HT Hwang1, N Sandeep1, M Zhao1, DQ Hu1, IS Lan2, M Coronado3, KB Kooiker4, G Fajardo1, D Bernstein1, S Reddy1.
1Department of Pediatrics (Cardiology), Stanford University; 2Department of Bioengineering, Stanford University; 3Whitman College, Washington; 4University of Washington
Background: In complex congenital heart disease patients such as those with tetralogy of Fallot, the right ventricle is subject to pressure overload stress leading to right ventricular hypertrophy (RVH) and eventually right ventricular failure (RVF). The role of chronic oxidative stress, in particular lipid peroxidation, in RVH and RVF in congenital heart disease is unknown.
Methods: Oxidative stress, mitochondrial structure, dynamics and respiration were assessed in the right ventricle of patients with congenital heart disease and in a murine model of RVH and RVF. The effect of 4-hydroxynonenal (4HNE; byproduct of lipid peroxidation) and carvedilol on mitochondrial dynamics and respiration was assessed in cardiomyocytes.
Results: Increased lipid peroxidation was associated with lower maximal respiration in patients with RVF [RVH 390.2±20.17 vs. RVF 204.1±34.73 pmol/(sec*ml), p=0.0032]. Our murine model of RVH and RVF mimicked the patient data and also demonstrated (i) decreased mitochondrial fission (DRP1, MFF) and fusion (OPA1) protein expression; (ii) decreased mitochondrial DNA content by 61%; and (iii) fragmented mitochondrial network in RVF. Cardiomyocyte treatment with 200 μM 4HNE decreased mitochondrial dynamics protein expression, increased leak respiration by 33%, and abolished ADP-mediated respiration. The ꞵ-blocker and antioxidant, Carvedilol prevented DRP1 and MFF from decreasing in response to 4HNE.
Conclusion: Mitochondria are the largest source and target of lipid peroxidation products. Lipid peroxidation in RVF is associated with impaired mitochondrial dynamics and membrane damage leading to reduced energy generation. Carvedilol improved mitochondrial fission, raising the potential for its use in RVF in children with congenital heart disease.