Anemia aggravates the systemic endothelial dysfunction after acute myocardial infarction

Background:

Anemia is frequently observed in patients with cardiovascular diseases (CVD) such as acute and chronic coronary syndromes as well as heart failure. Approximately 30 to 40% of patients with acute myocardial infarction (AMI) have evident anemia upon admission or during hospitalization. It is well known that anemia alone or in combination with other morbid conditions leads to poor prognosis in AMI. We recently showed that moderate blood loss anemia is associated with red blood cell (RBC) dysfunction and compensatory increase in flow-mediated dilation (FMD) responses. However, the effects of acute anemia on endothelial function after AMI are unclear. In this study, we evaluated the systemic endothelial function in an established blood loss acute anemic mouse model after AMI. We hypothesise that anemia aggravates the systemic endothelial dysfunction (ED) after AMI. 

Methods: 

Acute anemia was induced by repeated blood withdrawal for three consecutive days in male C57BL/6J mice. A separate group of anemic and sham mice were induced with AMI by left anterior descending artery (LAD)-ligation. Endothelial function was assessed using both in vivo and ex vivo techniques 24 h post-AMI. FMD responses were assessed using ultrasound-guided femoral transient ischemia model. The endothelial function in aorta, femoral and saphenous arteries were assessed using wire myograph. Immunohistochemistry was used to detect oxidative ROS product 4-Hyodroxynonenal (4-HNE) in the aorta. To investigate the role of reactive oxygen species (ROS) in anemia associated ED, additional group of mice were treated with N-Acetyl cysteine (NAC) for 4 weeks, anemia was induced, and endothelial function was assessed 24 h post-AMI. To demonstrate the specific role of RBCs in ED after AMI, RBCs from sham and anemic mice 24 h post-AMI were incubated with wildtype (WT) mice aortic rings and endothelial function was evaluated.

Results: 

FMD was significantly impaired in acute anemic mice 24 h post-AMI compared to their respective sham mice post-AMI. Endothelial nitric oxide (NO)-dependent relaxation responses were impaired in the aorta, femoral and saphenous arteries in anemic mice compared to sham mice 24 h post-AMI. Aortic tissues from anemic mice show an increase in 4-HNE levels 24 h post-AMI. NAC treatment improved both in vivo and ex vivo endothelium-dependent relaxation responses in acute anemic mice 24 h post-AMI. Co-incubation of RBCs from anemic mice 24 h post-AMI with WT aortic rings showed and attenuated endothelial NO-dependent relaxation responses.

Conclusion: 

Acute anemia is associated with reduced endothelial NO-dependent relaxation responses ex vivo, and impaired in vivo FMD responses after AMI, which was accompanied by an increased production of ROS in the arteries. NAC treatment improved the endothelial function in anemic mice after AMI. RBCs from anemic mice 24 h post-AMI induce ED in murine aortic rings concluding the potential role in ED. NAC supplementation is a potential therapeutic option to reverse the devastating ED in acute anemia after AMI.