Clin Res Cardiol (2021) DOI DOI https://doi.org/10.1007/s00392-021-01843-w

Ramipril modulates myeloid hematopoiesis after acute myocardial infarction and reduces cardiac and vascular inflammation

M. Molitor1, W.-S. Rudi2, V. Garlapati1, S. Finger3, J. Wild4, S. Karbach1, T. Münzel4, P. Wenzel1

1Zentrum für Kardiologie, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Mainz; 2Centrum für Thrombose und Hämostase, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Mainz; 3Abteilung für psychosomatische Medizin, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Mainz; 4Kardiologie 1, Zentrum für Kardiologie, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Mainz;

Objectives: ACE-inhibitors form a backbone of drug therapy after myocardial infarction (MI) in order to improve left ventricular function and survival. Inhibition of the renin-angiotensin-aldosterone-system (RAAS) also limits vascular inflammation due to limited infiltration of NADPH-oxidase 2 (Nox2)+ myeloid cells in ischemic heart failure. We aimed to elucidate the impact of early ACE-inhibitor treatment after MI on myeloid hematopoietic response in the bone marrow and spleen and their impact on systemic and vascular inflammation. Methods and Results: Myocardial infarction was induced to 8-12 week-old, male C57BL6/J mice by permanent ligation of the left anterior descending artery (LAD) or sham-operation. Drug treatment with the ACE-inhibitor Ramipril (10 mg/kgBW/d) was initiated immediately via drinking water and hematopoetic and systemic inflammatory response analysed after 48 hours and 7 days by flow cytometry and real-time PCR analyzation. Early ACE-inhibitor treatment reduced cardiac inflammation and circulating Ly6Chighinflammatory monocytes 48h post MI, while left ventricular function was not altered in the first days. This effect was accompanied by enhanced retention of Sca-1+c-Kit+hematopoietic stem cells and Sca-1-c-Kit+common myeloid and granulocyte-macrophage progenitors in the bone marrow and spleen with upregulation of retainment factors Angiopoetin 1,Vcam1, CxCl12and Kitl. Cell number of myeloid precursor cells normalized over 7 days. Long-term blockade of RAAS over 28 days reduced vascular accumulation of particular of Ly6Chighmonocytes/ macrophages and improved vascular endothelial function, paralleled by reduced production of reactive oxygen species in blood and vessels. Conclusion: Early ACE inhibition modulates the myeloid inflammatory response after MIdue to retention of myeloid precursor cells in their bone marrow and splenic reservoir. This results in reduction of cardiac and vascular inflammation with improvement of survival.

https://dgk.org/kongress_programme/jt2021/aP830.html