https://doi.org/10.1007/s00392-025-02625-4
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 Med. Klinik III - Gastroenterologie und Stoffwechselkrankheiten Aachen, Deutschland; 4Uniklinik RWTH Aachen Klinik für Kinder- und Jugendmedizin Aachen, Deutschland; 5Herzzentrum der Universität zu Köln Klinik III für Innere Medizin Köln, Deutschland; 6Klinikum Traunstein Kardiologie Traunstein, Deutschland
Background: Despite improved risk management and novel pharmacological therapies cardiovascular disease remains the leading cause of death worldwide. Therefore, novel therapeutic approaches are needed to reduce residual cardiovascular risk. We could recently show that intestinal immune cells regulate energy metabolism and play an important role in atherosclerosis. However, the role of intestinal immune cells in postmyocardial infarction (MI) is unknown.
Methods and Results: To investigate the role of intestinal immune cells in MI we performed sham procedure or LAD-ligation in wild type (n=12) or Integrin-β7–/– mice (n=12), which are deficient for intestinal immune cells with normal leukocyte counts in other organs. Furthermore, we analyzed functional cardiac parameters and characterized systemic and myocardial inflammation by spectral flow cytometry (FACS). Interestingly gut immune cell deficient β7–/– mice were protected against MI-induced ventricular dysfunction 4 weeks after LAD-ligation (Millar catheter: dp/dt max (after Dobutamine injection) 7623 mmHg ± 718.8 in sham WT, 3937 mmHg ± 771.2 in MI WT vs. 9318 mmHg ± 1626 in MI β7–/– mice, p<0.01; echocardiography: LV ejection fraction 63.44% ± 3.61 in sham WT, 39.24% ± 6.2 in MI WT vs. 61.81% ± 7.8 in MI β7–/– mice, p<0.05). Mechanistically, Integrin-β7–/– mice show reduced bone marrow hematopoiesis after 4 weeks (31% reduction of LSK) and 3 days (40% reduction of LSK and 42% of CMP) compared to WT mice after MI. Circulating immune cells such as neutrophils and Ly-6Chigh monocytes were significantly lower in Integrin-β7–/– mice 3 days and 4 weeks after MI (28% reduction of neutrophils, 46% reduction of Ly-6Chigh monocytes). Cardiac immune cell influx 3 days after MI was reduced in Integrin-β7–/– vs. WT mice (41% reduction of total leukocytes, 46% of neutrophils and 35% reduction of macrophages). We validated these findings in the UK Biobank proteomics subset (ID 71300) and found in 53,030 patients a positive association of circulating Integrin-β7 with lifetime prevalence of heart failure and cardiac arrest (p<0.05). Furthermore, higher Integrin-β7 levels were associated with mortality (5112 events; multivariable cox regression model adjusted for age, sex, hsCRP, BMI, NT-proBNP, diabetes, history of MI, coronary artery disease, total cholesterol and creatinine; Chi2: 4470.74; p<0.0001)
Conclusion: Here we identified gut immune cells to play an important role in myocardial remodeling after MI. These findings suggest that gut immune cells might be a novel therapeutical target for patients with acute MI and ischemic heart failure.