{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T14:12:26Z","timestamp":1791209546451,"version":"4.1.0"},"reference-count":34,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2013,8,27]]},"abstract":"<jats:sec>\n            <jats:title>Background\u2014<\/jats:title>\n            <jats:p>\n              Sarcoplasmic reticulum (SR) Ca\n              <jats:sup>2+<\/jats:sup>\n              leak through ryanodine receptor type 2 (RyR2) dysfunction is of major pathophysiological relevance in human heart failure (HF); however, mechanisms underlying progressive RyR2 dysregulation from cardiac hypertrophy to HF are still controversial.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results\u2014<\/jats:title>\n            <jats:p>\n              We investigated healthy control myocardium (n=5) and myocardium from patients with compensated hypertrophy (n=25) and HF (n=32). In hypertrophy, Ca\n              <jats:sup>2+<\/jats:sup>\n              \/calmodulin-dependent protein kinase II (CaMKII) and protein kinase A (PKA) both phosphorylated RyR2 at levels that were not different from healthy myocardium. Accordingly, inhibitors of these kinases reduced the SR Ca\n              <jats:sup>2+<\/jats:sup>\n              leak. In HF, however, the SR Ca\n              <jats:sup>2+<\/jats:sup>\n              leak was nearly doubled compared with hypertrophy, which led to reduced systolic Ca\n              <jats:sup>2+<\/jats:sup>\n              transients, a depletion of SR Ca\n              <jats:sup>2+<\/jats:sup>\n              storage and elevated diastolic Ca\n              <jats:sup>2+<\/jats:sup>\n              levels. This was accompanied by a significantly increased CaMKII-dependent phosphorylation of RyR2. In contrast, PKA-dependent RyR2 phosphorylation was not increased in HF and was independent of previous \u03b2-blocker treatment. In HF, CaMKII inhibition but not inhibition of PKA yielded a reduction of the SR Ca\n              <jats:sup>2+<\/jats:sup>\n              leak. Moreover, PKA inhibition further reduced SR Ca\n              <jats:sup>2+<\/jats:sup>\n              load and systolic Ca\n              <jats:sup>2+<\/jats:sup>\n              transients.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>\n              In human hypertrophy, both CaMKII and PKA functionally regulate RyR2 and may induce SR Ca\n              <jats:sup>2+<\/jats:sup>\n              leak. In the transition from hypertrophy to HF, the diastolic Ca\n              <jats:sup>2+<\/jats:sup>\n              leak increases and disturbed Ca\n              <jats:sup>2+<\/jats:sup>\n              cycling occurs. This is associated with an increase in CaMKII- but not PKA-dependent RyR2 phosphorylation. CaMKII inhibition may thus reflect a promising therapeutic target for the treatment of arrhythmias and contractile dysfunction.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.113.001746","type":"journal-article","created":{"date-parts":[[2013,7,20]],"date-time":"2013-07-20T05:56:56Z","timestamp":1374299816000},"page":"970-981","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":143,"title":["Ca\n            <sup>2+<\/sup>\n            \/Calmodulin-Dependent Protein Kinase II and Protein Kinase A Differentially Regulate Sarcoplasmic Reticulum Ca\n            <sup>2+<\/sup>\n            Leak in Human Cardiac Pathology"],"prefix":"10.1161","volume":"128","author":[{"given":"Thomas H.","family":"Fischer","sequence":"first","affiliation":[{"name":"From Abteilung Kardiologie und Pneumologie\/Herzzentrum (T.H.F., J.H., S.N., K.T., A.F., G.H., L.S.M., S.S.), Abteilung Thorax, Herz, Gef\u00e4\u00dfchirurgie\/Herzzentrum (T.T., F.A.S.), and Abteilung Medizinische Statistik (D.E.), Georg August Universit\u00e4t G\u00f6ttingen, G\u00f6ttingen, Germany; Abteilung Thorax, Herz, Gef\u00e4\u00dfchirurgie, Herz und Diabeteszentrum Nordrheinwestfalen, Bad Oeynhausen, Germany (A.R., J.G.); Abteilung Herz, Thorax, Gef\u00e4\u00dfchirurgie und Transplantationschirurgie, Medizinische Hochschule Hannover,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonas","family":"Herting","sequence":"additional","affiliation":[{"name":"From Abteilung Kardiologie und Pneumologie\/Herzzentrum (T.H.F., J.H., S.N., K.T., A.F., G.H., L.S.M., S.S.), Abteilung Thorax, Herz, Gef\u00e4\u00dfchirurgie\/Herzzentrum (T.T., F.A.S.), and Abteilung Medizinische Statistik (D.E.), Georg August Universit\u00e4t G\u00f6ttingen, G\u00f6ttingen, Germany; Abteilung Thorax, Herz, Gef\u00e4\u00dfchirurgie, Herz und Diabeteszentrum Nordrheinwestfalen, Bad Oeynhausen, Germany (A.R., J.G.); Abteilung Herz, Thorax, Gef\u00e4\u00dfchirurgie und Transplantationschirurgie, Medizinische Hochschule Hannover,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theodor","family":"Tirilomis","sequence":"additional","affiliation":[{"name":"From Abteilung Kardiologie und Pneumologie\/Herzzentrum (T.H.F., J.H., S.N., K.T., A.F., G.H., L.S.M., S.S.), Abteilung Thorax, Herz, Gef\u00e4\u00dfchirurgie\/Herzzentrum (T.T., F.A.S.), and Abteilung Medizinische Statistik (D.E.), Georg August Universit\u00e4t G\u00f6ttingen, G\u00f6ttingen, Germany; Abteilung Thorax, Herz, Gef\u00e4\u00dfchirurgie, Herz und Diabeteszentrum Nordrheinwestfalen, Bad Oeynhausen, Germany (A.R., J.G.); Abteilung Herz, Thorax, Gef\u00e4\u00dfchirurgie und Transplantationschirurgie, Medizinische Hochschule Hannover,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9","family":"Renner","sequence":"additional","affiliation":[{"name":"From Abteilung Kardiologie und Pneumologie\/Herzzentrum (T.H.F., J.H., S.N., K.T., A.F., G.H., L.S.M., S.S.), Abteilung Thorax, Herz, Gef\u00e4\u00dfchirurgie\/Herzzentrum (T.T., F.A.S.), and Abteilung Medizinische Statistik (D.E.), Georg August Universit\u00e4t G\u00f6ttingen, G\u00f6ttingen, Germany; Abteilung Thorax, Herz, Gef\u00e4\u00dfchirurgie, Herz und Diabeteszentrum Nordrheinwestfalen, Bad Oeynhausen, Germany (A.R., J.G.); Abteilung Herz, Thorax, Gef\u00e4\u00dfchirurgie und Transplantationschirurgie, Medizinische Hochschule Hannover,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Neef","sequence":"additional","affiliation":[{"name":"From Abteilung Kardiologie und Pneumologie\/Herzzentrum (T.H.F., J.H., S.N., K.T., A.F., G.H., L.S.M., S.S.), Abteilung Thorax, Herz, Gef\u00e4\u00dfchirurgie\/Herzzentrum (T.T., F.A.S.), and Abteilung Medizinische Statistik (D.E.), Georg August Universit\u00e4t G\u00f6ttingen, G\u00f6ttingen, Germany; Abteilung Thorax, Herz, Gef\u00e4\u00dfchirurgie, Herz und Diabeteszentrum Nordrheinwestfalen, Bad Oeynhausen, Germany (A.R., J.G.); Abteilung Herz, Thorax, Gef\u00e4\u00dfchirurgie und Transplantationschirurgie, Medizinische Hochschule Hannover,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl","family":"Toischer","sequence":"additional","affiliation":[{"name":"From Abteilung Kardiologie und Pneumologie\/Herzzentrum (T.H.F., J.H., S.N., K.T., A.F., G.H., L.S.M., S.S.), Abteilung Thorax, Herz, Gef\u00e4\u00dfchirurgie\/Herzzentrum (T.T., F.A.S.), and Abteilung Medizinische Statistik (D.E.), Georg August Universit\u00e4t G\u00f6ttingen, G\u00f6ttingen, Germany; Abteilung Thorax, Herz, Gef\u00e4\u00dfchirurgie, Herz und Diabeteszentrum Nordrheinwestfalen, Bad Oeynhausen, Germany (A.R., J.G.); Abteilung Herz, Thorax, Gef\u00e4\u00dfchirurgie und Transplantationschirurgie, Medizinische Hochschule Hannover,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Ellenberger","sequence":"additional","affiliation":[{"name":"From Abteilung Kardiologie und Pneumologie\/Herzzentrum (T.H.F., J.H., S.N., K.T., A.F., G.H., L.S.M., S.S.), Abteilung Thorax, Herz, Gef\u00e4\u00dfchirurgie\/Herzzentrum (T.T., F.A.S.), and Abteilung Medizinische Statistik (D.E.), Georg August Universit\u00e4t G\u00f6ttingen, G\u00f6ttingen, Germany; Abteilung Thorax, Herz, Gef\u00e4\u00dfchirurgie, Herz und Diabeteszentrum Nordrheinwestfalen, Bad Oeynhausen, Germany (A.R., J.G.); Abteilung Herz, Thorax, Gef\u00e4\u00dfchirurgie und Transplantationschirurgie, Medizinische Hochschule Hannover,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"F\u00f6rster","sequence":"additional","affiliation":[{"name":"From Abteilung Kardiologie und Pneumologie\/Herzzentrum (T.H.F., J.H., S.N., K.T., A.F., G.H., L.S.M., S.S.), Abteilung Thorax, Herz, Gef\u00e4\u00dfchirurgie\/Herzzentrum (T.T., F.A.S.), and Abteilung Medizinische Statistik (D.E.), Georg August Universit\u00e4t G\u00f6ttingen, G\u00f6ttingen, Germany; Abteilung Thorax, Herz, Gef\u00e4\u00dfchirurgie, Herz und Diabeteszentrum Nordrheinwestfalen, Bad Oeynhausen, Germany (A.R., J.G.); Abteilung Herz, Thorax, Gef\u00e4\u00dfchirurgie und Transplantationschirurgie, Medizinische Hochschule Hannover,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan D.","family":"Schmitto","sequence":"additional","affiliation":[{"name":"From Abteilung Kardiologie und Pneumologie\/Herzzentrum (T.H.F., J.H., S.N., K.T., A.F., G.H., L.S.M., S.S.), Abteilung Thorax, Herz, Gef\u00e4\u00dfchirurgie\/Herzzentrum (T.T., F.A.S.), and Abteilung Medizinische Statistik (D.E.), Georg August Universit\u00e4t G\u00f6ttingen, G\u00f6ttingen, Germany; Abteilung Thorax, Herz, Gef\u00e4\u00dfchirurgie, Herz und Diabeteszentrum Nordrheinwestfalen, Bad Oeynhausen, Germany (A.R., J.G.); Abteilung Herz, Thorax, Gef\u00e4\u00dfchirurgie und Transplantationschirurgie, Medizinische Hochschule Hannover,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Gummert","sequence":"additional","affiliation":[{"name":"From Abteilung Kardiologie und Pneumologie\/Herzzentrum (T.H.F., J.H., S.N., K.T., A.F., G.H., L.S.M., S.S.), Abteilung Thorax, Herz, Gef\u00e4\u00dfchirurgie\/Herzzentrum (T.T., F.A.S.), and Abteilung Medizinische Statistik (D.E.), Georg August Universit\u00e4t G\u00f6ttingen, G\u00f6ttingen, Germany; Abteilung Thorax, Herz, Gef\u00e4\u00dfchirurgie, Herz und Diabeteszentrum Nordrheinwestfalen, Bad Oeynhausen, Germany (A.R., J.G.); Abteilung Herz, Thorax, Gef\u00e4\u00dfchirurgie und Transplantationschirurgie, Medizinische Hochschule Hannover,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Friedrich A.","family":"Sch\u00f6ndube","sequence":"additional","affiliation":[{"name":"From Abteilung Kardiologie und Pneumologie\/Herzzentrum (T.H.F., J.H., S.N., K.T., A.F., G.H., L.S.M., S.S.), Abteilung Thorax, Herz, Gef\u00e4\u00dfchirurgie\/Herzzentrum (T.T., F.A.S.), and Abteilung Medizinische Statistik (D.E.), Georg August Universit\u00e4t G\u00f6ttingen, G\u00f6ttingen, Germany; Abteilung Thorax, Herz, Gef\u00e4\u00dfchirurgie, Herz und Diabeteszentrum Nordrheinwestfalen, Bad Oeynhausen, Germany (A.R., J.G.); Abteilung Herz, Thorax, Gef\u00e4\u00dfchirurgie und Transplantationschirurgie, Medizinische Hochschule Hannover,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerd","family":"Hasenfuss","sequence":"additional","affiliation":[{"name":"From Abteilung Kardiologie und Pneumologie\/Herzzentrum (T.H.F., J.H., S.N., K.T., A.F., G.H., L.S.M., S.S.), Abteilung Thorax, Herz, Gef\u00e4\u00dfchirurgie\/Herzzentrum (T.T., F.A.S.), and Abteilung Medizinische Statistik (D.E.), Georg August Universit\u00e4t G\u00f6ttingen, G\u00f6ttingen, Germany; Abteilung Thorax, Herz, Gef\u00e4\u00dfchirurgie, Herz und Diabeteszentrum Nordrheinwestfalen, Bad Oeynhausen, Germany (A.R., J.G.); Abteilung Herz, Thorax, Gef\u00e4\u00dfchirurgie und Transplantationschirurgie, Medizinische Hochschule Hannover,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars S.","family":"Maier","sequence":"additional","affiliation":[{"name":"From Abteilung Kardiologie und Pneumologie\/Herzzentrum (T.H.F., J.H., S.N., K.T., A.F., G.H., L.S.M., S.S.), Abteilung Thorax, Herz, Gef\u00e4\u00dfchirurgie\/Herzzentrum (T.T., F.A.S.), and Abteilung Medizinische Statistik (D.E.), Georg August Universit\u00e4t G\u00f6ttingen, G\u00f6ttingen, Germany; Abteilung Thorax, Herz, Gef\u00e4\u00dfchirurgie, Herz und Diabeteszentrum Nordrheinwestfalen, Bad Oeynhausen, Germany (A.R., J.G.); Abteilung Herz, Thorax, Gef\u00e4\u00dfchirurgie und Transplantationschirurgie, Medizinische Hochschule Hannover,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Sossalla","sequence":"additional","affiliation":[{"name":"From Abteilung Kardiologie und Pneumologie\/Herzzentrum (T.H.F., J.H., S.N., K.T., A.F., G.H., L.S.M., S.S.), Abteilung Thorax, Herz, Gef\u00e4\u00dfchirurgie\/Herzzentrum (T.T., F.A.S.), and Abteilung Medizinische Statistik (D.E.), Georg August Universit\u00e4t G\u00f6ttingen, G\u00f6ttingen, Germany; Abteilung Thorax, Herz, Gef\u00e4\u00dfchirurgie, Herz und Diabeteszentrum Nordrheinwestfalen, Bad Oeynhausen, Germany (A.R., J.G.); Abteilung Herz, Thorax, Gef\u00e4\u00dfchirurgie und Transplantationschirurgie, Medizinische Hochschule 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