Modeling Right Ventricular Heart Failure in Congenital Heart Disease

Purpose Heart failure is a significant cause of morbidity and mortality in congenital heart disease patients especially for the subset whose right ventricle functions as the systemic ventricle. The physiological and molecular differences in the right ventricle (RV) and left ventricle (LV) lead to different abilities to adapt to adverse conditions and respond to pharmacological therapeutics. Currently data describing the molecular changes that occur in the systemic RV are lacking. Available animal models create an RV with volume and/or pressure overload however the LV remains at high pressure. Ventricular-ventricular interactions have a critical impact on cardiac function and are likely to alter gene expression independent of RV function. Methods To explore the distinct genetic regulatory networks of the RV and LV, we sequenced RNA from the RV and LV of late fetal, 1-week old, and 1-month old piglets. We identified gene expression differences in both chambers over this time course. Further, we have established a novel large animal model which creates a high pressure systemic RV with a low pressure subpulmonic LV by performing a reverse arterial switch followed by an atrial septectomy to allow sufficient oxygenation via atrial mixing. Using samples isolated from the RV following the reverse arterial switch procedure, we will determine the transcriptomic changes associated with the systemic RV. Gene expression profiles will be compared to age matched normal RV to identify molecular pathways that are perturbed in the systemic RV and compared to our LV and RV postnatal remodeling data to identify beneficial and pathogenic pathways for the RV under increased loading conditions. Results Analysis of postnatal cardiac chambers shows differentially expressed RV genes cluster into distinct patterns. In preliminary studies to generate a systemic RV, our team has successfully executed acute surgery in four week old piglets. Biventricular function was maintained with adequate systemic oxygenation saturation and angiography established that both the right and left reimplanted coronary arteries were patent. Conclusion As predicted by the lack of RV response to LV based therapies, our data confirmed that the genetic signature of the RV and LV during postnatal cardiac remodeling is distinct. Creation of a novel systemic RV model provides a platform to develop new therapeutics for congenial heart disease patients.