Acute anemia is associated with left ventricular energy imbalance after myocardial infarction

Introduction: Anemia is frequently observed in patients with cardiovascular diseases (CVD) such as acute and chronic coronary syndromes as well as heart failure. Anemia alone or in combination with other morbid conditions leads to poor prognosis in acute myocardial infarction (AMI). Anemic mouse models and clinical patient data demonstrated that anemia is associated with an unchanged infarct size but with an increased mortality. The effects of anemia on left ventricle (LV) dysfunction have not been investigated. We hypothesise that energy imbalance in anemia contributes to the left ventricular dysfunction in AMI leading to worse prognosis. 

Methods: Acute anemia was induced by repeated blood withdrawal for 3 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. Heart function was assessed using cardiac magnetic resonance imaging (CMRI) at baseline, 3 days of anemia and 24 h after AMI. Proteomic analysis was performed in the remote and ischemic regions of the hearts before and after AMI in anemic and sham mice. Functional high resolution respirometry analysis was performed on isolated LV tissues in anemic and sham mice after AMI. Redox state of the remote and ischemic regions was analysed by assessing the colorimetric activity of antioxidant enzymes (SOD, Glutathione, catalase) and myeloperoxidase. 

Results: Assessment of heart function using CMRI demonstrated that acute anemia is associated with an unchanged PCr/ATP ratio at base line and 3 days after anemia. In the ischemic region, PCr/ATP ratio was significantly reduced after 24 h post-AMI in anemic mice compared to sham mice. The fractional shortening at base line and 3 days after anemia was unchanged whereas it was significantly decreased in the infarct region of anemic mice compared to sham mice post-AMI. Proteomic analysis of LVs revealed that energy imbalance is accompanied by altered respiration and ATP production related signalling pathways in the ischemic region of anemic mice compared to sham mice after AMI. Functional high resolution respirometry analysis of isolated LV tissues revealed that respiratory acceptor control ratio (RCR) and OXPHOS/ETS ratio was significantly decreased in the ischemic region of anemic mice compared to sham mice 24 h post-AMI. The total antioxidant capacity of LV was significantly decreased in anemic mice compared to sham mice at basal level and after AMI. Immunohistochemistry analysis further demonstrated an increased oxidative stress in the hearts of anemic mice compared to sham mice. Anemic mice, which were treated with N-Acetyl cysteine (NAC), showed normalized RCR and OXPHOS/ETS values after AMI.

Conclusion: Increased oxidative stress in anemia alters the mitochondrial respiration capacity in left ventricle and results in decreased PCr/ATP ratio and fractional shortening after myocardial infarction.