Xijian Ke , Jonathan S. Baillie , Enrico D. Lemma , Martin Bastmeyer , Markus Hecker , Nina D. Ullrich
{"title":"The role of connexin-43 in modeling arrhythmogenic diseases with induced pluripotent stem cell-derived cardiomyocytes","authors":"Xijian Ke , Jonathan S. Baillie , Enrico D. Lemma , Martin Bastmeyer , Markus Hecker , Nina D. Ullrich","doi":"10.1016/j.yjmcc.2025.05.008","DOIUrl":"10.1016/j.yjmcc.2025.05.008","url":null,"abstract":"<div><div>A common pathophysiological characteristic of arrhythmic diseases is the disruption of electrical signal transmission across the heart causing life-threatening rhythm disorders. These conditions are associated with decreased expression of connexin-43 (Cx43) at intercalated discs and its translocation to the lateral membranes, however, the underlying mechanisms remain unclear. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) offer a model for studying these pathophysiological processes. Here, we tested the hypothesis that chronic stress, usually preceding arrhythmic developments, modulates Cx43 expression. iPSC-CM were electrically stimulated at a normal rate and by tachypacing, and their electrical and Ca<sup>2+</sup> signaling properties were analyzed. Our data revealed that tachypacing significantly reduced Cx43 expression by a micro-RNA miR-1-dependent mechanism. Anti-miR-1 treatment restored Cx43 expression in conditions of stress, enhanced Na<sup>+</sup> currents, improved Ca<sup>2+</sup> propagation and synchronized electrical activity. These findings suggest miR-1 as a potential pharmacological target for mitigating arrhythmogenic remodeling and restoring robust electrical signal transmission in cardiomyocytes.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"204 ","pages":"Pages 79-88"},"PeriodicalIF":4.9,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144154692","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kyung Chan Park , Amir Mashia Jaafari , Christopher Anthony Smith , Althea Rennisa Lobo , Lorenzo Errichelli , Gül Şimşek , Mala Gunadasa-Rohling , Alexander Marchant , Maria O. Levitin , Virginia Castilla-Llorente , Patrick Vilela , Pawel Swietach
{"title":"A Langendorff-heart discovery pipeline demonstrates cardiomyocyte targeting by extracellular vesicles functionalized with beta-blockers using click-chemistry","authors":"Kyung Chan Park , Amir Mashia Jaafari , Christopher Anthony Smith , Althea Rennisa Lobo , Lorenzo Errichelli , Gül Şimşek , Mala Gunadasa-Rohling , Alexander Marchant , Maria O. Levitin , Virginia Castilla-Llorente , Patrick Vilela , Pawel Swietach","doi":"10.1016/j.yjmcc.2025.05.007","DOIUrl":"10.1016/j.yjmcc.2025.05.007","url":null,"abstract":"<div><div>Extracellular vesicles (EVs) are widely explored as vehicles for delivering therapeutic or experimental cargo to cardiomyocytes. Efforts to improve EV bioavailability in the heart, and reduce their off-target actions, require screening methods that can replicate the physiological and anatomical barriers present in the myocardium. Additionally, discovery pipelines must exercise control over EV dosage and timing, and provide a means of assessing cargo incorporation into cardiomyocytes specifically. These criteria are not generally met by experiments on cultured cells or animals. Here, we present a Langendorff-heart discovery pipeline that combines the strengths of <em>in vivo</em> and <em>in vitro</em> approaches. Langendorff-mode perfusion enables controlled exposure of beating hearts to re-circulated EVs. Following perfusion, cardiomyocytes can be isolated enzymatically for analysis, such as imaging. We tested this discovery pipeline by functionalizing EVs with beta-blockers (atenolol, metoprolol) using click-chemistry and incorporating the fluorescent protein NeonGreen2 to track the fate of EV cargo. Fluorescence in cardiomyocytes, including their nuclear regions, increased after Langendorff-treatment with beta-blocker decorated EVs, but only if these contained NeonGreen2, implicating the fluorescent cargo as the source of signal. Superior binding efficacy of beta-blockers was confirmed by referencing to the substantially lower signals obtained using wild-type EVs or EVs presenting myomaker or myomixer proteins, motifs that modestly enrich cardiac EV uptake in mice. Our findings demonstrate successful cardiomyocyte targeting using EVs decorated with beta-receptor binders. We propose the Langendorff-perfused heart as an intermediate step - nested between <em>in vitro</em> characterisation and animal testing - in discovery pipelines for seeking improved cardiac-specific EV designs.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"204 ","pages":"Pages 89-100"},"PeriodicalIF":4.9,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144142779","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cristina M. Risi , Maicon Landim-Vieira , Betty Belknap , P. Bryant Chase , Jose R. Pinto , Vitold E. Galkin
{"title":"The role of the troponin T interactions with actin in regulation of cardiac thin filament revealed by the troponin T pathogenic variant Ile79Asn","authors":"Cristina M. Risi , Maicon Landim-Vieira , Betty Belknap , P. Bryant Chase , Jose R. Pinto , Vitold E. Galkin","doi":"10.1016/j.yjmcc.2025.05.005","DOIUrl":"10.1016/j.yjmcc.2025.05.005","url":null,"abstract":"<div><div>Cardiac muscle contraction/relaxation cycle depends on the rising and falling Ca<sup>2+</sup> levels in sarcomeres that control the extent of interactions between myosin-based thick and actin-based thin filaments. Cardiac thin filament (cTF) consists of actin, tropomyosin (Tm) that regulates myosin binding to actin, and troponin complex that governs Tm position upon Ca<sup>2+</sup>-binding. Troponin has three subunits – Ca<sup>2+</sup>-binding troponin C (TnC), Tm stabilizing troponin T (TnT), and inhibitory troponin I (TnI). TnT N-terminus (TnT1) interactions with actin stabilize the inhibited state of cTF. TnC, TnI, and Tm work in concert to control actomyosin interactions. Cryo-electron microscopy (cryo-EM) provided factual structures of healthy cTF, but structures of cTF carrying missense mutations linked to human cardiomyopathy are unknown. Variant Ile79Asn in human cardiac TnT (TnT-I79N) increases myofilament Ca<sup>2+</sup> sensitivity and slows cross-bridge kinetics, leading to severe hypertrophic/restrictive cardiomyopathy. Here, we used TnT-I79N mutation as a tool to examine the role of TnT1 in the complex mechanism of cTF regulation. Comparison of the cryo-EM structures of murine wild type and TnT-I79N native cTFs at systolic Ca<sup>2+</sup> levels (pCa = 5.8) demonstrates that TnT-I79N causes 1) dissociation of the TnT1 loop from its actin interface that results in Tm release to a more activated position, 2) reduced interaction of TnI C-terminus with actin-Tm, and 3) increased frequency of Ca<sup>2+</sup>-bound regulatory units. Our data indicate that the TnT1 loop is a crucial element of the allosteric regulatory network that couples Tn subunits and Tm to maintain adequate cTF response to physiological Ca<sup>2+</sup> levels during a heartbeat.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"204 ","pages":"Pages 55-67"},"PeriodicalIF":4.9,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144134291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sebastiaan Lootens , Robin Van den Abeele , Vineesh Kappadan , Balvinder Handa , Matthias Duytschaever , Sebastien Knecht , Armin Luik , Annika Haas , Eike M. Wülfers , Arthur Santos Bezerra , Bjorn Verstraeten , Sander Hendrickx , Arstanbek Okenov , Timur Nezlobinsky , Fu Siong Ng , Nele Vandersickel
{"title":"Detection of regular rotational activity during cardiac arrhythmia using the Helmholtz decomposition for directed graphs","authors":"Sebastiaan Lootens , Robin Van den Abeele , Vineesh Kappadan , Balvinder Handa , Matthias Duytschaever , Sebastien Knecht , Armin Luik , Annika Haas , Eike M. Wülfers , Arthur Santos Bezerra , Bjorn Verstraeten , Sander Hendrickx , Arstanbek Okenov , Timur Nezlobinsky , Fu Siong Ng , Nele Vandersickel","doi":"10.1016/j.yjmcc.2025.05.002","DOIUrl":"10.1016/j.yjmcc.2025.05.002","url":null,"abstract":"<div><div>We introduce DGM-CURL, a novel method to detect reentry in cardiac activation based on the Helmholtz Decomposition for directed graphs. DGM-CURL is an extension to our open-source diagnostic framework Directed Graph Mapping (DGM). We compare DGM-CURL to two existing methods, Phase Mapping (PM), and Directed Cycle Search (DGM-CYCLE). Four datasets are explored: (1) simulated two-dimensional functional reentry, (2) simulated three-dimensional anatomical reentry, (3) clinical electroanatomical atrial tachycardia (AT) mapping data, and (4) experimental rat ventricular fibrillation (VF) optical mapping data. Results indicate general agreement between all three methods. Applying DGM-CURL on networks created by looking at differences in local activation times between nodes, we find that high curl values identify graph nodes that balance the inflow and outflow of these differences, indicating areas of reentry. We stress the importance of using multiple algorithms to detect rotational activity as each method is prone to errors. Using a combined approach decreases the susceptibility to errors and offers a more complete picture of the dynamics of rotational drivers in cardiac arrhythmias.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"204 ","pages":"Pages 40-54"},"PeriodicalIF":4.9,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144127705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Carlos H. Pereira , Hiroki Kittaka , Edward J. Ouille V , Jonathas F.Q. Almeida , Andrès F. Pélaez , Ali Keshavarzian , Lothar A. Blatter , Kathrin Banach
{"title":"Colitis induced ventricular alternans increases the risk for ventricular arrhythmia","authors":"Carlos H. Pereira , Hiroki Kittaka , Edward J. Ouille V , Jonathas F.Q. Almeida , Andrès F. Pélaez , Ali Keshavarzian , Lothar A. Blatter , Kathrin Banach","doi":"10.1016/j.yjmcc.2025.05.004","DOIUrl":"10.1016/j.yjmcc.2025.05.004","url":null,"abstract":"<div><div>Inflammatory bowel disease was linked to an increased risk for conduction defects and ventricular arrhythmia. It coincides with dysregulation of gut microbiota, increased inflammation, and deregulation of the renin-angiotensin system. In this study, we aimed to determine the mechanism of colitis-induced electrophysiological remodeling that increases the risk for ventricular arrhythmia.</div><div>In a mouse model of dextran sulfate sodium induced active colitis (3.5 %, 7 days) cardiac electrophysiological properties were quantified during active inflammation. Electrocardiographic recordings exhibited a prolonged QT duration in mice with active colitis compared to control. Field potential (FP) recordings of Langendorff perfused colitis-hearts exhibited increased FP dispersion, a reduced threshold for ventricular alternans, and an increased propensity for spatially discordant alternans. The increased propensity for alternans was also reflected in isolated ventricular myocytes where Ca<sup>2+</sup> transient alternans occurred at lower pacing frequencies and increased alternans ratios. The action potential was unchanged during colitis but myocytes exhibited a prolonged Ca<sup>2+</sup> transient duration that corresponded with attenuated phospholamban phosphorylation. Stimulating cellular SERCA activity (Istaroxime), normalized the propensity for alternans. Serum levels of Angiotensin II (AngII) were increased during colitis and Angiotensin-converting enzyme (ACE) inhibitor or AngII receptor type 1 blocker prevented the increased alternans inducibility in isolated myocytes and hearts.</div><div>Our data demonstrate that active colitis promotes reversible remodeling of ventricular Ca<sup>2+</sup> handling properties and increases the propensity for alternans and arrythmia. The changes can be prevented by ACE or AT1R inhibition supporting a cardiac benefit for controlling RAS signaling in patients with active colitis.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"204 ","pages":"Pages 68-78"},"PeriodicalIF":4.9,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144132446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Anti-transferrin receptor 1 antibody reduces angiotensin II-induced vascular remodeling","authors":"Yoshiro Naito , Takeshi Tsujino , Tadashi Matsuura , Masanori Asakura , Tohru Masuyama , Masaharu Ishihara","doi":"10.1016/j.yjmcc.2025.05.006","DOIUrl":"10.1016/j.yjmcc.2025.05.006","url":null,"abstract":"<div><div>Aortic abundance of transferrin receptor 1 (TfR1), a cellular iron receptor, is increased in several vascular diseases; however, the effects of anti-TfR1 antibody on vascular diseases remains largely unknown. Herein, we investigated our hypothesis that anti-TfR1 antibody can attenuate vascular remodeling. Mice were infused with angiotensin II (AngII) to induce vascular remodeling with or without anti-TfR1 antibody. Notably, anti-TfR1 antibody attenuated vascular remodeling in mice with AngII infusion. Moreover, anti-TfR1 antibody suppressed AngII-induced proliferation and migration in cultured vascular smooth muscle cells. Thus, targeting TfR1 with an antibody may have therapeutic potential for vascular remodeling.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"204 ","pages":"Pages 35-39"},"PeriodicalIF":4.9,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144124775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"What can skinned cardiomyocytes teach us about heart disease? Response to letter to the editor: Challenges in assessing myoflament calcium sensitivity and contractile function in HFpEF by Christophe Maack and Vasco Sequeira","authors":"Vivek Jani, David A. Kass","doi":"10.1016/j.yjmcc.2025.05.003","DOIUrl":"10.1016/j.yjmcc.2025.05.003","url":null,"abstract":"","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"204 ","pages":"Pages 32-34"},"PeriodicalIF":4.9,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144083786","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yufeng Liu , Tricia T. Wang , Yinsheng Lu , Muhammad Riaz , Yibing Qyang
{"title":"Cardiac macrophage: Insights from murine models to translational potential for human studies","authors":"Yufeng Liu , Tricia T. Wang , Yinsheng Lu , Muhammad Riaz , Yibing Qyang","doi":"10.1016/j.yjmcc.2025.05.001","DOIUrl":"10.1016/j.yjmcc.2025.05.001","url":null,"abstract":"<div><div>Macrophages are a cell type that are known to play dynamic roles in acute and progressive pathology. They are highly attuned to their microenvironments throughout maturation, tailoring their functional responses according to the specific tissues in which they reside and their developmental origin. Cardiac macrophages (cMacs) have emerged as focal points of interest for their interactions with the unique electrical and mechanical stimuli of the heart, as well as for their role in maintaining cardiac homeostasis. Through an in-depth analysis of their origin, lineage, and functional significance, this review aims to shed light on cMacs' distinct contributions to both normal physiological maintenance as well as disease progression. Central to our discussion is the comparison of cMac characteristics between mouse and human models, highlighting current challenges and proposing novel experimental tools for deciphering cMac function within the intricate human cardiac microenvironments based on current murine studies. Our review offers valuable insights for identifying novel therapeutic targets and interventions tailored to the distinct roles of these immune cells in cardiovascular diseases (CVDs).</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"204 ","pages":"Pages 17-31"},"PeriodicalIF":4.9,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144022406","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Population-based computational simulations elucidate mechanisms of focal arrhythmia following stem cell injection","authors":"Chelsea E. Gibbs , Patrick M. Boyle","doi":"10.1016/j.yjmcc.2025.04.010","DOIUrl":"10.1016/j.yjmcc.2025.04.010","url":null,"abstract":"<div><div>Following a myocardial infarction (MI), a large portion of ventricular cells are replaced by scar, leading to adverse structural remodeling and heart failure. The use of stem cell-derived cardiomyocytes has shown promise in restoring cardiac function in animal models following an MI but leads to rapid focal ventricular tachycardia (VT). The VT in these animals can be variable, and its underlying mechanisms remain unknown. In this study, we used three distinct computational models derived from histological images of post-MI non-human primate ventricles to understand how human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) grafts can affect focal VT individually and synergistically. Specifically, we explored whether grafts could work cooperatively to create new arrhythmia and if geometric features such as graft tortuosity, area, host isolation, and amount of surrounding scar inhibited or enhanced the effect. We observed at least one instance of graft-host excitation (GHE) for eleven of the twenty-five individual grafts examined. Since we used a stochastic population-of-models-based approach to generate graft boundaries, we found that the number of configurations with GHE varied from graft to graft. We also examined grafts in aggregate and found that the high prevalence of GHE when all grafts were included arose from combinations of individually arrhythmogenic grafts (i.e., the overall increase in arrhythmogenicity resulted from graft <em>complementarity</em> rather than graft <em>cooperativity</em>). Further analysis of graft spatial features showed that arrhythmogenic grafts tend to be in areas with high host isolation (i.e., spatially confined regions of surviving myocardium interdigitated with engrafted cells) and when graft area and tortuosity were also high. These insights can aid in the design of novel injection schemes that could result in safer therapy for patients.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"204 ","pages":"Pages 5-16"},"PeriodicalIF":4.9,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143899774","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}