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) Ca(2+) uptake, and a negative frequency response, which have all been related to a deficiency in the SR Ca(2+) ATPase (SERCA2a) pump.


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.
del MonteF
Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA.
Harding
S E
SE
Schmidt
U
U
Matsui
T
T
Kang
Z B
ZB
Dec
G W
GW
Gwathmey
J K
JK
Rosenzweig
A
A
Hajjar
R J
RJ
D002118:Calcium / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000503:physiopathology / Q000628:therapy; D002478:Cells, Cultured; D015870:Gene Expression; D015316:Genetic Therapy; D006333:Heart Failure / Q000503:physiopathology / Q000628:therapy*; D006801:Humans; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000201:enzymology*; D009200:Myocardial Contraction / Q000235:genetics*; D012519:Sarcoplasmic Reticulum / Q000201:enzymology
D000252:Calcium-Transporting ATPases; D002118:Calcium