Basic Research in Cardiology最新文献

{"title":"Dissecting myocardial and systemic drivers of cardiac dysfunction in the murine CVB3 myocarditis model using microRNA-guided viral detargeting.","authors":"Sarah Ochs, Sandra Pinkert, Sophia Borowski, Lisa Gerarda Maria Huis In 't Veld, Nicolas Kelm, Anja Geisler, Henry Fechner, Ziya Kaya, Anne Hausen, Karin Klingel, Matthias Martin Gaida, Antje Beling","doi":"10.1007/s00395-026-01187-4","DOIUrl":"10.1007/s00395-026-01187-4","url":null,"abstract":"<p><p>In murine coxsackievirus B3 myocarditis, the most widely used experimental model of viral myocarditis, functional alterations such as reduced cardiac output are frequently interpreted as surrogates of myocardial injury and inflammation, despite concurrent systemic illness. The relative contribution of systemic disease processes to these functional changes remains poorly defined. We therefore aimed to disentangle myocardial and systemic drivers of cardiac dysfunction using a microRNA-guided viral detargeting approach. We engineered a cardiomyocyte-detargeted virus by inserting target sequences for the muscle-enriched microRNA-1 into the viral genome, selectively suppressing viral replication in cardiac muscle while largely preserving systemic infection. This enabled direct comparison between conventional myocarditis and cardiac-attenuated infection in mice, using serial echocardiography as the primary non-invasive functional readout of cardiac performance. Day 3 post infection was analyzed as the acute phase and day 7 as a later stage associated with peak myocardial inflammation. Cardiac viral titers were profoundly reduced by detargeting (approximately 3-log at day 3 and 6-7-log at day 7), accompanied by absence of troponin T release, inflammatory cell infiltration, and histological myocarditis. Despite this, cardiac output was reduced at day 3 and remained impaired at day 7 in both groups. This reduction was associated with decreased left ventricular end-diastolic volume, while ejection fraction remained preserved. At day 3, additional reductions in cardiac output and global longitudinal strain were observed in control-virus-infected mice. At day 7, cardiac output remained comparably reduced despite marked differences in myocardial injury. These findings demonstrate that systemic infection substantially contributes to impaired cardiac function and that echocardiographic readouts reflect a composite phenotype. Functional alterations should therefore be interpreted in the context of systemic effects and integrated with cross-organ analyses to enable accurate interpretation in preclinical myocarditis models.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":" ","pages":"775-799"},"PeriodicalIF":9.2,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13372866/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148052244","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":"Historical account of reperfusion therapy and the development of cardioprotection beyond reperfusion.","authors":"Gerd Heusch,Petra Kleinbongard,Bernard J Gersh","doi":"10.1007/s00395-026-01198-1","DOIUrl":"https://doi.org/10.1007/s00395-026-01198-1","url":null,"abstract":"The only way to salvage myocardium from infarction is timely reperfusion of the occluded coronary artery. Timely reperfusion reduces infarct size and mortality. The history of reperfusion therapy from the first clinical use of intravenous streptokinase in patients with acute myocardial infarction by Sherry et al. in the late 1950s, over seminal experimental dog studies by Ross Jr. et al., demonstrating infarct size reduction by timely reperfusion in the early 1970s, to a more systematic use of initially streptokinase and a later tissue plasminogen activator in clinical trials (GISSI, TIMI), the addition of platelet inhibition (ISIS) and ultimately mechanical recanalization by percutaneous coronary intervention with stenting, is reviewed in detail. Cardioprotection beyond timely reperfusion was first demonstrated in the seminal experimental dog studies of ischemic conditioning by Murry, Reimer, and Jennings in the 1980s and initiated a tsunami of experimental studies in various experimental models to identify the underlying signal transduction, but has not yet been established in clinical practice. Clinical trials on various forms of ischemic conditioning, potentially cardioprotective drugs and transcutaneous vagal nerve stimulation, are still underway.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"40 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148462669","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":"Cardiomyocyte-specific depletion of integrin α3 preserves cardiac function after myocardial infarction.","authors":"Nicolai V Bogert,Anita A Kuhnle,Shabana Din,Xue Li,Markus Therre,Nadine Wambsgans,Mirko Völkers,Hugo A Katus,Florian Leuschner,Norbert Frey,Mathias H Konstandin","doi":"10.1007/s00395-026-01193-6","DOIUrl":"https://doi.org/10.1007/s00395-026-01193-6","url":null,"abstract":"Integrins, a family of transmembrane receptors that mediate cell-extracellular (ECM) interactions, play a pivotal role in the heart to maintain cardiac function and tissue integrity. As they sense extracellular signals, their expression changes in a microenvironment-dependent manner. Especially following myocardial infarction (MI), several alpha integrins are upregulated. Integrin α3 (ITGA3) expression has been found upregulated after MI, yet little is known about the function of ITGA3 in cardiac tissue. To evaluate the role of ITGA3 in vivo. we generated a mouse line with cardiomyocytes-specific ITGA3 depletion (ITGA3 KO). ITGA3 KO mice were characterized under baseline conditions and after permanent LAD ligation by echocardiography. Cardiac tissue was processed for histological staining (WGA/Sirius-Red) and molecular analysis by qPCR and WB. Identified changes were proven in vitro using coculturing model of neonatal rat cardiac fibroblasts (NRCFs) with siRNA treated neonatal rat cardiomyocytes (NRCMs) lacking ITGA3. ITGA3 KO mice did not show any disadvantageous alterations in cardiac function and structure under baseline conditions. After experimental MI, cardiac function was preserved and hypertrophic response diminished in ITGA3 KO. Development of fibrosis and the induction of pathological gene program was attenuated. Mechanistically, we identified an upregulation in Hippo signalling and activation of autophagic processes (ATG5 and p62 levels as well as enhanced LC3 II/I ratios) in ITGA3 KO mice after MI, which was confirmed by in-vitro experiments of NRCMs. Our findings show that in vivo depletion of ITGA3 in adult cardiomyocytes preserves cardiac function and reduces pathological remodelling after MI. Thus, interference with ITGA3 might be a novel translational approach to improve cardiac remodelling after ischemic injury.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"22 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148415746","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":"Cardiac unloading models for myocardial reverse remodeling.","authors":"Xinjie Xu,Yukun Luo,Tao Lei,Zichen Wu,Jiaying Cao,Jiansong Huang,Henan Zhang,Xiaoyan Li,Xiaying Deng,Dongjing Zhou,Yibo Zhang,Antoni Bayes-Genis,Liang Chen","doi":"10.1007/s00395-026-01196-3","DOIUrl":"https://doi.org/10.1007/s00395-026-01196-3","url":null,"abstract":"Myocardial reverse remodeling (RR) represents the structural, functional, cellular, and molecular recovery of the failing heart, leading to long-term prognostic improvements. This process can be mediated by various clinical modalities, including pharmacological treatment and interventional/surgical procedures. Among these approaches, left ventricular assist devices (LVADs) exhibit the most potent capacity for mechanical unloading and inducing RR, which has profoundly transformed the treatment paradigm and prognosis of end-stage heart failure. Furthermore, the implantation and explantation of LVAD devices facilitate the collection of paired patient samples before and after treatment, providing a unique real-world model for investigating this phenomenon. However, the scarcity of human myocardial samples is insufficient to meet the demands of elucidating the mechanisms of reverse cardiac remodeling and identifying novel therapeutic targets. Findings derived from human specimens require validation through experimental unloading models, which inherently offer novel perspectives on cardiac pathophysiology. Thus, reproducible models of myocardial unloading have become valuable complementary resources. This review systematically summarizes progress in understanding the relationship between mechanical load and myocardial phenotypes within various unloading models. We further discuss how these reproducible unloading models provide a solid foundation for elucidating the mechanisms of RR and ultimately developing novel therapies to improve patient outcomes.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"36 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148408045","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":"Molecular mechanisms of coronary microembolization-induced MINOCA.","authors":"Jasper Iske,Henriette Thau,Joshua M Mesfin,Christien M Beez,Petra Wolint,Jonas Hildinger,Nicolas Musigk,Timo Z Nazari-Shafti,Adam Penkalla,Volkmar Falk,Bettina Heidecker,Bertil Lindahl,Maximilian Y Emmert,Nikola Cesarovic","doi":"10.1007/s00395-026-01189-2","DOIUrl":"https://doi.org/10.1007/s00395-026-01189-2","url":null,"abstract":"Compared to classic myocardial infarction (cMI), myocardial infarction with non-obstructive coronary arteries (MINOCA) is characterized by symptoms consistent with acute coronary syndrome, but without demonstrable coronary obstruction. Therefore, its diagnosis remains challenging and often relies on cardiac magnetic resonance imaging (MRI), which is usually performed only days after the index event, leading to delayed diagnosis and initiation of therapy. Coronary microembolization (CME) has been described as one of the major pathologies underlying MINOCA. However, the molecular mechanisms of CME remain poorly understood, resulting in a lack of rapid diagnostic tools and specific therapy approaches. In this review, we describe the molecular underpinnings of CME-derived MINOCA: an inflammatory environment inducing significant cellular damage that is conserved between cMI and MINOCA. While we note that some of these inflammatory and cellular death pathways are shared with cMI, we dissect mechanistic distinctions in CME-derived MINOCA such as dysregulated immune responses and higher miRNA activity. Most importantly, as molecular treatments for MI are currently in late-stage clinical trials, we can thus differentiate which therapeutics may work better for MINOCA. Thus, these findings can be used as a roadmap for diagnostic biomarkers and targeted therapeutic approaches for MINOCA.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"365 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2026-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148385690","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":"Protection against postoperative atrial fibrillation via antiplatelet aggregation induced by remote ischemic preconditioning during off-pump coronary artery bypass grafting.","authors":"Qin Jiang,Yi Zheng,Keli Huang,Juan Du,Zhenglin Yang,Shengshou Hu","doi":"10.1007/s00395-026-01195-4","DOIUrl":"https://doi.org/10.1007/s00395-026-01195-4","url":null,"abstract":"Off-pump coronary artery bypass grafting (OPCABG) is associated with increased platelet aggregation and a higher incidence of postoperative atrial fibrillation (POAF). Remote ischemic preconditioning (RIPC) has been reported as a promising intervention to mitigate these adverse outcomes. Consecutive patients with cytochrome P450 family 2 subfamily C member 19 (CYP2C19) loss-of-function (LOF) genotype who underwent isolated OPCABG were randomly assigned to receive intermittent ischemia-reperfusion applied to the arm (RIPC group) or not intervention (control group). RIPC was performed after induction of anesthesia using three cycles of 5-min inflation separated by 5-min deflation. The primary outcome was the cumulative incidence of POAF within the first postoperative week, assessed by the intention-to-treat analysis. Secondary outcomes included POAF burden, biochemical indicators, and clinical trajectory. Among the 220 patients available for the primary endpoint analysis, POAF occurred in 27 of 109 patients (24.8%) in the RIPC group versus 46 of 111 patients (41.4%) in the control group (hazard ratio [HR]: 0.542, 95% confidence interval [CI]: 0.342 to 0.858; P = 0.01). The RIPC group also showed significantly lower values than the control group for AF burden (5.1% [IQR 2.3-11.3%] vs. 8.3% [IQR 4.1-19.1%]; P = 0.019), arachidonic acid- and adenosine diphosphate-stimulated platelet aggregation, inflammatory and prothrombotic index, and intensive care unit length of stay. In CYP2C19 LoF carriers, administration of RIPC favorably reduced the incidence and burden of POAF within 1 week after OPCABG, attenuated platelet aggregation and systemic inflammation, and shortened the duration of intensive care unit stay.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"39 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148372880","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":"Peroxisomal catalase and plasmalogen biosynthesis protect from oxidative stress in Barth syndrome cardiomyopathy.","authors":"Elsie Kajese,Malte Hachmann,Katharina J Ermer,Manuela Erk,Lin Alhasaan,Michael Kohlhaas,Heike Bömmel,Lisa Berberich,Christopher Carlein,Hanna Eberl,Katrin Streckfuß-Bömeke,Leticia Prates Roma,Süleyman Ergün,Christoph Maack,Srikanth Karnati,Jan Dudek","doi":"10.1007/s00395-026-01197-2","DOIUrl":"https://doi.org/10.1007/s00395-026-01197-2","url":null,"abstract":"Barth Syndrome (BTHS) is an inherited mitochondrial cardiomyopathy caused by variants in the gene encoding TAFAZZIN (Taz), a transacylase catalyzing the synthesis of the essential mitochondrial phospholipid cardiolipin (CL). Although defects in Taz deteriorate mitochondrial respiration, Ca2+-uptake, and redox regulation in cardiac myocytes, we previously observed an unexpected lack of oxidative cardiac damage, despite the development of cardiomyopathy in a BTHS mouse model with Taz-knockdown (KD). Furthermore, we revealed that the integrated stress response (ISR) governs metabolic rewiring in Taz-KD hearts to compensate for deficient mitochondrial FAO and to support GSH production. Here, we interrogated whether adaptive mechanisms in peroxisomes, which are closely associated with mitochondria and harbor antioxidative enzymes, can also compensate for the mitochondrial defects. We identified alterations in the peroxisomal biogenesis factors PEX14 and PEX19, indicating changes in the peroxisomal proteome in Taz-KD vs. WT hearts. While the enzymes of peroxisomal FAO were unchanged, levels of Lon Protease 2 (LONP2) and catalase were elevated in Taz-KD hearts. Inhibition or siRNA-mediated knockdown of catalase increased reactive oxygen species (ROS) and blunted the protection of mouse embryonic fibroblasts (MEF) with Taz-knockout (KO), but not in WT, from ROS-induced activation of the apoptotic caspase 3. Furthermore, we observed that the increase in plasmalogen synthesis in cardiac Taz-KD peroxisomes contributes to the activation of the ISR, since siRNA-mediated knockdown of the key enzyme GNPAT blunted the ISR and thereby increased cellular ROS in Taz-KO, but not WT MEFs. In conclusion, peroxisomes facilitate a counterregulatory response to dysfunctional mitochondria by activating a catalase-driven ROS defense and maintaining ISR-mediated metabolic alterations, both of which compensate for mitochondrial dysfunction and oxidative stress. Therefore, the so far poorly investigated mitochondrial-peroxisome crosstalk may represent a novel therapeutic target in an orphan disease with a poor prognosis.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"23 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148349156","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":"Bicuspid aortic valve stenosis is characterized by increased angiogenesis, inflammation, and a higher valvular-to-systemic calcification ratio than tricuspid aortic valve stenosis.","authors":"Alexander Brückner,Adrian Brandtner,Sarah Rieck,Hannah Billig,Werner Masson,Anna Weber,Farhad Bakhtiary,Wilhelm Röll,Christoph Bourauel,Frank A Schildberg,Baravan Al-Kassou,Sebastian Zimmer,Daniela Wenzel,Bernd K Fleischmann","doi":"10.1007/s00395-026-01191-8","DOIUrl":"https://doi.org/10.1007/s00395-026-01191-8","url":null,"abstract":"Calcific aortic valve stenosis is the most common valvular heart disease requiring treatment. Although both tricuspid (AVS) and bicuspid (bAVS) aortic valve stenoses become calcified and functionally impaired in advanced stages, the pathophysiology of these conditions remains unclear. We investigated this using a multitechnology approach on explanted AVS, bAVS, and aortic regurgitation (AR) control valves. Because of technical limitations in processing heavily calcified aortic valve tissue, we established Kawamoto's film method for human aortic valve tissue, enabling the production of well-preserved cryosections and high-quality immunostainings. Both bulk RNA-seq analysis and immunostainings revealed that angiogenesis, inflammation, and calcification are key features distinguishing bAVS from AVS. In fact, we found that angiogenic genes and CD31+ cells, as well as inflammatory genes and CD45+ cells, are significantly elevated in bAVS. The most striking difference between bAVS and AVS was the prominent expression of specific genes involved in tissue calcification, such as matrix metallopeptidase 12 (MMP12), dentin matrix acidic phosphoprotein 1 (DMP1), and proteoglycan 4 (PRG4), along with approximately 1.7-fold increased calcification as shown by micro-CT and von Kossa staining analysis in bAVS. These findings were corroborated in a retrospective analysis of 1108 AVS and bAVS patients who underwent transcatheter aortic valve implantation (TAVI). The bAVS patients exhibited significantly stronger aortic valve calcifications (1.6-fold) but a significantly lower vascular calcification burden. These data further suggest that AVS and bAVS are distinct disease entities, with bAVS exhibiting increased local inflammation, angiogenesis, and calcification, findings that may guide future therapeutic strategies.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"7 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2026-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148342365","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":"Functional rejuvenation of endothelial cell aging by transient reprogramming.","authors":"Katrin Kalies,Kai Knoepp,Laura Hehl,Simon Guerlach,Laura Sandiano,Andreas Simm,Jochen Dutzmann,Daniel Sedding","doi":"10.1007/s00395-026-01192-7","DOIUrl":"https://doi.org/10.1007/s00395-026-01192-7","url":null,"abstract":"Senescent endothelial cells (ECs), characterized by a reduced angiogenic and regenerative potential, are key players in the pathophysiology of cardiovascular diseases. Therefore, targeting these cells has been suggested as an effective therapeutic strategy to increase health. Here, we are the first to report that non-genetic overexpression of the Yamanaka factors induces partial functional rejuvenation and attenuation of senescence-associated features in endothelial cells. Methods to characterize the effects of the transient reprogramming included quantification of gene expression as well as measurements of cellular functions in vitro. Further, in vivo experiments were performed in a hind-limb ischemia model. The application of the pharmacological cocktail to replicative senescent ECs resulted in a robust but timely restricted activation of Oct3/4, Sox2, Klf4, and c-Myc (p < 0.0 and p < 0.01). This was associated with a significant reduction of senescence markers such as p16ink4a and p14arf (p < 0.01). Additionally, qPCR-based telomere length measurements were stabilized, and functional properties of senescent ECs, such as proliferation, migration, sprouting, and tube formation, were improved (p < 0.05). Continuous cultivation of the treated cells over the long term indicated that expression of p16ink4a and p14arf remained significantly low, while cell migration remained enhanced. In vivo, a significantly improved blood flow was observed at 7 and 14 days after hind-limb ischemia in 21 months old C57BL/6 mice (p < 0.001). In conclusion, we revealed that a partial attenuation of endothelial cell senescence-associated features can be induced by a short pharmacological overexpression of the Yamanaka factors. While the compounds used are individually approved for other indications, their combined use in this context highlights a conceptual translational potential, whereas the clinical applicability of this approach remains to be evaluated.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"32 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148335981","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":"Myofilament-level effects of aficamten increase diastolic chamber volumes and maintain cardiac output through preserved length-dependent force generation in healthy rat and canine myocardium.","authors":"Fruzsina Sárkány,Dániel Priksz,Béla Juhász,László Ádám Fazekas,Norbert Németh,Norbert Szentandrássy,Balázs Horváth,Zsigmond Máté Kovács,Attila Borbély,Arnold Péter Ráduly,Attila Tóth,Miklós Fagyas,Beáta Bódi,Zoltán Papp","doi":"10.1007/s00395-026-01194-5","DOIUrl":"https://doi.org/10.1007/s00395-026-01194-5","url":null,"abstract":"Clinical trial experience supports the use of myosin inhibitors in hypertrophic cardiomyopathy (HCM), while early proof-of-concept studies suggest potential benefit in selected patients with heart failure with preserved ejection fraction (HFpEF). However, concerns about systolic dysfunction arising from their negative inotropic effects may limit broader application. In a series of in vivo and in vitro experiments in healthy animal preparations, we investigated how aficamten, a next-generation cardiac myosin inhibitor, interacts with key determinants of myocardial contractile function. Echocardiographic examinations in sedated Wistar rats revealed that bolus administration of aficamten (2 mg·kg-1 i.v.) did not reduce cardiac output (CO) at pacing frequencies of 300 and 400 bpm, despite marked increases in end-diastolic (ED) and end-systolic left ventricular (LV) volumes and the associated decrease in LV ejection fraction (EF). In field-stimulated intact cardiomyocytes from Mongrel dogs, increasing aficamten concentrations (0.1-1 µM) decreased contraction amplitude and diastolic duration. These effects occurred across pacing frequencies (0.25-1.25 Hz) and in the absence of aficamten-specific changes in intracellular Ca2+ transients. In permeabilized LV cardiomyocytes from dog and rat hearts, aficamten decreased active force production (Fmax) and its Ca2+ sensitivity under isometric conditions in a similar manner. Importantly, the sarcomere length dependence of Fmax was preserved, while the length-dependent increase in Ca2+ sensitivity was attenuated at higher (0.1-0.2 µM) aficamten concentrations in both species. Our findings in healthy myocardium characterize aficamten as a myosin inhibitor that increases diastolic chamber volumes through reduced contractility, with diastolic function indices (i.e. E/e', IVRT) reflecting the expected hemodynamic consequences of increased preload rather than direct impairment of myofibrillar relaxation. This enhanced preload recruits preserved sarcomere length-dependent force generation to compensate for negative inotropy, thereby maintaining stroke volume and cardiac output.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"69 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148335915","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}