{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T23:55:41Z","timestamp":1791330941122,"version":"4.3.1"},"reference-count":46,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2012,3,16]]},"abstract":"<jats:sec>\n                    <jats:title>\n                      <jats:underline>Rationale:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>\n                      Previously, we demonstrated that a deoxycorticosterone acetate (DOCA)-salt hypertensive mouse model produces cardiac oxidative stress and diastolic dysfunction with preserved systolic function. Oxidative stress has been shown to increase late inward sodium current (I\n                      <jats:sub>Na<\/jats:sub>\n                      ), reducing the net cytosolic Ca\n                      <jats:sup>2+<\/jats:sup>\n                      efflux.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Objective:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>\n                      Oxidative stress in the DOCA-salt model may increase late I\n                      <jats:sub>Na<\/jats:sub>\n                      , resulting in diastolic dysfunction amenable to treatment with ranolazine.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Methods and Results:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>\n                      Echocardiography detected evidence of diastolic dysfunction in hypertensive mice that improved after treatment with ranolazine (E\/E\u2032:sham, 31.9\u00b12.8, sham+ranolazine, 30.2\u00b11.9, DOCA-salt, 41.8\u00b12.6, and DOCA-salt+ranolazine, 31.9\u00b12.6;\n                      <jats:italic>P<\/jats:italic>\n                      =0.018). The end-diastolic pressure-volume relationship slope was elevated in DOCA-salt mice, improving to sham levels with treatment (sham, 0.16\u00b10.01 versus sham+ranolazine, 0.18\u00b10.01 versus DOCA-salt, 0.23\u00b10.2 versus DOCA-salt+ranolazine, 0.17\u00b10.0 1 mm Hg\/L;\n                      <jats:italic>P<\/jats:italic>\n                      &lt;0.005). DOCA-salt myocytes demonstrated impaired relaxation, \u03c4, improving with ranolazine (DOCA-salt, 0.18\u00b10.02, DOCA-salt+ranolazine, 0.13\u00b10.01, sham, 0.11\u00b10.01, sham+ranolazine, 0.09\u00b10.02 seconds;\n                      <jats:italic>P<\/jats:italic>\n                      =0.0004). Neither late I\n                      <jats:sub>Na<\/jats:sub>\n                      nor the Ca\n                      <jats:sup>2+<\/jats:sup>\n                      transients were different from sham myocytes. Detergent extracted fiber bundles from DOCA-salt hearts demonstrated increased myofilament response to Ca\n                      <jats:sup>2+<\/jats:sup>\n                      with glutathionylation of myosin binding protein C. Treatment with ranolazine ameliorated the Ca\n                      <jats:sup>2+<\/jats:sup>\n                      response and cross-bridge kinetics.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Conclusions:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>Diastolic dysfunction could be reversed by ranolazine, probably resulting from a direct effect on myofilaments, indicating that cardiac oxidative stress may mediate diastolic dysfunction through altering the contractile apparatus.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.111.258251","type":"journal-article","created":{"date-parts":[[2012,2,17]],"date-time":"2012-02-17T00:54:18Z","timestamp":1329440058000},"page":"841-850","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":160,"title":["Ranolazine Improves Cardiac Diastolic Dysfunction Through Modulation of Myofilament Calcium Sensitivity"],"prefix":"10.1161","volume":"110","author":[{"given":"Joshua D.","family":"Lovelock","sequence":"first","affiliation":[{"name":"From the Section of Cardiology, University of Illinois at Chicago and the Jesse Brown VA Medical Center, Chicago, IL (J.D.L., E.-M.J., H.A.L., H.L., L.G., P.K., N.P., S.C.D.); the Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL (M.M.M., B.G.P., D.M.T., R.J.S.); the Division of Cardiology, Emory University School of Medicine, Atlanta, GA (J.D.L., D.S.); and Gilead, Palo Alto, CA (D.Z., L.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle M.","family":"Monasky","sequence":"additional","affiliation":[{"name":"From the Section of Cardiology, University of Illinois at Chicago and the Jesse Brown VA Medical Center, Chicago, IL (J.D.L., E.-M.J., H.A.L., H.L., L.G., P.K., N.P., S.C.D.); the Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL (M.M.M., B.G.P., D.M.T., R.J.S.); the Division of Cardiology, Emory University School of Medicine, Atlanta, GA (J.D.L., D.S.); and Gilead, Palo Alto, CA (D.Z., L.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Euy-Myoung","family":"Jeong","sequence":"additional","affiliation":[{"name":"From the Section of Cardiology, University of Illinois at Chicago and the Jesse Brown VA Medical Center, Chicago, IL (J.D.L., E.-M.J., H.A.L., H.L., L.G., P.K., N.P., S.C.D.); the Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL (M.M.M., B.G.P., D.M.T., R.J.S.); the Division of Cardiology, Emory University School of Medicine, Atlanta, GA (J.D.L., D.S.); and Gilead, Palo Alto, CA (D.Z., L.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harvey A.","family":"Lardin","sequence":"additional","affiliation":[{"name":"From the Section of Cardiology, University of Illinois at Chicago and the Jesse Brown VA Medical Center, Chicago, IL (J.D.L., E.-M.J., H.A.L., H.L., L.G., P.K., N.P., S.C.D.); the Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL (M.M.M., B.G.P., D.M.T., R.J.S.); the Division of Cardiology, Emory University School of Medicine, Atlanta, GA (J.D.L., D.S.); and Gilead, Palo Alto, CA (D.Z., L.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Liu","sequence":"additional","affiliation":[{"name":"From the Section of Cardiology, University of Illinois at Chicago and the Jesse Brown VA Medical Center, Chicago, IL (J.D.L., E.-M.J., H.A.L., H.L., L.G., P.K., N.P., S.C.D.); the Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL (M.M.M., B.G.P., D.M.T., R.J.S.); the Division of Cardiology, Emory University School of Medicine, Atlanta, GA (J.D.L., D.S.); and Gilead, Palo Alto, CA (D.Z., L.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bindiya G.","family":"Patel","sequence":"additional","affiliation":[{"name":"From the Section of Cardiology, University of Illinois at Chicago and the Jesse Brown VA Medical Center, Chicago, IL (J.D.L., E.-M.J., H.A.L., H.L., L.G., P.K., N.P., S.C.D.); the Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL (M.M.M., B.G.P., D.M.T., R.J.S.); the Division of Cardiology, Emory University School of Medicine, Atlanta, GA (J.D.L., D.S.); and Gilead, Palo Alto, CA (D.Z., L.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Domenico M.","family":"Taglieri","sequence":"additional","affiliation":[{"name":"From the Section of Cardiology, University of Illinois at Chicago and the Jesse Brown VA Medical Center, Chicago, IL (J.D.L., E.-M.J., H.A.L., H.L., L.G., P.K., N.P., S.C.D.); the Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL (M.M.M., B.G.P., D.M.T., R.J.S.); the Division of Cardiology, Emory University School of Medicine, Atlanta, GA (J.D.L., D.S.); and Gilead, Palo Alto, CA (D.Z., L.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lianzhi","family":"Gu","sequence":"additional","affiliation":[{"name":"From the Section of Cardiology, University of Illinois at Chicago and the Jesse Brown VA Medical Center, Chicago, IL (J.D.L., E.-M.J., H.A.L., H.L., L.G., P.K., N.P., S.C.D.); the Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL (M.M.M., B.G.P., D.M.T., R.J.S.); the Division of Cardiology, Emory University School of Medicine, Atlanta, GA (J.D.L., D.S.); and Gilead, Palo Alto, CA (D.Z., L.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Praveen","family":"Kumar","sequence":"additional","affiliation":[{"name":"From the Section of Cardiology, University of Illinois at Chicago and the Jesse Brown VA Medical Center, Chicago, IL (J.D.L., E.-M.J., H.A.L., H.L., L.G., P.K., N.P., S.C.D.); the Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL (M.M.M., B.G.P., D.M.T., R.J.S.); the Division of Cardiology, Emory University School of Medicine, Atlanta, GA (J.D.L., D.S.); and Gilead, Palo Alto, CA (D.Z., L.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Narayan","family":"Pokhrel","sequence":"additional","affiliation":[{"name":"From the Section of Cardiology, University of Illinois at Chicago and the Jesse Brown VA Medical Center, Chicago, IL (J.D.L., E.-M.J., H.A.L., H.L., L.G., P.K., N.P., S.C.D.); the Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL (M.M.M., B.G.P., D.M.T., R.J.S.); the Division of Cardiology, Emory University School of Medicine, Atlanta, GA (J.D.L., D.S.); and Gilead, Palo Alto, CA (D.Z., L.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dewan","family":"Zeng","sequence":"additional","affiliation":[{"name":"From the Section of Cardiology, University of Illinois at Chicago and the Jesse Brown VA Medical Center, Chicago, IL (J.D.L., E.-M.J., H.A.L., H.L., L.G., P.K., N.P., S.C.D.); the Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL (M.M.M., B.G.P., D.M.T., R.J.S.); the Division of Cardiology, Emory University School of Medicine, Atlanta, GA (J.D.L., D.S.); and Gilead, Palo Alto, CA (D.Z., L.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luiz","family":"Belardinelli","sequence":"additional","affiliation":[{"name":"From the Section of Cardiology, University of Illinois at Chicago and the Jesse Brown VA Medical Center, Chicago, IL (J.D.L., E.-M.J., H.A.L., H.L., L.G., P.K., N.P., S.C.D.); the Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL (M.M.M., B.G.P., D.M.T., R.J.S.); the Division of Cardiology, Emory University School of Medicine, Atlanta, GA (J.D.L., D.S.); and Gilead, Palo Alto, CA (D.Z., L.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Sorescu","sequence":"additional","affiliation":[{"name":"From the Section of Cardiology, University of Illinois at Chicago and the Jesse Brown VA Medical Center, Chicago, IL (J.D.L., E.-M.J., H.A.L., H.L., L.G., P.K., N.P., S.C.D.); the Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL (M.M.M., B.G.P., D.M.T., R.J.S.); the Division of Cardiology, Emory University School of Medicine, Atlanta, GA (J.D.L., D.S.); and Gilead, Palo Alto, CA (D.Z., L.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. John","family":"Solaro","sequence":"additional","affiliation":[{"name":"From the Section of Cardiology, University of Illinois at Chicago and the Jesse Brown VA Medical Center, Chicago, IL (J.D.L., E.-M.J., H.A.L., H.L., L.G., P.K., N.P., S.C.D.); the Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL (M.M.M., B.G.P., D.M.T., R.J.S.); the Division of Cardiology, Emory University School of Medicine, Atlanta, GA (J.D.L., D.S.); and Gilead, Palo Alto, CA (D.Z., L.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr","given":"Samuel C.","family":"Dudley","sequence":"additional","affiliation":[{"name":"From the Section of Cardiology, University of Illinois at Chicago and the Jesse Brown VA Medical Center, Chicago, IL (J.D.L., E.-M.J., H.A.L., H.L., L.G., P.K., N.P., S.C.D.); the Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL (M.M.M., B.G.P., D.M.T., R.J.S.); the Division of Cardiology, Emory University School of Medicine, Atlanta, GA (J.D.L., D.S.); and Gilead, Palo Alto, CA (D.Z., L.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa052256"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.289.2.194"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.296.18.2209"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.107.188965"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncpcardio1245"},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.106.628347"},{"key":"e_1_3_5_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2008.09.031"},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0805450"},{"key":"e_1_3_5_10_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-94-010-0658-3"},{"key":"e_1_3_5_11_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1996.sp021772"},{"key":"e_1_3_5_12_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.71.5.1231"},{"key":"e_1_3_5_13_2","first-page":"H1034","article-title":"Palmitoyl carnitine modifies sodium currents and induces transient inward current in ventricular myocytes","volume":"266","author":"Wu J","year":"1994","unstructured":"Wu J, Corr PB . 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