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SERCA2a gene therapy in heart failure: an anti‐arrhythmic positive inotrope
Author(s) -
Sikkel Markus B,
Hayward Carl,
MacLeod Kenneth T,
Harding Sian E,
Lyon Alexander R
Publication year - 2014
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12472
Subject(s) - inotrope , contractility , heart failure , medicine , cardiology , cardiac function curve , myocardial infarction , genetic enhancement , pharmacology , chemistry , gene , biochemistry
Therapeutic options that directly enhance cardiomyocyte contractility in chronic heart failure ( HF ) therapy are currently limited and do not improve prognosis. In fact, most positive inotropic agents, such as β‐adrenoreceptor agonists and PDE inhibitors, which have been assessed in HF patients, cause increased mortality as a result of arrhythmia and sudden cardiac death. Cardiac sarcoplasmic reticulum Ca 2 + ‐ ATP ase 2a ( SERCA2a ) is a key protein involved in sequestration of Ca 2 + into the sarcoplasmic reticulum ( SR ) during diastole. There is a reduction of SERCA2a protein level and function in HF , which has been successfully targeted via viral transfection of the SERCA2a gene into cardiac tissue in vivo . This has enhanced cardiac contractility and reduced mortality in several preclinical models of HF . Theoretical concerns have been raised regarding the possibility of arrhythmogenic adverse effects of SERCA2a gene therapy due to enhanced SR Ca 2 + load and induction of SR Ca 2 + leak as a result. Contrary to these concerns, SERCA2a gene therapy in a wide variety of preclinical models, including acute ischaemia/reperfusion, chronic pressure overload and chronic myocardial infarction, has resulted in a reduction in ventricular arrhythmias. The potential mechanisms for this unexpected beneficial effect, as well as mechanisms of enhancement of cardiac contractile function, are reviewed in this article.