QTVI Responses to Acetylcholinesterase Inhibition during Sequential Provocation in Persons with Spinal Cord Injury
Authors: La Fountaine Michael F , Nguyen Nhuquynh , Schilero Gregory J , Weir Joseph P , Bauman William A , Wecht Jill M 
Published: November 2023

BackgroundVagal modulation of heart rate periodicity occurs in response to presynaptic release of acetylcholine (Acyl) and post‐synaptic binding to muscarinic receptors at the sino‐atrial node (SAN). Acetylcholinesterase inhibition (ACI) prolongs Acyl action leading to enhanced depression of SAN discharge rate and variability. In persons with spinal cord injury (SCI) that are proximal to the 5th thoracic vertebra (T5), sympathetic nervous system (SNS) activity is reduced or absent following injury leading to unopposed vagal influence and predominant reliance for SAN responses to provocation. The QT variability index (QTVI) characterizes ventricular repolarization and SAN automaticity, which are affected by alterations to autonomic adaptations to the psychophysiological state (e.g., rest, stress).MethodsThis was a prospective, randomized, double‐blinded, and placebo‐controlled trial. Six participants [3 able‐bodied (AB) and 3 SCI proximal to T5] received placebo (normal saline) or a total dose of 0.2 mg/kg ACI (edrophonium) by IV push on two separate laboratory visits. Participants completed a sequential evaluation of continuous 5‐minute epochs of: 1) supine quiescence (Rest), 2) a standard cold fact test (CFT) and 3) a 70° head‐up tilt (HUT) while a digital electrocardiogram (ECG; Lead II) was performed. The agent or placebo was administered in a randomized manner upon completion of the 5‐minute rest and, the CFT was initiated 2‐minutes later. The 70° HUT was initiated 5 minutes after the CFT. ECG intervals were extracted (QT and RR) with the corresponding means (m) and variance (v) calculated. QTVI was calculated for each epoch (Rest, CFT, and HUT) as:
urn:x-wiley:08926638:fsb2fasebj311supplement107711:equation:fsb2fasebj311supplement107711-math-0001Because of known differences in QTVI between AB and SCI participants, the QTVI responses to sequential provocation were normalized to rest, which was set to zero. A mixed‐model repeated measures analysis of variance was performed to identify significant main (agent and provocation) and interaction effects for QTVI. Subsequent Bonferroni's post‐hoc tests were used to describe significant main effects.ResultsThe two groups were matched for demographics. The QTVI excursion to sequential provocation was not significantly different between groups for placebo (Figure 1, dotted line). However, there were significant provocation (p<0.05) and interaction effects (p<0.01) for QTVI excursion during ACI (Figure 1, solid line). Post‐hoc analyses revealed that the SCI group had a significantly greater QTVI excursion to HUT than the AB group (Figure 1, *p<0.01). The HUT response to ACI trended toward a significant difference compared to placebo in the SCI group (p=0.09).ConclusionThe use of QTVI to quantify responses to sequential provocation during ACI provides further verification of cardioautonomic dysfunction in persons with SCI proximal to T5. ACI and CFT yielded a 3‐fold decline in QTVI compared to placebo in AB, indicating a greater vagal drive; this response was blunted in the SCI group. During HUT with placebo, the AB cohort withdrew vagal control and mounted a SNS drive in an appropriate manner, which was blunted by the administration of ACI. During ACI administration, the exaggerated decline in QTVI during HUT in the SCI group suggests impaired SNS cardiac regulation. Collectively, these data appear to confirm vagal predominance and impaired SNS capacity in SCI proximal to T5.Support or Funding InformationVA RR&D National Center of Excellence for the Medical Consequences of SCI (B9212‐C)