Pulmonary hypertension in experimental HFpEF in rats - 17/02/23

Pulmonary hypertension (PH) is a common complication of heart failure with preserved ejection fraction (HFpEF) that is linked to worse disease morbidity and mortality. Despite being the most common form of PH, there are currently no approved therapies for the treatment of PH secondary to HFpEF. The underlying mechanisms of PH in HFpEF remain largely unknown. In this context, we sought to characterize the pathomechanisms underlying the pathogenesis of PH, as well as the right ventricular (RV)-pulmonary arterial (PA) coupling in an experimental model of obesity-associated HFpEF in rats.

Obesity-prone (OP) and -resistant Sprague Dawley rats were respectively fed with a high-fat or a standard rat chow diet for 12months (n=10 in each group) and evaluated by echocardiography, left (LV) and RV catheterization, histological and pulmonary artery vasoactive analyses.

Twelve-month high-fat diet fed OP rats presented with HFpEF, characterized by preserved LV ejection fraction, LV diastolic dysfunction (assessed by increased LV end-diastolic pressure) associated to concentric LV hypertrophy and fibrosis. In HFpEF rats, RV systolic pressure was increased (31.6±1.0 versus 26.3±0.5mmHg, P<0.001), with no significant changes in pulmonary artery muscularization and inflammatory cell infiltration. Ex vivo PA contraction to phenylephrine and endothelin-1 was similar in both groups of rats. In HFpEF rats, echocardiography showed an increase in PA diameter and PA-to-aorta diameter ratio associated with an increased RV/LV ratio. RV function was altered, with decreased fractional area change (FAC) and altered RV-PA coupling (assessed by TAPSE/PAPs). Circulating seric levels of sST2 increased in HFpEF rats, while NT-proBNP levels decreased.

Our experimental model of obesity-associated HFpEF naturally develops PH, as it occurs in patients. This PH was not associated with PA structural changes, nor sustained PA vasoreactive response. However, RV structure and function, as well as RV-PA coupling were altered.