Beta-3 adrenergic agonists reduce pulmonary vascular resistance and improve right ventricular performance in a porcine model of chronic pulmonary hypertension

Beta-3 adrenergic receptor (beta 3AR) agonists have been shown to produce vasodilation and prevention of ventricular remodeling in different conditions. Given that these biological functions are critical in pulmonary hypertension (PH), we aimed to demonstrate a beneficial effect of beta 3AR agonists in PH. An experimental study in pigs (n = 34) with chronic PH created by pulmonary vein banding was designed to evaluate the acute hemodynamic effect and the long-term effect of beta 3AR agonists on hemodynamics, vascular remodeling and RV performance in chronic PH. Ex vivo human experiments were performed to explore the expression of beta 3AR mRNA and the vasodilator response of beta 3AR agonists in pulmonary arteries. Single intravenous administration of the beta 3AR agonist BRL37344 produced a significant acute reduction in PVR, and two-weeks treatment with two different beta 3AR selective agonists, intravenous BRL37344 or oral mirabegron, resulted in a significant reduction in PVR (median of -2.0 Wood units/m(2) for BRL37344 vs. + 1.5 for vehicle, p = 0.04; and -1.8 Wood units/m(2) for mirabegron vs. + 1.6 for vehicle, p = 0.002) associated with a significant improvement in magnetic resonance-measured RV performance. Histological markers of pulmonary vascular proliferation (p27 and Ki67) were significantly attenuated in beta 3AR agonists-treated pigs. beta 3AR was expressed in human pulmonary arteries and beta 3AR agonists produced vasodilatation. beta 3AR agonists produced a significant reduction in PVR and improved RV performance in experimental PH, emerging as a potential novel approach for treating patients with chronic PH.This work was supported by Fonde Europeo de Desarrollo Regional (FEDER) Instituto de Salud Carlos III-Fondo de Investigacion Sanitaria PI13/02339 (to A. G-A), and the competitive grant ``CNIC-Translational 01-2009´´ (to BI). R F-J is recipient of a ``Rio Hortega´´ fellowship granted by the ISCIII. R F-J is recipient of the ``FICNIC´´ fellowship granted by the ``Fundacio Jesus Serra´´, ``Fundacion Interhospitalaria de Investigacion Cardiovascular (FIC)´´ and CNIC. A. G-A, B. I, L. F-F, R. F-J, M. S and JM. G-R are members of ``Red de Investigacion Cardiovascular´´ (RIC RD12/0042/0006 and RD12/0042/0054) from the Ministerio de Economia y Competitividad, ISCIII´´. The CNIC is supported by the Spanish Ministry of Economy and Competitiveness (MINECO) and the Pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505).S

Association of myocardial T1-mapping CMR with hemodynamics and RV performance in pulmonary hypertension

Early detection of right ventricular (RV) involvement in chronic pulmonary hypertension (PH) is essential due to prognostic implications. T1 mapping by cardiac magnetic resonance (CMR) has emerged as a noninvasive technique for extracellular volume fraction (ECV) quantification. We assessed the association of myocardial native T1 time and equilibrium contrast ECV (Eq-ECV) at the RV insertion points with pulmonary hemodynamics and RV performance in an experimental model of chronic PH. Right heart catheterization followed by immediate CMR was performed on 38 pigs with chronic PH (generated by surgical pulmonary vein banding) and 6 sham-operated controls. Native T1 and Eq-ECV values at the RV insertion points were both significantly higher in banded animals than in controls and showed significant correlation with pulmonary hemodynamics, RV arterial coupling, and RV performance. Eq-ECV values also increased before overt RV systolic dysfunction, offering potential for the early detection of myocardial involvement in chronic PH.Sin financiación7.815 JCR (2015) Q1, 6/124 Cardiac and cardiovascular system, 1/124 Radiology, nueclear medicine and medicine imagingUE