Unexpected Increase in Postoperative Atrial Fibrillation by Calcium-mediated Autonomic Denervation: Results of the CAP-AF2 Trial

Background In the CAP-AF trial, injection of calcium chloride (CaCl 2 ) into the four major atrial ganglionated plexi (GP) reduced the relative risk of postoperative atrial fibrillation (POAF) by 63% in patients undergoing coronary artery bypass surgery (CABG). Objective The CAP-AF2 trial intended to investigate if similar autonomic denervation could prevent POAF in patients with mitral regurgitation (MR) but without persistent AF who underwent surgery for MR. Methods The CAP-AF-2 trial was an investigator-initiated, single center, double-blind, randomized clinical trial. This trial planned to 1:1 randomize 320 adult patients to CaCl 2 vs. sodium chloride (NaCl, sham) injection into the four GP during surgery. The primary outcome was incidence of POAF (≥30 seconds) in 7 days. Secondary outcomes included length of hospitalization, POAF burden, actionable antiarrhythmic therapy for POAF, heart rate variability changes and plasma inflammatory markers. Results This trial was terminated after midterm analysis showing that the cumulative POAF incidence was higher in the CaCl 2 group (43/78, 55.13%) than the NaCl group (31/82, 37.80%; confidence interval of difference 1.01%-32.48%, P = 0.028). In the CaCl 2 group, more patients were hospitalized over 7 days (69.8% vs. 45.2%; p=0.033) and more patients required amiodarone therapy (p=0.039). AF burden, plasma inflammatory markers and heart rate variability were not different between the two groups. Frequent atrial bigeminy or nonsustained atrial tachycardia immediately preceded POAF in 76.7% (CaCl 2 ) and 29.0% (NaCl) patients, respectively ( P <0.001), consistent with triggers caused by higher sympathetic activity. Immunohistochemistry study obtained from GP and left atrium during surgery revealed parasympathetic dominance in patients receiving MV surgery but sympathetic dominance in patients undergoing CABG. Conclusions Unlike patients undergoing CABG, autonomic denervation increased the risk of POAF in patients receiving MR surgery, indicating distinct AF substrate in different cardiovascular diseases. Calcium-mediated autonomic denervation may have tipped the tissue autonomic balance toward sympathetic dominance and provided triggers for POAF. While autonomic denervation has emerged as a novel therapy to treat various cardiovascular diseases, it should only be performed with evidence supported by randomized clinical trials. The Chinese Clinical Trial Registry registration number: ChiCTR2000029314. website : http://www.chictr.org.cn/showproj.aspx?proj=48587 CLINICAL PERSPECTIVES What is new - Calcium-mediated autonomic denervation increased the incidence of post-operative atrial fibrillation (AF) in patient undergoing mitral valve surgery for severe mitral regurgitation, contradictory to the beneficial effects it exerted on patients undergoing coronary artery bypass surgery. Clinical implications - Each cardiovascular disease may have its distinct autonomic balance at the tissue level. - Mechanisms underlying the initiation and maintenance of AF vary greatly among cardiovascular diseases; autonomic denervation therefore can be beneficial or harmful. - Autonomic denervation for each cardiovascular disease should only be performed with evidence from randomized clinical trials to demonstrate its efficacy and safety.