{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T17:49:21Z","timestamp":1782928161123,"version":"3.54.5"},"reference-count":57,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"abstract":"\n Abstract<\/jats:title>\n \n Impaired Ca\n 2+<\/jats:sup>\n handling, and in particular leakage from the sarcoplasmic reticulum, is a critical mechanism in metabolic diseases affecting the heart. Phase\u2010plane loop analysis provides an integrated assessment of excitation\u2013contraction coupling (ECC) by capturing the dynamic relation between Ca\n 2<\/jats:sup>\n +<\/jats:sup>\n transients and mechanical contraction, exceeding standard time analysis limitations. Here, we investigated how mitochondrial encephalopathy, lactic acidosis and stroke\u2010like episodes metabolic disorder (MELAS) impairs the ECC using cardiac spheroids from diseased human induced pluripotent stem cells (m3243A>G mutation) and matched control (mtDNA mutation <10%). High\u2010speed dual\u2010mode imaging at 200\u00a0fps enabled simultaneous acquisition of Ca\n 2<\/jats:sup>\n +<\/jats:sup>\n dynamics and spheroid kinematics. To uncover disease\u2010specific mechanisms, supra\u2010threshold electric field stimulation was applied to simulate increased energy demand. After signal extraction, we built our interpretation of phase\u2010plane loops, comprising kinematic\u2010calcium (Ki\u2010Ca) loops, to quantify ECC efficiency. Time\u2010domain analysis demonstrated that MELAS cardiac spheroids showed significant reduction in beat duration at kinematics (1.068\u00a0\u00b1\u00a00.066\u00a0s\n vs<\/jats:italic>\n . 0.775\u00a0\u00b1\u00a00.094\u00a0s), as well as decreased Ca\n 2+<\/jats:sup>\n transient duration (0.984\u00a0\u00b1\u00a00.049\u00a0s\n vs<\/jats:italic>\n . 0.664\u00a0\u00b1\u00a00.042\u00a0s). Critically, Ki\u2010Ca loop analysis provided a more complete picture where MELAS samples displayed visibly different loops and a significant reduction of their area compared to controls (0.129\u00a0\u00b1\u00a00.056\n vs<\/jats:italic>\n . 0.082\u00a0\u00b1\u00a00.163). These findings demonstrate that Ki\u2010Ca loops provide a sensitive and integrative metric for detecting ECC dysfunction in human\n in vitro<\/jats:italic>\n cardiac models. This approach offers mechanistic insight into how mitochondrial metabolic disorders, such as MELAS, compromise the coupling between Ca\n 2<\/jats:sup>\n +<\/jats:sup>\n cycling and contractility.\n \n \n image<\/jats:alt-text>\n <\/jats:graphic>\n <\/jats:boxed-text>\n <\/jats:p>\n <\/jats:sec>\n \n Key points<\/jats:title>\n \n \n \n Phase\u2010plane Ki\u2010Ca loops effectively contribute to understanding the excitation\u2013contraction coupling (ECC) efficiency.<\/jats:p>\n <\/jats:list-item>\n \n Mitochondrial encephalopathy, lactic acidosis and stroke\u2010like episodes metabolic disorder (MELAS) impairs ECC in cardioid models.<\/jats:p>\n <\/jats:list-item>\n \n Cardiac challenge pacing protocol highlights beating anomaly in MELAS spheroids, uncovering ECC failure.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1113\/jp290473","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T17:16:35Z","timestamp":1782926195000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Kinematic\u2010calcium loops unravel impaired excitation\u2013contraction coupling in MELAS\u2010affected cardioids"],"prefix":"10.1113","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6899-5791","authenticated-orcid":false,"given":"Margherita","family":"Burattini","sequence":"first","affiliation":[{"name":"Department of Medicine and Surgery University of Parma Parma Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4013-7701","authenticated-orcid":false,"given":"Annalinda","family":"Pisano","sequence":"additional","affiliation":[{"name":"Department of Radiological, Oncological and Anatomopathological Sciences Sapienza University Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Gemma","family":"Pignataro","sequence":"additional","affiliation":[{"name":"Department of Radiological, Oncological and Anatomopathological Sciences Sapienza University Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6959-691X","authenticated-orcid":false,"given":"Giulia","family":"d'Amati","sequence":"additional","affiliation":[{"name":"Department of Radiological, Oncological and Anatomopathological Sciences Sapienza University Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8800-9672","authenticated-orcid":false,"given":"Silvana","family":"Pinelli","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery University of Parma Parma Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3622-4327","authenticated-orcid":false,"given":"Minh Long","family":"Hoang","sequence":"additional","affiliation":[{"name":"Department of Architecture and Engineering University of Parma Parma Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4730-2458","authenticated-orcid":false,"given":"Francesco Paolo","family":"Lo Muzio","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery University of Parma Parma Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4058-4368","authenticated-orcid":false,"given":"Michele","family":"Miragoli","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery University of Parma Parma Italy"},{"name":"IRCCS Humanitas Research Hospital Rozzano Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,1]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.apples.2022.100115","article-title":"2D and 3D in\u2010vitro models for mimicking cardiac physiology","volume":"12","author":"Abdelsayed G.","year":"2022","journal-title":"Applications in Engineering Science"},{"issue":"4","key":"e_1_2_6_3_1","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1161\/01.CIR.91.4.955","article-title":"Cardiac involvement in mitochondrial diseases","volume":"91","author":"Anan R.","year":"1995","journal-title":"Circulation"},{"issue":"7","key":"e_1_2_6_4_1","doi-asserted-by":"crossref","first-page":"1665","DOI":"10.3390\/biomedicines10071665","article-title":"Glutamate\u2010induced deregulation of krebs cycle in mitochondrial encephalopathy Lactic acidosis syndrome stroke\u2010like episodes (MELAS) syndrome is alleviated by ketone body exposure","volume":"10","author":"Belal S.","year":"2022","journal-title":"Biomedicines"},{"issue":"6868","key":"e_1_2_6_5_1","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1038\/415198a","article-title":"Cardiac excitation\u2013contraction coupling","volume":"415","author":"Bers D. 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