Adrenergic Receptor Polymorphism and Maximal Exercise Capacity after Orthotopic Heart Transplantation

Abstract

BackgroundMaximal 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.MethodsCPET 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.ResultsPeak 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.ConclusionSimilar 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.

Body composition and maximal exercise capacity after heart transplantation

“…Maximal exercise parameters were obtained by symptom‐limited incremental exercise testing applying an individualized ramp protocol performed on an electrically braked cycloergometer (Ergoline 900/911 digital, Ergoline GmbH, Germany). 8 A respiratory exchange ratio (RER) ≥ 1.1 at peak exercise was considered as a maximal test. Respiratory gas exchange was measured breath by breath.…”

“…However, most exercise studies indicate a persistent limitation of peak oxygen consumption (pVO 2 ) to 50–70% of the predicted values for age‐matched healthy controls in the late phase after HTx 2–5 . Reported predictors of pVO 2 as assessed by cardiopulmonary exercise testing (CPET) in HTx recipients with normal systolic left ventricular function are age, peak heart rate, β 1 ‐adrenergic receptor polymorphism, diastolic function, body mass index (BMI), and body fat percentage 5–8 …”

“… 2 , 3 , 4 , 5 Reported predictors of pVO 2 as assessed by cardiopulmonary exercise testing (CPET) in HTx recipients with normal systolic left ventricular function are age, peak heart rate, β 1 ‐adrenergic receptor polymorphism, diastolic function, body mass index (BMI), and body fat percentage. 5 , 6 , 7 , 8 …”

“…[2][3][4][5] Reported predictors of pVO 2 as assessed by cardiopulmonary exercise testing (CPET) in HTx recipients with normal systolic left ventricular function are age, peak heart rate, β 1 -adrenergic receptor polymorphism, diastolic function, body mass index (BMI), and body fat percentage. [5][6][7][8] Intuitively, exercise capacity after HTx should improve with increase of skeletal muscle mass. But respective studies were not conclusive because of small cohorts, short follow-up, and non-quantitative assessment of peripheral skeletal muscle mass.…”

The ASSOCIATIONS OF Β-Adrenoreceptors GENES POLYMORPHISMS WITH THE COURSE OF HEART FAILURE AND WITH THE LOW TRIIODOTHYRONINE SYNDROME (LITERATURE REVIEW AND OWN OBSERVATIONS)E

“…There is evidence that the maximum oxygen consumption (VO 2 ) is reduced in recipients who underwent heart transplantation from a donor carrying the Gly49 allele of the Ser49Gly polymorphism of the β 1 -AR gene [56]. According to the authors, patients whose donors were carriers of this genotype of Ser49Gly polymorphism require treatment with high doses of β-AB [56]. Another study searched for associations between genotypes of Arg389Gly and Ser49Gly polymorphisms of the β 1 -AR gene and survival of patients with HF.…”