Imad Libbus

Autonomic Regulation Therapy via Left or Right Cervical Vagus Nerve Stimulation in Patients With Chronic Heart Failure: Results of the ANTHEM-HF Trial

OBJECTIVE ANTHEM-HF evaluated a novel autonomic regulation therapy (ART) via either left or right vagus nerve stimulation (VNS) in patients with heart failure (HF) and reduced ejection fraction (HFrEF). METHODS AND RESULTS Sixty subjects (New York Heart Association [NYHA] functional class II-III, left ventricular ejection fraction (LVEF) ≤ 40%, left ventricular end-diastolic diameter ≥ 50 mm to < 80 mm) receiving optimal pharmacologic therapy were randomized at 10 sites. VNS systems were randomly implanted on the left (n = 31) or right (n = 29) side. All patients were successfully implanted and 59 were titrated over 10 weeks to a well tolerated stimulation intensity. One patient died 3 days after an embolic stroke that occurred during implantation. Common device-related adverse events after VNS titration were transient mild dysphonia, cough, and oropharyngeal pain, which were similar for left- and right-side VNS. After 6 months of ART, the adjusted left-right differences in LVEF, left ventricular end-systolic volume (LVESV), and left ventricular end-systolic diameter (LVESD) were 0.2% (95% CI -4.4 to 4.7), 3.7 mL (95% CI -7.0 to 14.4), and 1.3 mm (95% CI -0.9 to 3.6), respectively. In the combined population, absolute LVEF improved by 4.5% (95% CI 2.4-6.6), LVESV improved by -4.1 mL (95% CI -9.0 to 0.8), and LVESD improved by -1.7 mm (95% CI -2.8 to -0.7). Heart rate variability improved by 17 ms (95% CI 6.5-28) with minimal left-right difference. Six-minute walk distance improved an average of 56 m (95% CI 37-75); however, improvement was greater for right-side ART (77 m [95% CI 49-105]). NYHA functional class improved in 77% of patients (baseline to 6 months). CONCLUSIONS Chronic open-loop ART via left- or right-side VNS is feasible and well tolerated in HFrEF patients. Safety and efficacy measures are encouraging and warrant further study.

Autonomic Regulation Therapy for the Improvement of Left Ventricular Function and Heart Failure Symptoms: The ANTHEM-HF Study

BACKGROUND Outcomes of heart failure (HF) have improved dramatically with the use of blockers of the sympathetic and renin-angiotensin-aldosterone systems, as well as with more prevalent use of implantable cardiac defibrillators and cardiac resynchronization therapy. Despite these interventions, however, the overall prognosis of HF patients remains poor. Recently, stimulation of the right cervical vagus nerve in patients with symptomatic heart failure has been evaluated. Results suggest that vagal nerve stimulation provides sustained improvement in left ventricular (LV) function and symptoms associated with HF. However, much remains to be learned about the risks and benefits of therapies that alter autonomic regulatory function for the treatment of heart failure. METHODS The Autonomic Neural Regulation Therapy to Enhance Myocardial Function in Heart Failure (ANTHEM-HF) study has been designed to address several key clinical questions about the role of autonomic regulation therapy (ART) in patients with LV dysfunction and chronic symptomatic heart failure. CONCLUSIONS ANTHEM-HF should provide additional and valuable information regarding the safety and the relationship between the site and intensity of ART and its salutary effects on HF.

Extended Follow-Up of Patients with Heart Failure Receiving Autonomic Regulation Therapy in the ANTHEM-HF Study

OBJECTIVE Evaluate the effects of a novel autonomic regulation therapy (ART) via vagus nerve stimulation (VNS) in patients with chronic heart failure (HF) and reduced left ventricular ejection fraction during a 12-month follow-up period. METHODS The Autonomic Regulation Therapy for the Improvement of Left Ventricular Function and Heart Failure Symptoms (ANTHEM-HF) study enrolled 60 subjects with New York Heart Association class II-III HF and low left ventricular ejection fraction (≤40%), who received open-loop ART using VNS randomized to left or right cervical vagus nerve placement and followed for 6 months after titration to a therapeutic output current (2.0 ± 0.6 mA). Patients received chronic stimulation at a frequency of 10 Hz and pulse duration of 250 µsec. Forty-nine subjects consented to participate in an extended follow-up study for an additional 6 months (12 months total posttitration) to determine whether the effects of therapy were maintained. RESULTS During the 6-month extended follow-up period, there were no device malfunctions or device-related serious adverse effects. There were 7 serious adverse effects unrelated to the device, including 3 deaths (2 sudden cardiac deaths, 1 worsening HF death). There were 5 nonserious adverse events that were adjudicated to be device-related. Safety and tolerability were similar, and there were no significant differences in efficacy between left- and right-sided ART. Overall, mean efficacy measure values at 12 months were not significantly different from mean values at 6 months. CONCLUSIONS Chronic open-loop ART via left- or right-sided VNS continued to be feasible and well-tolerated in patients with HF with reduced EF. Improvements in cardiac function and HF symptoms seen after 6 months of ART were maintained at 12 months.

Autonomic regulation therapy suppresses quantitative T-wave alternans and improves baroreflex sensitivity in patients with heart failure enrolled in the ANTHEM-HF study☆☆☆

BACKGROUND Autonomic regulation therapy (ART) with chronic vagus nerve stimulation improves ventricular function in patients with chronic heart failure, but its effects on quantitative T-wave alternans (TWA), ventricular tachycardia (VT), baroreflex sensitivity, and autonomic tone remained unknown. OBJECTIVE Effects on TWA, a marker of risk of life-threatening arrhythmias; heart rate turbulence (HRT), an indicator of baroreflex sensitivity; heart rate variability; and VT incidence were studied in 25 patients with chronic symptomatic heart failure and reduced ejection fraction enrolled in the ANTHEM-HF study (NCT01823887). METHODS Twenty-four-hour ambulatory electrocardiographic recordings made before ART system (Cyberonics, Inc., Houston, TX) implantation involving the left or right vagus nerve and after 6 and 12 months of chronic therapy (10-Hz frequency, 250-μs pulse width, maximum tolerable current amplitude after 10 weeks of titration) at low-intensity (<2 mA; n = 10, 40%) or high-intensity (≥2 mA; n = 15, 60%) stimulation levels were analyzed. RESULTS At 12 months, peak TWA levels were reduced by 29% from 71.0 ± 4.6 to 50.5 ± 1.8 μV (P < .0001). The number of patients with severely abnormal TWA (≥60 μV) was reduced by 76% from 17 to 4 (P < .0005), and the number of patients with nonsustained VT decreased by 73% from 11 to 3 (P < .025). HRT slope (P < .025), high frequency heart rate variability (HRV) (P = .05), and square root of the mean squared differences of successive normal-to-normal interval HRV (P = .013) increased. The mean heart rate derived from 24-hour Holter electrocardiograms decreased by 10% from 77 ± 2 to 69 ± 2 beats/min (P = .0002). HRT onset was unchanged. CONCLUSION Chronic ART in patients with symptomatic heart failure improves cardiac electrical stability, as reflected by reduced TWA levels and heart rate, suppresses VT, and increases baroreceptor sensitivity. These observations deserve study in a larger population.

Estimation of patient compliance in application of adherent mobile cardiac telemetry device

In an in home usage outpatient setting, patient compliance is a key factor in determining the adoption and efficacy of treatment for any illness and is paramount for patient dependent medical technologies such as mobile patient monitoring systems. As a leader in the development of these technologies, Corventis has deployed its NUVANT™ Mobile Cardiac Telemetry System to thousands of patients around the world. The NUVANT system includes an externally worn adherent sensing device, the PiiX, whose proper application is critical to the on-patient longevity and thus performance of the NUVANT system. Patient compliance in this context is a universal challenge for such patient-applied adherent devices. Understanding and tracking a problem is key to solving it and the integrated suite of vital sign sensors in the Corventis PiiX offers a unique opportunity for extracting patient application compliance information from the incoming health data. Analysis of data from 5000 randomly selected patients has shown that improper application of the PiiX is a factor in 2.3% of patients. However, no reduction in adherent device longevity or performance was observed. Such information is a valuable feedback metric for product design, instructions for use, packaging of medical technologies, level of customer support and replacement costs.

Chronic cyclic vagus nerve stimulation has beneficial electrophysiological effects on healthy hearts in the absence of autonomic imbalance

Cardiovascular disease degrades the regulatory function of the autonomic nervous system. Cyclic vagus nerve stimulation (VNS) is an already FDA‐approved therapy for drug‐resistant epilepsy and depression, and has been shown to normalize autonomic function and improve objective measures of heart function and subjective measures of heart failure symptoms. However, it remains unclear whether VNS may induce negative effects in patients with potentially healthy hearts where VNS can be used for epileptic patients. Hence, this study aims to investigate the effects of VNS on the hearts of healthy rats with normal autonomic balance. Sprague–Dawley rats were implanted with stimulators and randomized to either Sham or VNS groups. Rats in VNS group received 10 weeks of chronic intermittent VNS via stimulation of the right cervical vagus nerve. Echocardiography was performed at Baseline (prior to VNS), Week 2, and Week 9. After 10 weeks, high‐resolution optical mapping was performed in ex vivo perfused hearts to evaluate the electrophysiological remodeling that occurs in the heart as a result of the VNS therapy. Chronic VNS modified the electrophysiological properties of healthy rat hearts by reducing the action potential duration at 50% (APD50) and 80% (APD80) repolarization. Chronic VNS also affected the restitution properties of the heart at the APD50 level and increased myocardial conduction velocity (CV). VNS did not induce any significant changes to ventricular ejection fraction (EF) and spatial dispersion of APD, thus indicating that VNS did not negatively affect cardiac function. VNS also reduced the susceptibility to ventricular arrhythmias (ventricular fibrillation [VF] and ventricular tachycardia [VT]) during ex vivo programmed electrical stimulation. In summary, chronic application of cyclic VNS induces changes to the electrophysiological properties of healthy rat hearts. The observed decrease in APD and increase in CV suggest that the beneficial effects of VNS do not require the presence of existing autonomic imbalance.

Intermittent electrical stimulation of the right cervical vagus nerve in salt-sensitive hypertensive rats: effects on blood pressure, arrhythmias, and ventricular electrophysiology

Hypertension (HTN) is the single greatest risk factor for potentially fatal cardiovascular diseases. One cause of HTN is inappropriately increased sympathetic nervous system activity, suggesting that restoring the autonomic nervous balance may be an effective means of HTN treatment. Here, we studied the potential of vagus nerve stimulation (VNS) to treat chronic HTN and cardiac arrhythmias through stimulation of the right cervical vagus nerve in hypertensive rats. Dahl salt‐sensitive rats (n = 12) were given a high salt diet to induce HTN. After 6 weeks, rats were randomized into two groups: HTN‐Sham and HTN‐VNS, in which VNS was provided to HTN‐VNS group for 4 weeks. In vivo blood pressure and electrocardiogram activities were monitored continuously by an implantable telemetry system. After 10 weeks, rats were euthanized and their hearts were extracted for ex vivo electrophysiological studies using high‐resolution optical mapping. Six weeks of high salt diet significantly increased both mean arterial pressure (MAP) and pulse pressure, demonstrating successful induction of HTN in all rats. After 4 weeks of VNS treatment, the increase in MAP and the number of arrhythmia episodes in HTN‐VNS rats was significantly attenuated when compared to those observed in HTN‐Sham rats. VNS treatment also induced changes in electrophysiological properties of the heart, such as reduction in action potential duration (APD) during rapid drive pacing, slope of APD restitution, spatial dispersion of APD, and increase in conduction velocity of impulse propagation. Overall, these results provide further evidence for the therapeutic efficacy of VNS in HTN and HTN‐related heart diseases.

Heart failure management

Patients with congestive heart failure consume a large portion of healthcare dollars. After the implementation of an outpatient inotropic infusion unit, case management, a restorative care pathway, and telemanagement at a community hospital, the number of hospital admissions, the inpatient length of stay, and overall costs decreased. At the same time, customer satisfaction and functional status increased. This article describes how the improved outcomes were accomplished.

Monitoring Changes in Fluid Status With a Wireless Multisensor Monitor: Results From the Fluid Removal During Adherent Renal Monitoring (FARM) Study

Body fluid assessment is important for managing chronic kidney disease (CKD) and heart failure (HF). However, accurate detection of fluid retention remains elusive. The Fluid Removal During Adherent Renal Monitoring (FARM) study is a prospective, nonrandomized trial examining the performance of a wireless, noninvasive, multisensor fluid monitoring system, applied to the chest, to determine its performance and reliability during hemodialysis. Patients undergoing regular hemodialysis (n=25) were monitored continuously for 2 consecutive dialysis sessions and the interdialysis period. Physiologic variables, including tissue impedance, were recorded. The volume of fluid removed and weight change during dialysis were measured. An average of 3.4±1.2 L of fluid was removed during dialysis, which was associated with an increase in bioimpedance of 11.3±7.2 Ω. Change in bioimpedance was highly correlated with the amount of fluid removed but less so with weight loss. Normalized bioimpedance change (21.0%±12.1% increase from baseline, P<001) was larger than the normalized weight change (3.6%±1.1%, P<.01), suggesting a higher sensitivity and dynamic range than weight change for detecting fluid removal. The fluid monitoring system accurately tracked fluid and weight loss in patients during hemodialysis, supporting its use as a tool for the management of patient fluid status in disease states.

Cervical vagus nerve stimulation augments spontaneous discharge in second- and higher-order sensory neurons in the rat nucleus of the solitary tract

Vagus nerve stimulation (VNS) currently treats patients with drug-resistant epilepsy, depression, and heart failure. The mild intensities used in chronic VNS suggest that primary visceral afferents and central nervous system activation are involved. Here, we measured the activity of neurons in the nucleus of the solitary tract (NTS) in anesthetized rats using clinically styled VNS. Our chief findings indicate that VNS at threshold bradycardic intensity activated NTS neuron discharge in one-third of NTS neurons. This VNS directly activated only myelinated vagal afferents projecting to second-order NTS neurons. Most VNS-induced activity in NTS, however, was unsynchronized to vagal stimuli. Thus, VNS activated unsynchronized activity in NTS neurons that were second order to vagal afferent C-fibers as well as higher-order NTS neurons only polysynaptically activated by the vagus. Overall, cardiovascular-sensitive and -insensitive NTS neurons were similarly activated by VNS: 3/4 neurons with monosynaptic vagal A-fiber afferents, 6/42 neurons with monosynaptic vagal C-fiber afferents, and 16/21 polysynaptic NTS neurons. Provocatively, vagal A-fibers indirectly activated C-fiber neurons during VNS. Elevated spontaneous spiking was quantitatively much higher than synchronized activity and extended well into the periods of nonstimulation. Surprisingly, many polysynaptic NTS neurons responded to half the bradycardic intensity used in clinical studies, indicating that a subset of myelinated vagal afferents is sufficient to evoke VNS indirect activation. Our study uncovered a myelinated vagal afferent drive that indirectly activates NTS neurons and thus central pathways beyond NTS and support reconsideration of brain contributions of vagal afferents underpinning of therapeutic impacts.NEW & NOTEWORTHY Acute vagus nerve stimulation elevated activity in neurons located in the medial nucleus of the solitary tract. Such stimuli directly activated only myelinated vagal afferents but indirectly activated a subpopulation of second- and higher-order neurons, suggesting that afferent mechanisms and central neuron activation may be responsible for vagus nerve stimulation efficacy.