(Circulation. 1999;100:2308.)
© 1999 American Heart Association, Inc.
Brief Rapid Communication |
Restoration of Contractile Function in Isolated Cardiomyocytes From Failing Human Hearts by Gene Transfer of SERCA2a
From the Cardiovascular Research Center (F.d.M., U.S., T.M., Z.B.K., A.R.) and the Heart Failure and Cardiac Transplantation Center (G.W.D., R.J.H.), Massachusetts General Hospital, Harvard Medical School, and Boston University School of Medicine (J.K.G.), Boston, Mass; and Imperial College, London, UK (S.E.H.).
Correspondence to Roger J. Hajjar, MD, Cardiovascular Research Center, Massachusetts General Hospital, 149 13th St, CNY-4, Boston, MA 02129. E-mail hajjar{at}cvrc.mgh.harvard.edu
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 new modality for the treatment of this disease.
Key Words: contractility • myocytes • gene therapy • sarcoplasmic reticulum
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K. R. Sipido Local Ca2+ Release in Heart Failure : Timing Is Important Circ. Res., November 24, 2000; 87(11): 966 - 968. [Full Text] [PDF]
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M. Cavagna, J M. O'Donnell, C. Sumbilla, G. Inesi, and M. G Klein Exogenous Ca2+-ATPase isoform effects on Ca2+ transients of embryonic chicken and neonatal rat cardiac myocytes J. Physiol., October 1, 2000; 528(1): 53 - 63. [Abstract] [Full Text] [PDF]
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R. J. Hajjar, F. del Monte, T. Matsui, and A. Rosenzweig Prospects for Gene Therapy for Heart Failure Circ. Res., March 31, 2000; 86(6): 616 - 621. [Abstract] [Full Text] [PDF]
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W. H. Barry Molecular Inotropy : A Future Approach to the Treatment of Heart Failure? Circulation, December 7, 1999; 100(23): 2303 - 2304. [Full Text] [PDF]
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A. L. Greene, M. J. Lalli, Y. Ji, G. J. Babu, I. Grupp, M. Sussman, and M. Periasamy Overexpression of SERCA2b in the Heart Leads to an Increase in Sarcoplasmic Reticulum Calcium Transport Function and Increased Cardiac Contractility J. Biol. Chem., August 4, 2000; 275(32): 24722 - 24727. [Abstract] [Full Text] [PDF]
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