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PMID: 19948504 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Targeted SERCA2a gene expression identifies molecular mechanism and therapeutic target for arrhythmogenic cardiac alternans.

Circulation. Arrhythmia and electrophysiology ·Vol. 2 ·No. 6 ·2009-12-00 ·Pages 686-94

Cutler MJ, Wan X, Laurita KR, Hajjar RJ, Rosenbaum DS

Abstract

Beat-to-beat alternans of cellular repolarization is closely linked to ventricular arrhythmias in humans. We hypothesized that sarcoplasmic reticulum calcium reuptake by SERCA2a plays a central role in the mechanism of cellular alternans and that increasing SERCA2a gene expression will retard the development of cellular alternans. In vivo gene transfer of a recombinant adenoviral vector with the transgene for SERCA2a (Ad.SERCA2a) was performed in young guinea pigs. Isolated myocytes transduced with Ad.SERCA2a exhibited improved sarcoplasmic reticulum Ca(2+) reuptake (P<0.05) and were markedly resistant to cytosolic calcium alternans (P<0.05) under repetitive constant action potential clamp conditions (ie, when alternation of action potential duration was prevented), proving that sarcoplasmic reticulum Ca(2+) cycling is an important mechanism in the development of cellular alternans. Similarly, SERCA2a overexpression in the intact heart demonstrated significant resistance to alternation of action potential duration when compared with control hearts (heart rate threshold, 484+/-25 bpm versus 396+/-11 bpm, P<0.01), with no change in action potential duration restitution slope. Importantly, SERCA2a overexpression produced a 4-fold reduction in susceptibility to alternans-mediated ventricular arrhythmias (P<0.05). These data provide new evidence that sarcoplasmic reticulum Ca(2+) reuptake directly modulates susceptibility to cellular alternans. Moreover, SERCA2a overexpression suppresses cellular alternans, interrupting an important pathway to cardiac fibrillation in the intact heart.

MeSH Terms
Action Potentials Adenoviridae/genetics Animals Arrhythmias, Cardiac/enzymology,genetics,physiopathology,prevention & control Calcium/metabolism Cardiac Pacing, Artificial Disease Models, Animal Genetic Vectors Guinea Pigs Heart Rate Myocardium/enzymology Patch-Clamp Techniques Sarcoplasmic Reticulum/enzymology Sarcoplasmic Reticulum Calcium-Transporting ATPases/genetics,metabolism Time Factors Transduction, Genetic Up-Regulation
Chemicals
Sarcoplasmic Reticulum Calcium-Transporting ATPases Calcium
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Cutler Michael J
The Heart and Vascular Research Center, MetroHealth Campus, Case Western Reserve University, Cleveland, OH 44109-1998, USA.
Wan Xiaoping
Laurita Kenneth R
Hajjar Roger J
Rosenbaum David S
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Article Info
Journal
Circulation. Arrhythmia and electrophysiology
Abbr.
Circ Arrhythm Electrophysiol
ISSN
1941-3084
DOI
10.1161/CIRCEP.109.863118
Published
2009-12-00
Pages
686-94
Language
English
Region
United States
NLM ID
101474365
PMCID
PMC2795134
Subset
IM
Grants
NHLBI NIH HHS · R01 HL054807 · United States
NHLBI NIH HHS · R01 HL054807-08 · United States
NHLBI NIH HHS · R01-HL54807 · United States
External Links
PubMed source DOI: 10.1161/CIRCEP.109.863118 PMC Full Text View journal details
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