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(Circulation. 2005;112:3131-3139.)
© 2005 American Heart Association, Inc.

Heart Failure

Supranormal Myocardial Creatine and Phosphocreatine Concentrations Lead to Cardiac Hypertrophy and Heart Failure

Insights From Creatine Transporter–Overexpressing Transgenic Mice

Julie Wallis, PhD; Craig A. Lygate, PhD; Alexandra Fischer, PhD; Michiel ten Hove, PhD; Jürgen E. Schneider, PhD; Liam Sebag-Montefiore, BSc; Dana Dawson, MD; Karen Hulbert, BSc; Wen Zhang; Mei Hua Zhang, PhD; Hugh Watkins, MD, PhD; Kieran Clarke, PhD; Stefan Neubauer, MD

From the Department of Cardiovascular Medicine (J.W., C.A.L., A.F., M.t.H., J.E.S., L.S.-M., D.D., K.H., M.H.Z., H.W., S.N.) and the University Laboratory of Physiology (W.Z., K.C.), University of Oxford, Oxford, England.

Correspondence to Prof Stefan Neubauer, Department of Cardiovascular Medicine, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX7, UK. E-mail stefan.Neubauer{at}cardiov.ox.ac.uk

Received July 4, 2005; revision received July 29, 2005; accepted August 29, 2005.

Background— Heart failure is associated with deranged cardiac energy metabolism, including reductions of creatine and phosphocreatine. Interventions that increase myocardial high-energy phosphate stores have been proposed as a strategy for treatment of heart failure. Previously, it has not been possible to increase myocardial creatine and phosphocreatine concentrations to supranormal levels because they are subject to tight regulation by the sarcolemmal creatine transporter (CrT).

Methods and Results— We therefore created 2 transgenic mouse lines overexpressing the myocardial creatine transporter (CrT-OE). Compared with wild-type (WT) littermate controls, total creatine (by high-performance liquid chromatography) was increased in CrT-OE hearts (66±6 nmol/mg protein in WT versus 133±52 nmol/mg protein in CrT-OE). Phosphocreatine levels (by ³¹P magnetic resonance spectroscopy) were also increased but to a lesser extent. Surprisingly, CrT-OE mice developed left ventricular (LV) dilatation (LV end-diastolic volume: 21.5±4.3 µL in WT versus 33.1±9.6 µL in CrT-OE; P=0.002), substantial LV dysfunction (ejection fraction: 64±9% in WT versus 49±13% in CrT-OE; range, 22% to 70%; P=0.003), and LV hypertrophy (by 3-dimensional echocardiography and magnetic resonance imaging). Myocardial creatine content correlated closely with LV end-diastolic volume (r=0.51, P=0.02), ejection fraction (r=–0.74, P=0.0002), LV weight (r=0.59, P=0.006), LV end-diastolic pressure (r=0.52, P=0.02), and dP/dt_max (r=–0.69, P=0.0008). Despite increased creatine and phosphocreatine levels, CrT-OE hearts showed energetic impairment, with increased free ADP concentrations and reduced free-energy change levels.

Conclusions— Overexpression of the CrT leads to supranormal levels of myocardial creatine and phosphocreatine, but the heart is incapable of keeping the augmented creatine pool adequately phosphorylated, resulting in increased free ADP levels, LV hypertrophy, and dysfunction. Our data demonstrate that a disturbance of the CrT-mediated tight regulation of cardiac energy metabolism has deleterious functional consequences. These findings caution against the uncritical use of creatine as a therapeutic agent in heart disease.

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