Department of Pharmacology-Toxicology, Radboud University Nijmegen Medical Centre, Geert Grooteplein 21, 6525 EZ, PO Box 9101, 6500 HB Nijmegen, The Netherlands. n.riksen@aig.umcn.nl
May, 2007
In patients with coronary artery disease, the 34C > T variant of the adenosine mono-phosphate deaminase gene (AMPD1), encoding a dysfunctional protein, predicts improved survival. We hypothesized that in subjects with this variant allele, ischaemia-induced intracellular adenosine formation is increased, augmenting reactive hyperaemia and ischaemic tolerance.We selected 10 healthy subjects with the CT genotype and 10 CC controls. The forearm vasodilator response to 2 and 5 min of ischaemia (venous occlusion plethysmography, expressed as percentage of maximum blood flow after 13 min of ischaemia) was higher in the CT group 56\% (49-74\%) and 77\% (71-86\%) vs. 49\% (42-53\%) and 60\% (55-70\%) in the CC group [median (interquartile range), P = 0.01]. Additionally, ischaemia-reperfusion injury was assessed in the thenar muscle using (99m)Tc-annexin A5 scintigraphy after forearm ischaemic exercise to detect externalized membrane phosphatidylserines. At reperfusion, (99m)Tc-annexin was administered intravenously. The change in annexin targeting between 1 and 4 h post-injection was -2.3\% (interquartile range -2.4 to -1.6\%) in the CT group vs. -0.3\% (-0.6 to 1.3\%) in controls (n = 7 in both groups, P = 0.03).The 34C > T variant of AMPD1 augments vasodilation and reduces tissue injury in response to forearm ischaemia. These mechanisms could contribute to the survival benefit of cardiovascular patients with this variant allele.