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 (CaCl2) 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 CaCl2 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 CaCl2 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 CaCl2 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% (CaCl2) 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 ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial The Chinese Clinical Trial Registry registration number: ChiCTR2000029314. website: http://www.chictr.org.cn/showproj.aspx?proj=48587 ### Funding Statement This work was sponsored by the LiaoNing Revitalization Talents Program (XLYC2001001) awarded to Dr. Huishan Wang. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Calcium-mediated Autonomic Denervation in Postoperative Atrial Fibrillation-2 (CAP-AF2) trial is a single-center, sham-controlled, double-blind, randomized clinical trial that was conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice Guideline. The protocol was approved by the Ethics Committee of the General Hospital of Northern Theater Command I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes After manuscript is accepted for publication, the de-identified data can be available to other researchers after an application approved by the corresponding authors