Straight to the heart: Pleiotropic antiarrhythmic actions of oral anticoagulants

Abstract

Mechanistic understanding of atrial fibrillation (AF) pathophysiology and the complex bidirectional relationship with thromboembolic risk remains limited. Oral anticoagulation is a mainstay of AF management. An emerging concept is that anticoagulants may themselves have potential pleiotropic disease-modifying effects. We here review the available evidence for hemostasis-independent actions of the oral anticoagulants on electrical and structural remodeling, and the inflammatory component of the vulnerable substrate.

Keywords: Anticoagulants; Atrial fibrillation; Calcium; Protease-activated receptors; Stroke; Thrombin.

Fig. 1:. DOAC inhibition sites.

Coagulant pathways converge in a common step culminating in the FXa-mediated proteolysis of prothrombin to active thrombin. Thrombin potently activates platelets and cleaves fibrinogen to fibrin, leading to clot stabilization. Classic antiplatelets agents prevent secondary platelet activation. The DOAC either inhibit FXa enzymatic activity and hence thrombin activation, or directly inhibit thrombin. The vitamin K-dependent oral anticoagulants like warfarin by contrast suppress block coagulant activity indirectly by preventing synthesis of the precurser factors FII (thrombin), FVII, FIX and FX.

Fig. 2.. Protease-activated receptors (PAR).

A) Simplified scheme depicting PAR activation. The N-terminal domain of the receptor is proteolytically cleaved at a specific recognition motif to generate a new N-terminus. The “tethered ligand” domain binds to and auto-activates the receptor, initiating G-protein-dependent signaling (possibly not in the case of PAR3). B) The relative selectivity of PAR for activation by thrombin and FXa. PAR1 is the predominant receptor for both coagulant proteases, PAR2 is potently activated by FXa and possibly by supraphysiological thrombin levels. PAR3 is cleaved by thrombin. PAR4 responds to thrombin (with 100-fold lower affinity than for PAR1) and modestly to FXa.

Fig. 3.. Candidate anti-arrhythmic mechanisms of anticoagulants.

A) Cellular PAR activation by FXa and/or thrombin leads to alterations in cardiomyocyte ion channels, Ca²⁺ handling, leading to prolonged action potential duration (APD) with enhanced susceptibility to early and delayed afterdepolarizations (EADs and DADs, respectively) and B) Summary of cellular effectors and ion channels reported to be modified downstream of PAR1-activation in cardiomyocytes, which potentially contribute to pro-arrhythmic responses to coagulant proteases: (1) PAR1 is coupled to activation of phospholipase C (PLC), generating the signaling mediators diacylglycerol (DAG) and inositol trisphosphate (IP₃). (2) IP₃ activates ligand-gated Ca²⁺ channels of the sarcoplasmic reticulum (SR) to raise intracellular Ca²⁺. PAR1 activation has been reported to modulate voltage-gated ion channels, including (3) L-type Ca²⁺ channels and (4) Na⁺ channels, and (5) and K⁺ channels such as ATP-sensitive K⁺ channels. Additional candidate mediators of PAR1-triggered arrhythmogenesis include (6) the Na⁺-H⁺ exchanger (NHE-1) and (7) phospholipase A2-derived lysophosphatidylcholine (LPC). The precise mechanism how LPC supports rhythm disorders requires further elucidation, although the generation of reactive oxygen species is a candidate mechanism.

Fig. 4.. Candidate mechanisms how anticoagulants may target the pro-arrhythmogenic substrate.

Inflammatory and fibrotic processes contribute to the vulnerable substrate. Some of them have been shown to be directly amplified by coagulant proteases and PAR activation, including myofibroblast differentiation with increased collagen deposition, cytokine and growth factor secretion, activation of NFKB-dependent inflammatory gene expression, production of reactive oxygen species (ROS), matrix metalloproteinase (especially MMP9) expression and activation, NLRP3 inflammasome priming and triggering, and feed-forward regulation of PAR activation. Application of DOACs suppresses these fibro-inflammatory mediators and may thus limit the progression to persistent arrhythmia forms.