Adrenergic Receptor Polymorphism and Maximal Exercise Capacity after Orthotopic Heart Transplantation

Mélanie Métrich; Fortesa Mehmeti; Helene Feliciano; David Martin; Julien Regamey; Piergiorgio Tozzi; Philippe Meyer; Roger Hullin; Swiss Transplant Cohort Study

doi:10.1371/journal.pone.0163475

Adrenergic Receptor Polymorphism and Maximal Exercise Capacity after Orthotopic Heart Transplantation

PLoS One. 2016 Sep 26;11(9):e0163475. doi: 10.1371/journal.pone.0163475. eCollection 2016.

Authors

Mélanie Métrich¹, Fortesa Mehmeti², Helene Feliciano³, David Martin¹, Julien Regamey¹, Piergiorgio Tozzi⁴, Philippe Meyer², Roger Hullin¹; Swiss Transplant Cohort Study

Affiliations

¹ Cardiology, Cardiovascular Department, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland.
² Cardiology, University Hospital Geneva, University of Geneva, Geneva, Switzerland.
³ Department of Radiology, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland.
⁴ Cardiac Surgery, Cardiovascular Department, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland.

Abstract

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 β1 and β2- 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 β1-AR (Ser49Gly, Arg389Gly) and the β2-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 β1-Ser49Ser alleles when compared with β1-Gly49 carriers (60±15% vs. 47±10% of the predicted value; p = 0.015), and by trend in cardiac allografts with the β1-AR Gly389Gly vs. β1-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 R2 = 0.56, p = 0.003). Peak VO2 was not different for the tested β2-AR polymorphisms. Independent predictors of peak VO2 (adjusted R2 = 0.55) were β1-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 β1-AR Gly49allele.

Conclusion: Similar LV cardiac motion kinetics at rest in donor hearts carrying either β1-AR Gly49 or β1-Ser49Ser variant suggests exercise-induced desensitization and down-regulation of the β1-AR Gly49 variant as relevant pathomechanism for reduced peak VO2 in β1-AR Gly49 carriers.

Grants and funding

This work was supported by grants from the Swiss Transplant Cohort Study (STCS No.0038; http://www.stcs.ch/) and the SWISSHEART Foundation (https://www.swissheart.ch/). RH receives support from the SWISS NATIONAL FOUNDATION (320030_147121/1; http://www.snf.ch/). The Swiss Transplant Cohort Study biobank provided the recipient DNA. The other funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.