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 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

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