Circulation最新文献

{"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":"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 in 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>_interaction<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":" ","pages":"1931-1943"},"PeriodicalIF":35.5,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11627316/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Precision Medicine in People at Risk for Diabetes and Atherosclerotic Cardiovascular Disease: A Fresh Perspective on Prevention.","authors":"Andreas L Birkenfeld, Paul W Franks, Viswanathan Mohan","doi":"10.1161/CIRCULATIONAHA.124.070463","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.124.070463","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"150 24","pages":"1910-1912"},"PeriodicalIF":35.5,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799437","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":"A Polygenic Predictor of Baseline QTc is Associated With Sotalol-Induced QT Prolongation.","authors":"Megan C Lancaster, Giovanni Davogustto, Edi Prifti, Claire Perret, Christian Funck-Brentano, Dan M Roden, Joe-Elie Salem","doi":"10.1161/CIRCULATIONAHA.124.070337","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.124.070337","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"150 24","pages":"1984-1986"},"PeriodicalIF":35.5,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799494","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":"Inositol 1,4,5-Trisphosphate Receptor 1 Gain-of-Function Increases the Risk for Cardiac Arrhythmias in Mice and Humans.","authors":"Bo Sun, Mingke Ni, Yanhui Li, Zhenpeng Song, Hui Wang, Hai-Lei Zhu, Jinhong Wei, Darrell Belke, Shitian Cai, Wenting Guo, Jinjing Yao, Shanshan Tian, John Paul Estillore, Ruiwu Wang, Mads Toft Sondergaard, Malene Brohus, Palle Duun Rohde, Yongxin Mu, Alexander Vallmitjana, Raul Benitez, Leif Hove-Madsen, Michael Toft Overgaard, Glenn I Fishman, Ju Chen, Shubhayan Sanatani, Arthur A M Wilde, Michael Fill, Josefina Ramos-Franco, Mette Nyegaard, S R Wayne Chen","doi":"10.1161/CIRCULATIONAHA.124.070563","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.124.070563","url":null,"abstract":"<p><strong>Background: </strong>Ca²⁺ mishandling in cardiac Purkinje cells is a well-known cause of cardiac arrhythmias. The Purkinje cell resident inositol 1,4,5-trisphosphate receptor 1 (ITPR1) is believed to play an important role in Ca²⁺ handling, and ITPR1 gain-of-function (GOF) has been implicated in cardiac arrhythmias. However, nearly all known disease-associated ITPR1 variants are loss-of-function and are primarily linked to neurological disorders. Whether ITPR1 GOF has pathological consequences, such as cardiac arrhythmias, is unclear. This study aimed to identify human ITPR1 GOF variants and determine the impact of ITPR1 GOF on Ca²⁺ handling and arrhythmia susceptibility.</p><p><strong>Methods: </strong>There are a large number of rare ITPR1 missense variants reported in open data repositories. Based on their locations in the ITPR1 channel structure, we selected and characterized 33 human ITPR1 missense variants from open databases and identified 21 human ITPR1 GOF variants. We generated a mouse model carrying a human ITPR1 GOF variant, ITPR1-W1457G (W1447G in mice).</p><p><strong>Results: </strong>We showed that the ITPR1-W1447G^± and recently reported ITPR1-D2594K^± GOF mutant mice were susceptible to stress-induced ventricular arrhythmias. Confocal Ca²⁺ and voltage imaging in situ in heart slices and Ca²⁺ imaging and patch-clamp recordings of isolated Purkinje cells showed that ITPR1-W1447G^± and ITPR1-D2594K^± variants increased the occurrence of stress-induced spontaneous Ca²⁺ release, delayed afterdepolarization, and triggered activity in Purkinje cells. To assess the potential role of ITPR1 variants in arrhythmia susceptibility in humans, we looked up a gene-based association study in the UK Biobank data set and identified 7 rare ITPR1 missense variants showing potential association with cardiac arrhythmias. Remarkably, in vitro functional characterization revealed that all these 7 ITPR1 variants resulted in GOF.</p><p><strong>Conclusions: </strong>Our studies in mice and humans reveal that enhanced function of ITPR1, a well-known movement disorder gene, increases the risk for cardiac arrhythmias.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":""},"PeriodicalIF":35.5,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799421","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":"Left Ventricular Ejection Fraction and Implantable Cardioverter-Defibrillator in Non-ischemic Heart Failure with Reduced Ejection Fraction: Insights from DANISH.","authors":"Seiko N Doi, Jawad H Butt, Jens Jakob Thune, Jens C Nielsen, Jens Haarbo, Niels E Bruun, Line L Olesen, Lars Videbæk, Finn Gustafsson, Hans Eiskjær, Christian Hassager, Jesper H Svendsen, Dan E Høfsten, Steen Pehrson, Lars Køber","doi":"10.1161/CIRCULATIONAHA.124.071777","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.124.071777","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":""},"PeriodicalIF":35.5,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142806350","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":"Scientific and Clinical Impacts of UK Biobank in Cardiovascular Medicine.","authors":"Adam J Lewandowski, Martin K Rutter, Rory Collins","doi":"10.1161/CIRCULATIONAHA.124.072449","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.124.072449","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"150 24","pages":"1907-1909"},"PeriodicalIF":35.5,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799439","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":"Letter by Huang et al Regarding Article, \"Atherosclerosis Is a Smooth Muscle Cell-Driven Tumor-Like Disease\".","authors":"Huixin Huang, Xuqi Yang, Kai Yang","doi":"10.1161/CIRCULATIONAHA.124.070427","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.124.070427","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"150 24","pages":"e517-e518"},"PeriodicalIF":35.5,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799433","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":"Cognitive Dysfunction in Heart Failure With Preserved Ejection Fraction: Uncovering the Consequences of an Overlooked Comorbidity.","authors":"Jesús Álvarez-García","doi":"10.1161/CIRCULATIONAHA.124.072220","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.124.072220","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"150 24","pages":"1928-1930"},"PeriodicalIF":35.5,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799506","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":"Low Penetrance Sarcomere Variants Contribute to Additive Risk in Hypertrophic Cardiomyopathy.","authors":"Joshua K Meisner, Aaron Renberg, Eric D Smith, Yao-Chang Tsan, Brynn Elder, Abbey Bullard, Owen Merritt, Sean L Zheng, Neal Lakdawala, Anjali Owens, Thomas D Ryan, Erin M Miller, Joseph Rossano, Kimberly Y Lin, Brian Claggett, Euan Ashley, Michelle Michels, Rachel Lampert, John C Stendahl, Dominic Abrahams, Christopher Semsarian, Victoria N Parikh, Matthew Wheeler, Jodie Ingles, Sharlene M Day, Sara Saberi, Mark W Russell, Michael Previs, Carolyn Ho, James S Ware, Adam S Helms","doi":"10.1161/CIRCULATIONAHA.124.069398","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.124.069398","url":null,"abstract":"<p><strong>Background: </strong>Classically, hypertrophic cardiomyopathy (HCM) has been viewed as a single-gene (monogenic) disease caused by pathogenic variants in sarcomere genes. Pathogenic sarcomere variants are individually rare and convey high risk for developing HCM (highly penetrant). Recently, important polygenic contributions have also been characterized. Low penetrance sarcomere variants (LowSVs) at intermediate frequencies and effect sizes have not been systematically investigated. We hypothesize that LowSVs may be common in HCM with substantial influence on disease risk and severity.</p><p><strong>Methods: </strong>Among all sarcomere variants observed in the Sarcomeric Human Cardiomyopathy Registry (SHaRe), we identified putative LowSVs defined by (1) population frequency greater than expected for highly penetrant (monogenic) HCM (allele frequency >5×10^-5 in the Genome Aggregation Database, gnomAD) and (2) moderate enrichment (>2×) in patients with HCM compared with gnomAD. LowSVs were examined for their association with disease severity and clinical outcomes. Functional effects of selected LowSVs were assessed using induced pluripotent stem cell-derived cardiomyocytes. Association of LowSVs with HCM-adjacent traits in the general population was tested using UK Biobank cardiac magnetic resonance imaging data.</p><p><strong>Results: </strong>Among 6045 patients and 1159 unique variants in sarcomere genes, 12 LowSVs were identified. LowSVs were collectively common in the general population (1:350) and moderately enriched in HCM (aggregate odds ratio, 14.9 [95% CI, 12.5-17.9]). Isolated LowSVs were associated with an older age of HCM diagnosis and fewer adverse events. However, LowSVs in combination with a pathogenic sarcomere variant conferred higher morbidity (eg, composite adverse event hazard ratio, 5.4 [95% CI, 3.0-9.8] versus single pathogenic sarcomere variant, 2.0 [95% CI, 1.8-2.2]; <i>P</i><0.001). An intermediate functional impact was validated for 2 specific LowSVs-<i>MYBPC3</i> c.442G>A (partial splice gain) and <i>TNNT2</i> c.832C>T (intermediate effect on contractile mechanics). Cardiac magnetic resonance imaging analysis of the general population revealed 5 of 12 LowSVs were significantly associated with HCM-adjacent traits without overt HCM.</p><p><strong>Conclusions: </strong>This study establishes a new class of low penetrance sarcomere variants that are relatively common in the population. When penetrant, isolated LowSVs cause mild HCM. In combination with pathogenic sarcomere variants, LowSVs markedly increase disease severity, supporting a clinically significant additive effect. Last, LowSVs also contribute to age-related remodeling even in the absence of overt HCM.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":""},"PeriodicalIF":35.5,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142779449","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":"Sickle Trait and Alpha Thalassemia Increase NOS-Dependent Vasodilation of Human Arteries Through Disruption of Endothelial Hemoglobin-eNOS Interactions.","authors":"Steven D Brooks, A Parker Ruhl, Xianke Zeng, Phillip Cruz, Sergio A Hassan, Olena Kamenyeva, Md Abdul Hakim, Lauryn A Ridley, Bianca M Nagata, Juraj Kabat, Sundar Ganesan, Rachel L Smith, Mary Jackson, Jessica Nino de Rivera, Alison J McLure, Jarrett M Jackson, Robert O Emeh, Naomi Tesfuzigta, Kyeisha Laurence, Stacy Joyce, Christina Yek, Sophana Chea, Derron A Alves, Brant E Isakson, Jessica Manning, Jeremy L Davis, Hans C Ackerman","doi":"10.1161/CIRCULATIONAHA.123.066003","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.123.066003","url":null,"abstract":"<p><strong>Background: </strong>Severe malaria is associated with impaired nitric oxide (NO) synthase (NOS)-dependent vasodilation, and reversal of this deficit improves survival in murine models. Malaria might have selected for genetic polymorphisms that increase endothelial NO signaling and now contribute to heterogeneity in vascular function among humans. One protein potentially selected for is alpha globin, which, in mouse models, interacts with endothelial NOS (eNOS) to negatively regulate NO signaling. We sought to evaluate the impact of alpha globin gene deletions on NO signaling and unexpectedly found human arteries use not only alpha but also beta globin to regulate eNOS.</p><p><strong>Methods: </strong>The eNOS-hemoglobin complex was characterized by multiphoton imaging, gene expression analysis, and coimmunoprecipitation studies of human resistance arteries. Novel contacts between eNOS and hemoglobin were mapped using molecular modeling and simulation. Pharmacological or genetic disruption of the eNOS-hemoglobin complex was evaluated using pressure myography. The association between alpha globin gene deletion and blood pressure was assessed in a population study.</p><p><strong>Results: </strong>Alpha and beta globin transcripts were detected in the endothelial layer of the artery wall. Imaging colocalized alpha and beta globin proteins with eNOS at myoendothelial junctions. Immunoprecipitation demonstrated that alpha globin and beta globin form a complex with eNOS and cytochrome b5 reductase. Modeling predicted negatively charged glutamic acids at positions 6 and 7 of beta globin to interact with positively charged arginines at positions 97 and 98 of eNOS. Arteries from donors with a glutamic acid-to-valine substitution at beta globin position 6 (sickle trait) exhibited increased NOS-dependent vasodilation. Alpha globin gene deletions were associated with decreased arterial alpha globin expression, increased NOS-dependent vasodilation, and lower blood pressure. Mimetic peptides that targeted the interactions between hemoglobin and eNOS recapitulated the effects of these genetic variants on human arterial vasoreactivity.</p><p><strong>Conclusions: </strong>Alpha and beta globin subunits of hemoglobin interact with eNOS to restrict NO signaling in human resistance arteries. Malaria-protective genetic variants that alter the expression of alpha globin or the structure of beta globin are associated with increased NOS-dependent vasodilation. Targeting the hemoglobin-eNOS interface could potentially improve NO signaling in diseases of endothelial dysfunction such as severe malaria or chronic cardiovascular conditions.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":""},"PeriodicalIF":35.5,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142779451","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}