Distinct effects of acute and chronic blood loss anemia on vascular function after acute myocardial infarction

Solga, I.; Sahin, A.; Yogathasan, V.; Hofer, L.; Celik, F.; Rai, A. E.; Hosen, M. R.; Wischmann, P.; Becher, S.; Polzin, A.; Gerdes, N.; Jung, C.; Kelm, M.; Chennupati, R.

doi:10.1101/2024.09.24.614629

bioRxiv · 10.1101/2024.09.24.614629

Distinct effects of acute and chronic blood loss anemia on vascular function after acute myocardial infarction

Solga, I.·Sahin, A.·Yogathasan, V.·Hofer, L.·Celik, F.·Rai, A. E.·Hosen, M. R.·Wischmann, P.·Becher, S.·Polzin, A.·Gerdes, N.·Jung, C.·Kelm, M.·Chennupati, R.

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Abstract

BackgroundAnemia is frequently observed in patients with cardiovascular diseases (CVD). Anemia alone or in combination with other morbid conditions leads to poor prognosis in acute myocardial infarction (AMI). We recently showed that moderate blood loss anemia is associated with red blood cell (RBC) dysfunction and a compensatory increase in flow-mediated dilation (FMD) responses which are compromised in chronic blood loss anemia However, the effects of acute anemia (AA) and chronic anemia (CA) on endothelial function after AMI are unclear. In this study, we evaluated systemic endothelial function following AMI in established murine models of blood loss acute and chronic anemia. We hypothesize that both AA and CA aggravate systemic endothelial dysfunction (ED) after AMI. Methods and resultsAA or CA was induced in male C57BL/6J mice by repeated blood withdrawal for three consecutive days or six weeks, respectively. Separate groups of anemic and non-anemic mice underwent AMI via left anterior descending artery (LAD) ligation (45 min), followed by reperfusion. Endothelial function was assessed using both in vivo and in vitro methods 24 h post-AMI. Impaired flow-mediated dilation (FMD, in vivo) and endothelium-dependent relaxation (EDR) responses were observed in the aorta, femoral, and saphenous arteries of AA mice compared to their respective control groups 24 h post AMI. The aorta and saphenous arteries from CA mice showed significantly reduced vascular smooth muscle (VSM) contractile responses after AMI. Analysis of oxidative products of nitric oxide (NO) in plasma revealed reduced nitrite and nitrate levels in both AA and CA mice compared to controls 24 h post-AMI. Immunohistochemistry of aortic tissues from both anemic groups showed increased reactive oxygen species (ROS) product 4-Hydroxynonenal (4-HNE). Co-incubation of RBCs from anemic mice or anemic ST-elevation myocardial infarction (STEMI) patients with aortic rings from wild type mice demonstrated attenuated VSM contractile and EDR responses. Supplementation with the ROS scavenger N-acetyl cysteine (NAC) for four weeks improved both in vivo and ex vivo EDR in AA and CA mice 24 h post-AMI. ConclusionAfter AMI, both AA and CA are associated with severe ED, while VSM contractile responses specifically reduced in CA mice. These effects are accompanied by increased ROS and partly mediated by RBCs. Antioxidant supplementation with NAC is a potential therapeutic option to reverse the severe vascular dysfunction in anemia following AMI. Graphical AbstractDistinct effects of acute and chronic anemia on vascular function 24 h post-AMI. After acute myocardial infarction, acute and chronic anemia are associated with increased reactive oxygen species (ROS) and inflammation in endothelial cells (EC), leading to the inhibition of endothelial nitric oxide synthase (eNOS) and subsequent endothelial dysfunction by limiting NO bioavailability. Chronic anemia is additionally associated with decreased vascular smooth muscle cell (VSMC) function due to increased oxidative stress, leading to SMC dysfunction. After N-Acetyl-L-Cysteine (NAC) treatment, vascular function is improved in both anemic groups. O_FIG O_LINKSMALLFIG WIDTH=98 HEIGHT=200 SRC="FIGDIR/small/614629v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@136583aorg.highwire.dtl.DTLVardef@da8708org.highwire.dtl.DTLVardef@d73539org.highwire.dtl.DTLVardef@e7516a_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Solga, I., Sahin, A., Yogathasan, V., Hofer, L., Celik, F., Rai, A. E., Hosen, M. R., Wischmann, P., Becher, S., Polzin, A., Gerdes, N., Jung, C., Kelm, M., Chennupati, R.. 2024-09-26. Distinct effects of acute and chronic blood loss anemia on vascular function after acute myocardial infarction. https://doi.org/10.1101/2024.09.24.614629

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