Decreased plasma levels of the brain-derived neurotrophic factor correlate with right heart congestion in pulmonary arterial hypertension

Katharina Schäfer; Khodr Tello; Oleg Pak; Manuel Richter; Mareike Gierhardt; Grazyna Kwapiszewska; Christine Veith; Ludger Fink; Henning Gall; Matthias Hecker; Baktybek Kojonazarov; Simone Kraut; Kevin Lo; Jochen Wilhelm; Friedrich Grimminger; Werner Seeger; Ralph T Schermuly; Hossein A Ghofrani; Daniel Zahner; Rüdiger Gerstberger; Norbert Weissmann; Akylbek Sydykov; Natascha Sommer

doi:10.1183/23120541.00230-2022

Decreased plasma levels of the brain-derived neurotrophic factor correlate with right heart congestion in pulmonary arterial hypertension

ERJ Open Res. 2023 Mar 6;9(2):00230-2022. doi: 10.1183/23120541.00230-2022. eCollection 2023 Mar.

Authors

Katharina Schäfer^{1

2}, Khodr Tello^{1

2}, Oleg Pak^{1

2}, Manuel Richter¹, Mareike Gierhardt^{1

3}, Grazyna Kwapiszewska^{4

5}, Christine Veith¹, Ludger Fink¹, Henning Gall¹, Matthias Hecker¹, Baktybek Kojonazarov⁵, Simone Kraut¹, Kevin Lo¹, Jochen Wilhelm^{1

5}, Friedrich Grimminger¹, Werner Seeger^{1

5}, Ralph T Schermuly¹, Hossein A Ghofrani^{1

6}, Daniel Zahner⁷, Rüdiger Gerstberger⁸, Norbert Weissmann¹, Akylbek Sydykov^{1

2}, Natascha Sommer^{1

2}

Affiliations

¹ Department of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Excellence Cluster Cardio-Pulmonary Institute (CPI), Justus-Liebig University, Giessen, Germany.
² These authors contributed equally.
³ Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) - CONICET - Partner Institute of the Max Planck Society, Buenos Aires, Argentina.
⁴ Ludwig Boltzmann Institute for Lung Vascular Research, Otto Loewi research Center, Medical University Graz, Graz, Austria.
⁵ Institute for Lung Health (ILH), Giessen, Germany.
⁶ Department of Medicine, Imperial College London, London, UK.
⁷ Central Laboratory Animal Facility, Justus-Liebig University, Giessen, Germany.
⁸ Institute of Veterinary Physiology and Biochemistry, Justus-Liebig University, Giessen, Germany.

Abstract

Background: The brain-derived neurotrophic factor (BDNF) may promote development of pulmonary hypertension and right ventricular (RV) failure. However, BDNF plasma levels were decreased in patients with left ventricular (LV) failure. Therefore, we investigated BDNF plasma levels in pulmonary hypertension patients and the role of BDNF in mouse models of pulmonary hypertension and isolated RV failure.

Methods: BDNF plasma levels were correlated to pulmonary hypertension in two patient cohorts, including either post- and pre-capillary pulmonary hypertension patients (first cohort) or only pre-capillary pulmonary hypertension patients (second cohort). In the second cohort, RV dimensions and load-independent function were determined by imaging and pressure-volume catheter measurements, respectively. For induction of isolated RV pressure overload, heterozygous Bdnf knockout (Bdnf^+/- ) mice were subjected to pulmonary arterial banding (PAB). For induction of pulmonary hypertension, mice with inducible knockout of BDNF in smooth muscle cells (Bdnf/Smmhc knockout) were exposed to chronic hypoxia.

Results: Plasma BDNF levels were decreased in patients with pulmonary hypertension. Following adjustment for covariables, BDNF levels negatively correlated in both cohorts with central venous pressure. In the second cohort, BDNF levels additionally negatively correlated with RV dilatation. In animal models, BDNF downregulation attenuated RV dilatation in Bdnf⁺ ^/- mice after PAB or hypoxic Bdnf/Smmhc knockout mice, although they developed pulmonary hypertension to a similar extent.

Conclusions: Similar to LV failure, circulating levels of BDNF were decreased in pulmonary hypertension patients, and low BDNF levels were associated with right heart congestion. Decreased BDNF levels did not worsen RV dilatation in animal models, and thus, may be the consequence, but not the cause of RV dilatation.