Anemia exacerbates regional left ventricular functional impairment and energetic imbalance in acute myocardial infarction
R Chennupati, V Yogathasan, M Cramer, P Wischmann, E Zweck, S Piel, M R Hosen, K Marjani, J Haurand, T Y Pang, A Lang, N Gerdes, U Floegel, M Kelm, C JungAbstract
Background and Purpose
Anemia is frequently observed in patients with cardiovascular diseases (CVD) such as acute myocardial infarction (AMI). Anemia, either alone or in combination with other morbid conditions, leads to a poor prognosis in AMI. Studies using anemic mouse models and clinical patient data have demonstrated that anemia is associated with an unchanged infarct size but increased mortality. However, the underlying mechanisms are not clear. We hypothesize that an energy imbalance in the heart contributes to left ventricular dysfunction in AMI, leading to a worse prognosis in anemia.
Methods
STEMI (ST-elevation myocardial infarction) patients with and without anemia were analyzed by cardiac magnetic resonance imaging (CMRI) to assess cardiac contractile function. Acute blood loss anemia was induced by repeated blood withdrawal for three consecutive days in male C57BL/6J mice with and without left anterior descending artery (LAD) ligation. Heart function was assessed using CMRI at baseline, after three days of anemia, and 24 hours post-AMI. Proteomic and respirometry analyses were performed on isolated LV tissues from anemic and sham mice after AMI. Flow cytometry and immunohistochemistry were used to analyse immune cell infiltration. Mitochondrial respiration was analyzed in LV biopsies from anemic ischemic cardiomyopathy (ICM) patients.
Results
Anemia in STEMI patients was associated with significantly worse infarct-region contractile function as assessed by CMRI-derived global longitudinal strain. In a mouse model, anemia did not affect baseline or pre-infarction regional function but led to a marked reduction in fractional shortening within the infarct region after AMI. This dysfunction was accompanied by ischemic myocardial energetic imbalance, evidenced by depletion of the phosphocreatine/ATP ratio, and altered mitochondrial respiration. These findings were validated in LV biopsies from anemic ICM patients. Mechanistically, anemia was associated with increased neutrophil infiltration, myeloperoxidase elevation, and oxidative stress, while anemic red blood cells (RBCs) directly impaired mitochondrial respiration in human cardiomyocytes. Importantly, antioxidant treatment with N-acetylcysteine fully restored mitochondrial coupling, demonstrating therapeutic reversibility.
Conclusion
Anemia worsens infarct-region LV dysfunction due to increased oxidative stress from dysfunctional RBCs and neutrophil infiltration, leading to altered mitochondrial respiration and contractile impairment. Antioxidant therapy emerges as a promising strategy to protect the anemic heart after AMI.