A dynamic and chamber-specific mitochondrial remodeling in right ventricular hypertrophy can be therapeutically targeted Jayan Nagendran, MD, Vikram.

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A dynamic and chamber-specific mitochondrial remodeling in right ventricular hypertrophy can be therapeutically targeted Jayan Nagendran, MD, Vikram Gurtu, BSc, David Z. Fu, BSc, Jason R.B. Dyck, PhD, Al Haromy, BSc, David B. Ross, MD, Ivan M. Rebeyka, MD, Evangelos D. Michelakis, MD The Journal of Thoracic and Cardiovascular Surgery Volume 136, Issue 1, Pages 168-178.e3 (July 2008) DOI: 10.1016/j.jtcvs.2008.01.040 Copyright © 2008 The American Association for Thoracic Surgery Terms and Conditions

Figure 1 Differences in mitochondrial membrane potential between human RV and LV myocardium. A and B, Confocal microscopy images of acutely TMRM and Hoechst loaded normal RV and LV myocardium from patient 1 (A) and normal RV and RVH from Patients 3 and 6, respectively (B). C, Mean TMRM fluorescence from all patients expressed in fluorescence units per area (n = 2 RV, n = 2 LV, n = 8 RVH). The Journal of Thoracic and Cardiovascular Surgery 2008 136, 168-178.e3DOI: (10.1016/j.jtcvs.2008.01.040) Copyright © 2008 The American Association for Thoracic Surgery Terms and Conditions

Figure 2 Similar mitochondrial membrane potential differences in adult rat RV and LV myocardium, also exist in isolated adult rat RV and LV cardiomyocytes. A, Confocal microscopy images of adult rat RV and LV myocardium loaded with TMRM and Hoechst. B, Isolated adult rat RV and LV cardiomyocytes loaded with TMRM and Hoechst. Merge panels also show differential interference contrast (DIC) channel for cell surface details. C, Mean TMRM fluorescence from all rat myocardial samples (n = 17 RV, n = 17 LV; ∗P < .01 vs RV myocardium). Mean TMRM fluorescence for individual cardiomyocytes (n = 58 RV, n = 83 LV; ∗P < .01 vs RV cardiomyocytes). TMRM, Tetramethyl–rhodamine methyl ester; DAPI, 4,6-diamino-2-phenylindole. The Journal of Thoracic and Cardiovascular Surgery 2008 136, 168-178.e3DOI: (10.1016/j.jtcvs.2008.01.040) Copyright © 2008 The American Association for Thoracic Surgery Terms and Conditions

Figure 3 Mitochondrial membrane potential progressively increases with the development of pathologic RVH. Upper third, Pulmonary artery acceleration time (PAAT; hatched bars) progressively decreased from control to 14 days to 28 days after monocrotaline (MCT) injection, while this was mirrored by a subsequent increase in RV free wall thickness (solid bars);∗P < .01 versus control; †P < .01 versus RV 14 days after MCT injection. Middle third, Mean TMRM fluorescence from all rat RV myocardial samples with progression of RVH after MCT injection (n = 17 control RV, n = 5 RV 14 days after MCT injection, n = 11 RV 28 days after MCT injection; ∗P < .01 vs control; †P < .01 vs RV 14 days after MCT injection). Bottom third, Representative confocal images of RV myocardium loaded with TMRM and Hoechst. The Journal of Thoracic and Cardiovascular Surgery 2008 136, 168-178.e3DOI: (10.1016/j.jtcvs.2008.01.040) Copyright © 2008 The American Association for Thoracic Surgery Terms and Conditions

Figure 4 DCA and NFAT inhibition reverse the mitochondrial hyperpolarization seen in RV cardiomyocytes from physiologic (neonatal RV) and pathologic (phenylephrine-induced) hypertrophy in vitro. A, Representative confocal images of neonatal rat cardiomyocytes treated with vehicle, phenylephrine (PE), phenylephrine plus dichloroacetate (PE+DCA), or phenylephrine plus VIVIT (PE+VIVIT) and cultured for 48 hours before loading with TMRM and Hoechst. Mean TMRM fluorescence for individual cardiomyocytes (n > 140 cardiomyocytes per treatment; ∗P < .01 vs control; †P < .01 vs phenylephrine). B, Immunocytochemistry performed in fixed neonatal cardiomyocytes after phenylephrine or phenylephrine+VIVIT treatment show the prevention of nuclear factor of activated T lymphocytes (NFAT, red) translocation into the nucleus (blue) by VIVIT (n = 6 plates per group [>150 cells/plate]; ∗P < .01 vs control; †P < .01 vs phenylephrine). C, Isolated neonatal rat RV and LV cardiomyocytes treated with vehicle, DCA, or VIVIT and cultured for 48 hours before loading with TMRM and Hoechst. Mean TMRM fluorescence for individual cardiomyocytes (n = 473 LV, n = 449 RV; ∗P < .01 vs LV cardiomyocytes; †P < .01 vs control). The Journal of Thoracic and Cardiovascular Surgery 2008 136, 168-178.e3DOI: (10.1016/j.jtcvs.2008.01.040) Copyright © 2008 The American Association for Thoracic Surgery Terms and Conditions

Figure 5 Targeted metabolic modulation by dichloroacetate (DCA) acutely improves RV inotropy in the ex vivo modified Langendorff perfused heart. A, Schematic of the isolated perfused RV (Langendorff preparation) to measure developed pressure. B, Representative real-time traces of the developed pressures from the normal RV (upper) and 28 days after monocrotaline injection RVH (lower) before and after the addition of DCA into the perfusate (shaded area). Note the significant increase in developed pressure only in the RVH hearts with acute DCA treatment. C, Mean data showing that DCA increased developed pressure (delta pressure from baseline developed pressure) in a dose-dependent manner in the RVH (n = 5) but not the normal RV (n = 6), whereas both normal and hypertrophied RV responded similarly to isoproterenol (∗P < .01 vs normal RV). D, Coronary sinus effluent was collected on ice from the modified Langendorff perfusions 5 minutes after a steady baseline was established and 10 minutes after initiating perfusion with DCA and was analyzed for lactate concentration (n = 6 RV, n = 5 RVH; ∗P < .01 vs normal RV; †P < .01 vs baseline). The Journal of Thoracic and Cardiovascular Surgery 2008 136, 168-178.e3DOI: (10.1016/j.jtcvs.2008.01.040) Copyright © 2008 The American Association for Thoracic Surgery Terms and Conditions

Verification of cardiomyocyte cell type Verification of cardiomyocyte cell type. Representative confocal microscopy image of isolated neonatal rat cardiomyocytes stained for myosin heavy chain (green) and DAPI (blue) to confirm the cell isolation methods were specific for attaining cardiomyocytes over fibroblasts and/or vascular cells, with more than 97% of cells staining positive for myosin heavy chain. The Journal of Thoracic and Cardiovascular Surgery 2008 136, 168-178.e3DOI: (10.1016/j.jtcvs.2008.01.040) Copyright © 2008 The American Association for Thoracic Surgery Terms and Conditions