Preconditioning the diabetic human myocardium

• Published in: Journal of cellular and molecular medicine 2010-06, Vol.14 (6b), p.1740-1746
• Main Authors: Sivaraman, Vivek, Hausenloy, Derek J., Wynne, Abigail M., Yellon, Derek M.
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Aged; AKT protein; Appendages; Bypass; Cardiomyocytes; Cardiovascular disease; Cell Hypoxia; Comparative analysis; Coronary artery; Coronary vessels; Diabetes; Diabetes mellitus; Diabetes Mellitus - enzymology; Diabetes Mellitus - pathology; Female; Heart; Heart surgery; human; Humans; Hypoxia; Ischemia; Ischemic Preconditioning, Myocardial - methods; Laboratories; Male; Middle Aged; Muscle contraction; myocardial infarction; Myocardium; Myocardium - enzymology; Myocardium - pathology; Original; Phosphorylation; preconditioning; Proto-Oncogene Proteins c-akt - metabolism; Signal transduction; Software; Surgery
• ISSN: 1582-1838; 1582-4934
• DOI: 10.1111/j.1582-4934.2009.00796.x

Our objective was to determine whether human diabetic myocardium is amenable to the cardioprotective actions of ischaemic preconditioning. Human right atrial appendages were harvested from diabetic and non‐diabetic patients undergoing elective coronary artery bypass graft surgery. The atrial trabeculae were isolated and subjected to 90 min. of hypoxia followed by 120 min. of reoxygenation, following which the percentage recovery of baseline contractile function was determined. The atrial trabeculae were randomized to: (i) controls (groups 1 and 3); (ii) standard hypoxic preconditioning (HPC) protocol consisting of 4 min. of hypoxia/16 min. of reoxygenation before the 90 min. index hypoxic period (groups 2 and 4); (iii) Prolonged HPC protocol consisting of: 7 min. of hypoxia /16 min. of reoxygenation before the index hypoxic period (group 5). In addition, basal levels of Akt phosphorylation were determined in right atrial appendages harvested from non‐diabetic patients and diabetic patients to determine whether PI3K‐Akt signalling is down‐regulated in the diabetic heart. Standard HPC improved baseline contractile function in human atrial trabeculae harvested from non‐diabetic patients (52.4 ± 3.8% with HPC versus 30.0 ± 3.2% in control: P= 0.001; N= 6/group), but not in atrial trabeculae isolated from diabetic patients (22.6 ± 3.3% with HPC versus 28.5 ± 1.9% in control: P > 0.05; N= 6/group). However, the prolonged HPC protocol did improve baseline contractile function in atrial trabeculae harvested from diabetic patients (42.0 ± 2.4% with HPC versus 28.5 ± 1.9% in control: P= 0.001; N≥ 6/group). Western blot analysis demonstrated lower levels of phosphorylated Akt in diabetic myocardium compared to non‐diabetic myocardium (0.13 ± 0.03 arbitrary units versus 0.39 ± 0.11 arbitrary units: P= 0.047; N≥ 4/group). From the data obtained it appears that the threshold for preconditioning the diabetic myocardium is elevated which may be related to the down‐regulation of the PI3K‐Akt pathway.