Hyun Tae Hwang1*, Nefthi Sandeep1*, Mingming Zhao1, Dong-Qing Hu1, Ingrid Sheu Lan2, Michael Coronado3, Kristina B Kooiker4, Giovanni Fajardo1, Daniel Bernstein1, Sushma Reddy1
1Department of Pediatrics (Cardiology), Stanford University; 2Department of Bioengineering, Stanford University; 3Whitman College (Walla Walla, Washington); 4University of Washington
Background: The right ventricle (RV) is uniquely at risk in patients with complex congenital heart disease (CHD). Despite successful repair, the RV is subject to pressure overload stress, leading to right ventricular hypertrophy (RVH) and eventually right ventricular failure (RVF). The critical role of mitochondrial dynamics in the development of RVH and RVF in CHD is unknown. As a major source of reactive oxygen species, mitochondria are susceptible to oxidative damage. We hypothesized that impaired energy generation in pressure overload-induced right ventricular failure is accompanied by blunted mitochondrial dynamics and increased lipid peroxidation.
Methods: Mitochondrial structure and function were assessed in RV tissue resected from patients with CHD and a murine model of RVH and RVF. The role of oxidative stress was assessed in the development of mitochondrial dysfunction.
Results: Patients with RV outflow tract obstruction leading to RVF demonstrated lower maximal respiration than those with moderate RVH. [390.2±20.17 vs. 204.1±34.73 pmol/(sec*ml), p=0.0032]. To understand the mechanism of impaired respiration, we used a murine model of RVH and RVF. RVF was characterized by decreased maximal respiration [Sham 744.3±49.3 vs. moderate RVH 513.2±112.6 vs. RVF 306±40.18, p<0.0001 (vs. Sham) and p=0.0394 (vs. RVH)], and mitochondrial fission (DRP1, MFF) and fusion (OPA1) compared with RVH. RVF exhibited increased lipid peroxidation and irregularly shaped mitochondria.
Conclusion: Pressure overload-induced RVF has impaired mitochondrial respiration and dynamics. These were associated with increased lipid peroxidation, which may promote the dysfunction.
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