Quantitative evaluation of heartbeat interval time series using Poincaré analysis reveals distinct patterns of heart rate dynamics during cycles of vagus nerve stimulation in patients with heart failure

Optimization of stimulation parameters is essential to maximizing therapeutic efficacy and minimizing side effects. The ANTHEM-HF study enrolled patients with heart failure who received chronic autonomic regulation therapy (ART) with an implantable vagus nerve stimulation (VNS) system on either the right (n = 30) or left side (n = 29). Acute effects of continuously cycling VNS on R-R interval dynamics were evaluated using post hoc Poincaré analysis of ECG recordings collected during multiple titration sessions over an 8–12 week period. During each titration session, VNS intensity associated with maximum tolerable dose was determined. Poincaré plots of R-R interval time series were created for epochs when VNS cycled from OFF to ON at varying intensity levels. VNS produced an immediate, relatively small change in beat-to-beat distribution of R-R intervals during the 14-sec ON time, which was correlated with stimulation current amplitude (r = 0.85, p = 0.05). During titration of right-sided stimulation, there was a strong correlation (r = 0.91, p = 0.01) between stimulus intensity and the Poincaré parameter of standard deviation, SD1, which is associated with high-frequency heart rate variability. The effect of VNS on instantaneous heart rate was indicated by a shift in the centroid of the beat-to-beat cloud distribution demarcated by the encircling ellipse. As anticipated, left-sided stimulation did not alter any Poincaré parameter except at high stimulation intensities (≥ 2 mA). Quantitative Poincaré analysis reveals a tight coupling in beat-to-beat dynamics during VNS ON cycles that is directly related to stimulation intensity, providing a useful measurement for confirming autonomic engagement.