Adrenergic Receptor Polymorphism and Maximal Exercise Capacity after Orthotopic Heart Transplantation

作者：Metrich Melanie; Mehmeti Fortesa; Feliciano Helene; Martin David; Regamey Julien; Tozzi Piergiorgio; Meyer Philippe; Hullin Roger^*

来源：PLos One, 2016, 11(9): e0163475.

DOI：10.1371/journal.pone.0163475

Background
Maximal exercise capacity after heart transplantion (HTx) is reduced to the 50-70% level of healthy controls when assessed by cardiopulmonary exercise testing (CPET) despite of normal left ventricular function of the donor heart. This study investigates the role of donor heart beta(1) and beta(2)-adrenergic receptor (AR) polymorphisms for maximal exercise capacity after orthotopic HTx.
Methods
CPET measured peak VO2 as outcome parameter for maximal exercise in HTx recipients >= 9 months and <= 4 years post-transplant (n = 41; mean peak VO2: 57 +/- 15% of predicted value). Donor hearts were genotyped for polymorphisms of the beta(1)-AR (Ser49Gly, Arg389-Gly) and the beta(2)-AR (Arg16Gly, Gln27Glu). Circumferential shortening of the left ventricle was measured using magnetic resonance based CSPAMM tagging.
Results
Peak VO2 was higher in donor hearts expressing the beta(1)-Ser49Ser alleles when compared with beta(1)-Gly49 carriers (60 +/- 15% vs. 47 +/- 10% of the predicted value; p = 0.015), and by trend in cardiac allografts with the beta(1)-AR Gly389Gly vs.beta(1)-Arg389 (61 +/- 15% vs. 54 +/- 14%, p = 0.093). Peak VO2 was highest for the haplotype Ser49Ser-Gly389, and decreased progressively for Ser49Ser-Arg389Arg > 49Gly-389Gly > 49Gly-Arg389Arg (adjusted R-2 = 0.56, p = 0.003). Peak VO2 was not different for the tested beta(2)-AR polymorphisms. Independent predictors of peak VO2 (adjusted R-2 = 0.55) were beta(1)-AR Ser49Gly SNP (p = 0.005), heart rate increase (p = 0.016), and peak systolic blood pressure (p = 0.031). Left ventricular (LV) motion kinetics as measured by cardiac MRI CSPAMM tagging at rest was not different between carriers and non-carriers of the beta(1)-AR Gly49allele.
Conclusion
Similar LV cardiac motion kinetics at rest in donor hearts carrying either beta(1)-AR Gly49 or beta(1)-Ser49Ser variant suggests exercise-induced desensitization and down-regulation of the beta(1)-AR Gly49 variant as relevant pathomechanism for reduced peak VO2 in beta(1)-AR Gly49 carriers.

• 出版日期2016-9-26