What is the clinical evidence from this study?

Study design: Other. Population: Atrial Fibrillation (n=49). Intervention: PSB36 (A1-R antagonist) and AMPCP (CD73 inhibitor) vs. Vehicle (1% DMSO). Primary outcome: Atrial fibrillation duration (p=<0.0001).

What does this research mean for the field?

Inhibition of the adenosine A1-receptor or CD73 significantly reduces atrial fibrillation duration and prevents arrhythmic events by altering atrial electrophysiology. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

June 12, 2020Open Access

Inhibition of Adenosine Pathway Alters Atrial Electrophysiology and Prevents Atrial Fibrillation

Q: What are the key findings of this study?

Inhibition of the adenosine A1-receptor with PSB36 or CD73 with AMPCP significantly reduced atrial fibrillation duration compared to vehicle in isolated rat hearts.

Q: What does this research mean for the field?

Inhibition of the adenosine A1-receptor or CD73 significantly reduces atrial fibrillation duration and prevents arrhythmic events by altering atrial electrophysiology. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

Key Result

Inhibition of the adenosine A1-receptor with PSB36 or CD73 with AMPCP significantly reduced atrial fibrillation duration compared to vehicle in isolated rat hearts.

Structured PICO

Does pharmacological blockade of endogenous adenosine production and signaling prevent atrial fibrillation in isolated rat hearts and human atrial appendages?

Population

38 male Wistar rats (300-400 g) for Langendorff isolated heart preparations, and 11 intact cardiac muscles from human right atrial appendages (hRAAs) from 11 patients in sinus rhythm undergoing coronary artery bypass surgery and/or valve replacement.

Intervention

A1-R agonist (CCPA, 50 nM), A1-R antagonist (PSB36, 40 nM), or CD73 inhibitor (AMPCP, 500 μM)

Comparator

Vehicle (1% DMSO)

Outcome

Atrial action potential duration at 90% repolarization (APD90), effective refractory period (ERP), and atrial fibrillation (AF) durationsurrogate

Inhibition of the adenosine pathway via A1-R antagonism or CD73 inhibition protects atria from arrhythmic events and reduces AF duration in preclinical models.

Main Result

Absolute Event Rate: 6.5% vs 11.5%

p-value: p=<0.0001

Limitations

Use of rodents as a translational model for AF carries limitations regarding differences with human physiology, such as reliance on IK,to currents for repolarization.
Small number of human patients limits statistical and clinical significance.
Experimental buffers may have generated a slight hypoxic environment over time, potentially contributing to intrinsic adenosine release.
The effect of intrinsic adenosine release on A1-R was not directly measured during perfusion experiments.

Abstract

Background Adenosine leads to atrial action potential (AP) shortening through activation of adenosine 1 receptors (A1-R) and subsequent opening of G protein-coupled inwardly rectifying K+ channels. Extracellular production of adenosine is drastically increased during stress and ischemia. Objective The aim of this study was to address whether the pharmacological blockade of endogenous production of adenosine and of its signaling prevents atrial fibrillation (AF) Methods The role of A1-R activation on atrial action potential duration, refractoriness and AF vulnerability was investigated in rat isolated beating heart preparations (Langendorff) with an A1-R agonist (CCPA, 50 nM) and antagonist (PSB36, 40 nM). Further, to interfere with the endogenous adenosine release, the ecto-5’-nucleotidase (CD73) inhibitor was applied (AMPCP, 500 μM). Isolated trabeculae from human right atrial appendages (hRAAs) were used for comparison. Results As expected, CCPA shortened AP duration at 90% of repolarization (APD90) and effective refractory period (ERP) in rat atria. PSB36 prolonged APD90 and ERP in rat atria and CD73 inhibition with AMPCP prolonged ERP in rats, confirming that endogenously produced amount of adenosine is sufficiently high to alter atrial electrophysiology. In human atrial appendages, CCPA shortened APD90, while PSB36 prolonged it. Rat hearts treated with CCPA are prone to AF. In contrast, PSB36 and AMPCP prevented AF events and reduced AF duration (vehicle 11.5±2.6 s; CCPA 40.6±16.1 s; PSB36 6.5±3.7 s; AMPCP 3.0±1.4 s; P<0.0001). Conclusion A1-R activation by intrinsic adenosine release alters atrial electrophysiology and promotes AF. Inhibition of adenosine pathway protects atria from arrhythmic events.

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