Howell, Neil John (2011)
Ph.D. thesis, University of Birmingham.
Aims: To examine the metabolic changes associated with LVH secondary to AS, to examine the role of GIK as an adjunct to myocardial protection during AVR, and to examine the mechanism of its action. Methods: 220 patients with LVH secondary to AS were randomised 1:1 to receive an infusion of GIK at the time of AVR. The primary endpoint of the trial was incidence of low cardiac output state. At pre-specified time points, biopsies of the LV anterior wall were taken for analysis of metabolic changes associated with LVH, and changes in the phosphorylation state of proteins identified as key regulators of metabolism and cardiac protection. Results: Patients with LVH were found to exhibit a profound down-regulation of the mRNA transcript levels of the master transcriptional regulators of metabolism resulting in a significantly abnormal metabolome. Treatment with GIK was associated with a reduction in LCOS from 33% in the control group to 10% in the treatment group, p=0.0001. Treatment with GIK was associated with a significant increase in the level of protein O-GlcNAcylation. Conclusions: In this trial, treatment with GIK was associated with a significant improvement in post-operative haemodynamics. Patients with LVH may benefit from metabolic therapies at the time of surgery
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