Pathological cardiac hypertrophy is a critical pathological process involved in the development of various cardiovascular diseases. Isochlorogenic acid A (ICAA) is a phenolic compound found in a wide spectrum of herbal medicines and plants, and several pharmacological properties of ICAA have been examined. However, there is currently no report on whether ICAA has therapeutic effect on pathological cardiac hypertrophy. Thus, the aim of this study was to explore the protective effects of ICAA on cardiac hypertrophy and clarify its potential mechanism. In our research, we found that ICAA effectively mitigated Ang II/TAC-induced cardiac hypertrophy and damage in vitro and in vivo. In terms of the mechanism, we proved that ICAA suppressed phosphorylation of receptor-interacting protein 3 (RIP3, RIPK3) and the activation of downstream calcium/calmodulin-dependent protein kinase II (CaMKII) signaling by directly binding to RIP3. MLKL was not required for RIP3 regulatory role in cardiac hypertrophy, and the effect of ICAA on cardiac hypertrophy was independent of RIP3/MLKL signaling cascade. Furthermore, RIP3 overexpression exacerbated Ang II-induced cardiac hypertrophy. Finally, we showed that ICAA had no obvious adverse effects on normal organs and even had protective effect. In conclusion, this study is the first to report that ICAA directly targets RIP3 to regulate the RIP3/CaMKII pathway, effectively inhibiting cardiac hypertrophy. Therefore, ICAA can be considered a novel therapeutic drug for the future prevention and treatment of cardiac hypertrophy.

Amid growing global concerns over obesity, the identification of novel lipid resources with potential health benefits has become a key focus in food science. Artemisia argyi, a traditional edible plant, is valued for its bioactive volatile oils, yet the effects of Artemisia argyi oil (AAO) on lipid metabolism and energy balance remain largely unexplored. Brown adipose tissue (BAT), which facilitates energy dissipation via non-shivering thermogenesis, is a key target for dietary strategies to combat obesity. Here, we demonstrate that AAO combats obesity by promoting BAT thermogenesis, resulting in significant reductions in weight gain, body fat, and improved insulin sensitivity. Mechanistically, AAO promotes Ucp1 transcription by directly activating ZFP516 expression and enhancing its interaction with LSD1. These findings identify AAO as a natural dietary component with potential to improve metabolic health through BAT activation, offering insights for its use in functional foods aimed at energy balance and weight management.

BACKGROUND:Cardiac fibrosis is a major determinant of adverse clinical outcomes of many heart diseases; currently, therapeutic strategy directly targeting fibroblasts is lacking. Nitric oxide-mediated nitrosative stress is associated with cardiac injury, and excessive nitric oxide can trigger S-nitrosylation (SNO) to specific cysteine thiol. This study aims to investigate the role of SNO in cardiac fibrosis and to identify potential therapeutic target. METHODS:SNO proteomic analysis was performed in cardiac tissue isolated from both mice subjected to transverse aortic constriction and spontaneous hypertensive rats. Elevated SNO of pyruvate kinase M2 (PKM2) was identified in cardiac fibroblasts, which was merely detected in cardiomyocytes. Cardiac fibroblast-specific PKM2 knockout mice and mice transfected with wild-type or SNO-resistant PKM2 mutant were used to determine the involvement of SNO of PKM2 (SNO-PKM2) in cardiac fibrosis. Unbiased proteomics and coimmunoprecipitation combined with mass spectrometry analysis were conducted to explore effectors mediating SNO-PKM2-induced activation of cardiac fibroblasts. A recently approved drug for rare blood disorder, mitapivat, was shown to dose-dependently relieve cardiac fibrosis. RESULTS:SNO of PKM2 at cysteine 49 and 326 increased in the heart tissue of patients with heart failure, heart tissue of murine cardiac fibrosis models, and cardiac fibroblasts stimulated with angiotensin II. SNO-PKM2 reduced pyruvate kinase activity and tetramerization of PKM2, and cardiac fibroblast-specific PKM2 knockout aggravated cardiac fibrosis, whereas cardiac fibroblast-specific PKM2 knockout mice transfected with SNO-resistant mutant rather than wild-type PKM2 had cardiac function. Mechanistically, SNO-PKM2 drove excessive mitochondrial fission and mitochondrial dysfunction through interfering with its interaction with actin regulatory protein gelsolin. TEPP-46, a pharmacological PKM2 activator, alleviated mitochondrial fission and cardiac fibrosis. Moreover, the US Food and Drug Administration-approved drug mitapivat showed preventive and therapeutical effects on cardiac fibrosis through activating PKM2. CONCLUSIONS:SNO-PKM2 specifically increases in cardiac fibroblasts and activated cardiac fibroblasts by inducing excessive mitochondrial fission through a gelsolin-dependent manner. Mitapivat is a potential therapeutic option for attenuating cardiac fibrosis.

Tumor necrosis factor (TNF) induces systemic inflammatory response syndrome (SIRS), and severe SIRS can serve as a model for studying animal death caused by organ failure. Through strategic cecectomy, we demonstrate that necroptosis in the cecum initiates the death process in TNF-treated mice, but it is not the direct cause of death. Instead, we show that it is the cardiac dysfunction downstream of cecum damage that ultimately leads to the death of TNF-treated mice. By in vivo and ex vivo physiological analyses, we reveal that TNF and the damage-associated molecular patterns (DAMPs) released from necroptotic cecal cells jointly target cardiac endothelial cells, triggering caspase-8 activation and subsequent cardiac endothelial damage. Cardiac endothelial damage is a primary cause of the deterioration of diastolic function in the heart of TNF-treated mice. Our research provides insights into the pathophysiological process of TNF-induced lethality.

Brown adipose tissue (BAT) is critical for non-shivering thermogenesis making it a promising therapeutic strategy to combat obesity and metabolic disease. However, the regulatory mechanisms underlying brown fat formation remain incompletely understood. Here, we found SOX4 is required for BAT development and thermogenic program. Depletion of SOX4 in BAT progenitors (Sox4-MKO) or brown adipocytes (Sox4-BKO) resulted in whitened BAT and hypothermia upon acute cold exposure. The reduced thermogenic capacity of Sox4-MKO mice increases their susceptibility to diet-induced obesity. Conversely, overexpression of SOX4 in BAT enhances thermogenesis counteracting diet-induced obesity. Mechanistically, SOX4 activates the transcription of EBF2, which determines brown fat fate. Moreover, phosphorylation of SOX4 at S235 by PKA facilitates its nuclear translocation and EBF2 transcription. Further, SOX4 cooperates with EBF2 to activate transcriptional programs governing thermogenic gene expression. These results demonstrate that SOX4 serves as an upstream regulator of EBF2, providing valuable insights into BAT development and thermogenic function maintenance.

BACKGROUND:Temporary cardiac pacemaker implantation (PM) via the femoral and subclavian veins is widely used in clinics to treat patients with severe bradycardia or tachycardia, but it is technically challenging and potentially associated with various complications.HYPOTHESIS:This study investigated the feasibility and safety of a novel method of PM implantation via the median cubital vein.METHODS:A total of 279 patients of the First Affiliated Hospital of Xiamen University between March 2020 and December 2021 who required no-emergency PM implantation were enrolled. The patients were divided into three groups based on the temporary PM implantation routes: F-control (n = 107), via the femoral vein; S-control (n = 67), via the subclavian vein, and N-group (n = 105), via the median cubital vein. The sheath placement time (SPT), electrode placement time (EPT), electrode arrival rate (EAR), rate of sensing and pacing (RSP), radiation quantity (RD), electrode dislocation rate (EDR) and average electrode retention time (AERT) were recorded and evaluated. In addition, the Hamilton Anxiety Scale (HAMA) and Self-Rating Depression Scale (SDS) were used to evaluate the comfort levels of patients in the three groups.RESULTS:There were no significant differences between the groups with regard to age, EAR, RSP, EPT, RD, and AERT (p > 0.05). However, the N-group had significantly lower SPT than the F-control and S-control groups (67.0 ± 22.0 s vs. 321.7 ± 122.2 s and 307.3 ± 128.5 s, p = 0.000). Additionally, the F-control had significantly higher EDR than the S-control group and the N-group (11 (10.3%) vs. 2 (3.0%) and 3 (2.9%), p = 0.036). Besides, comparison of the HAMA and SDS scores before and after PM implantation showed significant differences in the S-control group (p = 0.010) and the N-group (p = 0.000).CONCLUSIONS:Temporary PM implantation via the median cubital vein is safe, effective, and less time-consuming.

HomeCirculation: Arrhythmia and ElectrophysiologyVol. 16, No. 1Characteristics of Patients with Spontaneous Versus Drug-Induced Brugada Electrocardiogram: Sub-Analysis From the SABRUS Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBCharacteristics of Patients with Spontaneous Versus Drug-Induced Brugada Electrocardiogram: Sub-Analysis From the SABRUS Anat Milman, Avi Sabbag, Giulio Conte, Pieter G. Postema, Antoine Andorin, Jean-Baptiste Gourraud, Frederic Sacher, Philippe Mabo, Sung-Hwan Kim, Shingo Maeda, Yoshihide Takahashi, Tsukasa Kamakura, Takeshi Aiba, Jimmy JM Juang, Yoav Michowitz, Eran Leshem, Yuka Mizusawa, Elena Arbelo, Zhengrong Huang, Isabelle Denjoy, Carla Giustetto, Yanushi D. Wijeyeratne, Andrea Mazzanti, Ramon Brugada, Ruben Casado-Arroyo, Jean Champagne, Leonardo Calo, Georgia Sarquella-Brugada, Jacob Tfelt-Hansen, Silvia G. Priori, Masahiko Takagi, Christian Veltmann, Pietro Delise, Domenico Corrado, Elijah R. Behr, Fiorenzo Gaita, Gan-Xin Yan, Josep Brugada, Antoine Leenhardt, Arthur A.M. Wilde, Pedro Brugada, Kengo F. Kusano, Kenzo Hirao, Gi-Byoung Nam, Vincent Probst and Bernard Belhassen Anat MilmanAnat Milman Correspondence to: Anat Milman, MD PhD, Davidai Arrhythmia Center, Leviev Heart Center Sheba Medical Center, Tel Hashomer 5265601, Israel. Email E-mail Address: [email protected] https://orcid.org/0000-0002-8551-4101 Leviev Heart Institute, The Chaim Sheba Medical Centre, Tel Hashomer and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel (A.M., A.S., E.L.). Search for more papers by this author , Avi SabbagAvi Sabbag https://orcid.org/0000-0003-4295-6679 Leviev Heart Institute, The Chaim Sheba Medical Centre, Tel Hashomer and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel (A.M., A.S., E.L.). Search for more papers by this author , Giulio ConteGiulio Conte https://orcid.org/0000-0003-2248-3456 Heart Rhythm Management Centre, UZ-VUB, Brussels, Belgium (G.C., P.B.). Search for more papers by this author , Pieter G. PostemaPieter G. Postema https://orcid.org/0000-0003-2863-9159 European Reference Network for Rare & Low Prevalence Complex Diseases of the Heart (P.G.P., A.A., J.B.G., Y.M., E.A., Y.D.W., A.M., J.T.-H., S.G.P., D.C., E.R.B., F.G., A.A.M.W., V.P.). Amsterdam UMC, University of Amsterdam, Heart Centre and Department of Clinical and Experimental Cardiology, Amsterdam, the Netherlands (P.G.P., Y.M., A.A.M.W.). Search for more papers by this author , Antoine AndorinAntoine Andorin https://orcid.org/0000-0001-6848-5452 European Reference Network for Rare & Low Prevalence Complex Diseases of the Heart (P.G.P., A.A., J.B.G., Y.M., E.A., Y.D.W., A.M., J.T.-H., S.G.P., D.C., E.R.B., F.G., A.A.M.W., V.P.). Service de Cardiologie, CHU de Nantes (A.A., J.B.G., V.P.). Search for more papers by this author , Jean-Baptiste GourraudJean-Baptiste Gourraud https://orcid.org/0000-0002-6961-2131 European Reference Network for Rare & Low Prevalence Complex Diseases of the Heart (P.G.P., A.A., J.B.G., Y.M., E.A., Y.D.W., A.M., J.T.-H., S.G.P., D.C., E.R.B., F.G., A.A.M.W., V.P.). Service de Cardiologie, CHU de Nantes (A.A., J.B.G., V.P.). Search for more papers by this author , Frederic SacherFrederic Sacher https://orcid.org/0000-0001-8348-9320 Hôpital Cardiologique du Haut-Lévêque and University Bordeaux, LIRYC Instituteitute (F.S.). Search for more papers by this author , Philippe MaboPhilippe Mabo Cardiology and Vascular Disease Division, Rennes University Health Centre, Rennes, France (P.M.). Search for more papers by this author , Sung-Hwan KimSung-Hwan Kim https://orcid.org/0000-0001-6805-0416 Division of Cardiology, College of Medicine, The Catholic University of Korea, Seoul, Korea (S.-H.K.). Search for more papers by this author , Shingo MaedaShingo Maeda https://orcid.org/0000-0001-6964-0653 Heart Rhythm Centre, Tokyo Medical and Dental University, Tokyo (S.M., Y.T., K.H.). Search for more papers by this author , Yoshihide TakahashiYoshihide Takahashi https://orcid.org/0000-0003-0335-996X Heart Rhythm Centre, Tokyo Medical and Dental University, Tokyo (S.M., Y.T., K.H.). Search for more papers by this author , Tsukasa KamakuraTsukasa Kamakura https://orcid.org/0000-0003-2964-2544 Division of Arrhythmia & EleCentreophysiology, National Cerebral & Cardiovascular Centre, Osaka, Japan (T.K., T.A.). Search for more papers by this author , Takeshi AibaTakeshi Aiba https://orcid.org/0000-0003-1779-7282 Division of Arrhythmia & EleCentreophysiology, National Cerebral & Cardiovascular Centre, Osaka, Japan (T.K., T.A.). Search for more papers by this author , Jimmy JM JuangJimmy JM Juang https://orcid.org/0000-0003-4767-7636 Cardiovascular Centre and Division of Cardiology, National Taiwan University Hospital and University College of Medicine, Taipei, Taiwan (J.J.M.J.). Search for more papers by this author , Yoav MichowitzYoav Michowitz https://orcid.org/0000-0002-5665-3735 European Reference Network for Rare & Low Prevalence Complex Diseases of the Heart (P.G.P., A.A., J.B.G., Y.M., E.A., Y.D.W., A.M., J.T.-H., S.G.P., D.C., E.R.B., F.G., A.A.M.W., V.P.). Cardiology Department, Shaare Zedek Hospital, Affiliated to the Faculty of Medicine, Hebrew University, Jerusalem, Israel (Y.M.). Search for more papers by this author , Eran LeshemEran Leshem https://orcid.org/0000-0002-8896-460X Leviev Heart Institute, The Chaim Sheba Medical Centre, Tel Hashomer and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel (A.M., A.S., E.L.). Search for more papers by this author , Yuka MizusawaYuka Mizusawa https://orcid.org/0000-0003-1858-0923 Amsterdam UMC, University of Amsterdam, Heart Centre and Department of Clinical and Experimental Cardiology, Amsterdam, the Netherlands (P.G.P., Y.M., A.A.M.W.). Search for more papers by this author , Elena ArbeloElena Arbelo https://orcid.org/0000-0003-0424-6393 European Reference Network for Rare & Low Prevalence Complex Diseases of the Heart (P.G.P., A.A., J.B.G., Y.M., E.A., Y.D.W., A.M., J.T.-H., S.G.P., D.C., E.R.B., F.G., A.A.M.W., V.P.). Arrhythmia Section, Cardiology Department, Hospital Clínic, Universityersitat de Barcelona and bIDIBAPS, Instituteitut d’Investigació August Pi i Sunyer (IDIBAPS), Barcelona (E.A.). Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain (E.A.). Search for more papers by this author , Zhengrong HuangZhengrong Huang https://orcid.org/0000-0003-0007-9321 Department of Cardiology, the First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China (Z.H.). Search for more papers by this author , Isabelle DenjoyIsabelle Denjoy https://orcid.org/0000-0002-1786-9461 Service de Cardiologie et CNMR Maladies Cardiaques Héréditaires Rares, Hôpital Bichat, Paris and Université Paris Diderot, Sorbonne, France (I.D.). Search for more papers by this author , Carla GiustettoCarla Giustetto https://orcid.org/0000-0002-5102-3398 Division of Cardiology, Department of Medical Sciences, Città della Salute e della Scienza Hospital, University of Torino, Italy (C.G., F.G.). Search for more papers by this author , Yanushi D. WijeyeratneYanushi D. Wijeyeratne https://orcid.org/0000-0003-0656-5769 European Reference Network for Rare & Low Prevalence Complex Diseases of the Heart (P.G.P., A.A., J.B.G., Y.M., E.A., Y.D.W., A.M., J.T.-H., S.G.P., D.C., E.R.B., F.G., A.A.M.W., V.P.). Cardiovascular Sciences, St. George’s University of London and Cardiology Clinical Academic Group St. George’s University Hospitals NHS Foundation Trust, London, UK (Y.D.W., E.R.B.). Search for more papers by this author , Andrea MazzantiAndrea Mazzanti https://orcid.org/0000-0002-0208-2172 European Reference Network for Rare & Low Prevalence Complex Diseases of the Heart (P.G.P., A.A., J.B.G., Y.M., E.A., Y.D.W., A.M., J.T.-H., S.G.P., D.C., E.R.B., F.G., A.A.M.W., V.P.). Molecular Cardiology, Istituti Clinici Scientifici Maugeri IRCCS, Pavia, Italy (A.M.). Search for more papers by this author , Ramon BrugadaRamon Brugada https://orcid.org/0000-0001-6607-3032 Cardiovascular Genetics Center, University of Girona-IDIBGI and Medical Science Department, School of Medicine, University of Girona, Spain (R.B.). Search for more papers by this author , Ruben Casado-ArroyoRuben Casado-Arroyo Department of Cardiology, Erasme University Hospital, Universityersité Libre de Bruxelles, Belgium (R.C.-A.). Search for more papers by this author , Jean ChampagneJean Champagne https://orcid.org/0000-0001-9861-9351 Quebec Heart & Lung Institute, Quebec City, Canada (J.C.). Search for more papers by this author , Leonardo CaloLeonardo Calo https://orcid.org/0000-0002-6062-5286 Division of Cardiology, Policlinico Casilino, Roma, Italy (L.C.). Search for more papers by this author , Georgia Sarquella-BrugadaGeorgia Sarquella-Brugada https://orcid.org/0000-0002-6857-8904 Pediatric Arrhythmias, EleCentreophysiology and Sudden Death Unit Cardiology, Department Hospital Sant Joan de Déu, Barcelona - Universityersitat de Barcelona, Spain (G.S.-B.). Search for more papers by this author , Jacob Tfelt-HansenJacob Tfelt-Hansen European Reference Network for Rare & Low Prevalence Complex Diseases of the Heart (P.G.P., A.A., J.B.G., Y.M., E.A., Y.D.W., A.M., J.T.-H., S.G.P., D.C., E.R.B., F.G., A.A.M.W., V.P.). The Heart Centre, Copenhagen University Hospital and Department of Forensic Medicine, Faculty of Medical Sciences, University of Copenhagen, Denmark (J.T.-H.). Search for more papers by this author , Silvia G. PrioriSilvia G. Priori https://orcid.org/0000-0001-6877-0288 European Reference Network for Rare & Low Prevalence Complex Diseases of the Heart (P.G.P., A.A., J.B.G., Y.M., E.A., Y.D.W., A.M., J.T.-H., S.G.P., D.C., E.R.B., F.G., A.A.M.W., V.P.). Search for more papers by this author , Masahiko TakagiMasahiko Takagi https://orcid.org/0000-0001-7712-8529 Division of Cardiac Arrhythmia, Kansai Medical University Medical Centre, Moriguchi, Japan (M.T.). Search for more papers by this author , Christian VeltmannChristian Veltmann https://orcid.org/0000-0001-7587-1124 Hannover Heart Rhythm Centre, Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany (C.V.). Search for more papers by this author , Pietro DelisePietro Delise https://orcid.org/0000-0001-7190-4830 Division of Cardiology, Hospital of Peschiera del Garda, Veneto (P.D.). Search for more papers by this author , Domenico CorradoDomenico Corrado https://orcid.org/0000-0003-1487-0392 European Reference Network for Rare & Low Prevalence Complex Diseases of the Heart (P.G.P., A.A., J.B.G., Y.M., E.A., Y.D.W., A.M., J.T.-H., S.G.P., D.C., E.R.B., F.G., A.A.M.W., V.P.). Department of Cardiac, Thoracic & Vascular Sciences University of Padova, Italy (D.C.). Search for more papers by this author , Elijah R. BehrElijah R. Behr https://orcid.org/0000-0002-8731-2853 European Reference Network for Rare & Low Prevalence Complex Diseases of the Heart (P.G.P., A.A., J.B.G., Y.M., E.A., Y.D.W., A.M., J.T.-H., S.G.P., D.C., E.R.B., F.G., A.A.M.W., V.P.). Cardiovascular Sciences, St. George’s University of London and Cardiology Clinical Academic Group St. George’s University Hospitals NHS Foundation Trust, London, UK (Y.D.W., E.R.B.). Search for more papers by this author , Fiorenzo GaitaFiorenzo Gaita European Reference Network for Rare & Low Prevalence Complex Diseases of the Heart (P.G.P., A.A., J.B.G., Y.M., E.A., Y.D.W., A.M., J.T.-H., S.G.P., D.C., E.R.B., F.G., A.A.M.W., V.P.). Division of Cardiology, Department of Medical Sciences, Città della Salute e della Scienza Hospital, University of Torino, Italy (C.G., F.G.). Search for more papers by this author , Gan-Xin YanGan-Xin Yan https://orcid.org/0000-0002-3118-5680 Lankenau Medical Centre, Wynnewood, PA (G.X.Y.). Search for more papers by this author , Josep BrugadaJosep Brugada https://orcid.org/0000-0002-5662-8302 Search for more papers by this author , Antoine LeenhardtAntoine Leenhardt https://orcid.org/0000-0001-7368-4528 Search for more papers by this author , Arthur A.M. WildeArthur A.M. Wilde https://orcid.org/0000-0002-0528-0852 European Reference Network for Rare & Low Prevalence Complex Diseases of the Heart (P.G.P., A.A., J.B.G., Y.M., E.A., Y.D.W., A.M., J.T.-H., S.G.P., D.C., E.R.B., F.G., A.A.M.W., V.P.). Amsterdam UMC, University of Amsterdam, Heart Centre and Department of Clinical and Experimental Cardiology, Amsterdam, the Netherlands (P.G.P., Y.M., A.A.M.W.). Search for more papers by this author , Pedro BrugadaPedro Brugada https://orcid.org/0000-0003-3172-6106 Heart Rhythm Management Centre, UZ-VUB, Brussels, Belgium (G.C., P.B.). Search for more papers by this author , Kengo F. KusanoKengo F. Kusano Search for more papers by this author , Kenzo HiraoKenzo Hirao Heart Rhythm Centre, Tokyo Medical and Dental University, Tokyo (S.M., Y.T., K.H.). Search for more papers by this author , Gi-Byoung NamGi-Byoung Nam https://orcid.org/0000-0003-4391-5406 Division of Cardiology, Asan Medical Centre, University of Ulsan College of Medicine, Seoul, Korea (Gi-Byoung Nam). Search for more papers by this author , Vincent ProbstVincent Probst https://orcid.org/0000-0002-5492-8619 European Reference Network for Rare & Low Prevalence Complex Diseases of the Heart (P.G.P., A.A., J.B.G., Y.M., E.A., Y.D.W., A.M., J.T.-H., S.G.P., D.C., E.R.B., F.G., A.A.M.W., V.P.). Service de Cardiologie, CHU de Nantes (A.A., J.B.G., V.P.). Search for more papers by this author and Bernard BelhassenBernard Belhassen https://orcid.org/0000-0002-7468-2054 Heart Institute, Hadassah University Hospital, Jerusalem, Israel (B.B.) Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel (B.B.). Search for more papers by this author Originally published3 Jan 2023https://doi.org/10.1161/CIRCEP.122.011360Circulation: Arrhythmia and Electrophysiology. 2023;16Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 3, 2023: Ahead of Print Patients with Brugada syndrome (BrS) may display either a spontaneous (S) or a drug-induced (DI) ECG pattern. The latter group is considered at a lower risk of arrhythmic events (AE) and sudden cardiac death (SCD). The only study that compared these 2 groups in BrS associated with AEs comprised a small cohort of 44 patients.1The SABRUS study (Survey on Arrhythmic events in Brugada Syndrome) gathers the largest cohort of patients with BrS and AEs published to date.2 The data that support the findings of this study are available from the corresponding author upon reasonable request. Patients were divided into 2 groups according to their AE presentation: group A presented with aborted cardiac arrest before diagnosis of BrS and group B were Brugada patients implanted prophylactically with an ICD, which proved to be justified during follow-up. The present study compares DI-BrS and S-BrS patients from SABRUS. The study was approved by the Institutional Committee on Human Research at the Tel Aviv Sourasky Medical Center. Continuous variables are presented as mean±SD or median (interquartile range) and compared using the student t test or Mann-Whitney U test as appropriate. Categorical variables are presented by absolute numbers and proportions and compared using the χ2 test or Fisher exact test. All tests were 2-tailed, and a P<0.05 was considered statistically significant.Of the 678 SABRUS patients, 451 (66.5%) had S-BrS ECG and 227 (33.5%) had DI-BrS ECG (Table 1). Females predominated in the DI-ECG group (15.4% versus 5.3% in the S-ECG group, P<0.001), with less Asians than Whites (33.9% versus 42.8% in the S-ECG group, P=0.036). Higher inducibility rates of ventricular fibrillation (VF) at electrophysiologic study (EPS) were found in the S-ECG group (67.3% versus 55%.7 in the DI-ECG groups, respectively, P=0.022), with a similar rate of EPS performed in both groups (61.7% in the DI-ECG group versus 57.6% in the S-ECG group, P=0.315). There were no differences between DI-BrS ECG and S-BrS ECG patients regarding age at AE, proband status, history of syncope, AE presentation, family history of sudden cardiac death, fever-related events, and genetic analysis.Table 1. Patient Characteristics According to Brugada ECG TypeDrug-Induced BrECGSpontaneous BrECGPn=227 (33.5%)n=451 (66.5%)Age at AE, y (mean±SD)42±1442±150.969 Age at AE ≤169 (4)23 (5.1)0.532 Age at AE >16218 (96)428 (94.9)Gender Men192 (84.6)427 (94.7)<0.001 Women35 (15.4)24 (5.3)Ethnicity White130 (57.3)234 (51.9)0.036 Asian77 (33.9)193 (42.8) Other/unknown20 (8.8)24 (5.3)Arrhythmic event documentation Group A150 (66.1)276 (61.2)0.214 Group B77 (33.9)175 (38.8)Proband status181 (85.4)361 (86.4)0.736History of syncope82 (36.1)183 (40.6)0.262Fever during AE11 (5.9)24 (6)0.961Family history of SCD Yes46 (20.3)99 (22)0.851 No158 (69.6)310 (68.7) Unknown23 (10.1)42 (9.3)EPS performed140 (61.7)260 (57.6)0.315VF inducibility during EPS78 (55.7)175 (67.3)0.022Genetic analysis performed158 (69.6)327 (72.5)0.429SCN5A mutation present41 (25.9)102 (31.2)0.235AE indicates arrhythmic event; BrECG, Brugada electrocardiogram; EPS, electrophysiologic study; SCD, sudden cardiac death; and VF, ventricular fibrillation.To the best of our knowledge, this is the first study comparing BrS patients with S-ECG and DI-ECG in a large population cohort with AEs. Although a previous article by Tadros et al3 showed that 8% of patients tested by drug provocation for BrS could have false positive results, we assume, based on our findings of the SABRUS cohort,4 that all our patients with DI-ECG have proven BrS, and that the results of our study should be taken in this context only.Syncope combined with a spontaneous type 1 Brugada ECG has been shown to be useful for identifying Brugada patients at risk for AE. However, this is not relevant when a DI-ECG is encountered. In addition, the use of programmed ventricular stimulation has shown conflicting results. In a large series of patients with DI-BrS ECG, Sieira et al5 showed that VF inducibility rate was significantly lower than in patients with S-BrS ECG (13.2% versus 42.4%, respectively, P<0.01); however their cohort comprised a minority of patients with AEs. In our cohort comprising only patients with AEs, the lower inducibility rate is confirmed (55.7% versus 67.3%, respectively, P=0.022). These findings suggest that EPS is less useful for the management of BrS patients with DI-ECG, and do not inform necessarily on risk stratification strategies. These findings could actually represent a difference in the mechanism of arrhythmia generation of the 2 subgroups of Brugada patients, and future studies should test whether this could explain the lower arrhythmic risk of DI-ECG patients.Females predominated in our DI-ECG group. This is in line with the study by Nagayama et al1 in a smaller cohort.For the first time, SABRUS showed that Asians with AEs displayed significantly less DI-ECG compared with whites. This may suggest that a genetic predisposition of Asians plays a role in the occurrence of the S-BrS ECG type.No difference in the presence of SCN5A gene mutation was found between the DI-ECG and S-ECG groups. These findings agree with those reported by Nagayama et al1 in a similar, although significantly smaller patient cohort.In conclusion, DI-BrS patients represented a third of BrS cohort with AEs. They differed from S-BrS patients in gender, ethnicity, and VF inducibility rates. The most important observation is that this group of patients is less studied, and identifying high-risk DI-BrS patients is not an easy task. We encourage seeking new risk markers in this group in future studies.Article InformationSources of FundingNone.Nonstandard Abbreviations and AcronymsAEarrhythmic eventsBrSBrugada syndromeDIdrug-inducedICDimplantable cardiac defibrillatorSspontaneousSABRUSSurvey on Arrhythmic events in Brugada SyndromeVFventricular fibrillationDisclosures None.FootnotesFor Sources of Funding and Disclosures, see page 64.Correspondence to: Anat Milman, MD PhD, Davidai Arrhythmia Center, Leviev Heart Center Sheba Medical Center, Tel Hashomer 5265601, Israel. Email anatmilman@gmail.comReferences1. Nagayama T, Nagase S, Kamakura T, Wada M, Ishibashi K, Inoue YY, Miyamoto K, Noda T, Aiba T, Takaki HT, et al. Clinical and electrocardiographic differences in Brugada syndrome with spontaneous or drug-induced type 1 electrocardiogram.Circ J. 2019; 83:532–539. doi: 10.1253/circj.cj-18-0643CrossrefMedlineGoogle Scholar2. Milman A, Gourraud JB, Andorin A, Postema PG, Sacher F, Mabo P, Conte G, Giustetto C, Sarquella-Brugada G, Hochstadt A, et al. Gender differences in patients with Brugada syndrome and arrhythmic events: data from a survey on arrhythmic events in 678 patients.Heart Rhythm. 2018; 15:1457–1465. doi: 10.1016/j.hrthm.2018.06.019CrossrefMedlineGoogle Scholar3. Tadros R, Nannenberg EA, Lieve KV, Škorić-Milosavljević D, Lahrouchi N, Lekanne Deprez RH, Vendrik J, Reckman YJ, Postema PG, Amin AS, et al. Yield and pitfalls of ajmaline testing in the evaluation of unexplained cardiac arrest and sudden unexplained death.J Am Coll Cardiol EP. 2017; 3:1400–1408. doi: 10.1016/j.jacep.2017.04.005CrossrefGoogle Scholar4. Milman A, Andorin A, Gourraud JB, Sacher F, Mabo P, Kim SH, Maeda S, Takahashi Y, Kamakura T, Aiba T, et al. Age of first arrhythmic event in Brugada syndrome: data from the SABRUS (Survey on Arrhythmic Events in Brugada Syndrome) in 678 patients.Circ Arrhythm Electrophysiol. 2017; 10:e005222. doi: 10.1161/CIRCEP.117.005222LinkGoogle Scholar5. Sieira J, Ciconte G, Conte G, de Asmundis C, Chierchia GB, Baltogiannis G, Di Giovanni G, Saitoh Y, Casado-Arroyo R, Juliá J, et al. Long-term prognosis of drug-induced Brugada syndrome.Heart Rhythm. 2017; 14:1427–1433. doi: 10.1016/j.hrthm.2017.04.044CrossrefMedlineGoogle Scholar eLetters(0) eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. 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Sign In to Submit a Response to This Article Previous Back to top Next FiguresReferencesRelatedDetails January 2023Vol 16, Issue 1 Advertisement Article Information Metrics © 2023 American Heart Association, Inc.https://doi.org/10.1161/CIRCEP.122.011360PMID: 36595628 Originally publishedJanuary 3, 2023 KeywordsBrugada syndromeelectrocardiographyheart arrestsyncopeventricular fibrillationPDF download Advertisement Subjects Sudden Cardiac Death

Background: Peripartum cardiomyopathy (PPCM) is a potentially life-threatening complication of pregnancy, but identifying patients at higher risk of this condition remains difficult. Objectives: We conducted a study to identify new risk factors associated with PPCM and predictors of poor outcomes. Methods: This retrospective analysis included a total of 44 women with PPCM. As a control group, 79 women who gave birth around the same time as the PPCM patients and who did not have organic disease were included. A multivariate regression analysis was conducted to identify risk factors associated with PPCM and with delayed recovery. Results: All PPCM patients were discharged within 28 days. In comparison to the control group, PPCM patients had higher rates of preeclampsia (20.4% vs. 1.27%, P < 0.001), autoimmune disease (27.3% vs. 11.4%, P = 0.018), and cesarean delivery with preterm labor (31.8% vs. 17.7%, P = 0.037). The neonates of PPCM patients had lower birth weight (2.70 +/- 0.66 kg vs. 3.21 +/- 0.57 kg, P < 0.001). PPCM patients had higher levels of C-reactive protein, D-dimer, brain natriuretic peptide (BNP), and serum phosphorus, but lower levels of albumin and serum calcium (all P < 0.001). In all patients with PPCM, the left ventricular ejection fraction (LVEF) returned to normal (> 50%) within 28 days after admission. Subjects with early recovery (n = 34) had lower BNP than those with delayed recovery (n = 10) (649.7 +/- 526.0 pg/mL vs. 1444.1 +/- 1040.8 pg/mL, P = 0.002). Multivariate regression led to a three-point score system to predict PPCM (1 point each for the presence of pericardial effusion, left ventricular dilatation, and D-dimer level > 0.5 mg/mL). At a cutoff of > 2, this scoring system predicted delayed recovery with 95.5% sensitivity and 96.1% specificity. The negative pre-dictive value was 97.4% and the positive predictive value was 93.3%. Binary logistic regression indicated that PPCM patients with pulmonary hypertension, lower hemoglobin, or worse LVEF tended to require longer hospital stay (minimum 14 days). Conclusions: A risk score that consists of pericardial effusion, left ventricular dilatation, and D-dimer level > 0.5 mg/mL could help streamline the diagnosis of PPCM prior to confirmatory investigations. Moreover, a risk score that consists of pulmonary hypertension, lower hemoglobin and worse LVEF could help to predict poor outcomes in PPCM patients. (c) 2023 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

BACKGROUND: The cardiac-protective role of GSNOR (S-nitrosoglutathione reductase) in the cytoplasm, as a denitrosylase enzyme of S-nitrosylation, has been reported in cardiac remodeling, but whether GSNOR is localized in other organelles and exerts novel effects remains unknown. We aimed to elucidate the effects of mitochondrial GSNOR, a novel subcellular localization of GSNOR, on cardiac remodeling and heart failure (HF). METHODS: GSNOR subcellular localization was observed by cellular fractionation assay, immunofluorescent staining, and colloidal gold particle staining. Overexpression of GSNOR in mitochondria was achieved by mitochondria-targeting sequence-directed adeno-associated virus 9. Cardiac-specific knockout of GSNOR mice was used to examine the role of GSNOR in HF. S-nitrosylation sites of ANT1 (adenine nucleotide translocase 1) were identified using biotin-switch and liquid chromatography-tandem mass spectrometry. RESULTS: GSNOR expression was suppressed in cardiac tissues of patients with HF. Consistently, cardiac-specific knockout mice showed aggravated pathological remodeling induced by transverse aortic constriction. We found that GSNOR is also localized in mitochondria. In the angiotensin II–induced hypertrophic cardiomyocytes, mitochondrial GSNOR levels significantly decreased along with mitochondrial functional impairment. Restoration of mitochondrial GSNOR levels in cardiac-specific knockout mice significantly improved mitochondrial function and cardiac performance in transverse aortic constriction–induced HF mice. Mechanistically, we identified ANT1 as a direct target of GSNOR. A decrease in mitochondrial GSNOR under HF leads to an elevation of S-nitrosylation ANT1 at cysteine 160 (C160). In accordance with these findings, overexpression of either mitochondrial GSNOR or ANT1 C160A, non-nitrosylated mutant, significantly improved mitochondrial function, maintained the mitochondrial membrane potential, and upregulated mitophagy. CONCLUSIONS: We identified a novel species of GSNOR localized in mitochondria and found mitochondrial GSNOR plays an essential role in maintaining mitochondrial homeostasis through ANT1 denitrosylation, which provides a potential novel therapeutic target for HF.

目的 探讨经肘正中静脉行临时心脏起搏器置入术的可行性和安全性.方法 纳入2020年6-12月厦门大学附属第一医院住院部需临时心脏起搏器置入术患者184例,根据置入临时心脏起搏器的路径不同分为对照组和观察组.对照组采用经股静脉(76例)或锁骨下静脉(32例)路径;观察组采用经肘正中静脉(76例)路径,统计置管时间、电极到位时间、电极到位率、感知带动例数、放射量、电极脱位率以及并发症发生率.结果 与对照组比较,观察组的电极到位时间[(1.3±0.6)比(1.2±0.8)min,t=0.922,P=0.357]相近,电极到位率(100％比100％)一致,感知带动率(100％比100％)相同,放射量[(16.1±3.9)比(15.5±4.5)mGy,t=0.940,P=0.348]相似,差异无统计学意义(均P＞0.05);电极平均留置时间相似,电极脱位率方面,观察组患者与经锁骨下静脉患者类似,观察组较经股静脉患者低[2.6％(2/76)比10.5％(8/76),x2=8.950,P=0.003].观察组的置管时间[(0.5±0.1)比(4.2±1.3)min,t=24.741,P＜0.001]明显更短,并发症和不良操作发生率[1.3％(1/76)比 11.1％(12/108),x2=5.112,P=0.024]更低.结论 与传统路径比较,经肘正中静脉行临时心脏起搏器置入术疗效相似,但操作更简单,安全性更高,值得推广.

Obesity is caused by an excessive accumulation of fat,which poses a risk to human health.In China,the preva-lence rates of overweight and obesity in adults were esti-mated to be 30.1％and 11.9％,respectively,ranking the first in the world.Obesity is a major risk factor for hypertension.However,most of the overweight adults maintain normal blood pressure(BP),and only～43.6％of obese people developed hypertension.The mechanism and key link for promoting obesity to hypertension are still unclear.Genome-wide association studies(GWAS)attempt to discover genetic variations that associate with obesity and hypertension.1 Although these studies suggest a close relationship between obesity and hypertension,only 10％-20％of the increase in BP can be explained by increased body mass index(BMI).2-4 In this study,we observed that several genes were associated with both hypertension and obesity,which gave us an opportunity to find and identify the common genetic background of hypertension and obesity,or obesity-related hypertension.

Aortic dissection (AD) is a life-threatening disease with high morbidity and mortality, and effective pharmacotherapeutic remedies for it are lacking. Therefore, AD’s molecular pathogenesis and etiology must be elucidated. The aim of this study was to investigate the possible mechanism of mediator complex subunit 12 (human: MED12, mouse: Med12)involvement in AD. Firstly, we examined the expression of MED12 protein (human: MED12, mouse: Med12) in the aortic tissues of AD patients and AD mice. Subsequently, Med12 gene silencing was accomplished with RNA interference (siRNA). The effects of Med12 on AD and the possible biological mechanisms were investigated based on the proliferation, senescence, phenotypic transformation, and its involved signal pathway of mouse aortic smooth muscle cells (MOVAS), s. The results show that the expression of MED12 in the aortae of AD patients and AD mice was decreased. Moreover, the downregulation of Med12 inhibited the proliferation of MOVAS and promoted senescence. Further research found that Med12, as an inhibitor of the TGFβ1 signaling pathway, reduced the expression of Med12 and enhanced the activity of the TGFβ1 nonclassical signaling pathway, while TGFβ1 inhibited the phenotype transformation and proliferation of MOVAS by inhibiting Med12 synthesis. In conclusion, Med12 affected the phenotype, proliferation, and senescence of MOVAS through the TGFβ signaling pathway. This study provides a potential new target for the prevention and treatment of AD.

Myocardial infarction (MI) is a serious threat to people's life and health, which is significantly hindered by effective treatment formulations. Interestingly, our recent endeavour of designing selenium-containing polymeric hydrogel has been experimentally proved to be helpful in combating inflammatory responses and treating MI. The design was inspired by selenium with anti-inflammatory and anti-fibrosis activities, and the formulation could also serve as a support of myocardial tissue upon the failure of this function. In details, an injectable selenium-containing polymeric hydrogel, namely, poly[di-(1-hydroxylyndecyl) selenide/polypropylene glycol/polyethylene glycol urethane] [poly(DH-SE/PEG/PPG urethane)], was synthesised by combining a thermosensitive PPG block, DH-Se (which has oxidation-reduction properties), and hydrophilic PEG segments. Based on the established mouse model of MI, this formulation was experimentally validated to effectively promote the recovery of cardiac function. At the same time, we confirmed by enzyme-linked immunosorbent assay, Masson staining and Western blotting that this formulation could inhibit inflammation and fibrosis, so as to significantly improve left ventricular remodelling. In summary, a selenium-containing polymeric hydrogel formulation analysed in the current study could be a promising therapeutic formulation, which can provide new strategies towards the effective treatment of myocardial infarction or even other inflammatory diseases.

Endothelial dysfunction is the initial process of atherosclerosis. Heat shock protein 90 (Hsp90), as a molecular chaperone, plays a crucial role in various cardiovascular diseases. Hsp90 function is regulated by S-nitrosylation (SNO). However, the precise role of SNO-Hsp90 in endothelial dysfunction during atherosclerosis remains unclear. We here identified Hsp90 as a highly S-nitrosylated target in endothelial cells (ECs) by biotin switch assay combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS). The elevation of SNO-Hsp90 was observed in atherosclerotic human and rodent aortas as well as in oxidized LDL (oxLDL)-treated ECs. Inhibition of inducible nitric oxide synthase (iNOS) or transfection with Hsp90 cysteine 521 (Cys521) mutation plasmid decreased the level of SNO-Hsp90 in oxLDL-cultured ECs. Coimmunoprecipitation and proximity ligation assay demonstrated that SNO-Hsp90 at Cys521 suppressed the interaction between Hsp90 and activator of Hsp90 ATPase activity 1 (AHA1), but promoted the association of Hsp90 and cell division cycle 37 (CDC37). Hsp90 Cys521 mutation increased endothelial nitric oxide synthase (eNOS) activity and inhibited nuclear factor kappa-B (NF-κB) signaling, thereby increasing nitric oxide (NO) bioavailability and alleviating endothelial adhesion, inflammation and oxidative stress in oxLDL-treated ECs. Also, administration of endothelial-specific adeno-associated viruses of Cys521-mutated Hsp90 significantly mitigated vascular oxidative stress, macrophage infiltration and atherosclerosis lesion areas in high fat diet-fed ApoE-/- mice. In conclusion, SNO-Hsp90 at Cys521, that serves as a conformational switch, disrupts Hsp90/AHA1 interaction but promotes recruitment of CDC37 to exacerbate atherosclerosis.

Steroid receptor coactivator 3 (SRC-3) is a member of the p160 SRC family. This factor can interact with multiple nuclear hormone receptors and transcription factors to regulate the expression of their target genes. Although many physiological roles of SRC-3 have been revealed, its role in atherosclerosis is not clear. In this study, we found that SRC-3-/-ApoE-/- mice have reduced atherosclerotic lesions and necrotic areas in their aortas and aortic roots compared with SRC-3+/+ApoE-/- mice after Western diet (WD) feeding for 12 weeks. RNA-Seq and Western blot analyses of the aorta revealed that SRC-3 was required for maintaining the expression of ICAM-1, which was required for macrophage recruitment and atherosclerosis development. siRNA-mediated knockdown of SRC-3 in endothelial cells significantly reduced WD-induced atherosclerotic plaque formation. Additionally, treatment of ApoE-/- mice with SRC-3 inhibitor bufalin prevented atherosclerotic plaque development. SRC-3 deficiency reduced aortic macrophage recruitment. Accordingly, ICAM-1 expression was markedly decreased in the aortas of SRC-3-/-ApoE-/- mice and ApoE-/- mice with endothelial SRC-3 knockdown mediated by AAV9-shSRC-3 virus. Mechanistically, SRC-3 coactivated NF-κB p65 to increase ICAM-1 transcription in endothelial cells. Collectively, these findings demonstrate that inhibiting SRC-3 ameliorates atherosclerosis development, at least in part through suppressing endothelial activation by decreasing endothelial ICAM-1 expression via reducing NF-κB signaling.

Cardiac arrhythmias (CAs) are generally caused by disruption of the cardiac conduction system; interleukin-2 (IL-2) is a key player in the pathological process of CAs. This study aimed to investigate the molecular mechanism underlying the regulation of IL-2 and the sodium channel current of sodium voltage-gated channel beta subunit 3 (SCN3B) by miR-190a-5p in the progression of CAs. ELISA results suggested the concentration of peripheral blood serum IL-2 in patients with atrial fibrillation (AF) to be increased compared to that in normal controls; fluorescence in situ hybridization indicated that the expression of IL-2 in the cardiac tissues of patients with AF to be upregulated and that miR-190a-5p to be downregulated. Luciferase reporter assay, quantitative real-time-PCR, and whole-cell patch-clamp experiments confirmed the downregulation of IL-2 by miR-190a-5p and influence of the latter on the sodium current of SCN3B. Overall, miR-190a-5p suppressed the increase in SCN3B sodium current caused by endogenous IL-2, whereas miR-190a-5p inhibitor significantly reversed this effect. IL-2 was demonstrated to be directly regulated by miR-190a-5p. We, therefore, concluded that the miR-190a-5p/IL-2/SCN3B pathway could be involved in the pathogenesis of CAs and miR-190a-5p might acts as a potential protective factor in pathogenesis of CAs.

Abstract Background It is generally believed that the materials basis of traditional Chinese medicine (TCM) are chemical substances and their metabolites entering the systemic circulation or target organs. In this case, analyzing and screening the possible pharmacodynamic substances of drugs from the perspective of in vivo exposure might provide the basis or direction for network pharmacology, a powerful tool for exploring the bioactive components and potential targets of TCM. Based on these, this study aims to develop a novel strategy to quickly screen out the pharmacodynamic substances and mechanisms of TCM in diseases, and further applied it to the pharmacodynamic substances and action mechanism study of Sinomenii Caulis (SC) in treating myocardial infarction (MI). Methods Firstly, ultra-high performance liquid chromatography tandem high resolution mass spectrometry (UPLC-HRMS) technology was used to study the exposed components of SC in mice. According to the main exposed components, the key genes, proteins, and mechanisms of SC in MI were predicted by network pharmacology. Finally, the effects of SC and its main pharmacodynamic substances on MI were evaluated by building a model of MI in vivo, and the possible key proteins were docked and verified by molecular docking or western blotting. Results The analysis of substances exposed in vivo revealed that the main exposed substances in mice were sinomenine, magnoflorine, menisperine, and their metabolites. Network pharmacology and molecular docking, combined with exposure to substances of SC in vivo, revealed that sinomenine was the potential pharmacodynamic substance of SC. By establishing a mouse model of MI in vivo, it was found that sinomenine had the same therapeutic effect on MI as SC containing the same dose of sinomenine. By western blotting and molecular docking, sinomenine was found to play a therapeutic role by inhibiting AKT phosphorylation. Conclusions The study indicates that the rational combination of exposure research in vivo and network pharmacology might be beneficial to discover the pharmacodynamic substances and their mechanisms of TCM. Meanwhile, this is a pioneer report that sinomenine, the main exposed substance of SC, had the same therapeutic effect on MI as SC containing the same dose of and inhibited AKT phosphorylation.

The precise control of cardiomyocyte viability is imperative to combat myocardial ischemia-reperfusion injury (I/R), in which apoptosis and pyroptosis putatively contribute to the process. Recent researches indicated that GSDMD is involved in I/R as an executive protein of pyroptosis. However, its effect on other forms of cell death is unclear. We identified that GSDMD and GSDMD-N levels were significantly upregulated in the I/R myocardium of mice. Knockout of GSDMD conferred the resistance of the hearts to reperfusion injury in the acute phase of I/R but aggravated reperfusion injury in the chronic phase of I/R. Mechanistically, GSDMD deficiency induced the activation of PARylation and the consumption of NAD(+) and ATP, leading to cardiomyocyte apoptosis. Moreover, PJ34, a putative PARP-1 inhibitor, reduced the myocardial injury caused by GSDMD deficiency. Our results reveal a novel action modality of GSDMD in the regulation of cardiomyocyte death; inhibition of GSDMD activates PARylation, suggesting the multidirectional role of GSDMD in I/R and providing a new theory for clinical treatment.

Objective: To investigate the genetic characteristics and transcriptional regulation of the SCN5A gene of Brugada syndrome (BrS) patients in China. Methods: Using PubMed, Medline, China National Knowledge Internet (CNKI), and Wanfang Database, Chinese patients with BrS who underwent SCN5A gene testing were studied. Results: A total of 27 suitable studies involving Chinese BrS patients who underwent the SCN5A gene test were included. A total of 55 SCN5A gene mutations/variations were reported in Chinese BrS patients, including 10 from southern China and 45 from northern China. Mutations/variations of BrS patients from southern China mostly occurred in the regions of the α-subunit of Nav1.5, including DIII (Domain III), DIV, DIII-DIV, C-terminus regions, and the 3'UTR region. Furthermore, we analyzed the post-transcriptional modifications (PTMs) throughout the Nav1.5 protein encoded by SCN5A and found that the PTM changes happened in 72.7% of BrS patients from southern China and 26.7% from northern China. Conclusions: SCN5A mutations/variations of BrS patients in southern China mostly occurred in the DIII-DIV to C-terminus region and the 3'-UTR region of the SCN5A gene, different from northern China. PTM changes were consistent with the mutation/variation distribution of SCN5A, which might be involved in the regulation of the pathogenesis of BrS patients.