Heart failure in single right ventricle congenital heart disease: physiological and molecular considerations.

Because of remarkable surgical and medical advances over the past several decades, there are growing numbers of infants and children living with single ventricle congenital heart disease (SV), where there is only one functional cardiac pumping chamber. Nevertheless, cardiac dysfunction (and ultimately heart failure) is a common complication in the SV population, and pharmacological heart failure therapies have largely been ineffective in mitigating the need for heart transplantation. Given that there are several inherent risk factors for ventricular dysfunction in the setting of SV in addition to probable differences in molecular adaptations to heart failure between children and adults, it is perhaps not surprising that extrapolated adult heart failure medications have had limited benefit in children with SV heart failure. Further investigations into the molecular mechanisms involved in pediatric SV heart failure may assist with risk stratification as well as development of targeted, efficacious therapies specific to this patient population. In this review, we present a brief overview of SV anatomy and physiology, with a focus on patients with a single morphological right ventricle requiring staged surgical palliation. Additionally, we discuss outcomes in the current era, risk factors associated with the progression to heart failure, present state of knowledge regarding molecular alterations in end-stage SV heart failure, and current therapeutic interventions. Potential avenues for improving SV outcomes, including identification of biomarkers of heart failure progression, implications of personalized medicine and stem cell-derived therapies, and applications of novel models of SV disease, are proposed as future directions.

Ablation of Cyclophilin D Results in an Activation of FAK, Akt, and ERK Pathways in the Mouse Heart.

Cyclophilin D (CypD) is a mitochondrial chaperone that regulates the mitochondrial permeability transition pore. Metabolically, deletion of Ppif (the gene encoding CypD) in mice is associated with elevated levels of mitochondrial matrix Ca2+ that leads to increased glucose as relative to fatty acid oxidation. Here, we characterized the adaptive mechanisms involved in the regulation of glucose metabolism including the regulation of Akt and ERK kinases that we evaluated by Western blot analysis of Ppif-/- in comparison to wild type (WT) mouse hearts. CypD loss led to adaptive mechanisms in the heart resulting in an upregulation of focal adhesion kinase (phosphorylated at Tyr925) and increased phosphorylation of Akt at S473. The increased activity of this pathway (pAktS473 increased to 170% and 145% in Ppif-/- versus WT males and females, respectively) could be responsible for the observed metabolic switch towards glycolysis. Furthermore, the phosphorylation of ERK1/2 proteins was elevated following CypD ablation. In addition, we observed differences in protein expression and activity in male versus female hearts that were independent of CypD expression. This included an upregulation of pAktS473 (to 273% and 269% in Ppif-/- and WT females as compared to their corresponding males, respectively). Furthermore, decreased levels of endothelial nitric oxide synthase (eNOS) inhibitor asymmetric dimethylarginine were accompanied by an upregulation of eNOS in female mice. The higher extent of kinases phosphorylation may be responsible for the reported lowered tolerance of CypD animals to stress. Moreover, the higher nitric oxide production could be responsible for the cardioprotective properties observed only in female hearts. J. Cell. Biochem. 118: 2933-2940, 2017. © 2017 Wiley Periodicals, Inc.