Upregulation of Adenosine A1 Receptors Facilitates Sinoatrial Node Dysfunction in Chronic Canine Heart Failure by Exacerbating Nodal Conduction Abnormalities Revealed by Novel Dual-Sided Intramural Optical Mapping

Abstract

Background While sinoatrial node (SAN) dysfunction is a hallmark of human heart failure (HF), the underlying mechanisms remain poorly understood. We aimed to examine the role of adenosine in SAN dysfunction and tachy-brady arrhythmias in chronic HF. Methods and Results We applied multiple approaches to characterize SAN structure, function and adenosine A1 receptor (A1R) expression in control (n=17) and four month tachypacing-induced chronic HF (n=18) dogs. Novel intramural optical mapping of coronary-perfused right atrial preparations revealed that adenosine (10μM) markedly prolonged post-pacing SAN conduction time in HF by 206±99ms (vs. 66±21ms in control, p=0.02). Adenosine induced SAN intra-nodal conduction block and/or micro-reentry in 6/8 HF vs. 0/7 controls (p=0.007). Adenosine-induced SAN conduction abnormalities and automaticity depression caused post-pacing atrial pauses in HF vs. control (17.1±28.9s vs. 1.5±1.3s, p<0.001). Furthermore, 10μM adenosine shortened atrial repolarization and led to pacing-induced atrial fibrillation (AF) in 6/7 HF vs. 0/7 control (p=0.002). Adenosine-induced SAN dysfunction and AF were abolished/prevented by A1R antagonists (50μM Theophylline/1μM DPCPX). A1R protein expression was significantly upregulated during HF in the SAN (by 47±19%) and surrounding atrial myocardium (by 90±40%). Interstitial fibrosis was significantly increased within the SAN in HF vs. control (38±4% vs. 23±4%, p<0.001). Conclusions In chronic HF, A1R upregulation in SAN pacemaker and atrial cardiomyocytes may increase cardiac sensitivity to adenosine. This effect may exacerbate conduction abnormalities in the structurally impaired SAN leading to SAN dysfunction, and potentiate atrial repolarization shortening thereby facilitating AF. AF may further depress SAN function and lead to tachy-brady arrhythmias in HF.

Molecular Mapping of Sinoatrial Node HCN Channel Expression in the Human Heart

“…Cx43 expression was markedly lower in the SAN center than in CT and RAFW tissue, while HCN4 expression was higher in the SAN center than in the adjacent tissues (Figure 1C). In all 12 hearts, total Cx43 expression was significantly lower in SAN tissue than in the RAFW, with GAPDH normalized band density ratio of SAN/RAFW=0.18±0.05 (p<0.01), which attests to the purity of the SAN sample 8, 11 .…”

“…Species-dependent expression of HCN1 and HCN2 has also been reported in the SAN 6-8 , and a recent study reports HCN1 also contributes to stable heart rate in mouse SAN 10 . Heart failure (HF) results in significant SAN remodeling and dysfunction 11 . Studies on rabbit 12 and dog 7 SAN suggest that HF-induced SAN dysfunction is at least in part attributable to remodeling of I f and down-regulation of both HCN4 and HCN2.…”

Two‐Pore K + Channel TREK‐1 Regulates Sinoatrial Node Membrane Excitability

“…Importantly, SAN failure is associated with increased mortality in heart failure patients, in which bradyarrhythmias account for >40% of sudden deaths 45. Underlying causes of SAN dysfunction likely involve changes in tissue structure (eg, fibrosis), ion channel defects (eg, mutations in Scn5a or HCN genes), and neurohumoral dysregulation, although the precise molecular and cellular pathways leading to aberrant pacemaking remain unknown 46, 47. Moreover, despite the prevalence of SAN dysfunction, available therapies are limited by their efficacy or risk of procedural complication.…”

Sinus Node and Atrial Arrhythmias

“…In pacinginduced canine models of heart failure, marked upregulation of adenosine A1 receptors occurs with increased sensitivity to adenosine induced SN dysfunction and AF. 67 …”