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(Circulation. 2004;109:2780-2785.)
© 2004 American Heart Association, Inc.

Basic Science Reports

Gene Transfer of Parvalbumin Improves Diastolic Dysfunction in Senescent Myocytes

Fawzia Huq, MD; Djamel Lebeche, PhD; Vivek Iyer, MSE; Ronglih Liao, PhD; Roger J. Hajjar, MD

From the Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown (F.H., D.L., V.I., R.J.H.), and the Cardiac Muscle Research Laboratory, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston (R.L.), Mass.

Correspondence to Roger J. Hajjar, MD, Cardiovascular Research Center, Massachusetts General Hospital, 149 13th St, CNY-4, Charlestown, MA 02129. E-mail rhajjar{at}partners.org

Received June 5, 2003; de novo received January 6, 2004; accepted February 25, 2004.

Background— Impaired relaxation is a cardinal feature of senescent myocardial dysfunction. Recently, adenoviral gene transfer of parvalbumin, a small calcium-buffering protein found exclusively in skeletal muscle and neurons, has been shown to improve cardiomyocyte relaxation in disease models of diastolic dysfunction. The goal of this study was to investigate whether parvalbumin gene transfer could reverse diastolic dysfunction in senescent cardiomyocytes.

Methods and Results— Myocytes were isolated from senescent (26 months) and adult (6 months) F344/BN hybrid rats and were infected with Ad.Parv.GFP (where GFP is green fluorescent protein) or Ad.ßgal.GFP at a multiplicity of infection of 250 for 48 hours. Uninfected senescent and adult myocytes served as controls. After stimulation at a frequency of 0.5 Hz, intracellular calcium transients and myocyte contractility were measured using dual excitation spectrofluorometry and video-edge detection system (Ionoptix). Parvalbumin significantly improved relaxation parameters in senescent myocytes: Both the rate of calcium transient decay and the rate of myocyte relengthening were dramatically increased in senescent cardiac myocytes transduced with parvalbumin compared with nontransduced and GFP-expressing controls, with no effect on myocyte shortening.

Conclusions— Parvalbumin expression corrects impaired relaxation in aging myocytes. Given that abnormalities of myocyte relaxation underlie diastolic dysfunction in a large proportion of elderly patients with heart failure, gene transfer of parvalbumin may thus be a novel approach to target diastolic dysfunction in senescent myocardium.

Key Words: parvalbumin • aging • gene therapy • myocytes • diastole

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