An implant for long-term cervical vagus nerve stimulation in mice

Vagus nerve stimulation (VNS) is a neuromodulation therapy with the potential to treat a wide range of chronic conditions in which inflammation is implicated, including type 2 diabetes, obesity, atherosclerosis and heart failure. Many of these diseases have well-established mouse models but due to the significant surgical and engineering challenges that accompany a reliable interface for long-term VNS in mice, the therapeutic implications of this bioelectronic approach remain unexplored. Here, we describe a long-term VNS implant in mice, developed at 3 research laboratories and validated for between-lab reproducibility. Implant functionality was evaluated over 3-8 weeks in 81 anesthetized or conscious mice by determining the stimulus intensity required to elicit a change in heart rate (heart rate threshold, HRT). HRT was also used as a method to standardize stimulation dosing across animals. Overall, 60-90% of implants produced stimulus-evoked physiological responses for at least 4 weeks, with HRT values stabilizing after the second week of implantation. Furthermore, stimulation delivered through 6-week-old implants decreased TNF levels in a subset of mice with acute inflammation caused by endotoxemia. Histological examination of 4- to 6-week-old implants revealed fibrotic encapsulation and no gross fiber loss. This implantation and dosing approach provide a tool to systematically investigate the therapeutic potential of long-term VNS in chronic diseases modeled in the mouse, the most widely used vertebrate species in biomedical research.

P6462Use of an uniform tachycardia threshold to identify normotensive patients with acute pulmonary embolism at higher risk for adverse in-hospital outcome

Background Tachycardia, an early indicator of haemodynamic compromise and RV failure, is a reliable predictor of adverse outcomes in normotensive patients with acute pulmonary embolism (PE). However, different prognostic relevant thresholds have been proposed. Purpose To investigate the prognostic performance of different thresholds used for the definition of tachycardia in normotensive PE patients. Methods We performed a post-hoc analysis of normotensive patients with confirmed PE consecutively included in a single-centre and a multi-centre registry. Results Overall, 1576 PE patients (mean age: 67.7 [IQR, 59–79] years; females: 54.7%) were included in this analysis. During the in-hospital stay, 50 patients (3.2%) had an adverse outcome. The rate of an adverse in-hospital outcome (primary outcome) was higher in patients with a heart rate ≥100 bpm (4.6%) compared to patients with a heart rate of ≥110 bpm (4.1%). Using univariate logistic regression analysis, PE patients with a heart rate ≥100 bpm had an increased risk (OR 2.3 [95% CI 1.1–4.2]; p=0.020) for an adverse in-hospital outcome, while a heart rate of ≥110 bpm did not provide prognostic information (OR 1.5 [95% CI 0.8–2.7]; p=0.083). Additionally, both threshold defining tachycardia (heart rate ≥100 bpm and ≥110 bpm, respectively) were used for calculation of validated risk stratification scores (modified FAST and Bova score) and algorithm (ESC 2014 based on sPESI). ROC analysis revealed a larger AUC with regard to an in-hospital adverse outcome for all scores and algorithm calculated with a heart rate threshold of ≥100 bpm compared to ≥110 bpm (Table 1). Regardless of the score used, the risk of an in-hospital adverse outcome was highest when a heart rate threshold of ≥100 bpm was used (Table 1). Table 1. Prognostic performance Sensitivity Specificity PPV NPV OR (95% CI) AUC (95% CI) p-value p-value Mod. FAST score (HR ≥110) 0.36 (0.24–0.50) 0.76 (0.74–0.78) 0.05 (0.03–0.07) 0.97 (0.96–0.98) 1.8 (1.0–3.3) 0.63 (0.56–0.70) p=0.046 p=0.002 Mod. FAST score (HR ≥100) 0.54 (0.40–0.67) 0.68 (0.65–0.70) 0.05 (0.04–0.07) 0.98 (0.97–0.99) 2.5 (1.4–4.3) 0.64 (0.56–0.72) p=0.002 p=0.001 Bova score (HR ≥110) 0.28 (0.17–0.42) 0.82 (0.80–0.84) 0.05 (0.03–0.08) 0.97 (0.96–0.98) 1.7 (0.9–3.3) 0.63 (0.56–0.70) p=0.083 p=0.002 Bova score (HR ≥100) 0.48 (0.35–0.61) 0.74 (0.72–0.77) 0.06 (0.04–0.08) 0.98 (0.97–0.98) 2.7 (1.5–4.7) 0.68 (0.62–0.75) p=0.001 p<0.001 ESC 2014 incl. sPESI (HR ≥110) 0.62 (0.49–0.74) 0.64 (0.62–0.67) 0.05 (0.04–0.07) 0.98 (0.97–0.99) 3.1 (1.7–5.6) 0.64 (0.57–0.72) p<0.001 p=0.001 ESC 2014 incl. sPESI (HR ≥100) 0.60 (0.67–0.72) 0.70 (0.67–0.72) 0.06 (0.04–0.09) 0.98 (0.97–0.99) 3.4 (1.9–6.1) 0.67 (0.59–0.74) p<0.001 p<0.001 Conclusions Defining tachycardia by a heart rate of ≥100 bpm, as generally recommended, is sufficient for risk stratification of normotensive patients with acute PE and improves the identification of PE patients at higher risk of PE-related complications. The use of different thresholds for calculation of scores does not appear necessary. Acknowledgement/Funding This study was supported by the German Federal Ministry of Education and Research (BMBF 01EO1503).

Determination of heart rate threshold from heart rate kinetics during maximal graded exercise in soccer players

The main of the present study was to identify the heart rate threshold based on heart rate kinetics during graded maximal exercise in football players. Twenty-six male football players performed a maximal exercise test (Bruce protocol) on a motor-driven treadmill. Oxygen uptake (VO2) and heart rate (HR) were monitored, recorded and resampled at 3.5Hz. The ventilatory threshold (VT), and respiratory compensation (RC), heart rate deflection points (HRDP1 and HRDP2) and heart rate kinetics threshold (HRT) were determined by computerized methods. The heart rate variability (HRV) was assessed in the frequency domain. The HRT averaged 89.9 ± 1.2 % of the VO2 peak. The HRT showed poor correlations and significant differences compared with HRDP1 (r = 0.46) and VT (r = 0.51), but was not different from, and highly correlated with, HRDP2 (0.98) and RC (0.90). Bland Altman plots showed all athletes into 95% of limits of agreement, and intraclass correlation coefficient showed good agreements between points obtained from HRT compared with HRDP2 (0.96) and RC (0.98). The HRT was highly correlated with HRDP2 and RC, suggesting it could be a marker for cardiorespiratory fatigue.