{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2023,10,5]],"date-time":"2023-10-05T16:15:18Z","timestamp":1696522518370},"reference-count":32,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2016,1,27]],"date-time":"2016-01-27T00:00:00Z","timestamp":1453852800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Deutsche Forschungsgemeinschaft (DFG)","award":["SFB 1002 (A03)"],"award-info":[{"award-number":["SFB 1002 (A03)"]}]},{"name":"German Heart Foundation\/German Foundation of Heart Research"},{"name":"German Cardiac Society (DGK)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Artificial Organs"],"published-print":{"date-parts":[[2016,8]]},"abstract":"Abstract<\/jats:title>In heart failure, left ventricular assist device (LVAD<\/jats:styled-content>) implantation is performed to ensure sufficient cardiac output. Whereas some patients are subsequently weaned from LVAD<\/jats:styled-content> support, other patients still need heart transplantation. To elucidate underlying mechanisms, we assessed the arrhythmogenic SR<\/jats:styled-content>\u2010C<\/jats:styled-content>a2+<\/jats:sup> leak at the time of LVAD<\/jats:styled-content> implantation (HF<\/jats:styled-content>\u2010I<\/jats:styled-content>m) and heart transplantation (HF<\/jats:styled-content>\u2010T<\/jats:styled-content>x) and evaluated the effects of CaMKII<\/jats:styled-content>\u2010inhibition. Human left\u2010ventricular cardiomyocytes were isolated, paced at 1\u2009Hz for 10 beats to ensure SR<\/jats:styled-content>\u2010C<\/jats:styled-content>a2+<\/jats:sup> loading and scanned for diastolic C<\/jats:styled-content>a2+<\/jats:sup> sparks (confocal microscopy). In HF<\/jats:styled-content>\u2010I<\/jats:styled-content>m, the high diastolic spark frequency (CaSpF<\/jats:styled-content>) of 0.76\u2009\u00b1\u20090.12\u2009\u00d7\u2009100\u2009\u03bcm\u22121<\/jats:sup>\u2009\u00d7\u2009s\u22121<\/jats:sup> could be reduced to 0.48\u2009\u00b1\u20090.10\u2009\u00d7\u2009100\u2009\u03bcm\u22121<\/jats:sup>\u2009\u00d7\u2009s\u22121<\/jats:sup> by CaMKII<\/jats:styled-content> inhibition (AIP<\/jats:styled-content>, 1\u2009\u03bcM). The amplitude of C<\/jats:styled-content>a2+<\/jats:sup> sparks, width, and length was not significantly altered. In sum, CaMKII<\/jats:styled-content> inhibition yielded a clear tendency toward a reduction of the SR<\/jats:styled-content>\u2010C<\/jats:styled-content>a2+<\/jats:sup> leak (n cells\/patients\u2009=\u200976\/6 vs. 108\/6, P<\/jats:italic>\u2009=\u20090.08). In HF<\/jats:styled-content>\u2010Tx, we detected an even higher CaSpF of 1.00\u2009\u00b1\u20090.10 100\u2009\u03bcm\u22121<\/jats:sup>\u2009\u00d7\u2009s\u22121<\/jats:sup> and a higher SR<\/jats:styled-content>\u2010C<\/jats:styled-content>a2+<\/jats:sup> leak compared with HF<\/jats:styled-content>\u2010I<\/jats:styled-content>m (increase by 81\u2009\u00b1\u200933%, n cells\/patients\u2009=\u2009156\/7 vs. 130\/7, P<\/jats:italic>\u2009<\u20090.05), which fits to the further decreased LV<\/jats:styled-content> function. Here, CaMKII<\/jats:styled-content> inhibition likewise reduced CaSpF<\/jats:styled-content> (0.35\u2009\u00b1\u20090.09 100\u2009\u03bcm\u22121<\/jats:sup>\u2009\u00d7\u2009s\u22121,<\/jats:sup> P<\/jats:italic>\u2009=\u20090.06) and significantly reduced spark duration (n sparks\/patients\u2009=\u200958\/3 vs. 159\/3, P<\/jats:italic>\u2009<\u20090.05). Conclusively, the SR<\/jats:styled-content>\u2010C<\/jats:styled-content>a2+<\/jats:sup> leak was reduced by 69\u2009\u00b1\u200912% in HF<\/jats:styled-content>\u2010T<\/jats:styled-content>x upon CaMKII<\/jats:styled-content> inhibition (n cells\/patients\u2009=\u200953\/3 vs. 91\/3, P<\/jats:italic>\u2009<\u20090.05). These data show that the SR<\/jats:styled-content>\u2010C<\/jats:styled-content>a2+<\/jats:sup> leak correlates with the development of LV<\/jats:styled-content> function after LVAD<\/jats:styled-content> implantation and may represent an important pathomechanism. The fact that CaMKII<\/jats:styled-content> inhibition reduces the SR<\/jats:styled-content>\u2010C<\/jats:styled-content>a2+<\/jats:sup> leak in HF<\/jats:styled-content>\u2010T<\/jats:styled-content>x suggests that CaMKII<\/jats:styled-content> inhibition may be a promising option to beneficially influence clinical course after LVAD<\/jats:styled-content> implantation.<\/jats:p>","DOI":"10.1111\/aor.12677","type":"journal-article","created":{"date-parts":[[2016,1,27]],"date-time":"2016-01-27T11:27:54Z","timestamp":1453894074000},"page":"719-726","source":"Crossref","is-referenced-by-count":4,"title":["Inhibition of CaMKII<\/scp> Attenuates Progressing Disruption of C<\/scp>a2+<\/sup> Homeostasis Upon Left Ventricular Assist Device Implantation in Human Heart Failure"],"prefix":"10.1111","volume":"40","author":[{"given":"Thomas H.","family":"Fischer","sequence":"first","affiliation":[{"name":"Department for Cardiology and Pulmonology Georg\u2010August University G\u00f6ttingen Germany"},{"name":"German Center for Cardiovascular Research (DZHK) G\u00f6ttingen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Astrid","family":"Kleinw\u00e4chter","sequence":"additional","affiliation":[{"name":"Department for Cardiology and Pulmonology Georg\u2010August University G\u00f6ttingen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonas","family":"Herting","sequence":"additional","affiliation":[{"name":"Department for Cardiology and Pulmonology Georg\u2010August University G\u00f6ttingen Germany"},{"name":"German Center for Cardiovascular Research (DZHK) G\u00f6ttingen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J\u00f6rg","family":"Eiringhaus","sequence":"additional","affiliation":[{"name":"Department for Cardiology and Pulmonology Georg\u2010August University G\u00f6ttingen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nico","family":"Hartmann","sequence":"additional","affiliation":[{"name":"Department for Cardiology and Pulmonology Georg\u2010August University G\u00f6ttingen Germany"},{"name":"German Center for Cardiovascular Research (DZHK) G\u00f6ttingen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andr\u00e9","family":"Renner","sequence":"additional","affiliation":[{"name":"Department for Heart and Transplantation Surgery Heart Center Bad Oeynhausen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"Gummert","sequence":"additional","affiliation":[{"name":"Department for Heart and Transplantation Surgery Heart Center Bad Oeynhausen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Axel","family":"Haverich","sequence":"additional","affiliation":[{"name":"Department for Thoracic and Heart Surgery Medical University of Hannover Hannover Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan D.","family":"Schmitto","sequence":"additional","affiliation":[{"name":"Department for Thoracic and Heart Surgery Medical University of Hannover Hannover Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samuel","family":"Sossalla","sequence":"additional","affiliation":[{"name":"Department for Cardiology and Pulmonology Georg\u2010August University G\u00f6ttingen Germany"},{"name":"German Center for Cardiovascular Research (DZHK) G\u00f6ttingen Germany"},{"name":"Department for Internal Medicine III, Cardiology, Angiology, and Intensive Care Medicine University Medical Center Kiel 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