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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.


Related in: MedlinePlus

β1-AR and β2-AR SNPs and maximal exercise capacity.Peak VO2 is shown for β1-AR codon 49 and 389, β2-AR codon 16 and 27. Box graphs represent median, upper/lower quartiles and maximum/minimum values. *indicates a statistically significant difference (p <0.05) between SNP and peak VO2. Figures represent box plot for each genotype combination (homozygous for the major allele, WT/WT, heterozygous WT/minor allele and homozygous for minor allele).
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pone.0163475.g001: β1-AR and β2-AR SNPs and maximal exercise capacity.Peak VO2 is shown for β1-AR codon 49 and 389, β2-AR codon 16 and 27. Box graphs represent median, upper/lower quartiles and maximum/minimum values. *indicates a statistically significant difference (p <0.05) between SNP and peak VO2. Figures represent box plot for each genotype combination (homozygous for the major allele, WT/WT, heterozygous WT/minor allele and homozygous for minor allele).

Mentions: Fig 1 shows peak VO2 as a function of β-AR variant expression in the allograft. Patients with grafts carrying the β1-AR Gly49 allele had a significantly lower predicted percentage of peak VO2 when compared to homozygotes Ser49Ser (47.3±10.0% vs. 60.2±14.9%; p = 0.015). β1-AR Gly49 carriers had also more chronotropic incompetence than Ser49Ser group even if this was not significant (29±11 vs. 35±18; p = 0.327) (S3 Table). There was a trend towards increased peak VO2 with Gly389 carriers when compared to homozygotes Arg389Arg (61.4±14.9 vs. 53.6±14.1%; p = 0.093). Polymorphism of β2-AR 16 in the donor heart did not affect peak VO2 (p = 0.947), whereas peak VO2 was by trend lower in β2-AR Glu27Glu patients when compared to Gln27 carriers (50.9±13.6% vs. 58.5±14.9%; p = 0.193). α2C polymorphism did not interact with peak VO2 (p = 0.347), chronotropic reserve (p = 0.729), systolic (p = 0.971) or diastolic BP (p = 0.967) (Fig 2).


Adrenergic Receptor Polymorphism and Maximal Exercise Capacity after Orthotopic Heart Transplantation
β1-AR and β2-AR SNPs and maximal exercise capacity.Peak VO2 is shown for β1-AR codon 49 and 389, β2-AR codon 16 and 27. Box graphs represent median, upper/lower quartiles and maximum/minimum values. *indicates a statistically significant difference (p <0.05) between SNP and peak VO2. Figures represent box plot for each genotype combination (homozygous for the major allele, WT/WT, heterozygous WT/minor allele and homozygous for minor allele).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5036840&req=5

pone.0163475.g001: β1-AR and β2-AR SNPs and maximal exercise capacity.Peak VO2 is shown for β1-AR codon 49 and 389, β2-AR codon 16 and 27. Box graphs represent median, upper/lower quartiles and maximum/minimum values. *indicates a statistically significant difference (p <0.05) between SNP and peak VO2. Figures represent box plot for each genotype combination (homozygous for the major allele, WT/WT, heterozygous WT/minor allele and homozygous for minor allele).
Mentions: Fig 1 shows peak VO2 as a function of β-AR variant expression in the allograft. Patients with grafts carrying the β1-AR Gly49 allele had a significantly lower predicted percentage of peak VO2 when compared to homozygotes Ser49Ser (47.3±10.0% vs. 60.2±14.9%; p = 0.015). β1-AR Gly49 carriers had also more chronotropic incompetence than Ser49Ser group even if this was not significant (29±11 vs. 35±18; p = 0.327) (S3 Table). There was a trend towards increased peak VO2 with Gly389 carriers when compared to homozygotes Arg389Arg (61.4±14.9 vs. 53.6±14.1%; p = 0.093). Polymorphism of β2-AR 16 in the donor heart did not affect peak VO2 (p = 0.947), whereas peak VO2 was by trend lower in β2-AR Glu27Glu patients when compared to Gln27 carriers (50.9±13.6% vs. 58.5±14.9%; p = 0.193). α2C polymorphism did not interact with peak VO2 (p = 0.347), chronotropic reserve (p = 0.729), systolic (p = 0.971) or diastolic BP (p = 0.967) (Fig 2).

View Article: PubMed Central - PubMed

ABSTRACT

Background: Maximal exercise capacity after heart transplantion (HTx) is reduced to the 50&ndash;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 &ge;9 months and &le;4 years post-transplant (n = 41; mean peak VO2: 57&plusmn;15% of predicted value). Donor hearts were genotyped for polymorphisms of the &beta;1-AR (Ser49Gly, Arg389Gly) 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&plusmn;15% vs. 47&plusmn;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&plusmn;15% vs. 54&plusmn;14%, p = 0.093). Peak VO2 was highest for the haplotype Ser49Ser-Gly389, and decreased progressively for Ser49Ser-Arg389Arg &gt; 49Gly-389Gly &gt; 49Gly-Arg389Arg (adjusted R2 = 0.56, p = 0.003). Peak VO2 was not different for the tested &beta;2-AR polymorphisms. Independent predictors of peak VO2 (adjusted R2 = 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.

No MeSH data available.


Related in: MedlinePlus