Pub Date : 2024-09-23DOI: 10.1161/circulationaha.124.071021
Daniele Giacoppo,Claudio Laudani,Giovanni Occhipinti,Marco Spagnolo,Antonio Greco,Carla Rochira,Federica Agnello,Davide Landolina,Maria Sara Mauro,Simone Finocchiaro,Placido Maria Mazzone,Nicola Ammirabile,Antonino Imbesi,Carmelo Raffo,Sergio Buccheri,Davide Capodanno
{"title":"Response by Giacoppo et al to Letter Regarding Article \"Coronary Angiography, Intravascular Ultrasound, and Optical Coherence Tomography for Guiding of Percutaneous Coronary Intervention: A Systematic Review and Network Meta-Analysis\".","authors":"Daniele Giacoppo,Claudio Laudani,Giovanni Occhipinti,Marco Spagnolo,Antonio Greco,Carla Rochira,Federica Agnello,Davide Landolina,Maria Sara Mauro,Simone Finocchiaro,Placido Maria Mazzone,Nicola Ammirabile,Antonino Imbesi,Carmelo Raffo,Sergio Buccheri,Davide Capodanno","doi":"10.1161/circulationaha.124.071021","DOIUrl":"https://doi.org/10.1161/circulationaha.124.071021","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":null,"pages":null},"PeriodicalIF":37.8,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142324914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-23DOI: 10.1161/circulationaha.124.070368
Xinye Zhao,Thomas Williamson,Yanqing Gong,Jonathan A Epstein,Yi Fan
Ischemic heart disease is a leading cause of death worldwide, manifested clinically as myocardial infarction (and ischemic cardiomyopathy. Presently, there exists a notable scarcity of efficient interventions to restore cardiac function after myocardial infarction. Cumulative evidence suggests that impaired tissue immunity within the ischemic microenvironment aggravates cardiac dysfunction, contributing to progressive heart failure. Recent research breakthroughs propose immunotherapy as a potential approach by leveraging immune and stroma cells to recalibrate the immune microenvironment, holding significant promise for the treatment of ischemic heart disease. In this Primer, we highlight three emerging strategies for immunomodulatory therapy in managing ischemic cardiomyopathy: targeting vascular endothelial cells to rewire tissue immunity, reprogramming myeloid cells to bolster their reparative function, and utilizing adoptive T cell therapy to ameliorate fibrosis. We anticipate that immunomodulatory therapy will offer exciting opportunities for ischemic heart disease treatment.
缺血性心脏病是全球死亡的主要原因，临床表现为心肌梗塞（和缺血性心肌病）。目前，心肌梗塞后恢复心脏功能的有效干预措施明显不足。累积的证据表明，缺血微环境中受损的组织免疫会加重心脏功能障碍，导致进行性心力衰竭。最近的研究突破提出免疫疗法是一种潜在的方法，它利用免疫细胞和基质细胞重新调整免疫微环境，为缺血性心脏病的治疗带来了巨大希望。在这篇《入门》中，我们将重点介绍治疗缺血性心肌病的三种新兴免疫调节疗法策略：以血管内皮细胞为靶点重构组织免疫；对髓样细胞进行重编程以增强其修复功能；以及利用收养 T 细胞疗法改善纤维化。我们预计，免疫调节疗法将为缺血性心脏病的治疗提供令人兴奋的机会。
{"title":"Immunomodulatory Therapy for Ischemic Heart Disease.","authors":"Xinye Zhao,Thomas Williamson,Yanqing Gong,Jonathan A Epstein,Yi Fan","doi":"10.1161/circulationaha.124.070368","DOIUrl":"https://doi.org/10.1161/circulationaha.124.070368","url":null,"abstract":"Ischemic heart disease is a leading cause of death worldwide, manifested clinically as myocardial infarction (and ischemic cardiomyopathy. Presently, there exists a notable scarcity of efficient interventions to restore cardiac function after myocardial infarction. Cumulative evidence suggests that impaired tissue immunity within the ischemic microenvironment aggravates cardiac dysfunction, contributing to progressive heart failure. Recent research breakthroughs propose immunotherapy as a potential approach by leveraging immune and stroma cells to recalibrate the immune microenvironment, holding significant promise for the treatment of ischemic heart disease. In this Primer, we highlight three emerging strategies for immunomodulatory therapy in managing ischemic cardiomyopathy: targeting vascular endothelial cells to rewire tissue immunity, reprogramming myeloid cells to bolster their reparative function, and utilizing adoptive T cell therapy to ameliorate fibrosis. We anticipate that immunomodulatory therapy will offer exciting opportunities for ischemic heart disease treatment.","PeriodicalId":10331,"journal":{"name":"Circulation","volume":null,"pages":null},"PeriodicalIF":37.8,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142324915","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-23DOI: 10.1161/CIRCULATIONAHA.124.070870
Gregg W Stone, JoAnn Lindenfeld, Josep Rodés-Cabau, Stefan D Anker, Michael R Zile, Saibal Kar, Richard Holcomb, Michael P Pfeiffer, Antoni Bayes-Genis, Jeroen J Bax, Alan J Bank, Maria Rosa Costanzo, Stefan Verheye, Ariel Roguin, Gerasimos Filippatos, Julio Núñez, Elizabeth C Lee, Michal Laufer-Perl, Gil Moravsky, Sheldon E Litwin, Edgard Prihadi, Hemal Gada, Eugene S Chung, Matthew J Price, Vinay Thohan, Dimitry Schewel, Sachin Kumar, Stephan Kische, Kevin S Shah, Daniel J Donovan, Yiran Zhang, Neal L Eigler, William T Abraham
Background: An interatrial shunt may provide an autoregulatory mechanism to decrease left atrial pressure and improve heart failure (HF) symptoms and prognosis.
Methods: Patients with symptomatic HF with any left ventricular ejection fraction (LVEF) were randomized 1:1 to transcatheter shunt implantation versus a placebo procedure, stratified by reduced (≤40%) versus preserved (>40%) LVEF. The primary safety outcome was a composite of device-related or procedure-related major adverse cardiovascular or neurological events at 30 days compared with a prespecified performance goal of 11%. The primary effectiveness outcome was the hierarchical composite ranking of all-cause death, cardiac transplantation or left ventricular assist device implantation, HF hospitalization, outpatient worsening HF events, and change in quality of life from baseline measured by the Kansas City Cardiomyopathy Questionnaire overall summary score through maximum 2-year follow-up, assessed when the last enrolled patient reached 1-year follow-up, expressed as the win ratio. Prespecified hypothesis-generating analyses were performed on patients with reduced and preserved LVEF.
Results: Between October 24, 2018, and October 19, 2022, 508 patients were randomized at 94 sites in 11 countries to interatrial shunt treatment (n=250) or a placebo procedure (n=258). Median (25th and 75th percentiles) age was 73.0 years (66.0, 79.0), and 189 patients (37.2%) were women. Median LVEF was reduced (≤40%) in 206 patients (40.6%) and preserved (>40%) in 302 patients (59.4%). No primary safety events occurred after shunt implantation (upper 97.5% confidence limit, 1.5%; P<0.0001). There was no difference in the 2-year primary effectiveness outcome between the shunt and placebo procedure groups (win ratio, 0.86 [95% CI, 0.61-1.22]; P=0.20). However, patients with reduced LVEF had fewer adverse cardiovascular events with shunt treatment versus placebo (annualized rate 49.0% versus 88.6%; relative risk, 0.55 [95% CI, 0.42-0.73]; P<0.0001), whereas patients with preserved LVEF had more cardiovascular events with shunt treatment (annualized rate 60.2% versus 35.9%; relative risk, 1.68 [95% CI, 1.29-2.19]; P=0.0001; Pinteraction<0.0001). There were no between-group differences in change in Kansas City Cardiomyopathy Questionnaire overall summary score during follow-up in all patients or in those with reduced or preserved LVEF.
Conclusions: Transcatheter interatrial shunt implantation was safe but did not improve outcomes in patients with HF. However, the results from a prespecified exploratory analysis in stratified randomized groups suggest that shunt implantation is beneficial in patients with reduced LVEF and harmful in patients with preserved LVEF.
{"title":"Interatrial Shunt Treatment for Heart Failure: The Randomized RELIEVE-HF Trial.","authors":"Gregg W Stone, JoAnn Lindenfeld, Josep Rodés-Cabau, Stefan D Anker, Michael R Zile, Saibal Kar, Richard Holcomb, Michael P Pfeiffer, Antoni Bayes-Genis, Jeroen J Bax, Alan J Bank, Maria Rosa Costanzo, Stefan Verheye, Ariel Roguin, Gerasimos Filippatos, Julio Núñez, Elizabeth C Lee, Michal Laufer-Perl, Gil Moravsky, Sheldon E Litwin, Edgard Prihadi, Hemal Gada, Eugene S Chung, Matthew J Price, Vinay Thohan, Dimitry Schewel, Sachin Kumar, Stephan Kische, Kevin S Shah, Daniel J Donovan, Yiran Zhang, Neal L Eigler, William T Abraham","doi":"10.1161/CIRCULATIONAHA.124.070870","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.124.070870","url":null,"abstract":"<p><strong>Background: </strong>An interatrial shunt may provide an autoregulatory mechanism to decrease left atrial pressure and improve heart failure (HF) symptoms and prognosis.</p><p><strong>Methods: </strong>Patients with symptomatic HF with any left ventricular ejection fraction (LVEF) were randomized 1:1 to transcatheter shunt implantation versus a placebo procedure, stratified by reduced (≤40%) versus preserved (>40%) LVEF. The primary safety outcome was a composite of device-related or procedure-related major adverse cardiovascular or neurological events at 30 days compared with a prespecified performance goal of 11%. The primary effectiveness outcome was the hierarchical composite ranking of all-cause death, cardiac transplantation or left ventricular assist device implantation, HF hospitalization, outpatient worsening HF events, and change in quality of life from baseline measured by the Kansas City Cardiomyopathy Questionnaire overall summary score through maximum 2-year follow-up, assessed when the last enrolled patient reached 1-year follow-up, expressed as the win ratio. Prespecified hypothesis-generating analyses were performed on patients with reduced and preserved LVEF.</p><p><strong>Results: </strong>Between October 24, 2018, and October 19, 2022, 508 patients were randomized at 94 sites in 11 countries to interatrial shunt treatment (n=250) or a placebo procedure (n=258). Median (25th and 75th percentiles) age was 73.0 years (66.0, 79.0), and 189 patients (37.2%) were women. Median LVEF was reduced (≤40%) in 206 patients (40.6%) and preserved (>40%) in 302 patients (59.4%). No primary safety events occurred after shunt implantation (upper 97.5% confidence limit, 1.5%; <i>P</i><0.0001). There was no difference in the 2-year primary effectiveness outcome between the shunt and placebo procedure groups (win ratio, 0.86 [95% CI, 0.61-1.22]; <i>P</i>=0.20). However, patients with reduced LVEF had fewer adverse cardiovascular events with shunt treatment versus placebo (annualized rate 49.0% versus 88.6%; relative risk, 0.55 [95% CI, 0.42-0.73]; <i>P</i><0.0001), whereas patients with preserved LVEF had more cardiovascular events with shunt treatment (annualized rate 60.2% versus 35.9%; relative risk, 1.68 [95% CI, 1.29-2.19]; <i>P</i>=0.0001; <i>P</i><sub>interaction</sub><0.0001). There were no between-group differences in change in Kansas City Cardiomyopathy Questionnaire overall summary score during follow-up in all patients or in those with reduced or preserved LVEF.</p><p><strong>Conclusions: </strong>Transcatheter interatrial shunt implantation was safe but did not improve outcomes in patients with HF. However, the results from a prespecified exploratory analysis in stratified randomized groups suggest that shunt implantation is beneficial in patients with reduced LVEF and harmful in patients with preserved LVEF.</p><p><strong>Registration: </strong>URL: https://www.clinicaltrials.gov; Unique identifier: NCT03499236.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":null,"pages":null},"PeriodicalIF":35.5,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142281280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-23DOI: 10.1161/circulationaha.124.068242
Sradha S Kotwal,Vlado Perkovic
{"title":"Kidney Disease as a Cardiovascular Disease Priority.","authors":"Sradha S Kotwal,Vlado Perkovic","doi":"10.1161/circulationaha.124.068242","DOIUrl":"https://doi.org/10.1161/circulationaha.124.068242","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":null,"pages":null},"PeriodicalIF":37.8,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142324916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-23DOI: 10.1161/circulationaha.124.071344
Brittany Weber,Antonio Abbate
{"title":"Colchicine and Atherothrombosis: Another Piece of the Puzzle.","authors":"Brittany Weber,Antonio Abbate","doi":"10.1161/circulationaha.124.071344","DOIUrl":"https://doi.org/10.1161/circulationaha.124.071344","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":null,"pages":null},"PeriodicalIF":37.8,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142324873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"ECG Changes in a Patient With Recurrent Palpitations.","authors":"Kapil Rajendran,Arun Jude Alphonse,Vinayakumar Desabandhu","doi":"10.1161/circulationaha.124.071468","DOIUrl":"https://doi.org/10.1161/circulationaha.124.071468","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":null,"pages":null},"PeriodicalIF":37.8,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142324874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-23DOI: 10.1161/circulationaha.124.069731
Zaiyong Zhang
{"title":"Letter by Zhang Regarding Article, \"Coronary Angiography, Intravascular Ultrasound, and Optical Coherence Tomography for Guiding of Percutaneous Coronary Intervention: A Systematic Review and Network Meta-Analysis\".","authors":"Zaiyong Zhang","doi":"10.1161/circulationaha.124.069731","DOIUrl":"https://doi.org/10.1161/circulationaha.124.069731","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":null,"pages":null},"PeriodicalIF":37.8,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142324875","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-23DOI: 10.1161/circulationaha.124.069857
Andrea Bellavia,Sabina A Murphy
{"title":"Heterogeneity of Treatment Effects in Clinical Trials: Overview of Multivariable Approaches and Practical Recommendations.","authors":"Andrea Bellavia,Sabina A Murphy","doi":"10.1161/circulationaha.124.069857","DOIUrl":"https://doi.org/10.1161/circulationaha.124.069857","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":null,"pages":null},"PeriodicalIF":37.8,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142324918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-19DOI: 10.1161/cir.0000000000001282
Teresa L May,Erin A Bressler,Rebecca E Cash,Francis X Guyette,Steve Lin,Nicholas A Morris,Ashish R Panchal,Stacy M Perrin,Melissa Vogelsong,Joyce Yeung,Jonathan Elmer,
People who experience out-of-hospital cardiac arrest often require care at a regional center for continued treatment after resuscitation, but many do not initially present to the hospital where they will be admitted. For patients who require interfacility transport after cardiac arrest, the decision to transfer between centers is complex and often based on individual clinical characteristics, resources at the presenting hospital, and available transport resources. Once the decision has been made to transfer a patient after cardiac arrest, there is little direct guidance on how best to provide interfacility transport. Accepting centers depend on transferring emergency departments and emergency medical services professionals to make important and nuanced decisions about postresuscitation care that may determine the efficacy of future treatments. The consequences of early care are greater when transport delays occur, which is common in rural areas or due to inclement weather. Challenges of providing interfacility transfer services for patients who have experienced cardiac arrest include varying expertise of clinicians, differing resources available to them, and nonstandardized communication between transferring and receiving centers. Although many aspects of care are insufficiently studied to determine implications for specific out-of-hospital treatment on outcomes, a general approach of maintaining otherwise recommended postresuscitation care during interfacility transfer is reasonable. This includes close attention to airway, vascular access, ventilator management, sedation, cardiopulmonary monitoring, antiarrhythmic treatments, blood pressure control, temperature control, and metabolic management. Patient stability for transfer, equity and inclusion, and communication also must be considered. Many of these aspects can be delivered by protocol-driven care.
{"title":"Management of Patients With Cardiac Arrest Requiring Interfacility Transport: A Scientific Statement From the American Heart Association.","authors":"Teresa L May,Erin A Bressler,Rebecca E Cash,Francis X Guyette,Steve Lin,Nicholas A Morris,Ashish R Panchal,Stacy M Perrin,Melissa Vogelsong,Joyce Yeung,Jonathan Elmer,","doi":"10.1161/cir.0000000000001282","DOIUrl":"https://doi.org/10.1161/cir.0000000000001282","url":null,"abstract":"People who experience out-of-hospital cardiac arrest often require care at a regional center for continued treatment after resuscitation, but many do not initially present to the hospital where they will be admitted. For patients who require interfacility transport after cardiac arrest, the decision to transfer between centers is complex and often based on individual clinical characteristics, resources at the presenting hospital, and available transport resources. Once the decision has been made to transfer a patient after cardiac arrest, there is little direct guidance on how best to provide interfacility transport. Accepting centers depend on transferring emergency departments and emergency medical services professionals to make important and nuanced decisions about postresuscitation care that may determine the efficacy of future treatments. The consequences of early care are greater when transport delays occur, which is common in rural areas or due to inclement weather. Challenges of providing interfacility transfer services for patients who have experienced cardiac arrest include varying expertise of clinicians, differing resources available to them, and nonstandardized communication between transferring and receiving centers. Although many aspects of care are insufficiently studied to determine implications for specific out-of-hospital treatment on outcomes, a general approach of maintaining otherwise recommended postresuscitation care during interfacility transfer is reasonable. This includes close attention to airway, vascular access, ventilator management, sedation, cardiopulmonary monitoring, antiarrhythmic treatments, blood pressure control, temperature control, and metabolic management. Patient stability for transfer, equity and inclusion, and communication also must be considered. Many of these aspects can be delivered by protocol-driven care.","PeriodicalId":10331,"journal":{"name":"Circulation","volume":null,"pages":null},"PeriodicalIF":37.8,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142246858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-18DOI: 10.1161/circulationaha.124.069329
Jinxi Wang,Biyi Chen,Qian Shi,Grace Ciampa,Weiyang Zhao,Guangqin Zhang,Robert M Weiss,Tianqing Peng,Duane D Hall,Long-Sheng Song
BACKGROUNDExcitation-contraction (E-C) coupling processes become disrupted in heart failure (HF), resulting in abnormal Ca2+ homeostasis, maladaptive structural and transcriptional remodeling, and cardiac dysfunction. Junctophilin-2 (JP2) is an essential component of the E-C coupling apparatus but becomes site-specifically cleaved by calpain, leading to disruption of E-C coupling, plasmalemmal transverse tubule degeneration, abnormal Ca2+ homeostasis, and HF. However, it is not clear whether preventing site-specific calpain cleavage of JP2 is sufficient to protect the heart against stress-induced pathological cardiac remodeling in vivo.METHODSCalpain-resistant JP2 knock-in mice (JP2CR) were generated by deleting the primary JP2 calpain cleavage site. Stress-dependent JP2 cleavage was assessed through in vitro cleavage assays and in isolated cardiomyocytes treated with 1 μmol/L isoproterenol by immunofluorescence. Cardiac outcomes were assessed in wild-type and JP2CR mice 5 weeks after transverse aortic constriction compared with sham surgery using echocardiography, histology, and RNA-sequencing methods. E-C coupling efficiency was measured by in situ confocal microscopy. E-C coupling proteins were evaluated by calpain assays and Western blotting. The effectiveness of adeno-associated virus gene therapy with JP2CR, JP2, or green fluorescent protein to slow HF progression was evaluated in mice with established cardiac dysfunction.RESULTSJP2 proteolysis by calpain and in response to transverse aortic constriction and isoproterenol was blocked in JP2CR cardiomyocytes. JP2CR hearts are more resistant to pressure-overload stress, having significantly improved Ca2+ homeostasis and transverse tubule organization with significantly attenuated cardiac dysfunction, hypertrophy, lung edema, fibrosis, and gene expression changes relative to wild-type mice. JP2CR preserves the integrity of calpain-sensitive E-C coupling-related proteins, including ryanodine receptor 2, CaV1.2, and sarcoplasmic reticulum calcium ATPase 2a, by attenuating transverse aortic constriction-induced increases in calpain activity. Furthermore, JP2CR gene therapy after the onset of cardiac dysfunction was found to be effective at slowing the progression of HF and superior to wild-type JP2.CONCLUSIONSThe data presented here demonstrate that preserving JP2-dependent E-C coupling by prohibiting the site-specific calpain cleavage of JP2 offers multifaceted beneficial effects, conferring cardiac protection against stress-induced proteolysis, hypertrophy, and HF. Our data also indicate that specifically targeting the primary calpain cleavage site of JP2 by gene therapy approaches holds great therapeutic potential as a novel precision medicine for treating HF.
{"title":"Preventing Site-Specific Calpain Proteolysis of Junctophilin-2 Protects Against Stress-Induced Excitation-Contraction Uncoupling and Heart Failure Development.","authors":"Jinxi Wang,Biyi Chen,Qian Shi,Grace Ciampa,Weiyang Zhao,Guangqin Zhang,Robert M Weiss,Tianqing Peng,Duane D Hall,Long-Sheng Song","doi":"10.1161/circulationaha.124.069329","DOIUrl":"https://doi.org/10.1161/circulationaha.124.069329","url":null,"abstract":"BACKGROUNDExcitation-contraction (E-C) coupling processes become disrupted in heart failure (HF), resulting in abnormal Ca2+ homeostasis, maladaptive structural and transcriptional remodeling, and cardiac dysfunction. Junctophilin-2 (JP2) is an essential component of the E-C coupling apparatus but becomes site-specifically cleaved by calpain, leading to disruption of E-C coupling, plasmalemmal transverse tubule degeneration, abnormal Ca2+ homeostasis, and HF. However, it is not clear whether preventing site-specific calpain cleavage of JP2 is sufficient to protect the heart against stress-induced pathological cardiac remodeling in vivo.METHODSCalpain-resistant JP2 knock-in mice (JP2CR) were generated by deleting the primary JP2 calpain cleavage site. Stress-dependent JP2 cleavage was assessed through in vitro cleavage assays and in isolated cardiomyocytes treated with 1 μmol/L isoproterenol by immunofluorescence. Cardiac outcomes were assessed in wild-type and JP2CR mice 5 weeks after transverse aortic constriction compared with sham surgery using echocardiography, histology, and RNA-sequencing methods. E-C coupling efficiency was measured by in situ confocal microscopy. E-C coupling proteins were evaluated by calpain assays and Western blotting. The effectiveness of adeno-associated virus gene therapy with JP2CR, JP2, or green fluorescent protein to slow HF progression was evaluated in mice with established cardiac dysfunction.RESULTSJP2 proteolysis by calpain and in response to transverse aortic constriction and isoproterenol was blocked in JP2CR cardiomyocytes. JP2CR hearts are more resistant to pressure-overload stress, having significantly improved Ca2+ homeostasis and transverse tubule organization with significantly attenuated cardiac dysfunction, hypertrophy, lung edema, fibrosis, and gene expression changes relative to wild-type mice. JP2CR preserves the integrity of calpain-sensitive E-C coupling-related proteins, including ryanodine receptor 2, CaV1.2, and sarcoplasmic reticulum calcium ATPase 2a, by attenuating transverse aortic constriction-induced increases in calpain activity. Furthermore, JP2CR gene therapy after the onset of cardiac dysfunction was found to be effective at slowing the progression of HF and superior to wild-type JP2.CONCLUSIONSThe data presented here demonstrate that preserving JP2-dependent E-C coupling by prohibiting the site-specific calpain cleavage of JP2 offers multifaceted beneficial effects, conferring cardiac protection against stress-induced proteolysis, hypertrophy, and HF. Our data also indicate that specifically targeting the primary calpain cleavage site of JP2 by gene therapy approaches holds great therapeutic potential as a novel precision medicine for treating HF.","PeriodicalId":10331,"journal":{"name":"Circulation","volume":null,"pages":null},"PeriodicalIF":37.8,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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