Failure of Right Ventricular Adaptation in Children With Tetralogy of Fallot

Abstract

Background-The left ventricle (LV) adapts to chronic hypoxia by expressing protective angiogenic, metabolic, and antioxidant genes to improve O 2 delivery and energy production, and to minimize reoxygenation injury. The ability of the right ventricle (RV) to adapt to hypoxia in children with tetralogy of Fallot (TOF) is unknown. Methods and Results-Gene expression using real-time polymerase chain reaction was measured in RV myocardium obtained during surgical repair of TOF from 23 patients: 13 cyanotic and 10 acyanotic. Results were compared between the 2 groups and correlated with age at surgery, severity of cyanosis, and early postoperative course. The cyanotic patients were younger at surgery compared with acyanotic (5Ϯ3 versus 9Ϯ4 months; Pϭ0.01), had higher hematocrit (43Ϯ4 versus 38Ϯ3 grams/dL; Pϭ0.004), and lower O 2 saturations (84Ϯ4% versus 98Ϯ2%; (PϽ0.001). Cyanotic patients had a significantly lower expression of vascular endothelial growth factor (VEGF), glycolytic enzymes, and glutathione peroxidase (GPX) (PϽ0.05), and a higher expression of collagen (PϽ0.01) compared with acyanotic patients. Gene expression correlated inversely with severity of cyanosis ie, preoperative hematocrit (PϽ0.01) and positively with preoperative saturation (PϽ0.05). The relationship between gene expression and cyanosis was independent of age at surgery. Ca 2ϩ handling genes did not correlate with the severity of hypoxia. Lower angiogenic, glycolytic, and antioxidant gene expression correlated with increasing postoperative lactate (PϽ0.05). Conclusions-The

Hypoxia induces PGC-1α expression and mitochondrial biogenesis in the myocardium of TOF patients

“…The survival of TOF patients is dependent on many adaptive mechanisms to improve O 2 delivery and energy production along with mechanisms that minimize reoxygenation injury [5][6][7]. Under hypoxic conditions, because of the insufficient O 2 supply, the production of ATP by each mitochondrion is decreased.…”

“…TOF patients suffer from systemic chronic hypoxia and sustained pressure overload of the right ventricle. Survival is dependent on many adaptive mechanisms, including altered expression of protective angiogenic, metabolic and antioxidant genes in the myocardium, which improve O 2 delivery and energy production and minimize reoxygenation injury [5][6][7]. TOF patients usually undergo surgery at a young age to repair their malfunctions; however, delayed treatment of TOF is associated with maladaptive changes that result in decreased myocardial performance [6,8].…”

Heart Failure in Children

“…This finding has implications for long-term RV function in patients with TOF, and further study may identify therapeutic targets for early intervention. 45 There is no systematic clinical evidence for anticongestive therapy in RV failure in children. One basis for diuretic use comes from a 1972 report in a rhesus model of RV failure in which diuretic agents, including furosemide, relieved the clinical symptoms.…”

Update on Pharmacological Heart Failure Therapies in Children

“…17 Moreover, there are data to suggest that the right ventricles and LVs may be different in terms of gene expression, microRNA expression, and adaptation to fibrosis (Figure 1). [58][59][60] Although it is possible that these studies were also underpowered to detect a difference between groups, they clearly raise the question of whether the proven standard treatments for heart failure in those with a systemic LV can be extrapolated to those with a systemic ventricle that is not an LV. Similarly, there are no randomized trials demonstrating clear benefit of β-blockers in this subgroup of pediatric and young adult patients with a systemic ventricle that is not an LV.…”