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Background: Dilated cardiomyopathy (DCM) is one of the most frequent causes of heart failure and heart transplantation (HTx). The genetic basis of DCM among patients undergoing HTx remains to be further studied. This study aimed to characterize the genetic basis of DCM HTx in the Chinese population. Methods: In total, 208 unrelated DCM patients who underwent HTx at Fuwai Hospital between June 2004 and June 2017 were included in this study. Whole-exome sequencing (WES) was performed for all patients. Gene burden analysis, variant classification, and genotype–phenotype correlation analysis were subsequently performed. Results: After completing the bioinformatics analysis, gene burden analysis suggested that titin (TTN), filamin C (FLNC) and lamin A/C (LMNA) were significantly enriched with rare protein-altering variants. The frequencies of TTN and FLNC truncating variants in our cohort were 18.8% and 8.7%, respectively. Among the 165 rare variants in high evidence DCM-related genes, 27 (16.4%) and 59 (35.8%) were interpreted as pathogenic (P) and likely pathogenic (LP), respectively. In addition, 41 (47.7%) and 16 (18.6%) of these 86 P/LP variants are located in TTN and FLNC, respectively. The FLNC group contained more patients with NYHA class IV than the P/LP-negative group (FLNC, 16/18 vs. P/LP-negative, 81/123, P = 0.049). Conclusions: Based on WES, we provided a primary genetic spectrum of DCM patients undergoing HTx in the Chinese population. TTN and FLNC harbour the most P/LP variants. FLNC truncation may lead to severe clinical symptoms in DCM patients. [ABSTRACT FROM AUTHOR]

Tissue slicing-assisted digestion (TSAD) of adult cardiomyocytes has shown significant improvements over conventional chunk methods. However, it remains unclear how this method compares to Langendorff perfusion, the current standard of adult cardiomyocyte isolation. Using adult Bama minipigs, we performed cardiomyocyte isolation via these two distinct methods, and compared the resulting cellular quality, including viability, cellular structure, gene expression, and electrophysiological properties, of cardiomyocytes from 3 distinct anatomical regions, namely the left ventricle, right ventricle, and left atrial appendage. Our results revealed largely indistinguishable cell quality in all of the measured parameters. These findings suggest that that TSAD can be reliably used to isolate adult mammalian cardiomyocytes as a reliable alternative to perfusion in cardiomyocyte isolation from larger mammals, particularly when Langendorff perfusion is not feasible. [ABSTRACT FROM AUTHOR]

Hypertrophic cardiomyopathy (HCM) is the most common cardiac genetic disorder characterized by cardiomyocyte hypertrophy and cardiac fibrosis. Pathological cardiac remodeling in the myocardium of HCM patients may progress to heart failure. An in-depth elucidation of the lineage-specific changes in pathological cardiac remodeling of HCM is pivotal for the development of therapies to mitigate the progression. Here, we performed single-nucleus RNA-seq of the cardiac tissues from HCM patients or healthy donors and conducted spatial transcriptomic assays on tissue sections from patients. Unbiased clustering of 55,122 nuclei from HCM and healthy conditions revealed 9 cell lineages and 28 clusters. Lineage-specific changes in gene expression, subpopulation composition, and intercellular communication in HCM were discovered through comparative analyses. According to the results of pseudotime ordering, differential expression analysis, and differential regulatory network analysis, potential key genes during the transition towards a failing state of cardiomyocytes such as FGF12, IL31RA, and CREB5 were identified. Transcriptomic dynamics underlying cardiac fibroblast activation were also uncovered, and potential key genes involved in cardiac fibrosis were obtained such as AEBP1, RUNX1, MEOX1, LEF1, and NRXN3. Using the spatial transcriptomic data, spatial activity patterns of the candidate genes, pathways, and subpopulations were confirmed on patient tissue sections. Moreover, we showed experimental evidence that in vitro knockdown of AEBP1 could promote the activation of human cardiac fibroblasts, and overexpression of AEBP1 could attenuate the TGFβ-induced activation. Our study provided a comprehensive analysis of the lineage-specific regulatory changes in HCM, which laid the foundation for targeted drug development in HCM. [ABSTRACT FROM AUTHOR]

Background: Evidences shows that socioeconomic status is reversely associated with the risk of morbidity and mortality for people with cardiovascular disease via pro-inflammation mechanism, but the population profile is not deeply defined on. We aimed to investigate the impact of medical insurance coverage on postoperative systemic inflammatory reaction in two kinds of disease populations undergoing distinct cardiac procedures.Methods: A total of 515 patients receiving open mitral valve procedure with high-total expense from May 2013 through May 2021 in Sichuan Provincial People's Hospital were retrospectively collected and stratified according to medical insurance reimbursement: low coverage with high out-pocket (< 30%), medium coverage (≤ 60%, but ≥ 30%), and high coverage (> 60%). Another 118 cases undergoing atrium septum defect (ASD) or patent foramen ovale (PFO) occlusion and taking on consistent low-total expense and low-coverage (< 30%) were also classified according to their insured conditions. The postoperative systemic inflammatory response indexes were high sensitivity C-reactive protein (hs-CRP) and the neutrophil-lymphocyte ratio (NLR).Results: Low insurance reimbursement population undergoing open mitral valve procedure had a higher level of hs-CRP and NLR but not troponin I protein or lactate within 48 h postoperatively, and higher thoracic drainage, longer ventilation use and stay in intensive care unit. No significant difference in inflammatory indexes existed among diverse medical insurance coverage in population undergoing ASD/PFO occlusion.Conclusions: Higher inflammatory reaction and weaker clinical recovery was associated with lower insurance coverage population undergoing open mitral valve procedure but not ASD/PFO interventional occlusion procedure. [ABSTRACT FROM AUTHOR]

Dual-specificity phosphatase 6 (DUSP6) serves a specific and conserved function on the dephosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2). We previously identified Dusp6 as a regenerative repressor during zebrafish heart regeneration, therefore we propose to investigate the role of this repressor in mammalian cardiac repair. Utilizing a rat strain harboring Dusp6 nonsense mutation, rat neutrophil-cardiomyocyte co-culture, bone marrow transplanted rats and neutrophil-specific Dusp6 knockout mice, we find that Dusp6 deficiency improves cardiac outcomes by predominantly attenuating neutrophil-mediated myocardial damage in acute inflammatory phase after myocardial infarction. Mechanistically, Dusp6 is transcriptionally activated by p38-C/EBPβ signaling and acts as an effector for maintaining p-p38 activity by down-regulating pERK and p38-targeting phosphatases DUSP1/DUSP16. Our findings provide robust animal models and novel insights for neutrophil-mediated cardiac damage and demonstrate the potential of DUSP6 as a therapeutic target for post-MI cardiac remodeling and other relevant inflammatory diseases. Dusp6, an ERK specific phosphatase, was identified as a regenerative repressor during zebrafish heart regeneration. Here, the authors show that Dusp6 deficiency improves post infarctional cardiac repair by predominantly attenuating neutrophil-mediated myocardial damage in mammalian hearts. [ABSTRACT FROM AUTHOR]

Exosomes derived from human umbilical cord mesenchymal stem cells (UMSC‐Exos) have shown encouraging effects in regulating inflammation and attenuating myocardial injury. Macrophages are regulated dynamically in response to environmental cues. However, the underlying mechanisms by which UMSC‐Exos regulate macrophage polarization are still not well understood. Herein, it is aimed to explore the effects of UMSC‐Exos on macrophage polarization and their roles in cardiac repair after myocardial infarction (MI). These results show that UMSC‐Exos improve cardiac function by increasing M2 macrophage polarization and reducing excessive inflammation. RNA‐sequencing results identify Plcb3 as a key gene involved in UMSC‐Exo‐facilitated M2 macrophage polarization. Further bioinformatic analysis identifies exosomal miR‐24‐3p as a potential effector mediating Plcb3 downregulation in macrophages. Increasing miR‐24‐3p expression in macrophages effectively enhances M2 macrophage polarization by suppressing Plcb3 expression and NF‐κB pathway activation in the inflammatory environment. Furthermore, reducing miR‐24‐3p expression in UMSC‐Exos attenuates the effects of UMSC‐Exos on M2 macrophage polarization. This study demonstrates that the cardiac therapeutic effects of UMSC‐Exos are at least partially through promoting M2 macrophage polarization in an inflammatory microenvironment. Mechanistically, exosomal miR‐24‐3p is found to inhibit Plcb3 expression and NF‐κB pathway activation to promote M2 macrophage polarization. [ABSTRACT FROM AUTHOR]

The RNA editing tool CRISPR-CasRx has provided a platform for a range of transcriptome analysis tools and therapeutic approaches with its broad efficacy and high specificity. To enable the application of CasRx in vivo, we established a Credependent CasRx knock-in mouse. Using these mice, we specifically knocked down the expression of Meis1 and Hoxb13 in cardiomyocytes, which induced cardiac regeneration after myocardial infarction. We also knocked down the lncRNA Mhrt in cardiomyocytes with the CasRx knock-in mice, causing hypertrophic cardiomyopathy. In summary, we generated a Credependent CasRx knock-in mouse that can efficiently knock down coding gene and lncRNA expression in specific somatic cells. This in vivo CRISPR-CasRx system is promising for gene function research and disease modeling. [ABSTRACT FROM AUTHOR]

Cardiac function is closely related to heart metabolism. Heart failure patients undergoing LVAD support have shown varying degrees of remodeling of both cardiac function and morphology. However, the metabolic changes in patients with different outcomes are unclear. This study aimed to identify metabolic differences and evaluate metabolomics-based biomarkers in patients with non-improved/improved cardiac function after LVAD support. Sixteen patients were enrolled in this study. Plasma samples were analyzed by using untargeted metabolomic approaches. Multivariate statistical analysis and a Mann–Whitney U-test was performed to clarify the separation in metabolites and to identify changes in plasma metabolites between the two groups, respectively. The efficacy of candidate biomarkers was tested by the area under the curve receiver operating characteristic curve. Using the Metabolomics Standards Initiative level 2, a total of 1542 and 619 metabolites were detected in the positive and negative ion modes, respectively. Enrichment analysis showed that metabolites in improved cardiac function patients were mainly involved in carbohydrate metabolism and amino acid metabolism. Metabolites from non-improved cardiac function patients were mainly involved in hormone metabolism. Furthermore, we found tris(hydroxymethyl)aminomethane and 5-guanidino-3-methyl-2-oxopentanoic acid could serve as biomarkers to predict whether a patient's cardiac function would improve after LVAD support. [ABSTRACT FROM AUTHOR]

Persistent truncus arteriosus (PTA) is an uncommon and complex congenital cardiac malformation accounting for about 1.2% of all congenital heart diseases (CHDs), which is caused by a deficiency in the embryonic heart outflow tract's (OFT) septation and remodeling. PDGFRα and PDGFRβ double knockout (DKO) in cardiac neural crest cells (CNCCs) has been reported to cause PTA, but the underlying mechanisms remain unclear. Here, we constructed a PTA mouse model with PDGFRα and PDGFRβ double knockout in Pax3+ CNCCs and described the condensation failure into OFT septum of CNCC-derived cells due to disturbance of cell polarity in the DKO group. In addition, we further explored the mechanism with single-cell RNA sequencing. We found that two main cell differentiation trajectories into vascular smooth muscle cells (VSMCs) from cardiomyocytes (CMs) and mesenchymal cells (MSs), respectively, were interrupted in the DKO group. The process of CM differentiation into VSMC stagnated in a transitional CM I-like state, which contributed to the failure of OFT remodeling and muscular septum formation. On the other hand, a Penk+ transitional MS II cluster closely related to cell condensation into the OFT septum disappeared, which led to the OFT's septation absence directly. In conclusion, the disturbance of CNCC-derived cells caused by PDGFRα and PDGFRβ knockout can lead to the OFT septation disorder and the occurrence of PTA. [ABSTRACT FROM AUTHOR]

Drug-induced cardiotoxicity not only leads to the attrition of drugs during development, but also contributes to the high morbidity and mortality rates of cardiovascular diseases. Comprehensive testing for proarrhythmic risks of drugs has been applied in preclinical cardiac safety assessment for over 15 years. However, other mechanisms of cardiac toxicity have not received such attention. Of them, mitochondrial impairment is a common form of cardiotoxicity and is known to account for over half of cardiovascular adverse-event-related black box warnings imposed by the U.S. Food and Drug Administration. Although it has been studied in great depth, mitochondrial toxicity assessment has not yet been incorporated into routine safety tests for cardiotoxicity at the preclinical stage. This review discusses the main characteristics of mitochondria in cardiomyocytes, drug-induced mitochondrial toxicities, and high-throughput screening strategies for cardiomyocytes, as well as their proposed integration into preclinical safety pharmacology. We emphasize the advantages of using adult human primary cardiomyocytes for the evaluation of mitochondrial morphology and function, and the need for a novel cardiac safety testing platform integrating mitochondrial toxicity and proarrhythmic risk assessments in cardiac safety evaluation. [ABSTRACT FROM AUTHOR]

Cardiomyopathy affects approximately 1 in 500 adults and is the leading cause of death. Familial cases are common, and mutations in many genes are involved in cardiomyopathy, especially those in genes encoding cytoskeletal, sarcomere, and nuclear envelope proteins. Filamin C is an actin-binding protein encoded by filamin C (FLNC) gene and participates in sarcomere stability maintenance. FLNC was first demonstrated to be a causal gene of myofibrillar myopathy; recently, it has been found that FLNC mutation plays a critical role in the pathogenesis of cardiomyopathy. In this review, we summarized the physiological roles of filamin C in cardiomyocytes and the genetic evidence for links between FLNC mutations and cardiomyopathies. Truncated FLNC is enriched in dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy. Non-truncated FLNC is enriched in hypertrophic cardiomyopathy and restrictive cardiomyopathy. Two major pathomechanisms in FLNC-related cardiomyopathy have been described: protein aggregation resulting from non-truncating mutations and haploinsufficiency triggered by filamin C truncation. Therefore, it is important to understand the cellular biology and molecular regulation of FLNC to design new therapies to treat patients with FLNC-related cardiomyopathy. [ABSTRACT FROM AUTHOR]

Background: Sex differences present in the blood management of patients after coronary artery bypass grafts (CABG) surgeries. Tranexamic acid (TXA) performed well in maintaining hemostasis during and after surgeries. However, the impact of sex differences on blood control after CABG in patients who received TXA was not investigated.Methods: Overall, 29,536 patients undergoing CABG with TXA administration from 2009 to 2019 in our hospital were included. Propensity score matching was performed. Finally, 6808 males and 6808 females were matched based on 23 covariates.Results: Female patients had a 0.36-fold lower incidence of reoperations due to major hemorrhage or cardiac tamponade compared to males (1.3% vs. 2.0%, p = 0.001, OR = 0.64, 95%CI = 0.49-0.84). Females had a median of 100 ml less blood loss in 24 h (median 360 vs. 460 ml, p < 0.0001), 150 ml less in 48 h (median 580 vs. 730 ml, p < 0.0001), and 180 ml less in total (median 760 vs. 940 ml, p < 0.0001) than male patients. The red blood cell (RBC) transfusion rate in female was 1.53-fold higher than that in male (33.0% vs. 21.6%, OR = 1.53, 95% CI = 1.43-1.63, p < 0.0001). Females also had higher morbidities than males after CABGs.Conclusions: Females had less blood loss than males after CABG with the TXA treatment. Females still had a higher RBC transfusion rate after surgery. Morbidities in women were also higher than that in men. [ABSTRACT FROM AUTHOR]

Background: Severe mitral regurgitation (MR) is associated with progressive heart failure and impairment of survival. Degenerative MR accounts for most MV repair surgeries. Conventional mitral valve repair surgery requires cardiopulmonary bypass and is associated with significant morbidity and risks. Transapical beating‐heart mitral valve repair by artificial chordae implantation with transesophageal echocardiography (TEE) guidance has the potential to significantly reduce surgical morbidity. We report the first‐in‐human experience of degenerative MR repair using a novel artificial chordae implantation device (MitralstitchTM system). Methods: Ten patients with severe MR underwent transapical artificial chordae implantation using MitralstitchTM system. The procedure was performed through a small left thoracotomy under general anesthesia and TEE guidance. Patients underwent transthoracic echocardiography and other assessments during the follow‐up. Results: All 10 patients with an average age of 63.7 ± 9.6 years successfully received transapical artificial chordae implantation. Their MR reduced from severe to none or trace in five patients, mild in five patients before discharge. Five patients received one artificial chordal implantation, four patients received two, and one patient received three and edge‐to‐edge repair by locking two of them. The safety and efficacy endpoint were achieved in all patients at 1‐month follow‐up. At 1‐year follow‐up, six patients had mild MR, three patients had moderate MR, one patient had recurrence of severe MR and underwent surgical repair. Conclusions: The results of this first‐in‐human study show safety and feasibility of transapical mitral valve repair using MitralStitch system. Patient selection and technical refinement are crucial to improve the outcomes. [ABSTRACT FROM AUTHOR]

By detecting minute molecular changes in hundreds to millions of single cells, single-cell RNA sequencing allows for the comprehensive characterization of the diversity and dynamics of cells in the heart. Our understanding of the heart has been transformed through the recognition of cellular heterogeneity, the construction of regulatory networks, the building of lineage trajectories, and the mapping of intercellular crosstalk. In this review, we introduce cardiac progenitors and their transcriptional regulation during embryonic development, highlight cellular heterogeneity and cell subtype functions in cardiac health and disease, and discuss insights gained from the study of pluripotent stem-cell-derived cardiomyocytes. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cell (MSC) transplantation is regarded as a promising candidate for the treatment of ischaemic heart disease. The major hurdles for successful clinical translation of MSC therapy are poor survival, retention, and engraftment in the infarcted heart. Stromal cell-derived factor-1/chemokine receptor 4 (SDF-1/CXCR4) constitutes one of the most efficient chemokine/chemokine receptor pairs regarding cell homing. In this review, we mainly focused on previous studies on how to regulate the SDF-1/CXCR4 interaction through various priming strategies to maximize the efficacy of mesenchymal stem cell transplantation on ischaemic hearts or to facilitate the required effects. The strengthened measures for enhancing the therapeutic efficacy of the SDF-1/CXCR4 interaction for mesenchymal stem cell transplantation included the combination of chemokines and cytokines, hormones and drugs, biomaterials, gene engineering, and hypoxia. The priming strategies on recipients for stem cell transplantation included ischaemic conditioning and device techniques. [ABSTRACT FROM AUTHOR]

Inflammation and fibrosis are intertwined mechanisms fundamentally involved in heart failure. Detailed deciphering gene expression perturbations and cell–cell interactions of leukocytes and non-myocytes is required to understand cell-type-specific pathology in the failing human myocardium. To this end, we performed single-cell RNA sequencing and single T cell receptor sequencing of 200,615 cells in both human dilated cardiomyopathy (DCM) and ischemic cardiomyopathy (ICM) hearts. We sampled both lesion and mild-lesion tissues from each heart to sequentially capture cellular and molecular alterations to different extents of cardiac fibrosis. By which, left (lesion) and right ventricle (mild-lesion) for DCM hearts were harvest while infarcted (lesion) and non-infarcted area (mild-lesion) were dissected from ICM hearts. A novel transcription factor AEBP1 was identified as a crucial cardiac fibrosis regulator in ACTA2+ myofibroblasts. Within fibrotic myocardium, an infiltration of a considerable number of leukocytes was witnessed, especially cytotoxic and exhausted CD8+ T cells and pro-inflammatory CD4+ T cells. Furthermore, a subset of tissue-resident macrophage, CXCL8hiCCR2+HLA-DRhi macrophage was particularly identified in severely fibrotic area, which interacted with activated endothelial cell via DARC, that potentially facilitate leukocyte recruitment and infiltration in human heart failure. [ABSTRACT FROM AUTHOR]

Acute rejection (AR) is an important contributor to graft failure, which remains a leading cause of death after heart transplantation (HTX). The regulation of immune metabolism has become a new hotspot in the development of immunosuppressive drugs. In this study, Increased glucose metabolism of cardiac macrophages was found in patients with AR. To find new therapeutic targets of immune metabolism regulation for AR, CD45+ immune cells extracted from murine isografts, allografts, and untransplanted donor hearts were explored by single-cell RNA sequencing. Total 20 immune cell subtypes were identified among 46,040 cells. The function of immune cells in AR were illustrated simultaneously. Cardiac resident macrophages were substantially replaced by monocytes and proinflammatory macrophages during AR. Monocytes/macrophages in AR allograft were more active in antigen presentation and inflammatory recruitment ability, and glycolysis. Based on transcription factor regulation analysis, we found that the increase of glycolysis in monocytes/macrophages was mainly regulated by HIF1A. Inhibition of HIF1A could alleviate inflammatory cells infiltration in AR. To find out the effect of HIF1A on AR, CD45+ immune cells extracted from allografts after HIF1A inhibitor treatment were explored by single-cell RNA sequencing. HIF1A inhibitor could reduce the antigen presenting ability and pro-inflammatory ability of macrophages, and reduce the infiltration of Cd4+ and Cd8a+ T cells in AR. The expression of Hif1α in AR monocytes/macrophages was regulated by pyruvate kinase 2. Higher expression of HIF1A in macrophages was also detected in human hearts with AR. These indicated HIF1A may serve as a potential target for attenuating AR. [ABSTRACT FROM AUTHOR]

Background: The use of preoperative beta-blockers has been accepted as a quality standard for patients undergoing coronary artery bypass graft (CABG) surgery. However, conflicting results from recent studies have raised questions concerning the effectiveness of this quality metric. We sought to determine the influence of preoperative beta-blocker administration before CABG in patients with left ventricular dysfunction.Methods: The authors analyzed all cases of isolated CABGs in patients with left ventricular ejection fraction less than 50%, performed between 2012 January and 2017 June, at 94 centres recorded in the China Heart Failure Surgery Registry database. In addition to the use of multivariate regression models, a 1-1 propensity scores matched analysis was performed.Results: Of 6116 eligible patients, 61.7% received a preoperative beta-blocker. No difference in operative mortality was found between two cohorts (3.7% for the non-beta-blockers group vs. 3.0% for the beta-blocker group; adjusted odds ratio [OR] 0.82 [95% CI 0.58-1.15]). Few differences in the incidence of other postoperative clinical end points were observed as a function of preoperative beta-blockers except in stroke (0.7% for the non-beta-blocker group vs. 0.3 for the beta-blocker group; adjusted OR 0.39 [95% CI 0.16-0.96]). Results of propensity-matched analyses were broadly consistent.Conclusions: In this study, the administration of beta-blockers before CABG was not associated with improved operative mortality and complications except the incidence of postoperative stroke in patients with left ventricular dysfunction. A more granular quality metric which would guide the use of beta-blockers should be developed. [ABSTRACT FROM AUTHOR]

We investigated whether the totally video-assisted thoracoscopic mitral valve surgery provides superior clinical outcomes and less inflammatory injury reaction compared with conventional sternotomy. A total of 504 consecutive patients admitted for mitral valve surgery from May 2014 through May 2019 in a single center were retrospectively analyzed according to two distinct procedure approach: the totally video-assisted thoracoscopic approach (group A, n = 127) and standard median sternotomy (group B, n = 377). The primary end point was the durations of cardiopulmonary bypass, aortic cross-clamping, the ventilation time and intensive care unit of stay; the secondary endpoints included inflammation indexes like high sensitivity C-reactive protein, neutrophil-lymphocyte ratio and metabolic injury parameters cardiac Troponin and lactate. There was only one in-hospital death due to diffuse intravascular coagulation in group A, but similar complications such as repair failure, re-thoracotomy and stroke in both groups. The durations of cardiopulmonary bypass and aortic cross-clamping were significantly longer in group A. In contrast, ventilation time and intensive care unit of stay were shortened compared with these in group B. In addition, postoperative equivalent lactate clearance but lower high sensitivity C-reactive protein, neutrophil-lymphocyte ratio and cardiac Troponin level was in group A than those in group B within postoperative 24 hours(P < 0.05). The analysis of present study indicated despite relatively longer cardiopulmonary bypass time, the totally thoracoscopic mitral valve procedure seemed to be favorable with regard to the extent of inflammatory reaction, cardiac injury and postoperative recovery compared with conventional median sternotomy. [ABSTRACT FROM AUTHOR]

Background: The performance of traditional scores is significantly limited to predict mortality in high-risk cardiac surgery. The aim of this study was to compare the performance of STS, ESII and HiriSCORE models in predicting mortality in high-risk patients undergoing CABG. Methods: Cross-sectional analysis in the international prospective database of high-risk patients: HiriSCORE project. We evaluated 248 patients with STS or ESII (5–10%) undergoing CABG in 8 hospitals in Brazil and China. The main outcome was mortality, defined as all deaths occurred during the hospitalization in which the operation was performed, even after 30 days. Five variables were selected as predictors of mortality in this cohort of patients. The model's performance was evaluated through the calibration-in-the-large and the receiver operating curve (ROC) tests. Results: The mean age was 69.90±9.45, with 52.02% being female, 25% of the patients were on New York Heart Association (NYHA) class IV and 49.6% had Canadian Cardiovascular Society (CCS) class 4 angina, and 85.5% had urgency or emergency status. The mortality observed in the sample was 13.31%. The HiriSCORE model showed better calibration (15.0%) compared to ESII (6.6%) and the STS model (2.0%). In the ROC curve, the HiriSCORE model showed better accuracy (ROC = 0.74) than the traditional models STS (ROC = 0.67) and ESII (ROC = 0.50). Conclusion: Traditional models were inadequate to predict mortality of high-risk patients undergoing CABG. However, the HiriSCORE model was simple and accurate to predict mortality in high-risk patients. [ABSTRACT FROM AUTHOR]

Background: Data on the effect of smoking on In-hospital outcome in patients with left ventricular dysfunction undergoing coronary artery bypass graft (CABG) surgery are limited. We sought to determine the influence of smoking on CABG patients with left ventricular dysfunction.Methods: A retrospective study was conducted using data from the China Heart Failure Surgery Registry database. Eligible patients with left ventricular ejection fraction less than 50% underwent isolated CABGS were included. In addition to the use of multivariate regression models, a 1-1 propensity scores matched analysis was performed. Our study (n = 6531) consisted of 3635 smokers and 2896 non-smokers. Smokers were further divided into ex-smokers (n = 2373) and current smokers (n = 1262).Results: The overall in-hospital morality was 3.9%. Interestingly, current smokers have lower in-hospital mortality than non-smokers [2.3% vs 4.9%; adjusted odds ratio (OR) 0.612 (95% CI 0.395-0.947) ]. No difference was detected in mortality between ex-smokers and non-smokers [3.6% vs 4.9%; adjusted OR 0.974 (0.715-1.327)]. No significant differences in other clinical end points were observed. Results of propensity-matched analyses were broadly consistent.Conclusions: It is paradoxically that current smokers had lower in-hospital mortality than non-smokers. Future studies should be performed to further understand the biological mechanisms that may explain this 'smoker's paradox' phenomenon. [ABSTRACT FROM AUTHOR]

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Cardiac injury is a common complication of the coronavirus disease 2019 (COVID-19), and is associated with adverse clinical outcomes. In this study, we aimed to reveal the association of cardiac injury with coagulation dysfunction. We enrolled 181 consecutive patients who were hospitalized with COVID-19, and studied the clinical characteristics and outcome of these patients. Cardiac biomarkers high-sensitivity troponin I (hs-cTnI), myohemoglobin and creatine kinase-myocardial band (CK-MB) were assessed in all patients. The clinical outcomes were defined as hospital discharge or death. The median age of the study cohort was 55 (IQR, 46–65) years, and 102 (56.4%) were males. Forty-two of the 181 patients (23.2%) had cardiac injury. Old age, high leukocyte count, and high levels of aspartate transaminase (AST), D-dimer and serum ferritin were significantly associated with cardiac injury. Multivariate regression analysis revealed old age and elevated D-dimer levels as being strong risk predictors of in-hospital mortality. Interleukin 6 (IL6) levels were comparable in patients with or without cardiac injury. Serial observations of coagulation parameters demonstrated highly synchronous alterations of D-dimer along with progression to cardiac injury. Cardiac injury is a common complication of COVID-19 and is an independent risk factor for in-hospital mortality. Old age, high leukocyte count, and high levels of AST, D-dimer and serum ferritin are significantly associated with cardiac injury, whereas IL6 are not. Therefore, the pathogenesis of cardiac injury in COVID-19 may be primarily due to coagulation dysfunction along with microvascular injury. [ABSTRACT FROM AUTHOR]

Background and Objective: Heart failure (HF) is a global health issue, and coronary artery bypass graft (CABG) is one of the most effective surgical treatments for HF with coronary artery disease. Unfortunately, the incidence of postoperative acute kidney injury (AKI) is high in HF patients following CABG, and there are few tools to predict AKI after CABG surgery for such patients. The aim of this study is to establish a nomogram to predict the incidence of AKI after CABG in patients with impaired left ventricular ejection fraction (LVEF).Methods: From 2012 to 2017, Clinical information of 1208 consecutive patients who had LVEF< 50% and underwent isolated CABG was collected to establish a derivation cohort. A novel nomogram was developed using the logistic regression model to predict postoperative AKI among these patients. According to the same inclusion criteria and the same period, we extracted the data of patients from 6 other large cardiac centers in China (n = 540) from the China Heart Failure Surgery Registry (China-HFSR) database for external validation of the new model. The nomogram was compared with 3 other available models predicting renal failure after cardiac surgery in terms of calibration, discrimination and net benefit.Results: In the derivation cohort (n = 1208), 90 (7.45%) patients were diagnosed with postoperative AKI. The nomogram included 7 independent risk factors: female, increased preoperative creatinine(> 2 mg/dL), LVEF< 35%, previous myocardial infarction (MI), hypertension, cardiopulmonary bypass(CPB) used and perioperative blood transfusion. The area under the receiver operating characteristic curve (AUC) was 0.738, higher than the other 3 models. By comparing calibration curves and decision curve analyses (DCA) with other models, the novel nomogram showed better calibration and greater net benefit. Among the 540 patients in the validation cohort, 104 (19.3%) had postoperative AKI, and the novel nomogram performed better with respect to calibration, discrimination and net benefit.Conclusions: The novel nomogram is a reliable model to predict postoperative AKI following isolated CABG for patients with impaired LVEF. [ABSTRACT FROM AUTHOR]

With the rapid development of single‐cell sequencing technology, the Langendorff perfusion system has emerged as a common approach to decompose cardiac tissue and obtain living cardiomyocytes to study cardiovascular disease with the mechanism of cardiomyocyte biology. However, the traditional Langendorff perfusion system is difficult to master, and further, the viability and purity of cardiomyocytes are frequently unable to meet sequencing requirements due to complicated devices and manipulate processes. Here, we provide an optimized Langendorff perfusion system with a simplified and standardized operating protocol which utilizes gravity as the perfusion pressure, includes a novel method for bubbles removing and standardizes the criteria for termination of digestion. We obtained stable cardiomyocyte with high viability and purity after multiple natural gravity sedimentation. The combination of the optimized Langendorff perfusion system and the multiple natural gravity sedimentation provides a stable system for isolating adult mouse heart, which will provide higher‐quality cardiomyocytes for further experiments. [ABSTRACT FROM AUTHOR]

The double-root translocation (DRT) procedure is considered as a new choice for surgical management of complex congenital heart disease. Our study aims to investigate the left ventricular hemodynamic status after DRT by energy loss (EL), involving 42 patients who underwent DRT as well as 42 healthy volunteers as controls. The EL of left ventricle (LV) during different periods (rapid filling-RF, atrial contraction-AC, isovolumic contraction-IVC, rapid ejection-RE) of the same cardiac cycle were obtained and analyzed. Compared to the controls, global LV and apical three chamber-EL at AC and IVC periods in DRT group were higher (p < 0.05), and EL at RE period of DRT group was moderately lower. In the correlation analysis, the global EL at the RF was correlated with E wave (r = 0.47, p = 0.03), E/e′ (r = 0.50, p = 0.02), BSA (r = − 0.54, p = 0.01), and age (r = − 0.67, p < 0.001). AC and RE- global EL were significantly correlated with E/e′ (r = 0.49, r = 0.59, p < 0.05). There was a strong positive correlation between E/e′ and global EL at the IVC (r = 0.62, p = 0.003) and a moderate negative correlation with age (r = − 0.44, p = 0.04). The present study confirms that EL is a feasible and reproducible indicator for quantitatively evaluating LV hemodynamic status in patients who underwent DRT and reveals that DRT can lead to approximatively normal long-term hemodynamic performance of LV. [ABSTRACT FROM AUTHOR]

Formations of clots were found inside the hydrodynamic bearings of the left ventricular assisted devices (LVADs) and caused tremendous risks to the long-term use of these devices. For the hydrodynamic bearings used in the LVAD, not only the lubrication status but also the motion of the blood cells in the bearing will take great effect on the performance of the device. Based on the analysis of the hydrodynamic pressures distribution and the flowing trajectory of red blood cells in the lubrication film, the bearing is designed in a region where enough hydrodynamic pressure is generated to float the rotor to reduce the wear, and the entrainment of red blood cells in the gap of the bearing can be prevented to avoid the formation of clots. [ABSTRACT FROM AUTHOR]

The neonatal heart completely regenerates after apical resection (AR), providing a desirable research model to study the mechanism of cardiac regeneration and cardiomyocyte proliferation. However, AR‐induced neonatal heart regenerative phenomenon is controversial due to the variation of operative details in different laboratories. Here, we provide an optimized AR operation procedure with stable regeneration and high survival rate by achieving heart exposure, normalizing myocardium cut‐offs, and reducing operation duration. We also established a whole‐heart‐slice approach to estimate the myocardial regeneration after the AR operation, which ensures no false‐negative/positive results. The combination of the optimized AR operation and the whole‐heart‐slice analysis provides a stable system to study neonatal heart regeneration and cardiomyocyte proliferation in situ. [ABSTRACT FROM AUTHOR]

Congenital heart disease (CHD) is the major cause of morbidity/mortality in infancy and childhood. Using a mouse model to uncover the mechanism of CHD is essential to understand its pathogenesis. However, conventional 2D phenotyping methods cannot comprehensively exhibit and accurately distinguish various 3D cardiac malformations for the complicated structure of heart cavity. Here, a new automated tool based on microcomputed tomography (micro‐CT) image data sets known as computer‐assisted cardiac cavity tracking (CACCT) is presented, which can detect the connections between cardiac cavities and identify complicated cardiac malformations in mouse hearts automatically. With CACCT, researchers, even those without expert training or diagnostic experience of CHD, can identify complicated cardiac malformations in mice conveniently and precisely, including transposition of the great arteries, double‐outlet right ventricle and atypical ventricular septal defect, whose accuracy is equivalent to senior fetal cardiologists. CACCT provides an effective approach to accurately identify heterogeneous cardiac malformations, which will facilitate the mechanistic studies into CHD and heart development. [ABSTRACT FROM AUTHOR]

Arrhythmogenic cardiomyopathy (ACM) is a familial cardiomyopathy featured by fibrofatty replacement of cardiomyocytes. Responsible genetic factors are not discernible in approximately one‐third of ACM probands. To investigate this further, we performed whole genome sequencing in 14 mutation‐negative ACM probands who underwent cardiac transplantation, and we identified one ACM proband with a rare homozygous missense variant in PNPLA2 (c.245G > A, p.G82D), a rate‐limiting enzyme that hydrolyzes triglycerides into fatty acids and diacylglycerol. Bioinformatic analysis suggested that this missense variant may lead to loss of function and therefore impair lipid catabolism. Genetic screening in this proband's family also inferred that the homozygous variant cosegregated with disease. To validate the pathogenicity of this variant and confirm its association with ACM, we established a knockin mouse model carrying the orthologous human homozygous PNPLA2 variant. Interestingly, mice with the homozygous variant presented with arrhythmias and significant cardiac dysfunction at 12 weeks, whereas heterozygous mice were not affected. Moreover, those homozygous mice suffered sudden death and/or heart failure by the age of 14 weeks. Pathological examination showed that extensive lipogenesis in cardiomyocytes and cardiac fibrosis were prominent in the myocardium. Herein, our data demonstrated that the homozygous missense variant PNPLA2 (c.245G > A, p.G82D) associated with a recessive form of ACM. [ABSTRACT FROM AUTHOR]

The heart lacks complete regeneration capacity. In mice, the cardiac apex can regenerate 1 day after birth, although 7 days after birth the repair occurs with a fibrous scar. However, the key transcription factors (TFs) related to this loss of regeneration capacity remain largely unknown. We aimed to find candidates for key TFs using proteomic profiling and comparison during loss of neonatal mouse cardiac regeneration capacity, with preliminary validation using western blotting (WB) and real‐time quantitative polymerase chain reaction (RT‐qPCR). A total of 69 common discrepant TFs with similar variation trends in two TF response element experiments were identified, 18 of which were matched to known key signaling pathways of cardiac regeneration after pathway enrichment of downstream genes. Validation using RT‐qPCR‐selected DACH1, RBL1 (P107), and TBX20, and further validation with WB‐selected RBL1 (P107) and TBX20. We therefore identified two candidates for key TFs in the loss of mouse cardiac apex regeneration capacity. TBX20 has been biologically validated, and RBL1 (P107) needs to be validated in the future. [ABSTRACT FROM AUTHOR]

A 48-year-old man presented with chest pain and ischemic manifestations according to an electrocardiogram due to coronary artery compression from a cardiac mass and was admitted to the emergency room and underwent extensive debulking followed by right atrium and ventricular three-dimensional reconstruction with concomitant tricuspid valve remodeling. He recovered a normal sinus rhythm and was discharged from the hospital a week later with a diagnosis of cardiac malignant angiosarcoma according to the pathological examination. He survived and had a normal cardiac structure and function performance, but vertebral metastasis was suspected after more than 4 months of follow-up after the procedure. [ABSTRACT FROM AUTHOR]