Adrenergic Receptor Polymorphism and Maximal Exercise Capacity after Orthotopic Heart Transplantation

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 β(1) and β(2)- adrenergic receptor (AR) polymorphisms for maximal exercise capacity after orthotopic HTx. METHODS: CPET measured peak VO(2) as outcome parameter for maximal exercise in HTx recipients ≥9 months and ≤4 years post-transplant (n = 41; mean peak VO(2): 57±15% of predicted value). Donor hearts were genotyped for polymorphisms of the β(1)-AR (Ser49Gly, Arg389Gly) and the β(2)-AR (Arg16Gly, Gln27Glu). Circumferential shortening of the left ventricle was measured using magnetic resonance based CSPAMM tagging. RESULTS: Peak VO(2) was higher in donor hearts expressing the β(1)-Ser49Ser alleles when compared with β(1)-Gly49 carriers (60±15% vs. 47±10% of the predicted value; p = 0.015), and by trend in cardiac allografts with the β(1)-AR Gly389Gly vs. β(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 VO(2) was not different for the tested β(2)-AR polymorphisms. Independent predictors of peak VO(2) (adjusted R(2) = 0.55) were β(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 β(1)-AR Gly49allele. CONCLUSION: Similar LV cardiac motion kinetics at rest in donor hearts carrying either β(1)-AR Gly49 or β(1)-Ser49Ser variant suggests exercise-induced desensitization and down-regulation of the β(1)-AR Gly49 variant as relevant pathomechanism for reduced peak VO(2) in β(1)-AR Gly49 carriers.