Circulation最新文献

{"title":"Complete vs. Culprit-Only Revascularization in Older Patients with ST-segment Elevation Myocardial Infarction: An Individual Patient Meta-Analysis.","authors":"Gianluca Campo, Feix Böhm, Thomas Engstrøm, Pieter C Smits, Islam Y Elgendy, Gerry McCann, David Wood, Matteo Serenelli, Stefan James, Dan Eik Høfsten, Bianca Boxma-de Klerk, Adrian Banning, John A Cairns, Rita Pavasini, Goran Stankovic, Petr Kala, Henning Kelbæk, Emanuele Barbato, Ilija Srdanovic, Mohamed Hamza, Amerjeet S Banning, Simone Biscaglia, Shamir Mehta","doi":"10.1161/CIRCULATIONAHA.124.071493","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.124.071493","url":null,"abstract":"<p><p><b>Background:</b> Complete revascularization is the standard treatment for patients with ST-segment elevation myocardial infarction (STEMI) and multivessel disease. The Functional Assessment in Elderly MI Patients with Multivessel Disease (FIRE) trial confirmed the benefit of complete revascularization in a population of older patients, but the follow-up is limited to 1 year. Therefore, the long-term benefit ( > 1-year) of this strategy in older patients is debated. To address this, an individual patient data meta-analysis was conducted in STEMI patients aged 75 years or older enrolled in randomized clinical trials investigating complete vs. culprit-only revascularization strategies. <b>Methods:</b> PubMed, Embase, and the Cochrane database, were systematically searched to identify randomized clinical trials comparing complete vs. culprit-only revascularization. Individual patient-level data were collected from the relevant trials. The primary endpoint was death, myocardial infarction (MI), or ischemia-driven revascularization. The secondary endpoint was cardiovascular death or myocardial infarction. <b>Results:</b> Data from seven RCTs, encompassing 1733 patients (917 randomized to culprit-only and 816 to complete revascularization), were analyzed. The median age was 79 [77-83] years. Females were 595 (34%). Follow-up ranged from a minimum of six months to a maximum of 6.2 years (median 2.5 [1-3.8] years). Complete revascularization reduced the primary endpoint up to four years (HR 0.78, 95%CI 0.63-0.96), but not at the longest available follow-up (HR 0.83, 95%CI 0.69-1.01). Complete revascularization significantly reduced the occurrence of cardiovascular death or MI at the longest available follow-up (HR 0.76, 95%CI 0.58-0.99). This was observed even when censoring the follow-up at each year. Long-term rate of death did not differ between complete and culprit-only revascularization arms. <b>Conclusions:</b> In this individual patient data meta-analysis of older STEMI patients with multivessel disease, complete revascularization reduced the primary endpoint of death, MI or ischemia-driven revascularization up to 4-year. At the longest follow-up, complete revascularization reduced the composite of cardiovascular death or MI, but not the primary endpoint. <b>Clinical Study Registration:</b> PROSPERO CRD42022367898.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":null,"pages":null},"PeriodicalIF":35.5,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104924","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":"Therapeutic Effects of Heart Failure Medical Therapies on Standardized Kidney Outcomes: Comprehensive Individual Participant-Level Analysis of 6 Randomized Clinical Trials.","authors":"Jawad H Butt, John Jv McMurray, Brian L Claggett, Pardeep S Jhund, Brendon L Neuen, Finnian Mc Causland, Akshay Desai, Carolyn Sp Lam, Bertram Pitt, Marc A Pfeffer, Milton Packer, Iris Beldhuis, Adriaan A Voors, Faiez Zannad, Hiddo Jl Heerspink, Scott D Solomon, Muthiah Vaduganathan","doi":"10.1161/CIRCULATIONAHA.124.071110","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.124.071110","url":null,"abstract":"<p><p><b>Background:</b> Kidney outcomes have been variably defined using non-standardized composite endpoints in key heart failure (HF) trials, thus introducing complexity in their interpretation and cross-trial comparability. We examined the effects of steroidal mineralocorticoid receptor antagonists (MRAs), the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan, and sodium-glucose cotransporter-2 (SGLT2) inhibitors on composite kidney endpoints using uniform definitions in 6 contemporary HF trials. <b>Methods:</b> Individual participant-level data from trials of steroidal MRAs (EMPHASIS-HF, TOPCAT Americas), ARNI (PARADIGM-HF, PARAGON-HF), and SGLT2 inhibitors (DAPA-HF, DELIVER) were included. The standardized composite kidney endpoint was defined as a sustained decline (a reduction in estimated glomerular filtration rate (eGFR) confirmed by a subsequent measurement at least 30 days later) in eGFR by 40%, 50%, or 57%, end-stage kidney disease, or renal death. eGFR was recalculated in a standardized manner using the 2009 Chronic Kidney Disease Epidemiology Collaboration creatinine equation. <b>Results:</b> Among 28,690 participants across the 6 trials (median age 69 years [IQR, 62-76]; 9,656 [33.7% ] women), the proportion experiencing the composite kidney endpoint with a more stringent definition of a sustained decline in kidney function (eGFR threshold of 57%) ranged from 0.3% to 3.3%. The proportion of patients experiencing this endpoint with a less stringent definition (eGFR threshold of 40%) ranged from 1.0% and 10.0%. The steroidal MRAs doubled the risk of the composite kidney endpoint when applying the least stringent definition compared with placebo, but these effects were less apparent and no longer significant with application of more stringent definitions. ARNI appeared to consistently reduce the occurrence of the composite kidney endpoints irrespective of specific eGFR threshold applied. The potential benefits of SGLT2-inhibitors on the composite kidney endpoints appeared more apparent when defined by more stringent eGFR thresholds, although none of these effects individually were statistically significant. <b>Conclusions:</b> When applying standardized stringent kidney endpoint definitions, steroidal MRAs, ARNI, and SGLT2-inhibitors have either neutral or beneficial effects on kidney outcomes in HF. Applying less stringent definitions increased event rates but included acute declines in eGFR that might not ultimately reflect long-term effects on kidney disease progression.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":null,"pages":null},"PeriodicalIF":35.5,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104929","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":"Zibotentan in Microvascular Angina: A Randomized, Placebo-Controlled, Crossover Trial.","authors":"Andrew Morrow, Robin Young, George R Abraham, Stephen Hoole, John P Greenwood, Jayanth Ranjit Arnold, Mohamed El Shibly, Mayooran Shanmuganathan, Vanessa Ferreira, Roby Rakhit, Gavin Galasko, Aish Sinha, Divaka Perera, Rasha Al-Lamee, Ioakim Spyridopoulos, Ashish Kotecha, Gerald Clesham, Thomas J Ford, Anthony Davenport, Sandosh Padmanabhan, Lisa Jolly, Peter Kellman, Juan Carlos Kaski, Robin A Weir, Naveed Sattar, Julie Kennedy, Peter W Macfarlane, Paul Welsh, Alex McConnachie, Colin Berry","doi":"10.1161/CIRCULATIONAHA.124.069901","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.124.069901","url":null,"abstract":"<p><p><b>Background:</b> Microvascular angina is associated with dysregulation of the endothelin system and impairments in myocardial blood flow, exercise capacity, and health-related quality of life. The G allele of the noncoding single nucleotide polymorphism <i>RS9349379</i> enhances expression of the endothelin-1 gene (<i>EDN1</i>) in human vascular cells, potentially increasing circulating concentrations of Endothelin-1 (ET-1). Whether zibotentan, an oral <i>ET-A</i> receptor selective antagonist, is efficacious and safe for the treatment of microvascular angina is unknown. <b>Methods:</b> Patients with microvascular angina were enrolled in this double-blind, placebo-controlled, sequential crossover trial of zibotentan (10 mg daily for 12 weeks). The trial population was enriched to ensure a G allele frequency of 50% for the <i>RS9349379</i> single nucleotide polymorphism. Participants and investigators were blinded to genotype. The primary outcome was treadmill exercise duration (seconds) using the Bruce protocol. The primary analysis estimated the mean within-participant difference in exercise duration after treatment with zibotentan versus placebo. <b>Results:</b> A total of 118 participants (mean ±SD; years of age 63.5 [9.2 ]; 71 [60.2% ] females; 25 [21.2% ] with diabetes) were randomized. Among 103 participants with complete data, the mean exercise duration with zibotentan treatment compared with placebo was not different (between-treatment difference, -4.26 seconds [95 ] CI, -19.60 to 11.06] <i>P</i>=0.5871). Secondary outcomes showed no improvement with zibotentan. Zibotentan reduced blood pressure and increased plasma concentrations of ET-1. Adverse events were more common with zibotentan (60.2%) compared with placebo (14.4%; <i>P</i><0.001). <b>Conclusions:</b> Among patients with microvascular angina, short-term treatment with a relatively high dose (10 mg daily) of zibotentan was not beneficial. Target-related adverse effects were common.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":null,"pages":null},"PeriodicalIF":35.5,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104931","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":"Cardiovascular, Kidney and Safety Outcomes with GLP-1 Receptor Agonists Alone and in Combination with SGLT2 Inhibitors in Type 2 Diabetes: A Systematic Review and Meta-Analysis.","authors":"Brendon L Neuen, Robert A Fletcher, Lauren Heath, Adam Perkovic, Muthiah Vaduganathan, Sunil Badve, Katherine R Tuttle, Richard Pratley, Hertzel C Gerstein, Vlado Perkovic, Hiddo J L Heerspink","doi":"10.1161/CIRCULATIONAHA.124.071689","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.124.071689","url":null,"abstract":"<p><p><b>Background:</b> Glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors both improve cardiovascular and kidney outcomes in persons with type 2 diabetes. We conducted a systematic review and meta-analysis to assess the effects of GLP-1 receptor agonists on clinical outcomes with and without SGLT2 inhibitors. <b>Methods:</b> We searched MEDLINE and Embase databases from inception until July 12, 2024 for randomized, double-blind, placebo-controlled outcome trials of GLP-1 receptor agonists in type 2 diabetes that reported treatment effects by baseline use of SGLT2 inhibitors, with findings supplemented by unpublished data. We estimated treatment effects by baseline SGLT2 inhibitor use using inverse variance weighted meta-analysis. The main cardiovascular outcomes were major adverse cardiovascular events ([MACE] nonfatal myocardial infarction, stroke or cardiovascular death) and hospitalization for heart failure. Kidney outcomes included a composite of ≥50 % reduction in estimated glomerular filtration rate (eGFR ), kidney failure or death due to kidney failure, and annualized rate of decline in eGFR (eGFR slope). Serious adverse events and severe hypoglycemia were also evaluated. This meta-analysis was registered on PROSPERO (CRD42024565765). <b>Results:</b> We identified three trials with 1,743/17,072 (10.2%) participants with type 2 diabetes receiving an SGLT2 inhibitor at baseline. GLP-1 receptor agonists reduced the risk of MACE by 21% (HR 0.79, 95% CI 0.71-0.87), with consistent effects in those receiving and not receiving SGLT2 inhibitors at baseline (HR 0.77, 95% CI 0.54-1.09 and HR 0.79, 95% CI 0.71-0.87, respectively; P-heterogeneity=0.78). The effect on hospitalization for heart failure was similarly consistent regardless of SGLT2 inhibitor use (HR 0.58, 95% CI 0.36-0.93 and HR 0.73, 95% CI 0.63-0.85; P-heterogeneity=0.26). Effects on the composite kidney outcome (RR 0.79, 95% CI 0.66-0.95 ) and eGFR slope (0.78 mL/min/1.73m₂/year, 95% CI 0.57-0.98) also did not vary according to SGLT2 inhibitor use (P-heterogeneity=0.53 and 0.94, respectively). Serious adverse effects and severe hypoglycemia were also similar regardless of SGLT2 inhibitor use (P-heterogeneity=0.29 and 0.50, respectively). <b>Conclusions:</b> In persons with type 2 diabetes, the cardiovascular and kidney benefits of GLP-1 receptor agonists are consistent regardless of SGLT2 inhibitor use.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":null,"pages":null},"PeriodicalIF":35.5,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104921","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":"Catheter Ablation in Patients with End-Stage Heart Failure and Atrial Fibrillation: Two-year Follow-up of the CASTLE-HTx Trial.","authors":"Christian Sohns, Maximilian Moersdorf, Nassir F Marrouche, Leonard Bergau, Angelika Costard-Jaeckle, Harry J G M Crijns, Henrik Fox, Gerhard Hindricks, Nikolaos Dagres, Samuel Sossalla, Rene Schramm, Thomas Fink, Mustapha El Hamriti, Vanessa Sciacca, Maxim Didenko, Frank Konietschke, Volker Rudolph, Jan Gummert, Jan G P Tijssen, Philipp Sommer","doi":"10.1161/CIRCULATIONAHA.124.071517","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.124.071517","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":null,"pages":null},"PeriodicalIF":35.5,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104922","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":"Myocardial Ischemic Syndromes: A New Nomenclature to Harmonize Evolving International Clinical Practice Guidelines.","authors":"William E Boden, Raffaele De Caterina, Juan Carlos Kaski, C Noel Bairey Merz, Colin Berry, Mario Marzilli, Carl J Pepine, Emanuele Barbato, Giulio G Stefanini, Eva Prescott, Philippe Gabriel Steg, Deepak L Bhatt, Joseph A Hill, Filippo Crea","doi":"10.1161/CIRCULATIONAHA.123.065656","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.123.065656","url":null,"abstract":"<p><p>Since the 1960s, cardiologists have adopted several binary classification systems for acute myocardial infarction (MI) that facilitated improved patient management. Conversely, for chronic stable manifestations of myocardial ischemia, various classifications have emerged over time, often with conflicting terminology-eg, \"stable coronary artery disease\" (CAD), \"stable ischemic heart disease,\" and \"chronic coronary syndromes\" (CCS). While the 2019 European guidelines introduced CCS to impart symmetry with \"acute coronary syndromes\" (ACS), the 2023 American guidelines endorsed the alternative term \"chronic coronary disease.\" An unintended consequence of these competing classifications is perpetuation of the restrictive terms \"coronary\" and 'disease', often connoting only a singular obstructive CAD mechanism. It is now important to advance a more broadly inclusive terminology for both obstructive and non-obstructive causes of angina and myocardial ischemia that fosters conceptual clarity and unifies dyssynchronous nomenclatures across guidelines. We, therefore, propose a new binary classification of \"acute myocardial ischemic syndromes\" and \"non-acute myocardial ischemic syndromes,\" which comprises both obstructive epicardial and non-obstructive pathogenetic mechanisms, including microvascular dysfunction, vasospastic disorders, and non-coronary causes. We herein retain accepted categories of ACS, ST-segment elevation MI, and non-ST segment elevation MI, as important subsets for which revascularization is of proven clinical benefit, as well as new terms like ischemia and MI with non-obstructive coronary arteries. Overall, such a more encompassing nomenclature better aligns, unifies, and harmonizes different pathophysiologic causes of myocardial ischemia and should result in more refined diagnostic and therapeutic approaches targeted to the multiple pathobiological precipitants of angina pectoris, ischemia, and infarction.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":null,"pages":null},"PeriodicalIF":35.5,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104927","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":"Comparative Cardiovascular Effectiveness of Empagliflozin Versus Dapagliflozin in Adults With Treated Type 2 Diabetes: A Target Trial Emulation.","authors":"Kasper Bonnesen, Uffe Heide-Jørgensen, Diana H Christensen, Timothy L Lash, Sean Hennessy, Anthony Matthews, Lars Pedersen, Reimar W Thomsen, Morten Schmidt","doi":"10.1161/CIRCULATIONAHA.124.068613","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.124.068613","url":null,"abstract":"<p><strong>Background: </strong>Empagliflozin and dapagliflozin have proven cardiovascular benefits in people with type 2 diabetes at high cardiovascular risk, but their comparative effectiveness is unknown.</p><p><strong>Methods: </strong>This study used nationwide, population-based Danish health registries to emulate a hypothetical target trial comparing empagliflozin versus dapagliflozin initiation, in addition to standard care, among people with treated type 2 diabetes from 2014 through 2020. The outcome was a composite of myocardial infarction, ischemic stroke, heart failure (HF), or cardiovascular death (major adverse cardiovascular event). Participants were followed until an outcome, emigration, or death occurred; 6 years after initiation; or December 31, 2021, whichever occurred first. Logistic regression was used to compute inverse probability of treatment and censoring weights, controlling for 57 potential confounders. In intention-to-treat analyses, 6-year adjusted risks, risk differences, and risk ratios considering noncardiovascular death competing risks were estimated. Analyses were stratified by coexisting atherosclerotic cardiovascular disease and HF. A per-protocol design was performed as a secondary analysis.</p><p><strong>Results: </strong>There were 36 670 eligible empagliflozin and 20 606 eligible dapagliflozin initiators. In the intention-to-treat analysis, the adjusted 6-year absolute risk of major adverse cardiovascular event was not different between empagliflozin and dapagliflozin initiators (10.0% versus 10.0%; risk difference, 0.0% [95% CI, -0.9% to 1.0%]; risk ratio, 1.00 [95% CI, 0.91 to 1.11]). The findings were consistent in people with atherosclerotic cardiovascular disease (risk difference, -2.3% [95% CI, -8.2% to 3.5%]; risk ratio, 0.92 [95% CI, 0.74 to 1.14]) and without atherosclerotic cardiovascular disease (risk difference, 0.3% [95% CI, -0.6% to 1.2%]; risk ratio, 1.04 [95% CI, 0.93 to 1.16]) and in people with HF (risk difference, 1.1% [95% CI, -6.5% to 8.6%]; risk ratio, 1.04 [95% CI, 0.79 to 1.37]) and without HF (risk difference, -0.1% [95% CI, -1.0% to 0.8%]; risk ratio, 0.99 [95% CI, 0.90 to 1.09]). The 6-year risks of major adverse cardiovascular event were also not different in the per-protocol analysis (9.1% versus 8.8%; risk difference, 0.2% [95% CI, -2.1% to 2.5%]; risk ratio, 1.03 [95% CI, 0.80 to 1.32]).</p><p><strong>Conclusions: </strong>Empagliflozin and dapagliflozin initiators had no differences in 6-year cardiovascular outcomes in adults with treated type 2 diabetes with or without coexisting atherosclerotic cardiovascular disease or HF.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":null,"pages":null},"PeriodicalIF":35.5,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104923","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":"Endothelial-to-Mesenchymal Transition Contributes to Accelerated Atherosclerosis in Hutchinson-Gilford Progeria Syndrome.","authors":"Magda R Hamczyk, Rosa M Nevado, Pilar Gonzalo, María J Andrés-Manzano, Paula Nogales, Víctor Quesada, Aránzazu Rosado, Carlos Torroja, Fatima Sánchez-Cabo, Ana Dopazo, Jacob F Bentzon, Carlos López-Otín, Vicente Andrés","doi":"10.1161/CIRCULATIONAHA.123.065768","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.123.065768","url":null,"abstract":"<p><strong>Background: </strong>Atherosclerosis is the main medical problem in Hutchinson-Gilford progeria syndrome, a rare premature aging disorder caused by the mutant lamin-A protein progerin. Recently, we found that limiting progerin expression to vascular smooth muscle cells (VSMCs) is sufficient to hasten atherosclerosis and death in <i>Apoe</i>-deficient mice. However, the impact of progerin-driven VSMC defects on endothelial cells (ECs) remained unclear.</p><p><strong>Methods: </strong><i>Apoe</i>- or <i>Ldlr</i>-deficient C57BL/6J mice with ubiquitous, VSMC-, EC- or myeloid-specific progerin expression fed a normal or high-fat diet were used to study endothelial phenotype during Hutchinson-Gilford progeria syndrome-associated atherosclerosis. Endothelial permeability to low-density lipoproteins was assessed by intravenous injection of fluorescently labeled human low-density lipoprotein and confocal microscopy analysis of the aorta. Leukocyte recruitment to the aortic wall was evaluated by en face immunofluorescence. Endothelial-to-mesenchymal transition (EndMT) was assessed by quantitative polymerase chain reaction and RNA sequencing in the aortic intima and by immunofluorescence in aortic root sections. TGFβ (transforming growth factor β) signaling was analyzed by multiplex immunoassay in serum, by Western blot in the aorta, and by immunofluorescence in aortic root sections. The therapeutic benefit of TGFβ1/SMAD3 pathway inhibition was evaluated in mice by intraperitoneal injection of SIS3 (specific inhibitor of SMAD3), and vascular phenotype was assessed by Oil Red O staining, histology, and immunofluorescence in the aorta and the aortic root.</p><p><strong>Results: </strong>Both ubiquitous and VSMC-specific progerin expression in <i>Apoe</i>-null mice provoked alterations in aortic ECs, including increased permeability to low-density lipoprotein and leukocyte recruitment. Atherosclerotic lesions in these progeroid mouse models, but not in EC- and myeloid-specific progeria models, contained abundant cells combining endothelial and mesenchymal features, indicating extensive EndMT triggered by dysfunctional VSMCs. Accordingly, the intima of ubiquitous and VSMC-specific progeroid models at the onset of atherosclerosis presented increased expression of EndMT-linked genes, especially those specific to fibroblasts and extracellular matrix. Aorta in both models showed activation of the TGFβ1/SMAD3 pathway, a major trigger of EndMT, and treatment of VSMC-specific progeroid mice with SIS3 alleviated the aortic phenotype.</p><p><strong>Conclusions: </strong>Progerin-induced VSMC alterations promote EC dysfunction and EndMT through TGFβ1/SMAD3, identifying this process as a candidate target for Hutchinson-Gilford progeria syndrome treatment. These findings also provide insight into the complex role of EndMT during atherogenesis.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":null,"pages":null},"PeriodicalIF":35.5,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104925","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":"Restrictive Versus Liberal Transfusion in Patients with Type 1 or Type 2 Myocardial Infarction: A Prespecified Analysis of the Myocardial Ischemia and Transfusion (MINT) Trial.","authors":"Andrew P DeFilippis, J Dawn Abbott, Brandon M Herbert, Marnie H Bertolet, Bernard R Chaitman, Harvey D White, Andrew M Goldsweig, Tamar S Polonsky, Rajesh Gupta, Caroline Alsweiler, Johanne Silvain, Pedro G M de Barros E Silva, Graham S Hillis, Benoit Daneault, Meechai Tessalee, Mark A Menegus, Sunil V Rao, Renato D Lopes, Paul C Hébert, John H Alexander, Maria M Brooks, Jeffrey L Carson, Shaun G Goodman","doi":"10.1161/CIRCULATIONAHA.124.071208","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.124.071208","url":null,"abstract":"<p><strong>Background: </strong>The MINT trial raised concern for harm from a restrictive versus liberal transfusion strategy in patients with acute myocardial infarction (MI) and anemia. Type 1 and type 2 MI are distinct pathophysiological entities that may respond differently to blood transfusion. This analysis sought to determine if the effects of transfusion varied among patients with a type 1 or a type 2 MI and anemia. We hypothesized that the liberal transfusion strategy would be of greater benefit in type 2 than in type 1 MI.</p><p><strong>Methods: </strong>We compared rates of death or MI at 30 days in patients with type 1 (n=1460) and type 2 (n=1955) MI and anemia who were randomly allocated to a restrictive (threshold of 7 to 8 g/dL) or a liberal (threshold of 10 g/dL) transfusion strategy.</p><p><strong>Results: </strong>The primary outcome of death or MI was observed in 16% of type 1 MI and 15.4% of type 2 MI patients. The rate of death or MI was higher in patients with type 1 MI randomized to a restrictive (18.2%) versus liberal (13.2%) transfusion strategy (RR 1.32, 95% CI 1.04 - 1.67) with no difference observed between the restrictive (15.8% ) and liberal (15.1% ) transfusion strategies in patients with type 2 MI (RR 1.05 95% CI 0.85-1.29). The test for a differential effect of transfusion strategy by MI type was not statistically significant (P-_interaction = 0.16).</p><p><strong>Conclusions: </strong>The concern for harm with a restrictive transfusion strategy in patients with acute MI and anemia raised in the MINT primary outcome manuscript may be more apparent in patients with type 1 than type 2 MI.</p><p><strong>Clinical trial registration: </strong>ClinicalTrials.gov number, NCT02981407.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":null,"pages":null},"PeriodicalIF":35.5,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104928","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":"Transient Inhibition of Translation Improves Cardiac Function After Ischemia/Reperfusion by Attenuating the Inflammatory Response.","authors":"Christoph Hofmann, Adrian Serafin, Ole M Schwerdt, Johannes Fischer, Florian Sicklinger, Fereshteh S Younesi, Nikole J Byrne, Ingmar S Meyer, Ellen Malovrh, Clara Sandmann, Lonny Jürgensen, Verena Kamuf-Schenk, Claudia Stroh, Zoe Löwenthal, Daniel Finke, Etienne Boileau, Arica Beisaw, Heiko Bugger, Mandy Rettel, Frank Stein, Hugo A Katus, Tobias Jakobi, Norbert Frey, Florian Leuschner, Mirko Völkers","doi":"10.1161/CIRCULATIONAHA.123.067479","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.123.067479","url":null,"abstract":"<p><strong>Background: </strong>The myocardium adapts to ischemia/reperfusion (I/R) by changes in gene expression, determining the cardiac response to reperfusion. mRNA translation is a key component of gene expression. It is largely unknown how regulation of mRNA translation contributes to cardiac gene expression and inflammation in response to reperfusion and whether it can be targeted to mitigate I/R injury.</p><p><strong>Methods: </strong>To examine translation and its impact on gene expression in response to I/R, we measured protein synthesis after reperfusion in vitro and in vivo. Underlying mechanisms of translational control were examined by pharmacological and genetic targeting of translation initiation in mice. Cell type-specific ribosome profiling was performed in mice that had been subjected to I/R to determine the impact of mRNA translation on the regulation of gene expression in cardiomyocytes. Translational regulation of inflammation was studied by quantification of immune cell infiltration, inflammatory gene expression, and cardiac function after short-term inhibition of translation initiation.</p><p><strong>Results: </strong>Reperfusion induced a rapid recovery of translational activity that exceeds baseline levels in the infarct and border zone and is mediated by translation initiation through the mTORC1 (mechanistic target of rapamycin complex 1)-4EBP1 (eIF4E-binding protein 1)-eIF (eukaryotic initiation factor) 4F axis. Cardiomyocyte-specific ribosome profiling identified that I/R increased translation of mRNA networks associated with cardiac inflammation and cell infiltration. Short-term inhibition of the mTORC1-4EBP1-eIF4F axis decreased the expression of proinflammatory cytokines such as Ccl2 (C-C motif chemokine ligand 2) of border zone cardiomyocytes, thereby attenuating Ly6C^hi monocyte infiltration and myocardial inflammation. In addition, we identified a systemic immunosuppressive effect of eIF4F translation inhibitors on circulating monocytes, directly inhibiting monocyte infiltration. Short-term pharmacological inhibition of eIF4F complex formation by 4EGI-1 or rapamycin attenuated translation, reduced infarct size, and improved cardiac function after myocardial infarction.</p><p><strong>Conclusions: </strong>Global protein synthesis is inhibited during ischemia and shortly after reperfusion, followed by a recovery of protein synthesis that exceeds baseline levels in the border and infarct zones. Activation of mRNA translation after reperfusion is driven by mTORC1/eIF4F-mediated regulation of initiation and mediates an mRNA network that controls inflammation and monocyte infiltration to the myocardium. Transient inhibition of the mTORC1-/eIF4F axis inhibits translation and attenuates Ly6C^hi monocyte infiltration by inhibiting a proinflammatory response at the site of injury and of circulating monocytes.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":null,"pages":null},"PeriodicalIF":35.5,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104930","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}