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

Background-Failing human myocardium is characterized by abnormal relaxation , a deficient sarcoplasmic reticulum (SR) Ca2+ uptake, and a negative frequ ency response, which have all been related to a deficiency in the SR Ca2+ A TPase (SERCA2a) pump. Methods and Results-To test the hypothesis that an increase in SERCA2a coul d improve contractile function in cardiomyocytes, we overexpressed SERCA2a in human ventricular myocytes from 10 patients with end-stage heart failure and examined intracellular Ca2+ handling and contractile function. Overexp ression of SERCA2a resulted in an increase in both protein expression and p ump activity and induced a faster contraction velocity (26.7 +/- 6.7% versu s 16.6 +/- 2.7% shortening per second, P < 0.005) and enhanced relaxation v elocity (32.0 +/- 10.1% versus 15.1 +/- 2.4%, P < 0.005). Diastolic Ca2+ wa s decreased in failing cardiomyocytes overexpressing SERCA2a (270 +/- 26 ve rsus 347 +/- 30 nmol/L, P < 0.005), whereas systolic Ca2+ was increased (60 1 +/- 38 versus 508 +/- 25 nmol/L, P < 0.05), In addition, the frequency re sponse 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 moda lity for the treatment of this disease.