rhNRG-1 treatment attenuates pulmonary arterial and RV remodelling, and dysfunction in a rat model of MCT-induced PAH and has direct anti-remodelling effects on the pressure-overloaded RV.

Pulmonary arterial hypertension is a progressive syndrome based on diverse aetiologies, which is characterized by a persistent increase in pulmonary vascular resistance and overload of the right ventricle, leading to heart failure and death. Currently, none of the available treatments is able to cure pulmonary arterial hypertension; additional research is therefore needed to unravel the associated pathophysiological mechanisms. This review summarizes current knowledge related to this disorder, and the several experimental animal models that can mimic pulmonary arterial hypertension and are available for translational research.

Pulmonary arterial hypertension (PAH), the most serious chronic disorder of the pulmonary circulation, is characterized by pulmonary vasoconstriction and remodeling, resulting in increased afterload on the right ventricle (RV). In fact, RV function is the main determinant of prognosis in PAH. The most frequently used experimental models of PAH include monocrotaline- and chronic hypoxia-induced PAH, which primarily affect the pulmonary circulation. Alternatively, pulmonary artery banding (PAB) can be performed to achieve RV overload without affecting the pulmonary vasculature, allowing researchers to determine the RV-specific effects of their drugs/interventions. In this work, using two different degrees of pulmonary artery constriction, we characterize, in full detail, PAB-induced adaptive and maladaptive remodeling of the RV at 3 wk after PAB surgery. Our results show that application of a mild constriction resulted in adaptive hypertrophy of the RV, with preserved systolic and diastolic function, while application of a severe constriction resulted in maladaptive hypertrophy, with chamber dilation and systolic and diastolic dysfunction up to the isolated cardiomyocyte level. By applying two different degrees of constriction, we describe, for the first time, a reliable and short-duration PAB model in which RV adaptation can be distinguished at 3 wk after surgery. We characterize, in full detail, structural and functional changes of the RV in its response to moderate and severe constriction, allowing researchers to better study RV physiology and transition to dysfunction and failure, as well as to determine the effects of new therapies.

Ucn-2 levels are altered in human and experimental PAH. hUcn-2 treatment attenuates PAH and RV dysfunction in MCT-induced PH, has direct anti-remodelling effects on the pressure-overloaded RV, and improves pulmonary vascular function.

We have previously shown that treatment with recombinant human neuregulin-1 (rhNRG-1) improves pulmonary arterial hypertension (PAH) in a monocrotaline (MCT)-induced animal model, by decreasing pulmonary arterial remodelling and endothelial dysfunction, as well as by restoring right ventricular (RV) function.Additionally, rhNRG-1 treatment showed direct myocardial anti-remodelling effects in a model of pressure loading of the RV without PAH. This work aimed to study the intrinsic cardiac effects of rhNRG-1 on experimental PAH and RV pressure overload, and more specifically on diastolic stiffness, at both the ventricular and cardiomyocyte level. We studied the effects of chronic rhNRG-1 treatment on ventricular passive stiffness in RV and LV samples from MCT-induced PAH animals and in the RV from animals with compensated and decompensated RV hypertrophy, through a mild and severe pulmonary artery banding (PAB). We also measured passive tension in isolated cardiomyocytes and quantified the expression of myocardial remodelling-associated genes and calcium handling proteins. Chronic rhNRG-1 treatment decreased passive tension development in RV and LV isolated from animals with MCT-induced PAH. This decrease was associated with increased phospholamban phosphorylation, and with attenuation of the expression of cardiac maladaptive remodelling markers.Finally, we showed that rhNRG-1 therapy decreased RV remodelling and cardiomyocyte passive tension development in PAB-induced RV hypertrophy animals, without compromising cardiac function, pointing to cardiac-specific effects in both hypertrophy stages. In conclusion, we demonstrated that rhNRG-1 treatment decreased RV intrinsic diastolic stiffness, through the improvement of calcium handling and cardiac remodelling signalling. K E Y W O R D Sdiastolic function, diastolic stiffness, neuregulin-1, pulmonary arterial hypertension, right ventricle