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 frequency response, which have all been related to a deficiency in the SR Ca²⁺ 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 Ca²⁺ 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 Ca²⁺ was decreased in failing cardiomyocytes overexpressing SERCA2a (270±26 versus 347±30 nmol/L, P<0.005), whereas systolic Ca²⁺ 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 flew modality for the treatment of this disease.