SERCA2a gene therapy in heart failure: an anti-arrhythmic positive inotrope

Br J Pharmacol. 2014 Jan;171(1):38-54. doi: 10.1111/bph.12472.

Abstract

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)(+) -ATPase2a (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.

Keywords: anti-arrhythmic; arrhythmia; gene therapy; heart failure.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Action Potentials
  • Animals
  • Arrhythmias, Cardiac / enzymology
  • Arrhythmias, Cardiac / genetics
  • Arrhythmias, Cardiac / physiopathology
  • Arrhythmias, Cardiac / prevention & control*
  • Disease Models, Animal
  • Excitation Contraction Coupling
  • Genetic Therapy* / adverse effects
  • Heart Failure / enzymology
  • Heart Failure / genetics
  • Heart Failure / physiopathology
  • Heart Failure / therapy*
  • Heart Rate*
  • Humans
  • Myocardial Contraction*
  • Recovery of Function
  • Risk Factors
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / genetics
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism*
  • Treatment Outcome

Substances

  • Sarcoplasmic Reticulum Calcium-Transporting ATPases