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Project summary
The majority of patients with heart failure with preserved ejection fraction (HFpEF) develop secondary pulmonary hypertension (PH) and subsequent right ventricular (RV) failure. The underlying mechanisms are not well understood, but involve passive congestion, active vascular remodeling with impaired pulmonary gas exchange and systemic activation of the immune system. Here, we propose a mechanistic interdependence of these processes, in that active recruitment of immune cells into the lung´s perivascular space drives lung vascular remodeling thus impairing pulmonary gas exchange. The ensuing systemic hypoxemia will in turn promote systemic inflammation and accelerate the decline in left ventricular (LV) and right ventricular (RV) function.
Graphical Abstract: Previously, HFpEF has been linked to comorbidities via systemic inflammation, and to RV failure via congestion (thin black arrows). Here, we propose a novel concept of cardio-pulmonary interaction in HFpEF that is driven by a triangular maladaptive feed-forward loop mutually promoting inflammation, lung vascular remodeling, and hypoxemia in a reciprocal manner (thick arrows) with each component negatively impacting on ventricular function (thin arrows pointing towards LV and RV, respectively).
Project leader A04
CCM: Campus Charité Mitte
Project leader A04
CCM: Campus Charité Mitte
Publications
Liu SF, Nambiar Veetil N, Li Q, Kucherenko MM, Knosalla C, Kuebler WM. Pulmonary hypertension: Linking inflammation and pulmonary arterial stiffening. Front Immunol. 2022 Oct 5;13:959209. doi: 10.3389/fimmu.2022.959209. PMID: 36275740; PMCID: PMC9579293.
Peters L, Kuebler WM, Simmons S. Sphingolipids in Atherosclerosis: Chimeras in Structure and Function. Int J Mol Sci. 2022 Oct 8;23(19):11948. doi: 10.3390/ijms231911948. PMID: 36233252; PMCID: PMC9570378.Voelkel NF, Bogaard HJ, Kuebler WM. ARDS in the time of corona: context and perspective. Am J Physiol Lung Cell Mol Physiol. 2022 Oct 1;323(4):L431-L437. doi: 10.1152/ajplung.00432.2021. Epub 2022 Aug 23. PMID: 35997290; PMCID: PMC9529269.
Sinha M, Zabini D, Guntur D, Nagaraj C, Enyedi P, Olschewski H, Kuebler WM, Olschewski A. Chloride channels in the lung: Challenges and perspectives for viral infections, pulmonary arterial hypertension, and cystic fibrosis. Pharmacol Ther. 2022 Sep;237:108249. doi: 10.1016/j.pharmthera.2022.108249. Epub 2022 Jul 22. PMID: 35878810.
Jiang T, Samapati R, Klassen S, Lei D, Erfinanda L, Jankowski V, Simmons S, Yin J, Arenz C, Dietrich A, Gudermann T, Adam D, Schaefer M, Jankowski J, Flockerzi V, Nüsing R, Uhlig S, Kuebler WM. Stimulation of the EP3 receptor causes lung oedema by activation of TRPC6 in pulmonary endothelial cells. Eur Respir J. 2022 Oct 13;60(4):2102635. doi: 10.1183/13993003.02635-2021. PMID: 35450969.
Sang P, Kucherenko MM, Yao J, Li Q, Simmons S, Kuebler WM, Knosalla C. A Model of Reverse Vascular Remodeling in Pulmonary Hypertension Due to Left Heart Disease by Aortic Debanding in Rats. J Vis Exp. 2022 Mar 1;(181). doi: 10.3791/63502. PMID: 35311828.
Graw JA, Bünger V, Materne LA, Krannich A, Balzer F, Francis RCE, Pruß A, Spies CD, Kuebler WM, Weber-Carstens S, Menk M, Hunsicker O. Age of Red Cells for Transfusion and Outcomes in Patients with ARDS. J Clin Med. 2022 Jan 4;11(1):245. doi: 10.3390/jcm11010245. PMID: 35011986; PMCID: PMC8745782.
