{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T10:48:40Z","timestamp":1792666120251,"version":"4.5.0"},"reference-count":59,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"11","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2018,9,11]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>\n                      Advances in congestive heart failure (CHF) management depend on biomarkers for monitoring disease progression and therapeutic response. During systole, intracellular Ca\n                      <jats:sup>2+<\/jats:sup>\n                      is released from the sarcoplasmic reticulum into the cytoplasm through type-2 ryanodine receptor\/Ca\n                      <jats:sup>2+<\/jats:sup>\n                      release channels. In CHF, chronically elevated circulating catecholamine levels cause pathological remodeling of type-2 ryanodine receptor\/Ca\n                      <jats:sup>2+<\/jats:sup>\n                      release channels resulting in diastolic sarcoplasmic reticulum Ca\n                      <jats:sup>2+<\/jats:sup>\n                      leak and decreased myocardial contractility. Similarly, skeletal muscle contraction requires sarcoplasmic reticulum Ca\n                      <jats:sup>2+<\/jats:sup>\n                      release through type-1 ryanodine receptors (RyR1), and chronically elevated catecholamine levels in CHF cause RyR1-mediated sarcoplasmic reticulum Ca\n                      <jats:sup>2+<\/jats:sup>\n                      leak, contributing to myopathy and weakness. Circulating B-lymphocytes express RyR1 and catecholamine-responsive signaling cascades, making them a potential surrogate for defects in intracellular Ca\n                      <jats:sup>2+<\/jats:sup>\n                      handling because of leaky RyR channels in CHF.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      Whole blood was collected from patients with CHF, CHF following left-ventricular assist device implant, and controls. Blood was also collected from mice with ischemic CHF, ischemic CHF+S107 (a drug that specifically reduces RyR channel Ca\n                      <jats:sup>2+<\/jats:sup>\n                      leak), and wild-type controls. Channel macromolecular complex was assessed by immunostaining RyR1 immunoprecipitated from lymphocyte-enriched preparations. RyR1 Ca\n                      <jats:sup>2+<\/jats:sup>\n                      leak was assessed using flow cytometry to measure Ca\n                      <jats:sup>2+<\/jats:sup>\n                      fluorescence in B-lymphocytes in the absence and presence of RyR1 agonists that empty RyR1 Ca\n                      <jats:sup>2+<\/jats:sup>\n                      stores within the endoplasmic reticulum.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      Circulating B-lymphocytes from humans and mice with CHF exhibited remodeled RyR1 and decreased endoplasmic reticulum Ca\n                      <jats:sup>2+<\/jats:sup>\n                      stores, consistent with chronic intracellular Ca\n                      <jats:sup>2+<\/jats:sup>\n                      leak. This Ca\n                      <jats:sup>2+<\/jats:sup>\n                      leak correlated with circulating catecholamine levels. The intracellular Ca\n                      <jats:sup>2+<\/jats:sup>\n                      leak was significantly reduced in mice treated with the Rycal S107. Patients with CHF treated with left-ventricular assist devices exhibited a heterogeneous response.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>\n                      In CHF, B-lymphocytes exhibit remodeled leaky RyR1 channels and decreased endoplasmic reticulum Ca\n                      <jats:sup>2+<\/jats:sup>\n                      stores consistent with chronic intracellular Ca\n                      <jats:sup>2+<\/jats:sup>\n                      leak. RyR1-mediated Ca\n                      <jats:sup>2+<\/jats:sup>\n                      leak in B-lymphocytes assessed using flow cytometry provides a surrogate measure of intracellular Ca\n                      <jats:sup>2+<\/jats:sup>\n                      handling and systemic sympathetic burden, presenting a novel biomarker for monitoring response to pharmacological and mechanical CHF therapy.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.117.032703","type":"journal-article","created":{"date-parts":[[2018,3,28]],"date-time":"2018-03-28T05:25:15Z","timestamp":1522214715000},"page":"1144-1154","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":45,"title":["Ryanodine Receptor Calcium Leak in Circulating B-Lymphocytes as a Biomarker in Heart Failure"],"prefix":"10.1161","volume":"138","author":[{"given":"Alexander","family":"Kushnir","sequence":"first","affiliation":[{"name":"Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, Columbia University College of Physicians and Surgeons, New York (A.K., G.S., S.R.R., A.R.M.)."},{"name":"Department of Medicine, Division of Cardiology, Columbia University Medical Center, New York (A.K., E.C., S.J.G., D.L.B., P.C.C., M.Y., A.R.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaetano","family":"Santulli","sequence":"additional","affiliation":[{"name":"Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, Columbia University College of Physicians and Surgeons, New York (A.K., G.S., S.R.R., A.R.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven R.","family":"Reiken","sequence":"additional","affiliation":[{"name":"Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, Columbia University College of Physicians and Surgeons, New York (A.K., G.S., S.R.R., A.R.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellie","family":"Coromilas","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiology, Columbia University Medical Center, New York (A.K., E.C., S.J.G., D.L.B., P.C.C., M.Y., A.R.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah J.","family":"Godfrey","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiology, Columbia University Medical Center, New York (A.K., E.C., S.J.G., D.L.B., P.C.C., M.Y., A.R.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle L.","family":"Brunjes","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiology, Columbia University Medical Center, New York (A.K., E.C., S.J.G., D.L.B., P.C.C., M.Y., A.R.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo C.","family":"Colombo","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiology, Columbia University Medical Center, New York (A.K., E.C., S.J.G., D.L.B., P.C.C., M.Y., A.R.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melana","family":"Yuzefpolskaya","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiology, Columbia University Medical Center, New York (A.K., E.C., S.J.G., D.L.B., P.C.C., M.Y., A.R.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seth I.","family":"Sokol","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiology, Jacobi Medical Center, Bronx, NY (S.I.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard N.","family":"Kitsis","sequence":"additional","affiliation":[{"name":"Departments of 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