Badri Amurthur

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.

Autonomic regulation therapy to enhance myocardial function in heart failure patients: the ANTHEM-HFpEF study: ANTHEM-HFpEF study design

Approximately half of the patients presenting with new‐onset heart failure (HF) have HF with preserved left ventricular ejection fraction (HFpEF) and HF with mid‐range left ventricular ejection fraction (HFmrEF). These patients have neurohormonal activation like that of HF with reduced ejection fraction; however, beta‐blockers and angiotensin‐converting enzyme inhibitors have not been shown to improve their outcomes, and current treatment for these patients is symptom based and empiric. Sympathoinhibition using parasympathetic stimulation has been shown to improve central and peripheral aspects of the cardiac nervous system, reflex control, induce myocyte cardioprotection, and can lead to regression of left ventricular hypertrophy. Beneficial effects of autonomic regulation therapy (ART) using vagus nerve stimulation (VNS) have also been observed in several animal models of HFpEF, suggesting a potential role for ART in patients with this disease.

Quantitative Evaluation of Heartbeat Interval Time Series using Poincaré Analysis Reveals Distinct Patterns of Heart Rate Dynamics During Cycles of Vagus Nerve Stimulation in Patients with Heart Failure

BACKGROUND Optimization of stimulation parameters is essential to maximizing therapeutic efficacy and minimizing side effects. METHODS The ANTHEM-HF study enrolled patients with heart failure who received chronic autonomic regulation therapy (ART) with an implantable vagus nerve stimulation (VNS) system on either the right (n=30) or left side (n=29). Acute effects of continuously cycling VNS on R-R interval dynamics were evaluated using post hoc Poincaré analysis of ECG recordings collected during multiple titration sessions over an 8-12week period. During each titration session, VNS intensity associated with maximum tolerable dose was determined. Poincaré plots of R-R interval time series were created for epochs when VNS cycled from OFF to ON at varying intensity levels. RESULTS VNS produced an immediate, relatively small change in beat-to-beat distribution of R-R intervals during the 14-sec ON time, which was correlated with stimulation current amplitude (r=0.85, p=0.05). During titration of right-sided stimulation, there was a strong correlation (r=0.91, p=0.01) between stimulus intensity and the Poincaré parameter of standard deviation, SD1, which is associated with high-frequency heart rate variability. The effect of VNS on instantaneous heart rate was indicated by a shift in the centroid of the beat-to-beat cloud distribution demarcated by the encircling ellipse. As anticipated, left-sided stimulation did not alter any Poincaré parameter except at high stimulation intensities (≥2mA). CONCLUSION Quantitative Poincaré analysis reveals a tight coupling in beat-to-beat dynamics during VNS ON cycles that is directly related to stimulation intensity, providing a useful measurement for confirming autonomic engagement.

Acute Autonomic Engagement Assessed by Heart Rate Dynamics During Vagus Nerve Stimulation in Patients With Heart Failure in the ANTHEM-HF Trial

Chronic vagus nerve stimulation (VNS) applied to produce biomimetic levels of parasympathetic activation is feasible, well tolerated, safe, improves left ventricular ejection fraction, NYHA class, heart rate variability, and baroreflex function, and reduces T‐wave alternans (TWA) in patients with chronic heart failure. However, the acute effects of VNS on beat‐to‐beat heart rate dynamics have not been systematically characterized in humans.

Novel method to assess intrinsic heart rate recovery in ambulatory ECG recordings tracks cardioprotective effects of chronic autonomic regulation therapy in patients enrolled in the ANTHEM‐HF study

Postexercise heart rate recovery (HRR) is a powerful and independent predictor of mortality. Autonomic regulation therapy (ART) with chronic vagus nerve stimulation (VNS) has been shown to improve ventricular function in patients with chronic heart failure. However, the effect of ART on HRR in patients with heart failure remains unknown.