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Adrenergic Receptor Polymorphism and Maximal Exercise Capacity after Orthotopic Heart Transplantation

View Article: PubMed Central - PubMed

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.

No MeSH data available.


β1-AR 49 and β1-AR 389 haplotypes and peak VO2.Maximal exercise capacity was assessed by measuring peak VO2 and was expressed according to the patient haplotypes β1-49Gly+β1-Arg389Arg, β1-49Gly+β1-389Gly, β1-Ser49Ser+β1-Arg389Arg or β1-Ser49Ser+β1-389Gly. Box graphs represent median, upper/lower quartiles and maximum/minimum values.
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pone.0163475.g003: β1-AR 49 and β1-AR 389 haplotypes and peak VO2.Maximal exercise capacity was assessed by measuring peak VO2 and was expressed according to the patient haplotypes β1-49Gly+β1-Arg389Arg, β1-49Gly+β1-389Gly, β1-Ser49Ser+β1-Arg389Arg or β1-Ser49Ser+β1-389Gly. Box graphs represent median, upper/lower quartiles and maximum/minimum values.

Mentions: Peak VO2 was not different by ANOVA between the haplotypes of β1-49Gly+β1-Arg389Arg, β1-49Gly+β1-389Gly, β1-Ser49Ser+β1-Arg389Arg, β1-Ser49Ser+β1-389Gly. Nevertheless, peak VO2 correlated with the different haplotypes fitting to a linear regression (adjusted R2 = 0.17; p = 0.005) with lowest mean peak VO2 values for β1-49Gly+β1-Arg389Arg and β1-49Gly+β1-389Gly (Fig 3). This correlation remained consistent (adjusted R2 = 0.56; p = 0.003) when adjusted for other modalities affecting peak VO2 (ΔHR, maximal systolic BP, eGFR).


Adrenergic Receptor Polymorphism and Maximal Exercise Capacity after Orthotopic Heart Transplantation
β1-AR 49 and β1-AR 389 haplotypes and peak VO2.Maximal exercise capacity was assessed by measuring peak VO2 and was expressed according to the patient haplotypes β1-49Gly+β1-Arg389Arg, β1-49Gly+β1-389Gly, β1-Ser49Ser+β1-Arg389Arg or β1-Ser49Ser+β1-389Gly. Box graphs represent median, upper/lower quartiles and maximum/minimum values.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5036840&req=5

pone.0163475.g003: β1-AR 49 and β1-AR 389 haplotypes and peak VO2.Maximal exercise capacity was assessed by measuring peak VO2 and was expressed according to the patient haplotypes β1-49Gly+β1-Arg389Arg, β1-49Gly+β1-389Gly, β1-Ser49Ser+β1-Arg389Arg or β1-Ser49Ser+β1-389Gly. Box graphs represent median, upper/lower quartiles and maximum/minimum values.
Mentions: Peak VO2 was not different by ANOVA between the haplotypes of β1-49Gly+β1-Arg389Arg, β1-49Gly+β1-389Gly, β1-Ser49Ser+β1-Arg389Arg, β1-Ser49Ser+β1-389Gly. Nevertheless, peak VO2 correlated with the different haplotypes fitting to a linear regression (adjusted R2 = 0.17; p = 0.005) with lowest mean peak VO2 values for β1-49Gly+β1-Arg389Arg and β1-49Gly+β1-389Gly (Fig 3). This correlation remained consistent (adjusted R2 = 0.56; p = 0.003) when adjusted for other modalities affecting peak VO2 (ΔHR, maximal systolic BP, eGFR).

View Article: PubMed Central - PubMed

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.

No MeSH data available.