Molecular Mechanisms of Adenosine Stress T1 Mapping

Background: Adenosine stress T1 mapping is an emerging magnetic resonance imaging method to investigate coronary vascular function and myocardial ischemia without application of a contrast agent. Using gene-modified mice and 2 vasodilators, we elucidated and compared the mechanisms of adenosine myocardial perfusion imaging and adenosine T1 mapping.

Methods: Wild-type (WT), A_2AAR^-/- (adenosine A_2A receptor knockout), A_2BAR^-/- (adenosine A_2B receptor knockout), A₃AR^-/- (adenosine A₃ receptor knockout), and eNOS^-/- (endothelial nitric oxide synthase knockout) mice underwent rest and stress perfusion magnetic resonance imaging (n=8) and T1 mapping (n=10) using either adenosine, regadenoson (a selective A_2AAR agonist), or saline. Myocardial blood flow and T1 were computed from perfusion imaging and T1 mapping, respectively, at rest and stress to assess myocardial perfusion reserve and T1 reactivity (ΔT1). Changes in heart rate for each stress agent were also calculated. Two-way ANOVA was used to detect differences in each parameter between the different groups of mice.

Results: Myocardial perfusion reserve was significantly reduced only in A_2AAR^-/- compared to WT mice using adenosine (1.06±0.16 versus 2.03±0.52, P<0.05) and regadenoson (0.98±026 versus 2.13±0.75, P<0.05). In contrast, adenosine ΔT1 was reduced compared with WT mice (3.88±1.58) in both A_2AAR^-/- (1.63±1.32, P<0.05) and A_2BAR^-/- (1.55±1.35, P<0.05). Furthermore, adenosine ΔT1 was halved in eNOS^-/- (1.76±1.46, P<0.05) versus WT mice. Regadenoson ΔT1 was approximately half of adenosine ΔT1 in WT mice (1.97±1.50, P<0.05), and additionally, it was significantly reduced in eNOS^-/- mice (-0.22±1.46, P<0.05). Lastly, changes in heart rate was 2× greater using regadenoson versus adenosine in all groups except A_2AAR^-/-, where heart rate remained constant.

Conclusions: The major findings are that (1) although adenosine myocardial perfusion reserve is mediated through the A_2A receptor, adenosine ΔT1 is mediated through the A_2A and A_2B receptors, (2) adenosine myocardial perfusion reserve is endothelial independent while adenosine ΔT1 is partially endothelial dependent, and (3) ΔT1 mediated through the A_2A receptor is endothelial dependent while ΔT1 mediated through the A_2B receptor is endothelial independent.