doi: 10.1161/hc0802.105564
(Circulation. 2002;105:904.)
© 2002 American Heart Association, Inc.
Brief Rapid Communications |
Targeting Phospholamban by Gene Transfer in Human Heart Failure
From the Cardiovascular Research Center, Massachusetts General Hospital, Heart Failure and Cardiac Transplantation Center (F.d.M., G.W.D., R.J.H.), Harvard Medical School (J.K.G.), Boston, Mass; and the National Heart and Lung Institute (S.E.H.), Imperial College, London, UK.
Correspondence to Roger J. Hajjar, MD, Massachusetts General Hospital, Cardiovascular Research Center, 149 13th St, CNY-4, 4215, Charlestown, MA 02129. E-mail rhajjar{at}partners.org
Background— Myocardial cells from failing human hearts are characterized by abnormal calcium handling, a negative force-frequency relationship, and decreased sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) activity. In this study, we tested whether contractile function can be improved by decreasing the inhibitory effects of phospholamban on SERCA2a with adenoviral gene transfer of antisense phospholamban (asPL).
Methods and Results— Myocardial cells isolated from 9 patients with end-stage heart failure and 18 donor nonfailing hearts were infected with adenoviruses encoding for either the antisense of phospholamban (Ad.asPL), the SERCA2a gene (Ad.SERCA2a), or the reporter genes ß-galactosidase and green fluorescent protein (Ad.ßgal-GFP). Adenoviral gene transfer with Ad.asPL decreased phospholamban expression over 48 hours, increasing the velocity of both contraction and relaxation. Compared with cardiomyocytes infected with Ad.asPL (n=13), human myocytes infected with Ad.ßgal-GFP (n=8) had enhanced contraction velocity (20.3±3.9% versus 8.7±2.6% shortening/second; P<0.01) and relaxation velocity (26.0±6.2% versus 8.6±4.3% shortening/second; P<0.01). The improvement in contraction and relaxation velocities was comparable to cardiomyocytes infected with Ad.SERCA2a. Failing human cardiomyocytes had decreased contraction and Ca2+ release with increasing frequency (0.1 to 2 Hz). Phospholamban ablation restored the frequency response in the failing cardiomyocytes to normal; increasing frequency resulted in enhanced sarcoplasmic reticulum Ca2+ release and contraction.
Conclusion— These results show that gene transfer of asPL can improve the contractile function in failing human myocardium. Targeting phospholamban may provide therapeutic benefits in human heart failure.
Key Words: calcium • heart failure • gene therapy
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