Restoration of contractile function in isolated cardiomyocytes from failing human hearts by gene transfer of SERCA2a

Circulation. 1999 Dec 7;100(23):2308-11. doi: 10.1161/01.cir.100.23.2308.

Abstract

Background: Failing human myocardium is characterized by abnormal relaxation, a deficient sarcoplasmic reticulum (SR) Ca(2+) uptake, and a negative frequency response, which have all been related to a deficiency in the SR Ca(2+) ATPase (SERCA2a) pump.

Methods and results: To test the hypothesis that an increase in SERCA2a could improve contractile function in cardiomyocytes, we overexpressed SERCA2a in human ventricular myocytes from 10 patients with end-stage heart failure and examined intracellular Ca(2+) handling and contractile function. Overexpression of SERCA2a resulted in an increase in both protein expression and pump activity and induced a faster contraction velocity (26.7+/-6.7% versus 16.6+/-2.7% shortening per second, P<0.005) and enhanced relaxation velocity (32. 0+/-10.1% versus 15.1+/-2.4%, P<0.005). Diastolic Ca(2+) was decreased in failing cardiomyocytes overexpressing SERCA2a (270+/-26 versus 347+/-30 nmol/L, P<0.005), whereas systolic Ca(2+) was increased (601+/-38 versus 508+/-25 nmol/L, P<0.05). In addition, the frequency response was normalized in cardiomyocytes overexpressing SERCA2a.

Conclusions: These results support the premise that gene-based therapies and targeting of specific pathways in human heart failure may offer a new modality for the treatment of this disease.

Publication types

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

MeSH terms

  • Calcium / metabolism
  • Calcium-Transporting ATPases / analysis
  • Calcium-Transporting ATPases / genetics*
  • Calcium-Transporting ATPases / metabolism
  • Cardiomyopathy, Dilated / physiopathology
  • Cardiomyopathy, Dilated / therapy
  • Cells, Cultured
  • Gene Expression
  • Genetic Therapy*
  • Heart Failure / physiopathology
  • Heart Failure / therapy*
  • Humans
  • Muscle Fibers, Skeletal / cytology
  • Muscle Fibers, Skeletal / enzymology*
  • Myocardial Contraction / genetics*
  • Sarcoplasmic Reticulum / enzymology

Substances

  • Calcium-Transporting ATPases
  • Calcium