Differential Responses of the Right Ventricle to Abnormal Loading Conditions in Mice: Pressure vs. Volume Load

AIMS: Right ventricular (RV) dysfunction is a major determinant of long-term morbidity and mortality in congenital heart disease. The right ventricle (RV) is genetically different from the left ventricle (LV), but it is unknown as to whether this has consequences for the cellular responses to abnormal loading conditions. In the LV, calcineurin-activation is a major determinant of pathological hypertrophy and an important target for therapeutic strategies. We studied the functional and molecular adaptation of the RV in mouse models of pressure and volume load, focusing on calcineurin-activation. METHODS AND RESULTS: Mice were subjected to pulmonary artery banding (PAB), aorto-caval shunt (Shunt), or sham surgery (Control). Four weeks later, mice were functionally evaluated with cardiac magnetic resonance imaging, pressure measurements, and voluntary cage wheel exercise. Right ventricular hypertrophy and calcineurin-activation were assessed after sacrifice. Mice with increased pressure load (PAB) or volume load (Shunt) 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 reduced exercise capacity and induced moderate RV dilatation with normal RV output at rest. In contrast, Shunt did not increase MCIP1 expression, and only moderately increased beta/alpha-MHC ratio. Shunt did not affect exercise capacity, but increased RV volumes and output at rest. CONCLUSIONS: Pressure and volume load induced different functional and molecular adaptations in the RV. These results may have important consequences for therapeutic strategies to prevent RV failure in the growing population of adults with congenital heart disease.