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J Thorac Cardiovasc Surg 2008;136:168-178
© 2008 The American Association for Thoracic Surgery

Evolving Technology

A dynamic and chamber-specific mitochondrial remodeling in right ventricular hypertrophy can be therapeutically targeted

Jayan Nagendran, MDa,b, Vikram Gurtu, BSca, David Z. Fu, BSca, Jason R.B. Dyck, PhDc, Al Haromy, BSca, David B. Ross, MDb, Ivan M. Rebeyka, MDb, Evangelos D. Michelakis, MDa,*

a Pulmonary Hypertension Program, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
b Pulmonary Hypertension Program, Division of Cardiac Surgery, Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
c Pulmonary Hypertension Program, Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada

Received for publication July 5, 2007; revisions received December 4, 2007; accepted for publication January 29, 2008.

* Address for reprints: Evangelos D. Michelakis, MD, FACC, FAHA, Canada Research Chair in Pulmonary Hypertension, Director, Pulmonary Hypertension Program, Department of Medicine (Cardiology), University of Alberta Hospitals, 2C2 WCM Health Sciences Center, Edmonton, Alberta, T6G2B7, Canada. (Email: emichela{at}cha.ab.ca).

Objectives: The right ventricle fails quickly after increases in its afterload (ie, pulmonary hypertension) compared with the left ventricle (ie, systemic hypertension), resulting in significant morbidity and mortality. We hypothesized that the poor performance of the hypertrophied right ventricle is caused, at least in part, by a suboptimal mitochondrial/metabolic remodeling.

Methods/Results: We studied mitochondrial membrane potential, a surrogate for mitochondrial function, in human (n = 11) and rat hearts with physiologic (neonatal) and pathologic (pulmonary hypertension) right ventricular hypertrophy in vivo and in vitro. Mitochondrial membrane potential is higher in the normal left ventricle compared with the right ventricle but is highest in the hypertrophied right ventricle, both in myocardium and in isolated cardiomyocytes (P < .01). Mitochondrial membrane potential correlated positively with the degree of right ventricular hypertrophy in vivo and was recapitulated in phenylephrine-treated neonatal cardiomyocytes, an in vitro model of hypertrophy. The phenylephrine-induced mitochondrial hyperpolarization was reversed by VIVIT, an inhibitor of the nuclear factor of activated T lymphocytes, a transcription factor regulating the expression of several mitochondrial enzymes during cardiac development and hypertrophy. The clinically used drug dichloroacetate, known to increase the mitochondria-based glucose oxidation, reversed both the phenylephrine-induced mitochondrial hyperpolarization and nuclear factor of activated T lymphocytes (NFAT) activation. In Langendorff perfusions, dichloroacetate increased rat right ventricular inotropy in hypertrophied right ventricles (P < .01) but not in normal right ventricles, suggesting that mitochondrial hyperpolarization in right ventricular hypertrophy might be associated with its suboptimal performance.

Conclusions: The dynamic changes in mitochondrial membrane potential during right ventricular hypertrophy are chamber-specific, associated with activation of NFAT, and can be pharmacologically reversed leading to improved contractility. This mitochondrial remodeling might provide a framework for development of novel right ventricle–specific therapies.

Abbreviations and Acronyms DAPI = 4,6-diamino-2-phenylindole; DCA = dichloroacetate; LV = left ventricle/ventricular; LVH = left ventricular hypertrophy; NFAT = nuclear factor of activated T lymphocytes; PAAT = pulmonary artery acceleration time; PAH = pulmonary arterial hypertension; RV = right ventricle/ventricular; RVH = right ventricular hypertrophy; SMC = smooth muscle cells; TMRM = tetramethyl–rhodamine methyl ester




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