Clin Res Cardiol (2023). https://doi.org/10.1007/s00392-023-02180-w

Neonatal model of pulmonary artery banding– a unique model to investigate right ventricular plasticity and intraventricular crosstalk in neonatal mice

F. Ebach1, J. Nicke1, T. Hu1, B. Fleischmann1, M. Malek Mohammadi1

1Physiologie I Life & Brain Center, Universitätsklinikum Bonn, Bonn;

Introduction: The capacity of the left ventricular (LV) neonatal myocardium for adaptive regeneration following injury or pressure overload has been widely recognized. However, it is unclear whether the right ventricular (RV) myocardium has similar plasticity and how injury and regenerative response of one ventricle influences the other ventricle. While, in adults, LV pathologies account for the majority of cardiovascular disease burden, persistent pulmonary hypertension and the resulting RV pressure overload of varying degrees is a common symptom in neonatology that may lead to severe disease or even death. In contrast, surgically induced elevation of RV pressure by pulmonary artery banding has been shown to enhance LV function in young children with dilated cardiomyopathy often preventing the need for transplantation. Although its molecular mechanisms remain unknown, this observation indicates great plasticity of the RV and the existence of ventricular crosstalk shortly after birth. To investigate RV plasticity and regenerative potential and to explore the molecular mechanism of “interventricular” effects in the neonatal phase, we established a neonatal murine model of pulmonary artery banding to induce pressure overload on the RV as early as postnatal day 1 (P1). Methods: For the surgery we used wild-type CD1 mice on P1. Anesthesia was induced by isoflurane and maintained by hypothermia during the surgery. After opening of the chest, the main pulmonary artery (MPA) and aorta were carefully separated. A suture was placed around the base of the MPA (Figure 1) and then tied around a placeholder needle, constricting the lumen of the MPA to fit the needle’s size. After removing the needle, the chest and skin were closed and the mouse was rewarmed. After full recovery, it was placed back in the mother’s cage. Before surgery and 6h thereafter, analgetic treatment with buprenorphine was administered. Echo was performed on P7 and P14 to confirm the correct positioning of the constriction and to assess RV and LV function. Results: Echocardiography confirmed a persisting constriction of the main pulmonary artery with doppler flow measurements showing a markedly increased velocity in the MPA. Consequently, the RV was thickened and the septum was deviated to the left (Figure 2). Post-mortem anatomic inspection on P14 confirmed RV and right atrial enlargement with additional signs of central venous congestion, such as enlarged liver and kidneys. Discussion: We successfully established neonatal pulmonary artery banding in P1 mice and confirmed the desired hemodynamic effects by echocardiography and anatomic inspection. In further work, we will determine the needle size that can raise an adaptive response of the RV to pressure overload without causing decompensated RV failure. This new neonatal surgical model will enable us, for the first time, to gain insight into the plasticity of the neonatal RV and understand molecular mechanisms of myocardial adaptation to RV pressure overload and ventricular crosstalk. Therefore, this study will pave the way towards a better understanding of cardiac plasticity to identify novel therapeutic targets for patients, especially children with cardiovascular disease. Figure 1 Intraoperative view. 1: MPA, 2: aortic arch, 3: ductus arteriosus (obliterated) Figure 2 Short axis view on P14. RV: Right Ventricle, LV: left ventricle

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