Beta-3 adrenergic receptor (β3AR) 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 β3AR 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 β3AR agonists on hemodynamics, vascular remodeling and RV performance in chronic PH. Ex vivo human experiments were performed to explore the expression of β3AR mRNA and the vasodilator response of β3AR agonists in pulmonary arteries. Single intravenous administration of the β3AR agonist BRL37344 produced a significant acute reduction in PVR, and two-weeks treatment with two different β3AR selective agonists, intravenous BRL37344 or oral mirabegron, resulted in a significant reduction in PVR (median of −2.0 Wood units/m2 for BRL37344 vs. +1.5 for vehicle, p = 0.04; and −1.8 Wood units/m2 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 β3AR agonists-treated pigs. β3AR was expressed in human pulmonary arteries and β3AR agonists produced vasodilatation. β3AR 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.

The authors thank Gonzalo J. López for the high-quality cardiac magnetic resonance examinations. Tamara Córdoba, Oscar Sanz, Nuria Valladares, Eugenio Fernández and the rest of the staff working in the animal facilities and CNIC ś farm were outstanding in animal care and unconditional collaboration. Laura García, Alberto Barroso and Xavier Navarro provided us with the ablation clamps and catheters and assisted us during the denervation procedures. Paula Garcia-Lunar provided valuable support with tissue sampling when it was most needed. SOURCES OF FUNDING:This work has been partially funded by the grant "Translational research project from the Sociedad Española de Cardiología" (to Dr. García-Álvarez) and by an unrestricted grant from Medtronic. The CNIC is supported by the Ministerio de Ciencia, Innovación y Universidades and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505).IDIBAPS belongs to the CERCA Programme and receives partial funding from the Generalitat de Catalunya.

Background-Pulmonary hypertension (PH) and right ventricular (RV) dysfunction are strong predictors of morbidity and mortality among patients with congenital heart disease. Early detection of RV involvement may be useful in the management of these patients. We aimed to assess progressive cardiac adaptation and quantify myocardial extracellular volume in an experimental porcine model of PH because of aorto-pulmonary shunt using cardiac magnetic resonance (CMR). Methods and Results-To characterize serial cardiac adaptation, 12 pigs (aorto-pulmonary shunt [n=6] or sham operation[n=6]) were evaluated monthly with right heart catheterization, CMR, and computed tomography during 4 months, followed by pathology analysis. Extracellular volume by CMR in different myocardial regions was studied in 20 animals (aorto-pulmonary shunt [n=10] or sham operation [n=10]) 3 months after the intervention. All shunted animals developed PH. CMR evidenced progressive RV hypertrophy and dysfunction secondary to increased afterload and left ventricular dilatation secondary to volume overload. Shunt flow by CMR strongly correlated with PH severity, left ventricular enddiastolic pressure, and left ventricular dilatation. T1-mapping sequences demonstrated increased extracellular volume at the RV insertion points, the interventricular septum, and the left ventricular lateral wall, reproducing the pattern of fibrosis found on pathology. Extracellular volume at the RV insertion points strongly correlated with pulmonary hemodynamics and RV dysfunction. Conclusions-Prolonged systemic-to-pulmonary shunting in growing piglets induces PH with biventricular remodeling and myocardial fibrosis that can be detected and monitored using CMR. These results may be useful for the diagnosis and management of congenital heart disease patients with pulmonary overcirculation. Cardiac magnetic resonance (CMR) is the gold standard technique for the assessment of ventricular structure, function, and myocardial scarring. Additionally, it allows for accurate measurement of pulmonary-to-systemic flow ratio (Q p /Q s ) and may be helpful for quantifying and monitoring pulmonary vascular resistance (PVR). 6,7 The presence of late gadolinium enhancement (LGE) in children and young adults with CHD is a prognostic marker. [8][9][10] In recent years, T1 mapping has emerged as a noninvasive technique for the quantification of myocardial extracellular volume (ECV), holding the promise of early detection of myocardial involvement not detectable by LGE.11 In contrast to LGE imaging that detects patchy areas of dense scarring, T1 mapping evidences a diffuse fibrotic process. This novel technique has been scarcely used in this scenario. 12 We hypothesized that CMR may be useful to monitor serial changes in cardiac remodeling and pulmonary hemodynamics and may be able to detect early myocardial fibrosis in a translational animal model of aorto-pulmonary shunt.The aorto-pulmonary shunt in growing piglets has become a well-established model of congenital conditions with leftto-ri...

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