In Response
We thank Dr. He for his comments on our study1 and for the interesting points he raises. In our functional and molecular mapping study1 of human hearts ex vivo, we demonstrated that adenosine provokes atrial fibrillation (AF) with a higher activation frequency in the right atria (RA) versus the left atria (LA) due to localized reentrant drivers in lateral RA. Furthermore, our study revealed a high RA-to-LA protein expression gradient of adenosine A1 receptor and GIRK4, a subunit of its downstream channels (IK,Ado) in the human heart. This gradient led to significantly greater RA vs. LA repolarization sensitivity in response to adenosine. Selective atrial GIRK channel blockade counteracted adenosine-induced APD shortening and prevented AF induction.
The previous study2, which Dr. He referred to, had found that higher plasma level of adenosine deaminase (ADA) may be associated with low occurrence of paroxysmal AF. The higher ADA concentrations could accelerate the degradation of adenosine, which therefore exerted the protective effects on the onset of paroxysms of AF. This important study supports the hypothesis4 that higher levels of endogenous adenosine may lead to AF in patients, and the adenosine signaling pathway may prove to be a valuable target for pharmacological treatment of AF.
When pursuing this avenue of treatment, it is important to consider that adenosine is a key regulator within the cardiovascular system and throughout the body. Adenosine elicits various essential biological responses from the modulation of coronary flow, heart rate, and contraction, to cardioprotective effects during ischemia3. Although the reduction of endogenous adenosine levels by modulating its metabolism2 or blocking A1 receptors4 could potentially prevent AF, these methods would diminish the cardiac protective effects of adenosine and cause off target effects. We propose that targeting the atrial cardiomyocyte specific effectors (such as GIRK4 channels) in the adenosine A1 signaling pathway would provide an efficient treatment for human AF during conditions with increased endogenous adenosine.
Acknowledgments
This work was supported primarily by NIH HL115580 (to VVF).
Footnotes
Disclosures:
None
References
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