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(Circulation. 2005;112:2339-2346.)
© 2005 American Heart Association, Inc.

Molecular Cardiology

Decreased Contractile and Metabolic Reserve in Peroxisome Proliferator–Activated Receptor-–Null Hearts Can Be Rescued by Increasing Glucose Transport and Utilization

Ivan Luptak, MD; James A. Balschi, PhD; Yanqiu Xing, MD, PhD; Teresa C. Leone, PhD; Daniel P. Kelly, MD; Rong Tian, MD, PhD

From the NMR Laboratory for Physiological Chemistry, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, Mass (I.L., J.A.B., Y.X., R.T.), and Center for Cardiovascular Research, Washington University School of Medicine, St Louis, Mo (D.P.K., T.C.L.).

Correspondence to Rong Tian, MD, PhD, NMR Laboratory for Physiological Chemistry, 221 Longwood Ave, Rm 252, Boston, MA 02115. E-mail rtian{at}rics.bwh.harvard.edu

Received January 11, 2005; revision received June 7, 2005; accepted July 6, 2005.

Background— Downregulation of peroxisome proliferator–activated receptor- (PPAR) in hypertrophied and failing hearts leads to the reappearance of the fetal metabolic pattern, ie, decreased fatty acid oxidation and increased reliance on carbohydrates. Here, we sought to elucidate the functional significance of this shift in substrate preference.

Methods and Results— We assessed contractile function and substrate utilization using ¹³C nuclear magnetic resonance spectroscopy and high-energy phosphate metabolism using ³¹P nuclear magnetic resonance spectroscopy in perfused hearts isolated from genetically modified mice (PPAR^–/–) that mimic the metabolic profile in myocardial hypertrophy. We found that the substrate switch from fatty acid to glucose (3-fold down) and lactate (3-fold up) in PPAR^–/– hearts was sufficient for sustaining normal energy metabolism and contractile function at baseline but depleted the metabolic reserve for supporting high workload. Decreased ATP synthesis (measured by ³¹P magnetization transfer) during high workload challenge resulted in progressive depletion of high-energy phosphate content and failure to sustain high contractile performance. Interestingly, the metabolic and functional defects in PPAR^–/– hearts could be corrected by overexpressing the insulin-independent glucose transporter GLUT1, which increased the capacity for glucose utilization beyond the intrinsic response to PPAR deficiency.

Conclusions— These findings demonstrate that metabolic remodeling in hearts deficient in PPAR increases the susceptibility to functional deterioration during hemodynamic overload. Moreover, our results suggest that normalization of myocardial energetics by further enhancing myocardial glucose utilization is an effective strategy for preventing the progression of cardiac dysfunction in hearts with impaired PPAR activity such as hearts with pathological hypertrophy.

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