Abstract 1907: Right Ventricular Pressure Overload Leads to Early and Progressive Mitochondrial DNA Depletion in Children With Congenital Heart Disease
RV pressure and/or volume overload (RVPO/RVVO) caused by congenital heart disease (CHD) can be well tolerated for years before transition to RV failure and irreversible myocardial damage, providing a large time window for surgical repair. However, indications and timing for operation are not well established due to the lack of knowledge of the molecular mechanisms underlying the transition from compensation to failure. To test the hypothesis that the severity of the mitochondrial impairment can identify indications for operation and stratify surgical risk, we collected RV tissue from 20 patients with Tetralogy of Fallot and associated CHD undergoing cardiac surgery and compared makers of mitochondrial biogenesis in these hearts to non-failing (NF) hearts (n=5). Patients were arbitrarily divided in groups based on the pre-operative RVP by Doppler echocardiography or catheterization; group I: RVP <69 mmHg, group II: RVP=70 – 84 mmHg and group III: RVP>84 mmHg. Compared to NF, the mitochondrial DNA (mtDNA) content was reduced by 38% in group I, 63% in group II and 65% in group III (p<0.05 for all), demonstrating an inverse relationship between RVP and the mtDNA content (R2=0.44). Furthermore, the mtDNA levels were ~50% lower in RVPO compared to RVVO patients (p<0.05), suggesting a critical role of the high RV pressure in mtDNA depletion. The expression of the transcription factors regulating mitochondrial biogenesis e.g. TFAM, TFB2M and NRF2B2, was progressively decreased as the RVP rose, from ~35% in group I to ~50% in group III (p<0.05). In conclusion, RVPO causes progressive mtDNA depletion in patients with CHD likely by suppressing the expression of the transcription factors responsible for mitochondrial biogenesis. MtDNA depletion is an early and progressive event during RVPO in CHD. Early surgical relief of RVPO could be of benefit to improve outcomes in this population.