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Mitochondrial Membrane Potential is Different Between the Right and Left Ventricle in Humans and Rats
J. Nagendran, V. Gurtu, J. R. Dyck, D. B. Ross*, I. M. Rebeyka*, E. D. Michelakis. University of Alberta, Edmonton, AB, Canada,
BACKGROUND:
The right (RV) and left ventricle (LV) have recently been shown to have different embryologic origins, perhaps explaining why the RV fails early after increases in afterload (post-cardiac transplantation, congential heart disease and pulmonary hypertension) compared to the LV, which maintains normal function for many years after increases in afterload (aortic stenosis and systemic hypertension). Patients with pulmonary hypertension develop RV hypertrophy (RVH) and median survival is 3-5 years, compared to patients with LV hypertrophy (LVH) who survive for many decades and often asymptomatic. We hypothesized that the suboptimal performance of RVH compared to LVH is due to differences in the metabolic adaptation of the RV versus LV during hypertrophy. This has not been previously studied and is the first step of a comprehensive approach in identifying clinically relevant metabolic-molecular differences between the two ventricles. As a surrogate for metabolism and mitochondrial function, we used the mitochondrial membrane potential (ΔΨm) an excellent index of the respiratory activity (electron transport chain flux of electrons) and coupling of respiration to energy production.
METHODS:
We studied physiologic RVH (n=36) in neonatal rat hearts (which normally have RVH, that regresses within a few days after birth) and pathologic RVH (n=6) in rats with experimental pulmonary hypertension. We also studied surgical specimens of normal and hypertrophied ventricles from 16 patients (12 children, 0.6±0.1yr, 4 adults 38±9.8yr, normal RV n=2, RVH n=10, LVH n=3). Multi-photon confocal microscopy was used to measure ΔΨm in whole tissue and in isolated cardiomyocytes (n~700cells/ventricle). Tissues were stained with Tetramethylrhodamine methyl ester (TMRM), a positively-charged dye that selectively localizes within the negatively charged mitochondria (the higher the TMRM fluorescence the more hyperpolarized the ΔΨm).
RESULTS:
Both physiologic and pathologic RVH had higher ΔΨm compared to the normal RV in the rat and the same was true in human hearts (Figure). The normal ventricles had similar ΔΨm in the rat hearts and differed in human hearts. LVH had similar ΔΨm to the normal LV in humans.
CONCLUSIONS:
There are significant and previously unexplored differences in the mitochondrial function between the RV and LV, particularly during hypertrophy, in both rat and human hearts. The molecular identification of these differences might lead to better, and much needed, therapies for RV failure.
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