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 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

Mean circumferential strain at basal, mid-ventricular and apical slices of the left ventricle comparing β₁-AR Ser49Ser and β₁-Gly49 carriers along the cardiac cycle.

<p>The strain values were obtained using HARP analysis on tagged images acquired with a SF bSSFP CSPAMM tagging technique. All measurements were adapted to the systole duration of each exam. No statistically significant difference could be found between the two groups.</p

β₁-AR 49 and β₁-AR 389 haplotypes and peak VO_2.

<p>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.</p

β₁-AR and β₂-AR SNPs and maximal exercise capacity.

<p>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).</p

Distribution of adrenergic receptor variants among patients.

<p>WT = Wild-type; Mut = Mutant; MAF = mean allele frequency; MAF population.</p

Multivariable correlation between peak VO₂, β₁-AR genotype and clinical variables.

<p>ΔHR = Peak heart rate—resting heart rate; BP = Blood Pressure; eGFR = estimated glomerular filtration rate.</p

Epac enhances excitation-transcription coupling in cardiac myocytes.

International audienceEpac is a guanine nucleotide exchange protein that is directly activated by cAMP, but whose cardiac cellular functions remain unclear. It is important to understand cardiac Epac signaling, because it is activated in parallel to classical cAMP-dependent signaling via protein kinase A. In addition to activating contraction, Ca(2+) is a key cardiac transcription regulator (excitation-transcription coupling). It is unknown how myocyte Ca(2+) signals are decoded in cardiac myocytes to control nuclear transcription. We examine Epac actions on cytosolic ([Ca(2+)](i)) and intranuclear ([Ca(2+)](n)) Ca(2+) homeostasis, focusing on whether Epac alters [Ca(2+)](n) and activates a prohypertrophic program in cardiomyocytes. Adult rat cardiomyocytes, loaded with fluo-3 were viewed by confocal microscopy during electrical field stimulation at 1Hz. Acute Epac activation by 8-pCPT increased Ca(2+) sparks and diastolic [Ca(2+)](i), but decreased systolic [Ca(2+)](i). The effects on diastolic [Ca(2+)](i) and Ca(2+) spark frequency were dependent on phospholipase C (PLC), inositol 1,4,5 triphosphate receptor (IP(3)R) and CaMKII activation. Interestingly, Epac preferentially increased [Ca(2+)](n) during both diastole and systole, correlating with the perinuclear expression pattern of Epac. Moreover, Epac activation induced histone deacetylase 5 (HDAC5) nuclear export, with consequent activation of the prohypertrophic transcription factor MEF2. These data provide the first evidence that the cAMP-binding protein Epac modulates cardiac nuclear Ca(2+) signaling by increasing [Ca(2+)](n) through PLC, IP(3)R and CaMKII activation, and initiates a prohypertrophic program via HDAC5 nuclear export and subsequent activation of the transcription factor MEF2