Background: Atrial fibrillation (AF) is a significant risk factor for ischemic strokes, and making a robust risk stratification scheme would be important. Few studies have examined whether nonlinear dynamics of the heart rate could predict ischemic strokes in AF. We examined whether a novel complexity measurement of the heart rate variability called multiscale entropy (MSE) was a useful risk stratification measure of ischemic strokes in patients with permanent AF. Methods and Results: We examined 173 consecutive patients (age 69±11 years) with permanent AF who underwent 24-hour Holter electrocardiography from April 2005 to December 2006. We assessed several frequency ranges of the MSE and CHA2DS2-VASc score (1 point for congestive heart failure, hypertension, diabetes, vascular disease, an age 65 to 74 years, and a female sex and 2 points for an age≥75 years and a stroke or transient ischemic attack). We found 22 (13%) incident ischemic strokes during a mean follow up of 3.8-years. The average value of the MSE in the very-low frequency subrange (90-300 s, MeanEnVLF2) was significantly higher in patients who developed ischemic strokes than in those who did not (0.68 ±0.15 vs. 0.60±0.14, P<0.01). There was no significant difference in the C-statistic between the CHA2DS2-VASc score and MeanEnVLF2 (0.56; 95% confidence interval, 0.43-0.69 vs. 0.66; 95% confidence interval, 0.53-0.79). After an adjustment for the age, CHA2DS2-VASc score, and antithrombotic agent, a Cox hazard regression model revealed that the MeanEnVLF2 was an independent predictor of an ischemic stroke (hazard ratio per 1-SD increment, 1.80; 95% confidence interval, 1.17-2.07, P<0.01). Conclusion: The MeanEnVLF2 in 24-hour Holter electrocardiography is a useful risk stratification measure of ischemic strokes during the long-term follow-up in patients with permanent AF.
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