Editorial Commentary| Volume 19, ISSUE 12, P2107-2114, December 2022

Reduced sarcoplasmic reticulum Ca2+ pump activity is antiarrhythmic in ischemic cardiomyopathy

Published:August 23, 2022DOI:


      We have described an arrhythmic mechanism seen only in cardiomyopathy that involves increased mitochondrial Ca2+ handling and selective transfer of Ca2+ to the sarcoplasmic reticulum (SR). Modeling suggested that mitochondrial Ca2+ transfer to the SR via type 2a sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a) is a crucial element of this arrhythmic mechanism.


      We tested the role of SERCA2a in arrhythmias during ischemic cardiomyopathy.


      Myocardial infarction (MI) was induced in wild-type (Wt) and SERCA2a heterozygous knockdown (SERCA+/−) mice.


      Compared with Wt MI mice, SERCA2a heterozygous knockdown (SERCA+/−) MI mice had a substantially lower mortality after 3 weeks of MI without a significant change in MI area. Aside from a significant delay of the cytoplasmic Ca2+ transient decay existed in SERCA+/− compared with Wt, SERCA+/− did not affect cardiac systolic and diastolic function at the whole organ or single cell levels either before or after MI. After MI, SERCA+/− mice had reduced SERCA2a expression in the MI border zone compared with Wt MI mice. SERCA+/− mice had significantly decreased corrected QT intervals and less ventricular tachycardia compared with Wt MI mice. SERCA+/− cardiomyocytes from MI mice showed a reduced action potential duration and reduced triggered activity compared with Wt MI cardiomyocytes. Reduction in arrhythmic risk was accompanied by reduced diastolic SR Ca2+ sparks, reduced SR Ca2+ content, reduced oxidized ryanodine receptor, and increased calsequestrin 2 in SERCA+/− MI mice.


      SERCA2a knockdown was antiarrhythmic after MI without affecting overall systolic performance. Possible antiarrhythmic mechanisms included reduced SR free Ca2+ and reduced diastolic SR Ca2+ release.


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        • Jaski B.E.
        • Jessup M.L.
        • Mancini D.M.
        • et al.
        Calcium upregulation by percutaneous administration of gene therapy in cardiac disease (CUPID Trial), a first-in-human phase 1/2 clinical trial.
        J Card Fail. 2009; 15: 171-181
        • Jessup M.
        • Greenberg B.
        • Mancini D.
        • et al.
        Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID): a phase 2 trial of intracoronary gene therapy of sarcoplasmic reticulum Ca2+-ATPase in patients with advanced heart failure.
        Circulation. 2011; 124: 304-313
        • Liu B.
        • Lou Q.
        • Smith H.
        • et al.
        Conditional up-regulation of SERCA2a exacerbates RyR2-dependent ventricular and atrial arrhythmias.
        Int J Mol Sci. 2020; 21: 2535
        • Kawase Y.
        • Ly H.Q.
        • Prunier F.
        • et al.
        Reversal of cardiac dysfunction after long-term expression of SERCA2a by gene transfer in a pre-clinical model of heart failure.
        J Am Coll Cardiol. 2008; 51: 1112-1119
        • del Monte F.
        • Williams E.
        • Lebeche D.
        • et al.
        Improvement in survival and cardiac metabolism after gene transfer of sarcoplasmic reticulum Ca2+-ATPase in a rat model of heart failure.
        Circulation. 2001; 104: 1424-1429
        • Marx S.O.
        • Reiken S.
        • Hisamatsu Y.
        • et al.
        PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts.
        Cell. 2000; 101: 365-376
        • Chen Y.
        • Escoubet B.
        • Prunier F.
        • et al.
        Constitutive cardiac overexpression of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase delays myocardial failure after myocardial infarction in rats at a cost of increased acute arrhythmias.
        Circulation. 2004; 109: 1898-1903
        • Greenberg B.
        • Butler J.
        • Felker G.M.
        • et al.
        Calcium upregulation by percutaneous administration of gene therapy in patients with cardiac disease (CUPID 2): a randomised, multinational, double-blind, placebo-controlled, phase 2b trial.
        Lancet. 2016; 387: 1178-1186
        • Xie A.
        • Song Z.
        • Liu H.
        • et al.
        Mitochondrial Ca2+ influx contributes to arrhythmic risk in nonischemic cardiomyopathy.
        J Am Heart Assoc. 2018; 7e007805
        • Liu T.
        • Takimoto E.
        • Dimaano V.L.
        • et al.
        Inhibiting mitochondrial Na+/Ca2+ exchange prevents sudden death in a guinea pig model of heart failure.
        Circ Res. 2014; 115: 44-54
        • Weiss J.N.
        • Garfinkel A.
        • Karagueuzian H.S.
        • Chen P.S.
        • Qu Z.
        Early afterdepolarizations and cardiac arrhythmias.
        Heart Rhythm. 2010; 7: 1891-1899
        • Rutledge C.A.
        • Ng F.S.
        • Sulkin M.S.
        • et al.
        c-Src kinase inhibition reduces arrhythmia inducibility and connexin43 dysregulation after myocardial infarction.
        J Am Coll Cardiol. 2014; 63: 928-934
        • Protti A.
        • Sirker A.
        • Shah A.M.
        • Botnar R.
        Late gadolinium enhancement of acute myocardial infarction in mice at 7T: cine-FLASH versus inversion recovery.
        J Magn Reson Imaging. 2010; 32: 878-886
        • Pan X.
        • Liu J.
        • Nguyen T.
        • et al.
        The physiological role of mitochondrial calcium revealed by mice lacking the mitochondrial calcium uniporter.
        Nat Cell Biol. 2013; 15: 1464-1472
        • O’Connell T.D.
        • Rodrigo M.C.
        • Simpson P.C.
        Isolation and culture of adult mouse cardiac myocytes.
        Methods Mol Biol. 2007; 357: 271-296
        • Silberman G.A.
        • Fan T.H.
        • Liu H.
        • et al.
        Uncoupled cardiac nitric oxide synthase mediates diastolic dysfunction.
        Circulation. 2010; 121: 519-528
        • Jeong E.M.
        • Monasky M.M.
        • Gu L.
        • et al.
        Tetrahydrobiopterin improves diastolic dysfunction by reversing changes in myofilament properties.
        J Mol Cell Cardiol. 2013; 56: 44-54
        • MacKenzie L.
        • Bootman M.D.
        • Laine M.
        • et al.
        The role of inositol 1,4,5-trisphosphate receptors in Ca2+ signalling and the generation of arrhythmias in rat atrial myocytes.
        J Physiol. 2002; 541: 395-409
        • Bovo E.
        • Mazurek S.R.
        • Zima A.V.
        Oxidation of ryanodine receptor after ischemia-reperfusion increases propensity of Ca2+ waves during β-adrenergic receptor stimulation.
        Am J Physiol Heart Circ Physiol. 2018; 315: H1032-H1040
        • Bovo E.
        • Mazurek S.R.
        • Zima A.V.
        The role of RyR2 oxidation in the blunted frequency-dependent facilitation of Ca2+ transient amplitude in rabbit failing myocytes.
        Pflugers Arch. 2018; 470: 959-968
        • Guatimosim S.
        • Guatimosim C.
        • Song L.S.
        Imaging calcium sparks in cardiac myocytes.
        Methods Mol Biol. 2011; 689: 205-214
        • Periasamy M.
        • Reed T.D.
        • Liu L.H.
        • et al.
        Impaired cardiac performance in heterozygous mice with a null mutation in the sarco(endo)plasmic reticulum Ca2+-ATPase isoform 2 (SERCA2) gene.
        J Biol Chem. 1999; 274: 2556-2562
        • Fowler E.D.
        • Wang N.
        • Hezzell M.
        • et al.
        Arrhythmogenic late Ca2+ sparks in failing heart cells and their control by action potential configuration.
        Proc Natl Acad Sci U S A. 2020; 117: 2687-2692
        • Voigt N.
        • Li N.
        • Wang Q.
        • et al.
        Enhanced sarcoplasmic reticulum Ca2+ leak and increased Na+-Ca2+ exchanger function underlie delayed afterdepolarizations in patients with chronic atrial fibrillation.
        Circulation. 2012; 125: 2059-2070
        • Terentyev D.
        • Kubalova Z.
        • Valle G.
        • et al.
        Modulation of SR Ca release by luminal Ca2+ and calsequestrin in cardiac myocytes: effects of CASQ2 mutations linked to sudden cardiac death.
        Biophys J. 2008; 95: 2037-2048
        • Zima A.V.
        • Mazurek S.R.
        Functional impact of ryanodine receptor oxidation on intracellular calcium regulation in the heart.
        Rev Physiol Biochem Pharmacol. 2016; 171: 39-62
        • Kalyanasundaram A.
        • Lacombe V.A.
        • Belevych A.E.
        • et al.
        Up-regulation of sarcoplasmic reticulum Ca2+ uptake leads to cardiac hypertrophy, contractile dysfunction and early mortality in mice deficient in CASQ2.
        Cardiovasc Res. 2013; 98: 297-306
        • Davia K.
        • Bernobich E.
        • Ranu H.K.
        • et al.
        SERCA2A overexpression decreases the incidence of aftercontractions in adult rabbit ventricular myocytes.
        J Mol Cell Cardiol. 2001; 33: 1005-1015
        • Lyon A.R.
        • Bannister M.L.
        • Collins T.
        • et al.
        SERCA2a gene transfer decreases sarcoplasmic reticulum calcium leak and reduces ventricular arrhythmias in a model of chronic heart failure.
        Circ Arrhythm Electrophysiol. 2011; 4: 362-372
        • Eisner D.
        • Caldwell J.
        • Trafford A.
        Sarcoplasmic reticulum Ca2+-ATPase and heart failure 20 years later.
        Circ Res. 2013; 113: 958-961
        • Prasad V.
        • Lorenz J.N.
        • Lasko V.M.
        • et al.
        SERCA2 haploinsufficiency in a mouse model of Darier disease causes a selective predisposition to heart failure.
        Biomed Res Int. 2015; 2015251598
        • Louch W.E.
        • Hougen K.
        • Mork H.K.
        • et al.
        Sodium accumulation promotes diastolic dysfunction in end-stage heart failure following Serca2 knockout.
        J Physiol. 2010; 588: 465-478