Associations between Sympathetic Nerve Activity and Ischemia in Takotsubo Syndrome and Stable Ischemic Heart Disease

Background Patients with stable ischemic heart disease (IHD) frequently experience ambulatory myocardial ischemia. Takotsubo Syndrome (TTS) often mimics IHD and is associated with heightened sympathetic activity. We hypothesized that skin sympathetic nerve activity (SKNA) differs between participants with prior TTS, stable IHD, and reference controls and that SKNA increases relative to electrocardiographic (ECG) evidence of ischemia. Methods Simultaneous recordings of SKNA and ECG (neuECG) measured ST height and average SKNA (aSKNA) in ambulatory participants with a history of TTS (n=6), stable IHD (n=7), and reference controls (n=19). Ambulatory ischemia was defined as ischemic ST segment depression ≥0.5 mm. SKNA burst frequency, duration, amplitude, and total area above the threshold were calculated during ischemic and non-ischemic episodes. Results Baseline aSKNA was similar between TTS, IHD, and reference controls (0.980± 0.061 µV vs 0.916±0.050 µV vs 1.098±0.291 µV respectively, p=0.06). Ischemic episodes (n=15) were identified in 2 TTS and 4 IHD participants, while reference controls had none. Among the TTS and IHD groups, ischemic ST depression was associated with increased heart rate and elevated aSKNA from baseline. An analysis of SKNA burst patterns at similar heart rates revealed that SKNA total burst area was significantly higher during ischemic episodes than non-ischemic episodes (0.301±0.380 µV.s and 0.165±0.205 µV.s, p=0.023) in both the TTS and IHD participants. Conclusions Compared with heart rate-matched non-ischemic episodes, ischemic episodes were associated with larger SKNA burst areas in the TTS and IHD groups. The neuECG may be a useful tool in studying the pathophysiology of sympathetic nervous system-related ischemia. Clinical Perspective ### Competing Interest Statement Indiana University was awarded U.S. patent no.10,448,852 for inventing neuECG recording and Peng-Sheng Chen is a co-inventor. Dr. C. Noel Bairey Merz serves as Board of Director for iRhythm, fees paid through CSMC from Abbott Diagnostics and Sanofi. I, Dr. Janet Wei, served on an advisory board for Abbott Vascular. The other authors have no conflicts of interest to disclose. ### Funding Statement This study was supported in part by NIH Grants R01HL139829, OT2 OD028190, an AHA award 23IPA1052289, R01HL146158, U54AG065141. ### 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 institutional review board of the Cedars-Sinai Medical Center approved a prospective observational study of participants undergoing ambulatory monitoring with neuECG 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 Data available upon request.