Study On The Adaptation Mechanism Of Hypoxic Right Ventricle Under Pressure / Capacity Overload

Background:One important determinant of longevity in congenital heart disease is right ventricular (RV) function, and this is especially true in cyanotic congenital heart disease. However, there is paucity of data concerning RV remodeling (RVR) in the setting of chronic hypoxia. Dimethyloxalglycine (DMOG) is a competitive inhibitor of hypoxia-inducible factor (HIF)-hydroxylated prolyl hydroxylase and has been shown to play an important role against ischemia-reperfusion myocardial injury.Methods:We tested the hypothesis that DMOG prevents the development RVR following chronic hypoxia exposure. Rats were injected with saline or DMOG and exposed to room air or continued hypoxia for 4 wk. In addition, we explored the response of myocardial erythropoietin and its receptor to hypoxic exposure.Results:Treatment with DMOG attenuated myocardial fibrosis, apoptosis, and oxidative stress, leading to enhanced RV contractile function. As an end point of HIF-dependent cardioprotection, a novel pathway in which nuclear factor kappa B links HIF-1 transcription was defined.Conclusions:This study support a role for HIF-1 stabilizers in the treatment of RVR and bring into question the commonly held concept that RVR follows a linear relationship with increased RV afterload.AimsRight ventricular (RV) dysfunction is a major determinant of long-term morbidity and mortality in cyanotic congenital heart disease (CCHD) The right ventricle (RV) is genetically different from the left ventricle (LV), but it is unknown whether this has consequences for the cellular responses to abnormal loading conditions. In the LV, calcineurinactivation is a major determinant of pathological hypertrophy and an important target for therapeutic strategies. We studied the functional and molecular adaptation of the chronic hypoxia induced RH in mouse models of pressure and volume load, focusing on calcineurin-activation.Methodsand resultsRats were exposed continued hypoxia for 4 wk, then subjected to pulmonary artery banding (PAB), PR, or sham surgery (Control). Four weeks later, rats were functionally evaluated with cardiac echocardiography, magnetic resonance imagingand pressure measurements. Right ventricular hypertrophy and calcineurin-activation were assessed after sacrifice.ResultRats with increased pressure load (PAB) or PR of the RV developed similar degrees of hypertrophy,yet revealed different functional and molecular adaptation. Pulmonary artery banding increased expression of Modulatory-Calcineurin-Interacting-Protein 1 (MCIP1), indicating calcineurin-activation, and the ratio of beta/alpha-Myosin Heavy Chain (MHC). In addition, PAB induced moderate RV dilatation with normal RV output at rest. In contrast, PR did not increase MCIP1 expression, but increased RV volumes and output.ConclusionsPressure and volume load induced different functional and molecular adaptations in the RV. These results may have important consequences for therapeutic strategies to prevent chronic hypoxia induced RH in the growing population of cyanotic congenital heart disease.