Thrombin receptors as candidate therapeutic targets to prevent post-operative atrial fibrillation

Issam Abu-Taha (Essen)1, C. Mittendorf (Essen)1, M. Kamler (Essen)2, D. Dobrev (Essen)1, A. Fender (Essen)1

1Universitätsklinikum Essen Institut für Pharmakologie Essen, Deutschland; 2Universitätsklinikum Essen Klinik für Thorax- und Kardiovaskuläre Chirurgie Essen, Deutschland


Background: Post-operative atrial fibrillation (poAF) develops in up to 30% of patients undergoing cardiac surgery. It is generally a transient phenomenon, with peak incidence 48-72h after surgery. Long considered benign, poAF is now known to predict late poAF recurrences, and to increase morbidity, stroke risk and mortality. The underlying mechanisms are incompletely understood, and clinical management remains challenging. A pre-existing atrial cardiomyopathy, encompassing Ca2+-handling abnormalities and an overactive NLRP3-inflammasome/CaMKII axis, is thought to predispose to poAF by providing a vulnerable substrate for pro-inflammatory triggers in the acute peri-operative phase. We have previously linked protease-activated receptor PAR4, a low-affinity thrombin receptor, with NLRP3 inflammasome activation in ventricular myocardium of mice with diet-induced obesity. The role of PAR4 as a potential trigger of poAF is unknown.

Methods and Results: Atrial myocardium of patients with no prior history of AF was collected during cardiac surgery. Atrial tissue and cardiomyocytes from patients who subsequently developed poAF expressed higher levels of PAR4 compared to patients remaining in sinus rhythm after surgery. The NLRP3 inflammasome effector caspase-1 and its maturation product IL-1β were also more abundant in poAF-prone atria, as were phosphorylated CaMKII and mTOR. The same pattern of increased caspase-1, IL-1β, phospho-CaMKII and phospho-mTOR was recapitulated in cultured mouse atrial cardiomyocytes (HL-1 cells) exposed to a selective PAR4-activating, but not PAR1-activating peptide, and in atria from mice subjected to sham surgery, coinciding with transiently upregulated PAR4 expression. Atria from PAR4-/- mice showed lower abundance of caspase-1, IL-1β, phospho-CaMKII and phospho-mTOR compared to wild-types.

Conclusions: Upregulation of thrombin receptor PAR4 in atrial myocardium may enhance susceptibility to poAF by promoting pro-arrhythmic signaling through the CaMKII/mTOR/NLRP3 inflammasome axis. Selective PAR4 antagonists are currently in clinical development for platelet inhibition with low adverse bleeding risk. These new agents could constitute a novel therapeutic option for poAF prevention. 

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