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dc.contributor.authorLovelock, Joshua D.
dc.contributor.authorMonasky, Michelle M.
dc.contributor.authorJeong, Euy-Myoung
dc.contributor.authorLardin, Harvey A.
dc.contributor.authorLiu, Hong
dc.contributor.authorPatel, Bindiya G.
dc.contributor.authorTaglieri, Domenico M.
dc.contributor.authorGu, Lianzhi
dc.contributor.authorKumar, Praveen
dc.contributor.authorPokhrel, Narayan
dc.contributor.authorZeng, Dewan
dc.contributor.authorBelardinelli, Luiz
dc.contributor.authorSorescu, Dan
dc.contributor.authorSolaro, R. John
dc.contributor.authorDudley, Samuel C. Jr
dc.date.accessioned2013-11-19T19:34:10Z
dc.date.available2013-11-19T19:34:10Z
dc.date.issued2012-03
dc.identifier.bibliographicCitationLovelock JD, Monasky MM, Jeong EM, Lardin HA, Liu H, Patel BG, Taglieri DM, Gu L, Kumar P, Pokhrel N, Zeng D, Belardinelli L, Sorescu D, Solaro RJ, Dudley SC Jr. Ranolazine improves cardiac diastolic dysfunction through modulation of myofilament calcium sensitivity. Circulation Research. 2012 Mar 16;110(6):841-50. doi: 10.1161/CIRCRESAHA.111.258251en_US
dc.identifier.issn1524-4571
dc.identifier.urihttp://hdl.handle.net/10027/10543
dc.descriptionThis is a copy of an article published in the Circulation Research © 2012 American Heart Association available at http://circres.ahajournals.org/en_US
dc.description.abstractRATIONALE: 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(Na)), reducing the net cytosolic Ca(2+) efflux. OBJECTIVE: Oxidative stress in the DOCA-salt model may increase late I(Na), resulting in diastolic dysfunction amenable to treatment with ranolazine. METHODS AND RESULTS: Echocardiography detected evidence of diastolic dysfunction in hypertensive mice that improved after treatment with ranolazine (E/E':sham, 31.9 ± 2.8, sham+ranolazine, 30.2 ± 1.9, DOCA-salt, 41.8 ± 2.6, and DOCA-salt+ranolazine, 31.9 ± 2.6; P=0.018). The end-diastolic pressure-volume relationship slope was elevated in DOCA-salt mice, improving to sham levels with treatment (sham, 0.16 ± 0.01 versus sham+ranolazine, 0.18 ± 0.01 versus DOCA-salt, 0.23 ± 0.2 versus DOCA-salt+ranolazine, 0.17 ± 0.0 1 mm Hg/L; P<0.005). DOCA-salt myocytes demonstrated impaired relaxation, τ, improving with ranolazine (DOCA-salt, 0.18 ± 0.02, DOCA-salt+ranolazine, 0.13 ± 0.01, sham, 0.11 ± 0.01, sham+ranolazine, 0.09 ± 0.02 seconds; P=0.0004). Neither late I(Na) nor the Ca(2+) transients were different from sham myocytes. Detergent extracted fiber bundles from DOCA-salt hearts demonstrated increased myofilament response to Ca(2+) with glutathionylation of myosin binding protein C. Treatment with ranolazine ameliorated the Ca(2+) response and cross-bridge kinetics. CONCLUSIONS: 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.en_US
dc.description.sponsorshipThis study was supported by grants R01 HL085558, R01 HL073753, P01 HL058000, and a Veterans Affairs MERIT grant (S.C.D.); T32 HL007692 (J.D.L., M.M.M.); R01 HL090851 and ARRA supplement R01HL090851–02S1 (D.S.); and HL022231, RO1 HL064035, and PO1 HL062426 (R.J.S.).en_US
dc.language.isoen_USen_US
dc.publisherCirculation Researchen_US
dc.subjectdiastoleen_US
dc.subjectranolazineen_US
dc.subjectOxidative stressen_US
dc.titleRanolazine Improves Cardiac Diastolic Dysfunction Through Modulation of Myofilament Calcium Sensitivityen_US
dc.typeArticleen_US


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