Gut immune cells are upregulated in heart failure and aggravate left ventricular dysfunction in mice

Maximilian Neuhaus (Aachen)1, N. Tabaza (Aachen)1, N. Ganesh (Aachen)1, L. B. Quintana Selek (Aachen)1, M. Sausen (Aachen)1, M. C. Arrivas (Aachen)1, S. Just (Aachen)1, B. Kurt (Aachen)1, J. Spießhöfer (Aachen)2, A. Schippers (Aachen)3, N. Wagner (Aachen)3, M. Lehrke (Aachen)1, N. Marx (Aachen)1, F. Kahles (Aachen)1

1Uniklinik RWTH Aachen Med. Klinik I - Kardiologie, Angiologie und Internistische Intensivmedizin Aachen, Deutschland; 2Uniklinik RWTH Aachen Med. Klinik V - Klinik für Pneumologie und Internistische Intensivmedizin Aachen, Deutschland; 3Uniklinik RWTH Aachen Klinik für Kinder- und Jugendmedizin Aachen, Deutschland


Background Cardiovascular disease continues to be the main cause of death worldwide, despite improved risk management and modern pharmacological therapies. Thus, novel therapeutic approaches have to be identified to reduce cardiovascular morbidity and mortality. Data from the last 2 decades have shown that inflammation plays an important role in cardiovascular disease. Next to the spleen and the bone marrow, the gut contains one of the largest immune cell reservoirs of our bodies. We could recently show that gut immune cells regulate energy metabolism and play an important role in atherosclerosis. However, the role of intestinal immune cells in heart failure is unknown.


Methods and Results To investigate the role of gut immune cells in heart failure we performed sham procedure or transaortic constriction (TAC) in C57BL/6J mice to induce pressure-overload induced cardiac hypertrophy and analyzed intestinal leukocytes by spectral flow cytometry (FACS). Mice with established heart failure (5 weeks after TAC surgery) had higher numbers of intestinal immune cells compared to mice without heart failure (intraepithelial space: 2.5-fold increase of αβ and γδ T cells, p<0.05; lamina propria: 10-fold increase of T cells, p=0.036, 2.6-fold increase of macrophages, p<0.001). To explore the functional role of activated gut immune cells in heart failure we performed TAC surgery in wild type (n=10) or Integrin-β7–/– mice (n=11), which are selectively deficient for intestinal immune cells with normal leukocyte counts in other organs. Interestingly gut immune cell deficient Integrin-β7–/– mice were protected against left ventricular dysfunction induced by TAC surgery [LV ejection fraction (EF-SAX): 58.9 ± 4.4% in sham WT, 35.3 ± 7.0% in TAC WT, 45.0 ± 9.4% in TAC β7–/–, p<0.05; LV fractional shortening: 30.7 ± 3.1% in sham WT, 17.9 ± 4.6% in TAC WT, 23.1 ± 5.9% in TAC β7–/–, p<0.05, analyzed by echocardiography].


Conclusion Here we identified an interorgan-crosstalk network between the intestinal immune system and the myocardium in mice with heart failure. Future work is needed to investigate the underlying mechanisms. These findings suggest that gut immune cells might be a novel therapeutical target for heart failure.

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