Basic Research in Cardiology最新文献

{"title":"Dose-dependent effects and mechanisms of exercise-like stimulation on cardiac injury and contractile function: outcomes of the MICRO-ATHLETE study.","authors":"Tom T J Luiken, Carla Cofiño-Fabres, José M Rivera-Arbeláez, Danique Snippert, Ellen J S Denessen, Sacha K Lamers, Nicoleta Cius, Koen van den Dries, Alma M A Mingels, Dick H J Thijssen, Robert C J J Passier, Thijs M H Eijsvogels","doi":"10.1007/s00395-026-01182-9","DOIUrl":"https://doi.org/10.1007/s00395-026-01182-9","url":null,"abstract":"<p><p>Observational studies revealed that exercise produces cardiac troponin release and cardiac fatigue in athletes. However, human in vivo studies offer limited insights into the underlying mechanisms of these potential deleterious effects. This study investigated exercise-induced cardiac troponin release, cardiac fatigue, and its potential mechanisms in a versatile in vitro Engineered Heart Tissue (EHT) model. EHTs were subjected to exercise-like electrical pulse stimulation (EL-EPS) at 2.5 Hz (150 bpm) for 2 or 4 h and compared to non-stimulated controls and doxorubicin (DOX)-exposed tissues. High-sensitive cardiac troponin T (hs-cTnT), lactate dehydrogenase (LDH), and cardiomyocyte contractile function were measured at baseline, immediately after EL-EPS, and after 20 h of recovery. Cell death was quantified by nuclear and mitochondrial DNA concentrations and tissue integrity was assessed using microscopy following exposure. Following 2 and 4 h of EL-EPS, and after DOX exposure, we found increased hs-cTnT and LDH levels and reduced contractile function compared to control. After recovery, contractile function remained impaired after 4 h EL-EPS and DOX exposure, whereas the effects were abolished after recovery for the 2 h EL-EPS group. Elevated nuclear and mitochondrial DNA release was found following DOX, but not after 2 and 4 h EL-EPS. Finally, EL-EPS was associated with the formation of actin aggregates. EL-EPS induced dose-dependent increases in hs-cTnT and LDH concentrations in conjugation with signs of cardiac fatigue, but without elevated markers of permanent cell death (i.e., mitochondrial/nuclear DNA). These findings suggest that exercise-induced elevations of cardiac biomarker concentrations are indicative of reversible cardiac injury.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":" ","pages":""},"PeriodicalIF":8.0,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147810384","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":"Activation of the C3a-C3aReceptor-axis is associated with endothelial dysfunction and glycocalyx damage in ST-elevation myocardial infarction.","authors":"Carl Vahldieck,Samuel Löning,Constantin Hamacher,Benedikt Fels,Tanja Svensson,Bettina Rudzewski,Joachim Weil,Kristina Kusche","doi":"10.1007/s00395-026-01181-w","DOIUrl":"https://doi.org/10.1007/s00395-026-01181-w","url":null,"abstract":"Complement activation is an early event in ischemia-reperfusion injury during ST-elevation myocardial infarction (STEMI) and drives endothelial dysfunction via glycocalyx (eGC) degradation. While downstream fragments such as C5a contribute to vascular injury, the role of the early anaphylatoxin C3a remains unclear. This study delineates the effects of the C3a:C3a-Receptor-axis on endothelial function, cytoskeletal dynamics, and eGC integrity. Sixty-four first-time STEMI patients and sixty-four age- and sex-matched healthy controls were enrolled. Patients were stratified into quartiles based on serum C3a concentrations, and comparisons were performed between the lowest vs. highest quartiles as well as between all STEMI patients vs. controls. Inflammatory and glycocalyx parameters were assessed via ELISA, AFM nanoindentation, and monocyte adhesion assays. NO bioavailability was measured chemiluminescence-based. C3a-receptor-antagonists (SB290157 and JR14a), C5a-Receptor1-antagonism (PMX53), as well as Rac1-Inhibition (NSC23766) were used to verify pathway specificity and downstream signaling involvement. High C3a levels were associated with marked endothelial injury: eGC height was reduced (- 44%; p < 0.001), cortical stiffness increased (+ 35%; p < 0.001), and shedding of Syndecan-1 and heparan sulfate was elevated (+ 203%, p < 0.001; + 181%, p < 0.01). NO bioavailability decreased by 34% (p < 0.05). C3a correlated inversely with eGC height (r =  - 0.736) and positively with Syndecan-1 (r = 0.856). Treatment with recombinant C3a (250 ng/mL) induced cortical stiffening (+ 10.8%; p < 0.001), eGC loss (- 24.7%; p < 0.001), actin polymerization (+ 27.9%; p < 0.001), Rac1 activation (p < 0.05), reduced NO (- 38%; p < 0.05), and increased monocyte adhesion (+ 37%), all reversed by both C3a-Receptor-inhibitiors and by Rac1-inhibition. C3a:C3a-Receptor signaling drives Rac1-mediated cytoskeletal stiffening, eGC degradation, NO reduction, and leukocyte adhesion, promoting endothelial dysfunction in STEMI in both macrovascular and microvascular endothelial cells. This pathway represents a potential therapeutic target to mitigate complement-mediated vascular injury in acute myocardial infarction.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"71 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147754650","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":"Publisher Correction: The CNP analogue vosoritide mediates PDE2-sensitive anti-arrhythmogenic effects in mouse hearts with STZ-induced type 1 diabetes.","authors":"Rebecca Firneburg, Katharina Tergau, Eleder Cachorro, Mario Schubert, Anindita Dhara, Xiaojing Luo, Erik Klapproth, Kaomei Guan, Ali El-Armouche, Susanne Kämmerer","doi":"10.1007/s00395-026-01175-8","DOIUrl":"https://doi.org/10.1007/s00395-026-01175-8","url":null,"abstract":"","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":" ","pages":""},"PeriodicalIF":8.0,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147761047","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":"Deubiquitinase USP43 exacerbates myocardial ischemia-reperfusion injury by stabilizing ASK1 and activating the JNK/P38 MAPK pathway.","authors":"Wei Sun,Hongjie Shi,Guowei Fu,Hui Zhao,Tingju Wei,Junjie Zhao,Peng Zhang,Linyun Ren","doi":"10.1007/s00395-026-01180-x","DOIUrl":"https://doi.org/10.1007/s00395-026-01180-x","url":null,"abstract":"Myocardial ischemia-reperfusion injury (MIRI) remains a major challenge in reperfusion therapy for acute myocardial infarction. The role of deubiquitinating enzyme ubiquitin-specific protease 43 (USP43) in this process, however, remains largely unexplored. In this study, we found that USP43 expression was significantly upregulated in murine hearts subjected to ischemia/reperfusion and in primary cardiomyocytes following hypoxia/reoxygenation. Genetic knockout of Usp43 conferred substantial protection against ischemia/reperfusion-induced myocardial injury, inflammation, and cardiomyocyte death, whereas cardiac-specific overexpression of USP43 exacerbated these detrimental effects. Consistent with these findings, USP43 knockdown attenuated hypoxia/reoxygenation-induced damage in primary cardiomyocytes, while its overexpression promoted cell death. Mechanistically, integrated transcriptomic and biochemical assays revealed apoptosis signal-regulating kinase 1 (ASK1) as a key USP43 substrate. USP43 directly binds to ASK1 and removes its K48-linked ubiquitin chains, thereby shielding ASK1 from proteasomal degradation. This post-translational modification leads to ASK1 protein stabilization and hyperactivation of the downstream ASK1-JNK/P38 mitogen-activated protein kinase (MAPK) signaling. Importantly, pharmacologically inhibiting ASK1 rescued the detrimental phenotype caused by USP43 overexpression. In summary, we identify USP43 as a novel regulator that exacerbates MIRI by promoting ASK1-mediated cell death. Targeting the USP43-ASK1 signaling axis may therefore warrant further investigation as a research target to elucidate the mechanisms of MIRI.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"9 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147731263","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":"Analyzing the role of ATP-dependent potassium channels in the regulation of coronary metabolic vasodilation during exercise.","authors":"Salman I Essajee,Cooper M Warne,Johnathan D Tune,Gregory M Dick","doi":"10.1007/s00395-026-01179-4","DOIUrl":"https://doi.org/10.1007/s00395-026-01179-4","url":null,"abstract":"The purpose of this meta-analysis is to compile, integrate, and assess studies that have investigated the role of ATP-dependent potassium channels (KATP channels) in coronary metabolic vasodilation in vivo. KATP channels are important modulators of membrane potential and vascular reactivity and are commonly proposed as regulating coronary blood flow in response to myocardial metabolism. For example, the electro-metabolic hypothesis of Lederer and colleagues (Zhao et al., Proc Natl Acad Sci 117:7461-70, 2020) suggests a pathway where myocardial metabolic activity reduces intracellular ATP, thus activating myocardial KATP channels to elicit vasodilation. The data collected here suggest that KATP channels are involved in determining resting vascular tone, but that their contribution does not increase with metabolism (a tonic 15% decrease in flow by glibenclamide). Furthermore, inhibiting KATP channels with glibenclamide impairs cardiac function by reducing coronary flow at rest, a clear indicator of ischemia, but this effect is overcome by endogenous mediators of vasodilation during increases in metabolism. These findings are inconsistent with the negative feedback/KATP channel version electro-metabolic hypothesis. Other cardiac K+ channels remain viable as candidates to mediate the vasodilatory mechanisms in this electro-metabolic paradigm. An amendment to the electro-metabolic hypothesis is proposed whereby the scheme is altered to feedforward. Specifically, we suggest considering the opening of other types of K+ channels in direct proportion to heart rate, ones whose activity can be linked directly to the increased frequency of cardiac action potentials or those that respond to mitochondrial factors or increased intracellular Na+. Whether the feedforward mechanism we propose can be supported experimentally remains to be determined.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"8 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147719508","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":"Call for candidates: Editor-in-Chief Basic Research in Cardiology.","authors":"","doi":"10.1007/s00395-026-01178-5","DOIUrl":"https://doi.org/10.1007/s00395-026-01178-5","url":null,"abstract":"","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"1 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147695169","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":"Empagliflozin improves metabolism and prevents myocardial and coronary dysfunction in streptozotocin-diabetic and non-diabetic rats subjected to ischemia/reperfusion.","authors":"Carmine Rocca,Anna De Bartolo,Maria Concetta Granieri,Vittoria Rago,Francesco Conforti,Lidia Urlandini,Naomi Romeo,Letizia Mattii,Raffaele De Caterina,Pasquale Pagliaro,Tommaso Angelone,Claudia Penna,Rosalinda Madonna","doi":"10.1007/s00395-026-01177-6","DOIUrl":"https://doi.org/10.1007/s00395-026-01177-6","url":null,"abstract":"Diabetes heightens cardiovascular risk. The selective sodium-glucose cotransporter 2 inhibitor empagliflozin (EMPA) shows cardiovascular benefits in heart failure, type 2 diabetes and chronic kidney disease. While EMPA protects against myocardial ischemia/reperfusion injury (MIRI) in diabetic and non-diabetic hearts, its mechanisms and impact on specific endpoints, including autophagy, angiocrine signaling, and metabolic flexibility, remain incompletely defined. We explored the systemic and myocardial effects of chronic EMPA pretreatment on these endpoints in diabetic and non-diabetic animals subjected to MIRI. In streptozotocin (STZ, 65 mg/kg) diabetic rats, EMPA (15 mg/kg/d, 4 weeks) reduced water intake without affecting hyperphagia or weight loss. EMPA ameliorated glucose and lipid profiles, tended to restore myocardial GLUT4 and counteract alterations in myocardial hydroxymethylglutaryl-CoA synthase (HMGCS2) and 3-oxoacid CoA-transferase 1 (OXCT1) levels. EMPA improved biomarkers of myocardial damage (BNP, NT-proBNP, CK-MB, galectin 3), inflammation (cardiac NLRP3, plasma IL-1β), oxidative stress (plasma SOD and malondialdehyde), angiocrine imbalance (VEGF and apelin), fibrosis, and collagen deposition, while showing a tendency to improve autophagy and apoptosis signaling. Ex vivo, EMPA improved baseline contractility and post-ischemic recovery of left ventricular pressure (dLVP from baseline: ~+4% in STZ+EMPA vs. -25% in STZ; ~+3% in EMPA vs. -28% in MIRI), enhanced coronary flow recovery, and reduced cardiac contracture, infarct size, and coronary LDH leakage in both diabetic and non-diabetic hearts. These effects may be associated with post-ischemic histological improvements, reduced vascular congestion, increased eNOS phosphorylation, activation of cardioprotective pathways, and inhibition of mPTP opening. Consistently, EMPA enhances wound healing and preserves eNOS phosphorylation in high-glucose (HG) human cardiac microvascular endothelial cells. In human cardiomyocytes, EMPA reduced hypoxia/reoxygenation (H/R) cell death, preserved nitrate and nitrite levels-effects abolished in the presence of L-NAME-and improved mitochondrial membrane potential in HG and/or H/R conditions. EMPA improved metabolic health and protected myocardial and coronary function likely via a permissive microvascular and myocardial phenotype that limits reperfusion injury, supporting its use against MIRI in normal and diabetic settings.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"439 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147702155","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":"Correction: Intravenously delivered mesenchymal stem cells prevent microvascular obstruction formation after myocardial ischemia/reperfusion injury.","authors":"Junzhuo Wang, Ziwei Chen, Qing Dai, Jinxuan Zhao, Zilun Wei, Jiaxin Hu, Xuan Sun, Jun Xie, Biao Xu","doi":"10.1007/s00395-026-01170-z","DOIUrl":"https://doi.org/10.1007/s00395-026-01170-z","url":null,"abstract":"","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":" ","pages":""},"PeriodicalIF":8.0,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147637802","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":"Genetic background is associated with distinct patterns of proarrhythmogenic remodeling leading to atrial fibrillation in pigs with ischemic heart failure.","authors":"Zhihao Zhang,Julia Vlcek,Christina Heger,Valerie Pauly,Nora Hesse,Dominik Schüttler,Daphne Merkus,Eckhard Wolf,Ivica Medugorac,Stefan Kääb,Philipp Tomsits,Sebastian Clauss","doi":"10.1007/s00395-026-01176-7","DOIUrl":"https://doi.org/10.1007/s00395-026-01176-7","url":null,"abstract":"Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, driven by electrical and structural remodeling that promotes proarrhythmic substrates. Interindividual variability in susceptibility to remodeling triggers, such as myocardial ischemia, suggests the involvement of genetic determinants. Ischemic heart failure (IHF) was induced by a 90-min occlusion of the left anterior descending artery in pigs. After 30 days, animals underwent in vivo assessments, including right and left heart catheterization, electrocardiography, and electrophysiological studies, with AF inducibility tested by burst pacing. Atrial fibrosis was quantified using Masson's trichrome staining, and remodeling-associated gene expression was analyzed by quantitative PCR. Genetic background was assessed through single-nucleotide polymorphism (SNP) genotyping using the Porcine SNP60 BeadChip, with data analyzed against reference SNP datasets. Following myocardial infarction, all animals developed IHF with reduced ejection fraction and increased AF susceptibility. Overall, IHF was associated with enhanced atrial fibrosis, but a subset of animals displayed no fibrotic remodeling. Genetic analysis identified two groups of pigs with different genetic backgrounds within the cohort: a Pietrain-dominant and a Landrace-dominant background. Pietrain-dominant pigs developed significantly more atrial fibrosis, whereas Landrace-dominant pigs exhibited a pronounced shortening of the atrial effective refractory period. Differential regulation of fibrosis-associated genes, including FN, MMP2, TGFB, and JNK1, was observed between genetic backgrounds. These findings indicate that genetic background is associated with distinct patterns of atrial remodeling in response to IHF, influencing key determinants of AF susceptibility.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"15 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147636063","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":"Comparing anti-platelet and anti-thrombin therapies in the ischaemia-reperfusion injured coronary microcirculation of healthy and diabetic mice.","authors":"Joanne L Mitchell,Juma El-Awaisi,Dean Kavanagh,Bernhard Nieswandt,Robert F Storey,Neena Kalia","doi":"10.1007/s00395-026-01168-7","DOIUrl":"https://doi.org/10.1007/s00395-026-01168-7","url":null,"abstract":"Patients with type 2 diabetes mellitus (T2DM) face increased risk of heart failure after myocardial infarction (MI), despite successful PCI and dual anti-platelet therapy (DAPT), due to coronary microvascular obstruction. This study examined whether DAPTs provide vasculoprotective benefits in injured coronary microvessels, including in the setting of chronic hyperglycaemia. Mice were fed a normal (ND) or high-fat diet (HFD) for 16 weeks and treated with vehicle, aspirin plus ticagrelor, clopidogrel, prasugrel or cangrelor, anti-GPIbα antibody, or dabigatran. Intravital imaging assessed platelet, neutrophil, and fibrin presence in the beating heart subjected to ischaemia-reperfusion injury (IRI). Laser speckle contrast imaging evaluated overall ventricular perfusion, and infarct size was determined histologically. IRI increased platelet and neutrophil accumulation in coronary capillaries and reduced perfusion. DAPTs, particularly using prasugrel, and anti-GPIbα reduced platelet numbers but increased neutrophil infiltration. Despite limited perfusion improvement, infarct size decreased. Fibrin deposition was also extensive and contributed to platelet recruitment, as shown using dabigatran. HFD-fed mice demonstrated markedly elevated thromboinflammatory cell accumulation. DAPT with prasugrel reduced platelet and neutrophil presence, but left a significant residual presence of both. Despite perfusion improvements, infarcts remained larger. Our data do not support a simple linear relationship between reduced platelet microthrombi, improved perfusion, and infarct limitation. Whilst early platelet inhibition confers cardioprotection independently of flow recovery in healthy mice, metabolic compromise uncouples microvascular flow from myocardial tissue survival. This may explain the diminished cardioprotective efficacy of DAPTs in patients with T2DM and supports exploring combination vasculoprotective therapies targeting multiple microvascular perturbations.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"13 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147585621","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}