CRP. Finally, we note that CRP—an acute-phase pro- tein produced by the liver—is reported to have declined from the coronary sinus effluent within 1 h, which is inconsistent with the reported half-life of CRP of w19 h (5). Asif Machhada, BSc Alexander V. Gourine, PhD *Gareth L. Ackland, PhD, MD *Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Pharmacology and Physiology University College London Gower Street London WC1E 6BT United Kingdom E-mail: g.ackland@ucl.ac.uk http://dx.doi.org/10.1016/j.jacc.2015.04.083 Please note: Dr. Machhada has received PhD Studentship support from the Medical Research Council and the Rosetrees Trust. Dr. Gourine has received research grant support from the British Heart Foundation and the Wellcome Trust. Dr. Ackland has received research grant support from the British Heart Foundation and the British Journal of Anaesthesia/Royal College of Anaesthe- tists Basic Science Fellowship. Part of this work was undertaken at UCLH/UCL, who received a proportion of funding from the UK Department of Health’s National Institute for Health Research Biomedical Research Centers funding scheme. REFERENCES 1. Stavrakis S, Humphrey MB, Scherlag BJ, et al. Low-level transcutaneous electrical vagus nerve stimulation suppresses atrial fibrillation. J Am Coll Cardiol 2015;65:867–75. 2. Andersson U, Tracey KJ. Neural reflexes in inflammation and immunity. J Exp Med 2012;209:1057–68. 3. Machhada A, Ang R, Ackland GL, et al. Control of ventricular excitability by neurons of the dorsal motor nucleus of the vagus nerve. Heart Rhythm 2015 Jun 5 [E-pub ahead of print]. 4. Liu T, Li G, Li L, Korantzopoulos P. Association between C-reactive protein and recurrence of atrial fibrillation after successful electrical cardioversion: a meta-analysis. J Am Coll Cardiol 2007;49:1642–8. 5. Pepys MB, Hirschfield GM. C-reactive protein: a critical update. J Clin Invest 2003;111:1805–12. REPLY: Vagal Modulation of Atrial Fibrillation We thank Dr. Machhada and colleagues for their insightful comments regarding the effects of low- level tragus stimulation (LLTS) on C-reactive protein (CRP). Although the CRP levels appear to be non- normally distributed in the LLTS group, the assump- tions of constant variance and normality were reasonable for this model on the basis of the residual plots, as pointed out in the statistical methods of our paper (1). In addition, in our statistical model we did control for baseline CRP levels. The final results thus reflect the effect of LLTS after adjustment for baseline CRP levels. Atrial fibrillation is characterized by systemic inflammation, which is supported by the elevated levels of inflammatory cytokines, including tumor necrosis factor (TNF)-a and CRP, in our patient population (1). Importantly, the magnitude of decrease in inflammatory cytokine levels by LLTS is consistent with the difference between controls and pre–rheumatoid arthritis patients (1). This effect is unlikely the result of anesthesia or body mass index, both of which have been shown to affect CRP levels (2), given that the exposure of the con- trol and experimental groups to each of these fac- tors was balanced between the 2 groups. We cannot comment on the exact time course of CRP in our study, as we did not obtain serial measurements of CRP. The plasma half-life of CRP was determined in ambulatory healthy volunteers (3). It is unknown whether anesthesia affects the plasma half-life of CRP. However, a recent study showed that anes- thesia significantly decreased CRP transiently 30 min post-operatively compared with pre-operative levels (2). It should be noted that the anti-inflammatory effect of LLTS on TNF-a is consistent with its half- life of approximately 18 min (4). In addition, other studies have shown a significant decrease in TNF-a after just 20 min of vagus nerve stimulation (5). In summary, the overall results of our study sup- port the notion that vagal stimulation modulates inflammation. Stavros Stavrakis, MD, PhD Mary Beth Humphrey, MD, PhD *Sunny S. Po, MD, PhD *Heart Rhythm Institute University of Oklahoma Health Sciences Center 1200 Everett Drive, TCH 6E103 Oklahoma City, Oklahoma 73104 E-mail: sunny-po@ouhsc.edu http://dx.doi.org/10.1016/j.jacc.2015.06.1086 Please note: The authors have reported that they have no relationships relevant to the contents of this paper to disclose. REFERENCES 1. Stavrakis S, Humphrey MB, Scherlag BJ, et al. Low-level transcutaneous electrical vagus nerve stimulation suppresses atrial fibrillation. J Am Coll Cardiol 2015;65:867–75. 2. Lindholm EE, Aune E, Seljeflot I, Otterstad JE, Kirkeboen KA. Biomarkers of inflammation in major vascular surgery: a prospective randomised trial. Acta Anaesthesiol Scand 2015;59:773–87. 3. Vigushin DM, Pepys MB, Hawkins PN. Metabolic and scintigraphic studies of radioiodinated human C-reactive protein in health and disease. J Clin Invest 1993;91:1351–7. 4. Oliver JC, Bland LA, Oettinger CW, et al. Cytokine kinetics in an in vitro whole blood model following an endotoxin challenge. Lymphokine Cytokine Res 1993;12:115–20. 5. Wang H, Yu M, Ochani M, et al. Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature 2003;421: 384–8. Letters JACC VOL. 66, NO. 8, 2015 AUGUST 25, 2015:976 – 81 978