Comprehensive Echocardiographic Assessment of Right Ventricle Function in a Rat Model of Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a progressive disease caused by vasoconstriction and remodeling of the small arteries in the lungs. This remodeling leads to increased pulmonary vascular resistance, worsened right ventricular function, and premature death. Currently approved therapies for PAH largely target pulmonary vasodilator pathways; however, recent emerging therapeutic modalities are focused on other novel pathways involved in the pathogenesis of the disease, including right ventricle (RV) remodeling. Imaging techniques that allow longitudinal assessment of novel therapeutics are very useful for determining the efficacy of new drugs in preclinical studies. Noninvasive trans-thoracic echocardiography remains the standard approach to evaluating heart function and is widely used in rodent models. However, echocardiographic evaluation of the RV can be challenging due to its anatomical position and structure. In addition, standardized guidelines are lacking for echocardiography in preclinical rodent models, making it difficult to carry out a uniform assessment of RV function across studies in different laboratories. In preclinical studies, the monocrotaline (MCT) injury model in rats is widely used to evaluate drug efficacy for treating PAH. This protocol describes the echocardiographic evaluation of the RV in naïve and MCT-induced PAH rats.

The dog's role in the preclinical assessment of QT interval prolongation.

During the development of a new therapeutic, few pharmacodyamic outcomes currently receive as much scrutiny as the effect of a potential medication on the electrocardiographic QT interval. The recent withdrawal from marketing of several drugs due to potential drug-related cardiac arrhythmias have greatly increased concern about drug-related changes on the QT interval. In order to reduce the incidence of these idiosyncratic episodes, regulatory agencies have suggested that sponsors use more rigorous methodology during the safety evaluation of new pharmaceuticals. Along with enhanced electrocardiographic assessments during clinical trials, advanced preclinical examinations of effect on QT interval and ventricular repolarization have become de rigueur. In this arena, the beagle dog is the preclinical species often associated with the most reliable predictivity for human safety assessment. To this end, canine models of cardiovascular safety assessment are discussed along with the relevance of these assays to human electrocardiography.