Chronic vagus nerve stimulation is associated with multi-year improvement in intrinsic heart rate recovery and left ventricular ejection fraction in ANTHEM-HF

Purpose Disturbed autonomic function is implicated in high mortality rates in heart failure patients. High-intensity vagus nerve stimulation therapy was shown to improve intrinsic heart rate recovery and left ventricular ejection fraction over a period of 1 year. Whether these beneficial effects are sustained across multiple years and are related to improved baroreceptor response was unknown. Methods All patients (n = 21) enrolled in the ANTHEM-HF clinical trial (NCT01823887, registered 4/3/2013) with 24 h ambulatory electrocardiograms at all time points and 54 normal subjects (PhysioNet database) were included. Intrinsic heart rate recovery, based on ~ 2000 spontaneous daily activity-induced heart rate acceleration/deceleration events per patient, was analyzed at screening and after 12, 24, and 36 months of chronic vagus nerve stimulation therapy (10 or 5 Hz, 250 μs pulse width, 18% duty cycle, maximum tolerable current amplitude). Results In response to chronic high-intensity vagus nerve stimulation (≥ 2.0 mA), intrinsic heart rate recovery (all time points, p < 0.0001), heart rate turbulence slope, an indicator of baroreceptor reflex gain (all, p ≤ 0.02), and left ventricular ejection fraction (all, p ≤ 0.04) were improved over screening at 12, 24, and 36 months. Intrinsic heart rate recovery and heart rate turbulence slope were inversely correlated at both screening (r = 0.67, p < 0.002) and 36 months (r = 0.78, p < 0.005). Conclusion This non-randomized study provides evidence of an association between improvement in intrinsic heart rate recovery and left ventricular ejection fraction during high-intensity vagus nerve stimulation for a period of ≥ 3 years. Correlated favorable effects on heart rate turbulence slope implicate enhanced baroreceptor function in response to chronic, continuously cyclic vagus nerve stimulation as a physiologic mechanism.

P4423Extreme bradycardia in athletes is due to intrinsic changes within the heart

Background It is well known that athletes and in particular endurance athletes have lower resting heart rates than non-athletes. This has generally been considered a healthy adaptation. Traditionally this was thought be due to increased vagal tone. Several studies have shown that endurance athletes continue to have lower heart rates in the absence of autonomic influence suggesting bradycardia is due to intrinsic changes within the heart. A subset of endurance athletes have very low heart rates with Tour de France cyclists having described heart rates in the 30s. It is unclear whether in these elite athletes with very low heart rates the profound bradycardia is due to autonomic influence or intrinsic changes within the heart. Aim The aim of this study was to determine if extreme bradycardia in athletes is due to excess vagal tone or more profound intrinsic changes within the heart. Methods We recruited three cohorts for this study: non-athlete controls (NA), endurance athletes with a documented resting heart rate >40 (EA) and endurance athletes with a resting heart rate <40 (BA). All participants underwent baseline testing including ECG, echocardiography and VO2 max testing. All participants came back on a second occasion for treatment with dual autonomic blockade (DAB) to determine intrinsic heart rate in the following manner. After resting supine for five minutes resting heart rate was measured. Participants were then administered 0.04mg/kg of intravenous atropine. After five minutes participants were then administered 0.05mg/kg of intravenous metoprolol. This was repeated every five minutes until there was no further drop in heart rate or 0.2mg/kg had been administered. The resting heart rate at this stage was recorded as the intrinsic heart rate. Parasympathetic blockade was confirmed by lack of response to Valsalva manoeuvre and sympathetic blockade was confirmed by lack of response to metoprolol. VO2 max testing was then performed to determine maximum heart rate. Results 9 NA (7 male), 10 EA (8 male) and 5 BA (4 male) participated in this study. The average age was similar in all groups (NA 32.9y, EA 32.4y, BA 31.4y). The average resting heart rate was 71.7 in the NA group, 48.3 in the EA group and 41.6 in the BA group (p<0.05 for comparisons between all three groups). Following dual autonomic blockade resting heart rate was 86.0 in the NA group, 76.9 in the EA group and 64.4 in the BA group (p<0.05 for comparisons between all three groups). Maximum heart rate under DAB was 140.1 in the NA group, 138.0 in the EA group and 140.4 in the BA group. These differences were not significant. Conclusion In athletes with very low heart rates, bradycardia is due to more profound intrinsic changes within the heart. Acknowledgement/Funding NHMRC Project Grant

Circadian control of intrinsic heart rate via a sinus node clock and the pacemaker channel

ABSTRACTIn the human, there is a circadian rhythm in the resting heart rate and it is higher during the day in preparation for physical activity. Conversely, slow heart rhythms (bradyarrhythmias) occur primarily at night. Although the lower heart rate at night is widely assumed to be neural in origin (the result of high vagal tone), the objective of the study was to test whether there is an intrinsic change in heart rate driven by a local circadian clock. In the mouse, there was a circadian rhythm in the heart rate in vivo in the conscious telemetrized animal, but there was also a circadian rhythm in the intrinsic heart rate in denervated preparations: the Langendorff-perfused heart and isolated sinus node. In the sinus node, experiments (qPCR and bioluminescence recordings in mice with a Per1 luciferase reporter) revealed functioning canonical clock genes, e.g. Bmal1 and Per1. We identified a circadian rhythm in the expression of key ion channels, notably the pacemaker channel Hcn4 (mRNA and protein) and the corresponding ionic current (funny current, measured by whole cell patch clamp in isolated sinus node cells). Block of funny current in the isolated sinus node abolished the circadian rhythm in the intrinsic heart rate. Incapacitating the local clock (by cardiac-specific knockout of Bmal1) abolished the normal circadian rhythm of Hcn4, funny current and the intrinsic heart rate. Chromatin immunoprecipitation demonstrated that Hcn4 is a transcriptional target of BMAL1 establishing a pathway by which the local clock can regulate heart rate. In conclusion, there is a circadian rhythm in the intrinsic heart rate as a result of a local circadian clock in the sinus node that drives rhythmic expression of Hcn4. The data reveal a novel regulator of heart rate and mechanistic insight into the occurrence of bradyarrhythmias at night.