{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T09:09:20Z","timestamp":1788772160866,"version":"build-2803163510"},"reference-count":32,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T00:00:00Z","timestamp":1788566400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Major Science and Technology Projects of Henan Province","award":["251100310200"],"award-info":[{"award-number":["251100310200"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Background: Cardiac contractility modulation (CCM) improves cardiac performance in heart failure, but its acute spatial effects on myocardial voltage and calcium-transient behavior remain incompletely characterized, particularly in the setting of early myocardial remodeling. Methods: In this exploratory, fixed-sequence study, isolated Langendorff-perfused hearts from Control and isoproterenol (ISO)-treated rats (n = 5 per group) underwent simultaneous voltage and calcium optical mapping during a 40-s protocol consisting of pre-stimulation (Base), active CCM stimulation (CCM-ON), and post-stimulation (CCM-OFF) phases. Global metrics were derived across the mapped ventricular surface and regional metrics from predefined regions proximal and distal to the stimulation electrodes. No time-matched sham-stimulation condition was included. Results: Relative optical action-potential (AP) and calcium-transient (CaT) amplitudes were approximately 5\u20136% higher during CCM-ON and CCM-OFF than during Base in both groups. Global AP duration at 90% repolarization (APD90) showed modest phase-dependent prolongation, whereas global CaT duration at 90% recovery (CTD90) showed modest shortening. Global CTD90 was longer overall in ISO-treated hearts, without a group-by-phase interaction. Three-way repeated-measures analyses identified phase-by-region interactions for CTD90 and AP\u2013CaT delay (the interval from the 50% AP upstroke to the 50% CaT upstroke) and a group-by-region interaction for CTD90, with no significant phase-by-group-by-region interactions. CTD90 spatial dispersion and the absolute proximal\u2013distal difference in AP\u2013CaT delay showed phase effects, whereas mapped-surface APD90 dispersion did not change detectably. Conclusions: During the acute CCM sequence, CaT recovery and AP\u2013CaT timing showed spatially nonuniform phase-associated patterns in Control hearts and ISO-treated hearts with features compatible with early remodeling, without a parallel detectable increase in mapped-surface APD90 dispersion. These exploratory, hypothesis-generating findings support a spatial dissociation between calcium-related temporal responses and mapped-surface APD90 dispersion under the present experimental conditions.<\/jats:p>","DOI":"10.3390\/life16091484","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T08:07:06Z","timestamp":1788768426000},"page":"1484","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Global and Regional Voltage and Calcium-Transient Responses to Acute Cardiac Contractility Modulation in Isoproterenol-Treated Rat Hearts with Features Compatible with Early Remodeling"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7459-8891","authenticated-orcid":false,"given":"Kaihao","family":"Gu","sequence":"first","affiliation":[{"name":"College of Biomedical Engineering, Fudan University, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danyue","family":"Mao","sequence":"additional","affiliation":[{"name":"College of Biomedical Engineering, Fudan University, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5863-8988","authenticated-orcid":false,"given":"Guoliang","family":"Hao","sequence":"additional","affiliation":[{"name":"Henan Key Laboratory of Cardiac Electrophysiology, Henan Academy of Innovations in Medical Science, Zhengzhou 451100, China"},{"name":"Henan SCOPE Research Institute of Electrophysiology Co., Ltd., Kaifeng 475000, China"},{"name":"Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Electronic Engineering, School of Information Science and Technology, Fudan University, Shanghai 200438, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaomei","family":"Wu","sequence":"additional","affiliation":[{"name":"College of Biomedical Engineering, Fudan University, Shanghai 200433, China"},{"name":"Yiwu Research Institute,  Fudan University, Yiwu 322000, China"},{"name":"Shanghai Engineering Research Center of Assistive Devices, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1161\/CIRCULATIONAHA.113.001878","article-title":"Pathological ventricular remodeling: Mechanisms: Part 1 of 2","volume":"128","author":"Burchfield","year":"2013","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Zhao, K., Mao, Y., Li, Y., Yang, C., Wang, K., and Zhang, J. (2022). The roles and mechanisms of epigenetic regulation in pathological myocardial remodeling. Front. Cardiovasc. Med., 9.","DOI":"10.3389\/fcvm.2022.952949"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1161\/CIRCRESAHA.117.310230","article-title":"Calcium and excitation\u2013contraction coupling in the heart","volume":"121","author":"Eisner","year":"2017","journal-title":"Circ. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"8001","DOI":"10.1038\/s41598-020-64949-7","article-title":"Chronic sympathetic hyperactivity triggers electrophysiological remodeling and disrupts excitation\u2013contraction coupling in heart","volume":"10","author":"Joca","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_5","first-page":"H228","article-title":"Impaired Ca2+ handling is an early manifestation of pressure-overload hypertrophy in rat hearts","volume":"271","author":"Chang","year":"1996","journal-title":"Am. J. Physiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1016\/j.jacc.2020.11.044","article-title":"Etiology-dependent impairment of diastolic cardiomyocyte calcium homeostasis in heart failure with preserved ejection fraction","volume":"77","author":"Frisk","year":"2021","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1093\/cvr\/cvad178","article-title":"Remodelling of cAMP dynamics within the SERCA2a microdomain in heart failure with preserved ejection fraction caused by obesity and type 2 diabetes","volume":"120","author":"Lai","year":"2024","journal-title":"Cardiovasc. Res."},{"key":"ref_8","first-page":"e895","article-title":"2022 AHA\/ACC\/HFSA guideline for the management of heart failure","volume":"145","author":"Heidenreich","year":"2022","journal-title":"Circulation"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1002\/ejhf.2814","article-title":"Inotropic therapy in patients with advanced heart failure: A clinical consensus statement","volume":"25","author":"Gustafsson","year":"2023","journal-title":"Eur. J. Heart Fail."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1002\/ejhf.1349","article-title":"Cardiac contractility modulation: Mechanisms of action in heart failure with reduced ejection fraction and beyond","volume":"21","author":"Kherad","year":"2019","journal-title":"Eur. J. Heart Fail."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/ehf2.14575","article-title":"Enhancing myocardial function with cardiac contractility modulation: Potential and challenges","volume":"11","author":"Li","year":"2024","journal-title":"ESC Heart Fail."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1515\/cdbme-2018-1131","article-title":"Pacing electrode modeling and simulation of cardiac contractility modulation","volume":"4","author":"Roller","year":"2018","journal-title":"Curr. Dir. Biomed. Eng."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1016\/j.jchf.2018.04.010","article-title":"A randomized controlled trial to evaluate the safety and efficacy of cardiac contractility modulation","volume":"6","author":"Abraham","year":"2018","journal-title":"JACC Heart Fail."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e006512","DOI":"10.1161\/CIRCHEARTFAILURE.119.006512","article-title":"Safety, performance, and efficacy of cardiac contractility modulation delivered by the 2-lead Optimizer Smart system: The FIX-HF-5C2 study","volume":"13","author":"Wiegn","year":"2020","journal-title":"Circ. Heart Fail."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1146\/annurev-physiol-042022-020541","article-title":"Mechanisms and implications of electrical heterogeneity in cardiac function in ischemic heart disease","volume":"87","author":"Zhou","year":"2025","journal-title":"Annu. Rev. Physiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1969","DOI":"10.1161\/CIRCRESAHA.117.310083","article-title":"Calcium signaling and cardiac arrhythmias","volume":"120","author":"Landstrom","year":"2017","journal-title":"Circ. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1161\/01.RES.75.1.105","article-title":"Progressive ventricular remodeling in response to diffuse isoproterenol-induced myocardial necrosis in rats","volume":"75","author":"Teerlink","year":"1994","journal-title":"Circ. Res."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Kho, C. (2023). Targeting calcium regulators as therapy for heart failure: Focus on the sarcoplasmic reticulum Ca-ATPase pump. Front. Cardiovasc. Med., 10.","DOI":"10.3389\/fcvm.2023.1185261"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2120","DOI":"10.1016\/j.jacc.2006.10.082","article-title":"Therapy with cardiac contractility modulation electrical signals improves left ventricular function and remodeling in dogs with chronic heart failure","volume":"49","author":"Imai","year":"2007","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e15085","DOI":"10.14814\/phy2.15085","article-title":"Acute effects of cardiac contractility modulation on human induced pluripotent stem cell-derived cardiomyocytes","volume":"9","author":"Feaster","year":"2021","journal-title":"Physiol. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e12106","DOI":"10.14814\/phy2.12106","article-title":"Acute effects of nonexcitatory electrical stimulation during systole in isolated cardiac myocytes and perfused heart","volume":"2","author":"Blinova","year":"2014","journal-title":"Physiol. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.1159\/000358705","article-title":"Biventricular pacing cardiac contractility modulation improves cardiac contractile function via upregulating SERCA2 and miR-133 in a rabbit model of congestive heart failure","volume":"33","author":"Ning","year":"2014","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1178","DOI":"10.1016\/S0140-6736(16)00082-9","article-title":"Calcium upregulation by percutaneous administration of gene therapy in patients with cardiac disease (CUPID 2): A randomised, multinational, double-blind, placebo-controlled, phase 2b trial","volume":"387","author":"Greenberg","year":"2016","journal-title":"Lancet"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Salazar-Ram\u00edrez, F., Ramos-Mondrag\u00f3n, R., and Garc\u00eda-Rivas, G. (2020). Mitochondrial and Sarcoplasmic Reticulum Interconnection in Cardiac Arrhythmia. Front. Cell Dev. Biol., 8.","DOI":"10.3389\/fcell.2020.623381"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1161\/CIRCRESAHA.118.312708","article-title":"Mitochondrial ROS drive sudden cardiac death and chronic proteome remodeling in heart failure","volume":"123","author":"Dey","year":"2018","journal-title":"Circ. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1515\/med-2022-0415","article-title":"Cardiac contractility modulation ameliorates myocardial metabolic remodeling in a rabbit model of chronic heart failure through activation of the AMPK and PPAR-\u03b1 pathway","volume":"17","author":"Zhang","year":"2022","journal-title":"Open Med."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Lyasnikova, E., Sukhareva, K., Vander, M., Zaitsev, K., Firulyova, M., Sergushichev, A., Sorokina, M., Trukshina, M., Galenko, V., and Lelyavina, T. (2024). Molecular effects of cardiac contractility modulation in patients with heart failure of ischemic aetiology uncovered by transcriptome analysis. Front. Cardiovasc. Med., 11.","DOI":"10.3389\/fcvm.2024.1321005"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.yjmcc.2011.04.010","article-title":"The acute inotropic effects of cardiac contractility modulation are associated with action potential duration shortening and mediated by \u03b21-adrenoceptor signalling","volume":"51","author":"Winter","year":"2011","journal-title":"J. Mol. Cell Cardiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3831","DOI":"10.1038\/s41467-024-47850-z","article-title":"Cardiac function is regulated by the sodium-dependent inhibition of the sodium-calcium exchanger NCX1","volume":"15","author":"Scranton","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Feaster, T.K., Feric, N., Pallotta, I., Narkar, A., Casciola, M., Graziano, M.P., Aschar-Sobbi, R., and Blinova, K. (2022). Acute effects of cardiac contractility modulation stimulation in conventional 2D and 3D human induced pluripotent stem cell-derived cardiomyocyte models. Front. Physiol., 13.","DOI":"10.3389\/fphys.2022.1023563"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"H572","DOI":"10.1152\/ajpheart.1999.276.2.H572","article-title":"Modulation of repolarization in rabbit Purkinje and ventricular myocytes coupled by a variable resistance","volume":"276","author":"Huelsing","year":"1999","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e030433","DOI":"10.1161\/JAHA.123.030433","article-title":"Sequence-dependent repolarization is modulated by endogenous action potential duration gradients rather than electrical coupling in ventricular myocardium","volume":"14","author":"Blair","year":"2025","journal-title":"J. Am. Heart Assoc."}],"container-title":["Life"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-1729\/16\/9\/1484\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T08:26:23Z","timestamp":1788769583000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-1729\/16\/9\/1484"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,5]]},"references-count":32,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["life16091484"],"URL":"https:\/\/doi.org\/10.3390\/life16091484","relation":{},"ISSN":["2075-1729"],"issn-type":[{"value":"2075-1729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,5]]}}}