, and a therapeutic splice-switching antisense oligonucleotide in mice and cardiomyocytes. RESULTS:Reperfusion significantly increased global protein lactylation in human and murine myocardium. Proteomics identified HNRNPK as a key target, specifically lactylated at lysine 405 (K405la). Ischemia-induced K405la promoted HNRNPK binding to Jag2 pre-mRNA, suppressing exon 10 skipping and shifting splicing from the Jag2 (Jagged2) short (Jag2-S) to the long (Jag2-L) isoform. Jag2-L, but not Jag2-S, exhibited high affinity for Notch1, hyperactivating Notch-NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) signaling and exacerbating inflammation and infarct size. Mice expressing a lactylation-deficient variant (HNRNPK-K405R) were protected from ischemia/reperfusion injury. Treatment with a specific antisense oligonucleotide (Jag2-i9) that blocks the HNRNPK-Jag2 interaction prevented Jag2-L production and attenuated cardiac dysfunction. CONCLUSIONS:HNRNPK lactylation acts as a metabolic sensor coupling lactate accumulation to pathogenic Jag2 splicing. Targeting this metabolic-splicing axis offers a precise therapeutic strategy to limit inflammation and preserve cardiac function in ischemic heart disease. REGISTRATION:URL: http://www.chictr.org.cn; Unique identifier: ChiCTR2400091959.
BACKGROUND:Fibrosis assessed through late gadolinium enhancement (LGE) in cardiac magnetic resonance imaging and genetics have emerged as risk markers of ventricular arrhythmias in nonischemic dilated cardiomyopathy. Conduction corridors detected within LGE (ie, LGE corridors) have been associated with ventricular arrhythmias in ischemic cardiomyopathy. This study sought to evaluate major ventricular arrhythmic events (MVAs) according to the presence of LGE corridors combined with high-risk genotypes (HRGs) in nonischemic dilated cardiomyopathy. METHODS:We studied consecutive patients with nonischemic dilated cardiomyopathy from 22 European centers who had undergone genetic testing and cardiac magnetic resonance imaging. RESULTS:Among 925 patients (mean age, 54.5 years [interquartile range, 43.7-63.9 years]; 64% men; mean left ventricular ejection fraction, 37.6% [26.9%-44.8%]; LGE in 24.3%), LGE corridors were present in 160 patients (17.3%), and HRG in 119 (12.9%). After a median follow-up of 5.4 years (interquartile range, 3.3-7.7), 95 patients (10.3%) experienced an MVA. In multivariable competing-risk analysis adjusted for left ventricular ejection fraction and extent of LGE, the number of LGE corridors and HRGs were independently associated with MVA (subdistribution hazard ratio, 1.25 [95% CI, 1.11-1.42]; P<0.001; and subdistribution hazard ratio, 2.28 [95% CI, 1.32-3.96]; P=0.003, respectively). An optimal cutoff of ≥4 LGE corridors predicted MVA. A stepwise risk stratification algorithm to predict MVA integrating LGE, the presence of ≥4 LGE corridors, and HRG outperformed left ventricular ejection fraction ≤35%-based classification proposed in guidelines (5-year time-dependent area under the curve, 0.72 [95% CI, 0.65-0.78] versus 0.57 [95% CI, 0.51-0.64]; P=0.001), showing a progressive increase in arrhythmic risk across categories (Gray test P<0.001), and allowing clinically meaningful arrhythmic risk classification. CONCLUSIONS:LGE corridors and HRGs provide additive value for arrhythmic risk stratification in patients with nonischemic dilated cardiomyopathy. These findings support MVA multiparametric prediction over the traditional left ventricular ejection fraction ≤35% threshold.
BACKGROUND:Direct reprogramming of cardiac fibroblasts (CFs) into induced cardiomyocytes (iCMs) holds promise as a therapeutic strategy for heart regeneration. After myocardial infarction (MI), resident quiescent CFs (QCFs) activate and differentiate into myofibroblasts (MFs) in the infarcted region that drive pathological cardiac fibrosis. Converting these injury-activated MFs into iCMs could simultaneously alleviate fibrosis and replenish lost cardiomyocytes. However, whether the marked heterogeneity of CFs in the infarcted heart, and in particular the activation of QCFs into MFs, creates an intrinsic barrier that limits the reprogramming of these injury-activated MFs remains unknown. METHODS:To define the molecular basis of this heterogeneity, we purified PDGFRα+ CFs and used Postn lineage tracing to distinguish injury-activated MFs from quiescent CFs, enabling matched comparison of their reprogramming competence and single-cell RNA sequencing (scRNA-seq) profiling of post-MI CF subpopulations. A targeted in vitro shRNA screen was conducted against 9 MF-enriched TFs as candidate molecular barriers for cardiac reprogramming. The lead candidate was validated in mouse MFs, human iPSC-derived MFs, primary human MFs, and in vivo using dual-recombinase-mediated lineage tracing. Mechanistic insights were gained through integrated bulk RNA-seq, scRNA-seq and Cleavage Under Targets and Tagmentation (CUT&Tag), together with functional assays including DNA-binding-deficient and domain-swap MEOX1 mutants. RESULTS:We identified the upregulated transcription factor MEOX1, a known fibrosis determinant downstream of the key post-MI cytokines transforming growth factor-beta 1 and interleukin-1 beta, as the principal molecular barrier responsible for the profound reprogramming resistance of MFs. MEOX1 knockdown markedly enhanced reprogramming efficiency in both mouse and human MFs and enabled GATA4-free reprogramming combinations. This inhibition depended on the transcriptional activation activity of MEOX1, as disrupting its DNA-binding domain or fusing it to a repressor domain rescued reprogramming. Integrated scRNA-seq and CUT&Tag analyses revealed that MEOX1 binds and stabilizes a fibrotic, MF-defining transcriptional program that antagonizes the cardiogenic program while also modulating the inflammatory response; its knockdown disrupted this fibrotic network to favor iCM fate acquisition. Using stringent dual-recombinase lineage tracing, we demonstrated that MEOX1 knockdown enables highly efficient in vivo MF-to-iCM conversion, leading to significant reductions in cardiac fibrosis and substantial improvement in cardiac function after MI. CONCLUSIONS:Our study identifies pathological MEOX1 upregulation as a key mechanism underlying the reprogramming resistance of post-MI mouse MFs and activated human MFs. Overcoming this barrier achieves unprecedented, lineage-confirmed in vivo reprogramming efficiency, thereby addressing a significant obstacle for the clinical translation of in situ reprogramming therapies.
Immune checkpoint inhibitor (ICI)-associated myocarditis is uncommon but has been described as an important and potentially fatal complication of cancer treatment. Increasing evidence from a variety of data sources have reframed this complication as part of ICI-associated myotoxicity (ICI-M), a systemic cardiomuscular syndrome in which myocarditis, myositis, conduction disease, ventricular arrhythmias, dysphagia, pseudo-myasthenic oculobulbar signs, and respiratory muscle failure may coexist. Elevated troponin with ICI use is not synonymous with myocarditis but instead should trigger a structured evaluation that considers symptoms, ECG findings, troponin and creatine kinase concentrations, structural and functional assessments including left ventricular function, pathology when feasible, and exclusion of alternative causes including other cardiotoxic therapies. The severity of ICI-M is heterogeneous and can now be stratified using the presence of active thymoma, cardiomuscular symptoms, low QRS-voltage, left ventricular ejection fraction <50%, and magnitude of troponin elevation. Low-risk cases such as patients with abnormal cardiac biomarkers only may be monitored closely, whereas severe ICI-M requires monitored admission, early respiratory and swallowing assessment, ICI interruption, and rapid multidisciplinary immunosuppression. Corticosteroids are generally recommended; however, severe, progressive, or refractory disease increasingly supports pathophysiology-directed-based therapies, including abatacept and ruxolitinib. Abatacept inhibits CD80/CD86-CD28 co-stimulation and can be titrated to CD86 receptor occupancy of the monocytes. Ruxolitinib inhibits Janus kinase/signal transducer and activator of transcription cytokine signaling pathway and may complement abatacept bioactivity. Evidence is promising for these therapies but not definitive, pending prospective trials. Rechallenge is often avoided but could be reassessed in selected patients under strict surveillance.
AIM:The American College of Cardiology/American Heart Association Scientific Statement, "Clinical Considerations for the Care of the Tactical Athlete With Cardiovascular Abnormalities," was written to provide guidance and education for clinicians caring for the tactical athlete (ie, firefighters, law enforcement officers, military) with cardiovascular disease or risk for cardiovascular disease, and for the organizations overseeing the care and wellness of these athletes. The considerations are shaped by the interaction between occupational demands and fit for full duty assessments, including risk discussions about how a cardiovascular event in a tactical athlete could impact teammates' well-being, community safety, and overall mission success. METHODS:This scientific statement is organized into 11 sections focused on cardiovascular disease processes and other topics that are relevant when considering the potential risks and benefits of performing tasks specific to the tactical athlete. Task forces, comprised of experts in tactical athlete domains, sports cardiology, and the respective topics covered, were assigned to each section, and specific "Clinical Considerations Tables" for clinicians to reference were prepared. Comprehensive literature reviews and an emphasis on tactical athlete-focused data, as available, were integral in the writing of all clinical considerations presented. The framework mirrors that of the recently published, "Clinical Considerations for Competitive Sports Participation for Athletes With Cardiovascular Abnormalities: A Scientific Statement From the American Heart Association and American College of Cardiology." STRUCTURE:The specific sections in this document include: Section 1: Tactical Tasks Classification; Section 2: The Tactical Athlete Preparticipation Cardiac Evaluation; Section 3: Ethical and Legal Aspects of Tactical Clinical Management; Section 4: Genetic Cardiomyopathies; Section 5: Myocarditis and Other Acquired Cardiac Conditions; Section 6: Congenital Heart Disease; Section 7: Aortopathy, Bicuspid Aortic Valve, and Spontaneous Coronary Artery Dissection; Section 8: Syncope, SCA, Arrhythmias, and Devices; Section 9: Cardiac Channelopathies; Section 10: Older Tactical Athlete; Section 11: Environmental Exposures, PED/S, and Additional Cardiac Conditions and Considerations. Each section provides a summary detailing the rationale for key clinical considerations and the respective Clinical Considerations Table(s).
BACKGROUND:Pulmonary hypertension (PH) is a life-threatening cardiovascular disorder characterized by irreversible pulmonary vascular remodeling and poor prognosis. RNA pseudouridylation, the most evolutionarily conserved RNA epigenetic modification, and its catalytic enzyme pseudouridine synthase 7 (PUS7) remained uncharacterized in PH, representing a major gap in the understanding of the epigenetic pathogenesis of the disease. METHODS:We generated the first single-base resolution pseudouridine (Ψ) landscape in lung tissues of patients with PH using bisulfite-induced deletion sequencing. PUS7 expression was analyzed in hypoxic pulmonary artery endothelial cells, the lung tissues of patients with PH, and SU5416-hypoxia rodent model. The functional roles of PUS7 were investigated through genetic manipulation (PUS7-deficiency cells, adeno-associated virus serotype-mediated overexpression, endothelial cell-specific knockdown, and heterozygous knockout mice) and pharmacological inhibition with NSC107512. RESULTS:Bisulfite-induced deletion sequencing revealed global Ψ dysregulation in the lung tissues of patients with PH. Among PUS family members, PUS7 was the most markedly upregulated in these tissues and in the hypoxic pulmonary artery endothelial cells. Both gene knockdown and pharmacological inhibition with NSC107512 ameliorated PH, whereas adeno-associated virus serotype-mediated PUS7 overexpression exacerbated disease progression. RNA immunoprecipitation sequencing and mutagenesis studies demonstrated that PUS7 bound to and catalyzed Ψ at position 688 of TGFBI (transforming growth factor β-induced protein) mRNA, thereby stabilizing TGFBI and activating phosphatidylinositol 3-kinase-protein kinase B signaling pathway. Furthermore, hypoxia-inducible factor 2α bound directly to the PUS7 promoter, establishing a hypoxia-inducible factor 2α/PUS7/TGFBI/phosphatidylinositol 3-kinase-protein kinase B positive feedback loop that drives PH pathogenesis. CONCLUSIONS:PUS7-mediated pseudouridylation serves as a novel epigenetic driver of PH through the hypoxia-inducible factor 2α/PUS7/TGFBI/phosphatidylinositol 3-kinase-protein kinase B axis, positioning PUS7 as a promising therapeutic target for this devastating disease.
Optimal outcomes for congenital heart surgery depend on the expertise and judgment of an integrated multidisciplinary clinical team. The best outcomes require a comprehensive understanding of the patient's anatomy and physiology, an appropriate therapeutic plan, a meticulously executed operation that is technically optimal and facilitated by lesion-specific anesthesia and perfusion strategies, and skilled perioperative care. A principal factor contributing to adverse outcomes is the presence of important residual lesions after surgery, which may necessitate early unplanned cardiac reinterventions during the index hospitalization. Such reinterventions occur in ≈5% of all pediatric cardiac operations, with a higher incidence in younger patients and more complex procedures. The presence of significant residual lesions and the need for unplanned reinterventions are strongly associated with increased morbidity, mortality, and resource use. Wide center-level variation in the incidence and timing of unplanned reinterventions suggests an opportunity for quality improvement. In this scientific statement, we summarize the incidence, risk factors, and clinical outcomes of important residual lesions and early unplanned cardiac reinterventions. We review postoperative monitoring strategies and clinical indicators suggestive of a residual lesion, and we provide an overview of the noninvasive imaging modalities used for their identification and quantification. The roles of diagnostic and interventional cardiac catheterization in the management of residual lesions are discussed, along with surgical considerations for early reoperation. We highlight the importance of communication with patients and families. Last, key areas for future investigations are identified.
BACKGROUND:Survival to hospital admission for out-of-hospital cardiac arrest is an important resuscitation outcome to gauge emergency medical service (EMS) agency performance. However, its correlation with EMS rates of survival to hospital discharge and favorable neurological survival is unclear. METHODS:Using the Cardiac Arrest Registry to Enhance Survival (CARES), we identified adults with nontraumatic out-of-hospital cardiac arrests during 2 periods: 2015 through 2019 (before the COVID-19 pandemic) and 2022 through 2024 (after the peak pandemic years). Multivariable hierarchical logistic regression was used to derive EMS agency-level risk-standardized survival rates for hospital admission, hospital discharge, and favorable neurological survival during each period. We then assessed the correlation between EMS agency rates of survival to admission versus discharge and favorable neurological survival using weighted linear regression, and whether the correlations differed by neighborhood income (above versus below median household income) and race and ethnicity (categorized as predominantly White [>80% of residents], majority Black or Hispanic [>50% of residents], or integrated). RESULTS:A total of 544 296 events from 1838 EMS agencies met inclusion criteria (252 137 pre-COVID; 292 159 post-COVID). During the period of 2015 to 2019, EMS rates of survival to admission were strongly correlated with survival to discharge (weighted r=0.68 [95% CI, 0.64-0.72]) and favorable neurological survival (weighted r=0.54 [95% CI, 0.43-0.59]). These correlations were similar during the period of 2022 through 2024 (weighted r=0.63 [95% CI, 0.59-0.66] and weighted r=0.48 [95% CI, 0.44-0.53], respectively). Neighborhood racial and ethnic composition modified the correlation between EMS rates of survival to admission and survival outcomes at discharge in both periods (all interactions <0.05), but the correlations remained strong in each neighborhood group. Similar findings were found for the interactions by neighborhood income strata. CONCLUSIONS:EMS agency rates of survival to hospital admission are strongly correlated with their rates of survival to hospital discharge and favorable neurological survival. These findings support the use of survival to hospital admission as a performance metric for EMS systems.
BACKGROUND:The use of anti-programmed cell death-1 (PD-1) antibody increases heart failure (HF) risk in patients with cancer with preexisting cardiovascular conditions. However, the underlying mechanism remains incompletely understood. METHODS:To evaluate the effects of anti-PD-1 antibody on transverse aortic constriction (TAC)-induced cardiac remodeling and HF, anti-PD-1 antibody-treated mice; T cell-, myeloid-, and CD8+ T cell-specific Pdcd1 knockout; C-X-C motif chemokine receptor 3 (Cxcr3) knockout; and granzyme B (Gzmb) knockout mice combined with flow cytometry, Western blotting, immunofluorescence staining, pharmacological approaches, and bulk RNA-sequencing analyses were used. RESULTS:Administration of anti-PD-1 antibody, T cell-, or CD8+ T cell-specific Pdcd1 deletion, but not myeloid-specific Pdcd1 knockout, aggravated TAC-induced cardiomyopathy and HF in mice. Mechanistically, PD-1 blockade or deletion increased myocardial infiltration of CXCR3+ CD8+ T cells, leading to granzyme B/perforin-mediated impairment of cardiomyocyte mitochondrial complex I to exacerbate TAC-induced cardiac injury and HF. TAC-enhanced chemotaxis, between cardiac fibroblast-derived CXCL9/CXCL10 and CXCR3+ CD8+ T cells, was a driving force for recruiting CXCR3+ CD8+ T cells under the conditions of PD-1 blockade or deletion. The worsened TAC-induced cardiomyopathy caused by anti-PD-1 antibody or T cell-specific Pdcd1 deletion was rescued by genetic deletion or pharmacological blockade of granzyme B and CXCR3. CONCLUSIONS:Anti-PD-1 antibody enhances myocardial infiltration of CXCR3+ CD8+ T cells under TAC condition through CXCL9/CXCL10-mediated chemotaxis. The increased granzyme B and perforin likely derived from CD8+ T cells impair function of mitochondrial respiratory chain complexes to cause cardiomyocyte apoptosis, thereby exacerbating TAC-induced cardiomyopathy and HF. CXCL9/CXCL10-CXCR3+ CD8+ T cell axis may represent a promising target for combating anti-PD-1 antibody-associated cardiotoxicity.
