{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T02:48:54Z","timestamp":1791946134336,"version":"4.3.4"},"reference-count":62,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Arrhythmia and Electrophysiology"],"published-print":{"date-parts":[[2025,6]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>\n                      Sinoatrial node (SAN) dysfunction is commonly associated with atrial dysrhythmia (tachy-brady syndrome) and is a particularly important feature of inherited atrial cardiomyopathies leading to artificial pacemaker implantation. Essential MYL4 (myosin light chain-4) is an atrial-selective protein that associates with the myosin light chain and participates importantly in cardiacmuscle contraction.\n                      <jats:italic toggle=\"yes\">MYL4<\/jats:italic>\n                      gene variants encoding dysfunctional versions of MYL4 cause familial atrial cardiomyopathy with a high incidence of early SAN dysfunction (SND) and pacemaker requirement. In this study, we used a rat line, genetically modified to express an\n                      <jats:italic toggle=\"yes\">E11K<\/jats:italic>\n                      gene mutation responsible for familial atrial cardiomyopathy, to address the mechanisms underlying SND.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      Cardiac structure and function were assessed by echocardiography and in vivo telemetry recording. SAN function was studied in vivo with intracardiac electrophysiology and ex vivo with optical mapping. Mechanisms underlying SND were interrogated in vitro with the use of voltage and current clamp with tight-seal patch-clamp and Ca\n                      <jats:sup>2+<\/jats:sup>\n                      imaging of isolated SAN cardiomyocytes. Gene expression was assessed by quantitative polymerase chain reaction, and fibrosis was determined with Masson\u2019s trichrome stain.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      Mutant\n                      <jats:italic toggle=\"yes\">Myl4-p.E11K<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">+\/+<\/jats:italic>\n                      <\/jats:sup>\n                      rats exhibited worse SAN function compared with wild-type controls. In vivo, SND was demonstrated by \u224863% increase in sinus node recovery time compared with wild type. In vitro, SAN conduction velocity was reduced by \u2248 50% for\n                      <jats:italic toggle=\"yes\">Myl4-p.E11K<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">+\/+<\/jats:italic>\n                      <\/jats:sup>\n                      compared with wild type. Isolated SAN cells showed \u224850% reduction in funny current and L-type Ca\n                      <jats:sup>2+<\/jats:sup>\n                      -current densities. Dysregulation of Ca\n                      <jats:sup>2<\/jats:sup>\n                      <jats:sup>+<\/jats:sup>\n                      homeostasis was observed in\n                      <jats:italic toggle=\"yes\">Myl4-p.E11K<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">+\/+<\/jats:italic>\n                      <\/jats:sup>\n                      , with \u224830% slower time to peak and Ca\n                      <jats:sup>2+<\/jats:sup>\n                      decay. Masson\u2019s trichrome staining showed \u224845% increase in SAN region collagen deposition in\n                      <jats:italic toggle=\"yes\">Myl4-p.E11K<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">+\/+.<\/jats:italic>\n                      <\/jats:sup>\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>\n                      <jats:italic toggle=\"yes\">Myl4-p.E11K<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">+\/+<\/jats:italic>\n                      <\/jats:sup>\n                      mutation causes progressive SND with aging, as a result of extensive abnormalities in the underlying determinants of SAN function, including ion-channel properties, Ca\n                      <jats:sup>2+<\/jats:sup>\n                      -homeostasis, and SAN structure. These observations provide new insights into the mechanisms of SAN abnormality in atrial cardiomyopathy.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circep.124.013180","type":"journal-article","created":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T05:00:17Z","timestamp":1748322017000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["Mechanisms Underlying Sinus Node Dysfunction in a Rat Model of Genetic Atrial Cardiomyopathy"],"prefix":"10.1161","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-1107-0033","authenticated-orcid":true,"given":"Edouard","family":"Marcoux","sequence":"first","affiliation":[{"name":"Research Center, Montreal Heart Institute (E.M., M.M., D.S., P.N., L.R.V., M.G.S., J.-C.T., S.N.), Universit\u00e9 de Montr\u00e9al, Canada."},{"name":"Faculty of Pharmacy (E.M.), Universit\u00e9 de Montr\u00e9al, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Mackasey","sequence":"additional","affiliation":[{"name":"Research Center, Montreal Heart Institute (E.M., M.M., D.S., P.N., L.R.V., M.G.S., J.-C.T., S.N.), Universit\u00e9 de Montr\u00e9al, Canada."},{"name":"Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada (M.M., D.S., S.N.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6557-6690","authenticated-orcid":true,"given":"Deanna","family":"Sosnowski","sequence":"additional","affiliation":[{"name":"Research Center, Montreal Heart Institute (E.M., M.M., D.S., P.N., L.R.V., M.G.S., J.-C.T., S.N.), Universit\u00e9 de Montr\u00e9al, Canada."},{"name":"Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada (M.M., D.S., S.N.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3733-1393","authenticated-orcid":true,"given":"Patrice","family":"Naud","sequence":"additional","affiliation":[{"name":"Research Center, Montreal Heart Institute (E.M., M.M., D.S., P.N., L.R.V., M.G.S., J.-C.T., S.N.), Universit\u00e9 de Montr\u00e9al, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louis R.","family":"Villeneuve","sequence":"additional","affiliation":[{"name":"Research Center, Montreal Heart Institute (E.M., M.M., D.S., P.N., L.R.V., M.G.S., J.-C.T., S.N.), Universit\u00e9 de Montr\u00e9al, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin G.","family":"Sirois","sequence":"additional","affiliation":[{"name":"Research Center, Montreal Heart Institute (E.M., M.M., D.S., P.N., L.R.V., M.G.S., J.-C.T., S.N.), Universit\u00e9 de Montr\u00e9al, Canada."},{"name":"Department of Pharmacology and Physiology, Faculty of Medicine (M.G.S., J.-C.T., S.N.), Universit\u00e9 de Montr\u00e9al, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8200-8983","authenticated-orcid":true,"given":"Jean-Claude","family":"Tardif","sequence":"additional","affiliation":[{"name":"Research Center, Montreal Heart Institute (E.M., M.M., D.S., P.N., L.R.V., M.G.S., J.-C.T., S.N.), Universit\u00e9 de Montr\u00e9al, Canada."},{"name":"Department of Pharmacology and Physiology, Faculty of Medicine (M.G.S., J.-C.T., S.N.), Universit\u00e9 de Montr\u00e9al, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2437-5785","authenticated-orcid":true,"given":"T. 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