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Effect of Atrial Fibrillation on Atrial Thrombogenesis in Humans: Impact of Rate and Rhythm
Study Questions:
What are the relative effects of heart rate versus heart rhythm on measures of thrombogenicity in atrial fibrillation (AF)?
Methods:
The authors studied measures of thrombogenicity in patients undergoing catheter ablation for AF while in sinus rhythm. These patients were all in continuous sinus rhythm for at least 48 hours prior to the procedure (by continuous monitoring), and received therapeutic anticoagulation with warfarin (target international normalized ratio [INR] 2-3) for at least 6 weeks prior to the procedure. All were bridged with low molecular weight heparin immediately prior to the procedure. Patients were excluded if they had valvular heart disease; left ventricular dysfunction; prior myocardial infarction or unstable angina; recent attempted ablation within 3 months; chronic renal, liver, or inflammatory disease; or were taking antiplatelet agents. Of the 55 subjects, 20 patients underwent burst atrial pacing TO INDUCE AF starting at the cycle length of 250 ms, another 20 subjects underwent atrial pacing at 150 bpm, and another 15 subjects served as a control group with neither AF induction nor pacing. Blood samples were taken from the left atrium, right atrium, and femoral vein at baseline and at 15 minutes after pacing or 15 minutes later in the control group. Platelet activation (P-selectin), thrombin generation (thrombin-antithrombin [TAT] complex), endothelial dysfunction (asymmetric dimethyl arginine [ADMA]), and platelet-derived inflammation (soluble CD 40 ligand) were measured.
Results:
Measures of platelet aggregation increased significantly in both the AF-induced (p < 0.001) and pacing (p < 0.05) groups, but decreased significantly in the control subjects (p < 0.001). Thrombin generation increased specifically in the left atrium compared with the femoral vein in both the AF and pacing group (p < 0.01), but decreased in the control patients (p < 0.001). In the AF subgroup, ADMA and CD 40 levels increased significantly at all assay sites (p < 0.01 for ADMA, and p < 0.001 for CD 40), but these levels were unchanged in the pacing and control groups.
Conclusions:
The authors concluded that rapid atrial rates and AF in humans both result in increased platelet activation and thrombin generation. The authors also observed that prothrombotic activation occurs to a greater extent in the human left atrium compared with the systemic circulation. The authors further observed that AF additionally induces endothelial dysfunction and inflammation. The authors opined that these findings suggest that although rapid atrial rates increase the thrombogenic risk, AF may further potentiate this risk.
Perspective:
This interesting study attempted to dissect the differential effect on thrombogenicity of AF per se, versus a rapid atrially paced rhythm versus no arrhythmia, in patients with known AF who were in sinus rhythm at the time of attempted AF ablation. There are a number of assumptions made in the study that must be kept in mind in its interpretation. First, is the assumption that the assays used actually measure the biological activity inferred by the authors (assumptions that P-selectin = platelet activation; TAT = thrombin generation; ADMA = endothelial dysfunction; CD40 = platelet-derived inflammation)? Also, the authors assume that measured assay levels reflect the effect of rhythm or rate in the immediately preceding 15 minutes, and that nothing else affects the levels. These are significant assumptions. Nonetheless, the markedly divergent results between both the AF and atrially paced groups versus the controls certainly strongly suggest that tachycardia—whether AF related or from a paced atrial rhythm—is strongly associated with a state of increased platelet aggregation and thrombin generation, a sign of incipient thrombogenicity. These data are very intriguing and certainly support a thrombosis-inducing effect of AF that may be both rate and rhythm related. The clinical implications could be significant, but clearly require further study.
Keywords: P-Selectin, Biomarkers, Warfarin, Atrial Fibrillation, Platelet Activation, Catheter Ablation
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