Dabigatran-related Effect on Progression of Atrial Fibrosis in Patients With Atrial Fibrillation

Atrial fibrillation (AF) is one of the most common cardiac arrhythmia in medical practice in both the clinical and hospital settings. In addition to a three-fold increase in the risk of mortality, AF patients are at an increased risk of developing a stroke. This risk increased from 6.7% for those who are 50-59 years of age to 36.2% for those between 80-89 years of age. One of the most serious complications of AF is thromboembolism (TE), including both Transient Ischemic Attack (TIA) and stroke, which can be fatal or disabling in many patients and is associated with either type of AF - recurrent or persistent. Image-based methods of risk-stratification and clinical scoring systems, such as the CHADS2 score, have the potential to advance our understanding of the mechanisms governing AF recurrence as well as thrombus formation and can improve our ability to prevent these potentially devastating complications.

Treatments for AF include antiarrhythmic drug therapy, anticoagulation, catheter ablation, and cardioversion, all of which have been thoroughly studied. Anticoagulation is undisputably effective in preventing strokes in patients with AF, reducing the incidence of stroke by 3 fold in high-risk patients. Pradaxa® (Dabigatran etexilate) is a new oral anticoagulant that was approved by the FDA on October 19, 2010 for reducing the risk of stroke and systemic embolism in patients with non-valvular AF. Pradaxa is a direct and reversible inhibitor of thrombin, the penultimate protease in the coagulation process. Thrombin converts fibrinogen to fibrin, which participates in forming the matrix of blood clots. Pradaxa® inhibits formation of thrombus by inhibiting the conversion of fibrinogen to fibrin. Prior to approval of Pradaxa®, warfarin has been the only other oral anticoagulant available in the US for reducing the risk of stroke associated with AF, but its use is limited because of a number of undesirable characteristics. Recently, the RE-LY study showed Pradaxa® 150mg bid was statistically significantly superior to warfarin in reducing the risk of strokes in patients with AF, although there was no statistically significant difference in risk of hemorrhage between warfarin and Pradaxa®. Pradaxa® will be used for its approved indication in this study.

The link between AF and stroke is complex but remodeling of the left atrium (LA) may play a central role. Atrial remodeling refers to any persistent change in atrial structure and function. Fibrosis, an extensive deposition of extracellular matrix components (specifically collagen and fibronectin), is the major causative component of structural remodeling of LA. AF promotes fibrosis and this structural remodeling in turn leads to increased heterogeneity of electrical conduction in the LA which can contribute to AF progression. Late gadolinium enhancement magnetic resonance imaging (LGE-MRI), is a noninvasive technique that allows us to detect and quantify structural remodeling of the LA tissue in patients with AF . Changes in the composition of LA tissue is detected by LGE-MRI based on the delayed enhancement property of the gadolinium-based contrast agent, whose slow washout kinetics relative to normal surrounding tissue, can be quantified as increased fibrosis (structural remodeling of myocardium prior to any ablation) or scar (inflammation and tissue remodeling post ablation). Preliminary findings from our lab demonstrate a significantly larger amount of atrial remodeling / fibrosis detected using LGE-MRI in those patients with strokes compared to those without.

Thrombin (the protease inhibited by Pradaxa®), also is a potent mitogen for connective-tissue producing cells which are prone to developing fibrosis and a chemoattractant for fibroblasts, thus playing an important role in development of tissue fibrosis. Bogatkevich et al. recently demonstrated Pradaxa restrained fibrotic events in lung fibroblasts, suggesting that thrombin inhibition could be an effective strategy for inhibiting fibrosis in other organs, including the heart.

We suggest the characteristics of the fibrosis that we quantify in the left atrium will be similar to the fibrosis seen in the other organs such as lungs, skin and kidney. We hypothesize that Pradaxa will inhibit left atrial structural remodeling (measured as percent fibrosis) associated with AF.