European Heart Journal Advance Access originally published online on March 21, 2007
European Heart Journal 2007 28(9):1085-1091; doi:10.1093/eurheartj/ehm032
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Augmented hyperaemia and reduced tissue injury in response to ischaemia in subjects with the 34C > T variant of the AMPD1 gene
1 Department of Pharmacology–Toxicology, Radboud University Nijmegen Medical Centre, Geert Grooteplein 21, 6525 EZ, PO Box 9101, 6500 HB Nijmegen, The Netherlands
2 Department of Internal Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
3 Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
4 Department of Nuclear Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
5 Department of Epidemiology and Biostatistics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Received 1 October 2006; revised 31 January 2007; accepted 23 February 2007; online publish-ahead-of-print 21 March 2007.
* Corresponding author. Tel: +31 24 3613691; fax: +31 24 3614214. E-mail address: n.riksen{at}aig.umcn.nl
Aims: 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.
Methods and results: 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 99mTc-annexin A5 scintigraphy after forearm ischaemic exercise to detect externalized membrane phosphatidylserines. At reperfusion, 99mTc-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).
Conclusion: 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.
Key Words: Adenosine • AMPD1 genotype • Ischaemia • Blood flow • Scintigraphy