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BACKGROUND: Autonomic regulation therapy (ART) utilizing cervical vagus nerve stimulation (VNS) appeared to be safe and to improve autonomic tone, symptoms, and cardiac mechanical function in patients with symptomatic heart failure and reduced ejection fraction in the ANTHEM-HF Study. The ANTHEM-HFpEF Study is the first investigation to evaluate the safety and feasibility of ART in patients with symptomatic heart failure and preserved or mildly reduced ejection fraction (HFpEF, HFmrEF). METHODS: This open-label interventional study enrolled 52 patients with HFpEF or HFmrEF, NYHA Class II-III, and LVEF ≥40%, who received stable guideline-directed medical therapy. All patients were successfully implanted with LivaNova VNS Therapy® system with an electrical lead surrounding the right cervical vagus nerve. RESULTS: Adverse event incidence was low. At 12 months, NYHA class (p <0.0001), 6-min walk distance (p <0.05), and quality of life (p <0.0001) were improved. Cardiac mechanical function measures were normal at baseline, except for left ventricular mass index in women and E/e' ratio in all patients, which were elevated at baseline, and were unchanged by ART. Autonomic tone and reflexes improved, indicated by 29% decrease in low-frequency/high-frequency heart rate variability to normal levels (p = 0.028) and by increased heart rate turbulence slope (p = 0.047). T-wave alternans (p = 0.001) and T-wave heterogeneity (p = 0.001) were reduced from abnormal to normal ranges. Nonsustained ventricular tachycardia incidence decreased (p = 0.027). CONCLUSIONS: ART appeared well-tolerated and safe in patients with HFpEF or HFmrEF. Chronic ART did not alter mechanical function measures but was associated with improved heart failure symptoms, exercise tolerance, autonomic tone, and cardiac electrical stability. CLINICAL TRIAL REGISTRY: Autonomic Neural Regulation Therapy to Enhance Myocardial Function in Heart Failure with Preserved Ejection Fraction [ClinicalTrials.gov #NCT03163030, registered 05/22/2017].
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Cardiopatías , Insuficiencia Cardíaca , Disfunción Ventricular Izquierda , Femenino , Humanos , Arritmias Cardíacas , Enfermedad Crónica , Corazón , Insuficiencia Cardíaca/terapia , Insuficiencia Cardíaca/tratamiento farmacológico , Pronóstico , Calidad de Vida , Volumen Sistólico/fisiología , Resultado del Tratamiento , Función Ventricular Izquierda/fisiologíaRESUMEN
Autonomic imbalance with a sympathetic dominance is acknowledged to be a critical determinant of the pathophysiology of chronic heart failure with reduced ejection fraction (HFrEF), regardless of the etiology. Consequently, therapeutic interventions directly targeting the cardiac autonomic nervous system, generally referred to as neuromodulation strategies, have gained increasing interest and have been intensively studied at both the pre-clinical level and the clinical level. This review will focus on device-based neuromodulation in the setting of HFrEF. It will first provide some general principles about electrical neuromodulation and discuss specifically the complex issue of dose-response with this therapeutic approach. The paper will thereafter summarize the rationale, the pre-clinical and the clinical data, as well as the future prospectives of the three most studied form of device-based neuromodulation in HFrEF. These include cervical vagal nerve stimulation (cVNS), baroreflex activation therapy (BAT), and spinal cord stimulation (SCS). BAT has been approved by the Food and Drug Administration for use in patients with HfrEF, while the other two approaches are still considered investigational; VNS is currently being investigated in a large phase III Study.
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Objectives: Implantation and use of vagus nerve stimulation (VNS) systems is a proven treatment strategy for epilepsy and depression, and extensive research regarding vagal control of the heart has led to the idea of VNS as a potential adjunct treatment for heart failure with reduced ejection fraction (HFrEF). We describe our experience with the implantation of an investigational VNS system to manage patients living with HFrEF. Methods: As part of the ongoing ANTHEM-HFrEF (Autonomic Regulation Therapy to Enhance Myocardial Function and Reduce Progression of Heart Failure with Reduced Ejection Fraction) Pivotal Study, a 67-year-old male patient with a history of ischemic cardiomyopathy was randomized to implantation of the VITARIA System (LivaNova Inc). The electrical lead requires no mapping for placement around the vagus nerve. The surgical procedure was completed uneventfully under general anesthesia, and the device was activated in the operating room after surgery. Results: Following successful implantation and activation of the VNS system, the patient was discharged to home on the same day. Conclusions: Current, ongoing studies, such as the ANTHEM-HFrEF Pivotal Study, are designed to determine the long-term effects of VNS on heart failure symptoms, hospitalization rates, and survival. The VNS-implantation procedure was straightforward.
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The ANTHEM-HF, INOVATE-HF, and NECTAR-HF clinical studies of autonomic regulation therapy (ART) using vagus nerve stimulation (VNS) systems have collectively provided dose-ranging information enabling the development of several working hypotheses on how stimulation frequency can be utilized during VNS for tolerability and improving cardiovascular outcomes in patients living with heart failure (HF) and reduced ejection fraction (HFrEF). Changes in heart rate dynamics, comprising reduced heart rate (HR) and increased HR variability, are a biomarker of autonomic nerve system engagement and cardiac control, and appear to be sensitive to VNS that is delivered using a stimulation frequency that is similar to the natural operating frequency of the vagus nerve. Among prior studies, the ANTHEM-HF Pilot Study has provided the clearest evidence of autonomic engagement with VNS that was delivered using a stimulation frequency that was within the operating range of the vagus nerve. Achieving autonomic engagement was accompanied by improvement from baseline in six-minute walk duration (6MWD), health-related quality of life, and left ventricular EF (LVEF), over and above those achieved by concomitant guideline-directed medical therapy (GDMT) administered to counteract harmful neurohormonal activation, with relative freedom from deleterious effects. Autonomic engagement and positive directional changes have persisted over time, and an exploratory analysis suggests that improvement in autonomic tone, symptoms, and physical capacity may be independent of baseline NT-proBNP values. Based upon these encouraging observations, prospective, randomized controlled trials examining the effects on symptoms and cardiac function as well as natural history have been warranted. A multi-national, large-scale, randomized, controlled trial is well underway to determine the outcomes associated with ART using autonomic nervous system engagement as a guide for VNS delivery.
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Heart failure with reduced left ventricular ejection fraction is a progressive disease that claims > 352,000 lives annually in the United States alone. Despite the development of an extensive array of pharmacologic and device therapies, prognosis remains poor. Disruption in autonomic balance in the form of heightened sympathetic nerve activity and reduced vagal tone have been established as major causes of heart failure progression. Interest in chronic neuromodulation mediated by vagus nerve stimulation (VNS) has intensified in recent years. This review focuses on four main goals: (1) To review the preclinical evidence that supports the concept of a cardioprotective effect of VNS on autonomic function and cardiac electrical stability along with the underlying putative mechanisms. (2) To present the initial clinical experience with chronic VNS in patients with heart failure and highlight the controversial aspects of the findings. (3) To discuss the latest findings of the multifactorial effects of VNS on autonomic tone, baroreceptor sensitivity, and cardiac electrical stability and the state-of-the-art methods employed to monitor these relationships. (4) To discuss the implications of the current findings and the gaps in knowledge that require attention in future investigations.
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Introduction: Although heart failure (HF) outcomes have improved dramatically with the use of guideline directed medical therapy and implantable devices, the overall prognosis of patients with HF and reduced ejection fraction (HFrEF) remains poor. Autonomic Regulation Therapy (ART) using chronic vagus nerve stimulation (VNS) has been evaluated in the ANTHEM-HF study, using changes in heart rate (HR) dynamics as a biomarker of autonomic nervous system engagement and cardiac control to guide VNS titration. ART was associated with sustained improvement in cardiac function and HF symptoms in patients with HFrEF and persistent HF symptoms despite guideline-directed medical therapy (GDMT). We sought to determine whether the responsiveness of the autonomic nervous system to ART, as reflected in HR response to vagus stimulation during the VNS duty cycle, is maintained after long-term chronic VNS administration. Methods: Fifteen patients with HFrEF and implanted with a VNS systems in the ANTHEM-HF study were evaluated after 4.7 ± 0.3 years (range: 4.0-5.0 years) of chronic ART. ECG electrodes were placed on each patient's wrists, and ECG rhythm strips were recorded. Instantaneous HR time series was computed at each patient's chronically programmed VNS intensity and during progressively increasing VNS intensity. HR during active stimulation (on-time) was compared to HR just prior to initiation of each stimulation cycle (off-time). Results: Persistent autonomic engagement was observed in a majority of patients (11 of 15, 73%) after chronic ART for four or more years. The average magnitude of HR reduction during ART on-time in all patients was 2.4 ± 3.2 bpm at the chronically programmed VNS pulse parameter settings. Conclusion: Autonomic responsiveness to VNS persists in patients with HFrEF who received chronic ART for up to 5 years as a supplement to GDMT. This suggests that the effects of ART on autonomic engagement and cardiac control remain durable over time. Clinical Trial Registration: [ClinicalTrials.gov], identifier [#NCT01823887, CTRI registration #CTRI/2012/05/002681].
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PURPOSE: Autonomic regulation therapy (ART) for heart failure (HF) is delivered using vagus nerve stimulation (VNS), and has been associated with improvement in cardiac function and HF symptoms. VNS is delivered using an implantable pulse generator (IPG) and a lead placed around the cervical vagus nerve. Because HF patients may receive concomitant cardiac defibrillation therapy, testing was conducted to determine the effect of defibrillation (DF) on VNS system performance. METHODS: Normal swine (n = 4) with VNS system implants on the right cervical vagus nerve received sequential defibrillation shocks with three defibrillation systems: an implantable cardioverter defibrillator (ICD), a subcutaneous ICD (S-ICD), and an external cardioverter defibrillator (ECD). Each system delivered a series of bipolar high-energy shocks and reverse-polarity high-energy shocks. RESULTS: The specified cardiac defibrillation shocks were delivered successfully from each of the three defibrillation systems to all animals. After each shock series, interrogation of the IPG confirmed that software and data were unchanged from pre-programmed values. After all of the defibrillation shocks were delivered, the IPGs underwent and passed comprehensive electrical testing demonstrating proper system function. No shifts in IPG parameters or ART system failures were observed, and histologic evaluation of the vagus nerve revealed no anatomic changes. CONCLUSIONS: Implantable VNS systems were tested in vivo for immunity to defibrillation via ICD, S-ICD, and ECD, and were found to be unaffected by a series of high-energy defibrillation shocks. These results confirm that ART systems are capable of continuing to function after defibrillation and the cervical vagus nerve is anatomically unaffected.
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Desfibriladores Implantables , Insuficiencia Cardíaca , Estimulación del Nervio Vago , Animales , Antiarrítmicos , Desfibriladores Implantables/efectos adversos , Cardioversión Eléctrica/métodos , Electrocardiografía , Insuficiencia Cardíaca/terapia , Humanos , PorcinosRESUMEN
BACKGROUND: The effect of beta-blockade (BB) on response to vagus nerve stimulation (VNS) has not been reported in patients with heart failure and reduced ejection fraction (HFrEF). In the ANTHEM-HF Study, 60 patients received chronic cervical VNS. Background pharmacological therapy remained unchanged during the study, and VNS intensity was stable once up-titrated. Significant improvement from baseline occurred in resting 24-hour heart rate (HR), 24-hour HR variability (SDNN), left ventricular EF (LVEF), 6-minute walk distance (6MWD), and quality of life (MLWHFS) at 6â¯months post-titration. We evaluated whether response to VNS was related to percentage of target BB dose (PTBBD) at baseline. METHODS: Patients were categorized by baseline PTBBD, then analyzed for changes from baseline in symptoms and function at 6â¯months after VNS titration. RESULTS: All patients received BB, either PTBBDâ¯≥â¯50â¯% (16 patients, 27â¯%; group 1) or PTBBDâ¯<â¯50â¯% (44 patients, 73â¯%; group 2). Heart rate, systolic blood pressure, LVEF, use of ACE/ARB, and use of MRA were similar between the two groups at baseline. Six months after up-titration, VNS reduced HR and significantly improved SDNN, LVEF, 6MWD, and MLWHFS equally in both groups. CONCLUSIONS: In the ANTHEM-HF study, VNS responsiveness appeared to be independent of the baseline BB dose administered.
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Vagal nerve stimulation (VNS) has a strong pathophysiological rationale as a potentially beneficial treatment for heart failure with reduced ejection fraction. Despite several promising preclinical studies and pilot clinical studies, the two large, controlled trials-NECTAR-HF and INOVATE-HF-failed to demonstrate the expected benefit. It is likely that clinical application of VNS in phase III studies was performed before a sufficient degree of understanding of the complex pathophysiology of autonomic electrical modulation had been achieved, therefore leading to an underestimation of its potential benefit. More knowledge on the complex dose-response issue of VNS (i.e., pulse amplitude, frequency, duration and duty cycle) has been gathered since these trials and a new randomized study is currently underway with an adaptive design and a refined approach in an attempt to deliver the proper dose to a more selected group of patients.
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Insuficiencia Cardíaca , Estimulación del Nervio Vago , Disfunción Ventricular Izquierda , Sistema Nervioso Autónomo , Corazón , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/terapia , Frecuencia Cardíaca , Humanos , Resultado del TratamientoRESUMEN
BACKGROUND: Vagus Nerve Stimulation (VNS) delivers Autonomic Regulation Therapy (ART) for heart failure (HF), and has been associated with improvement in cardiac function and heart failure symptoms. VNS is delivered using an implantable pulse generator (IPG) and lead with electrodes placed around the cervical vagus nerve. Because HF patients may receive concomitant cardiac defibrillation therapy, testing was conducted to determine the effect of defibrillation (DF) on the VNS system. METHODS: DF testing was conducted on three ART IPGs (LivaNova USA, Inc.) according to international standard ISO14708-1, which evaluated whether DF had any permanent effects on the system. Each IPG was connected to a defibrillation pulse generator and subjected to a series of high-energy pulses. RESULTS: The specified series of pulses were successfully delivered to each of the three devices. All three IPGs passed factory electrical tests, and interrogation confirmed that software and data were unchanged from the pre-programmed values. No shifts in parameters or failures were observed. CONCLUSIONS: Implantable VNS systems were tested for immunity to defibrillation, and were found to be unaffected by a series of high-energy defibrillation pulses. These results suggest that this VNS system can be used safely and continue to function after patients have been defibrillated.
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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.
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Estimulación del Nervio Vago , Sistema Nervioso Autónomo , Frecuencia Cardíaca , Humanos , Volumen Sistólico , Resultado del Tratamiento , Nervio Vago , Función Ventricular IzquierdaRESUMEN
BACKGROUND: The ANTHEM-HF pilot study was an open-label study that evaluated the safety and feasibility of autonomic regulation therapy (ART) utilizing cervical vagus nerve stimulation (VNS) for patients with chronic HF with reduced EF (HFrEF). Patients in NYHA class II-III with EF ≤40% (n = 60) received ART for 6 months post-titration. ART was associated with sustained improvement in left ventricular (LV) function and HF symptoms at 6 and 12 months. METHODS: Continuously cyclic VNS was maintained to determine longer-term safety and chronic effects of ART. Echocardiographic parameters and HF symptoms were assessed throughout a follow-up period of at least 42 months. RESULTS: Between 12 and 42 months after initial titration, there were no device-related SAEs or malfunctions. There were 10 SAEs adjudicated to be unrelated to VNS, including 5 deaths. There were 6 non-serious adverse events that were adjudicated to be device-related (2 oropharyngeal pain, 1 implant site pain, 2 voice alteration, and 1 hoarseness). At 42 months, there was significant improvement from baseline in LVEF, NYHA class, 6-min walk distance, and MLHFQ score. However, these improvements at 42 months were not significantly different from mean values at 6 and 12 months. CONCLUSIONS: In a 42-month follow-up, ART was durable, safe, and was associated with beneficial effects on LVEF and 6-min walk distance. Long term, chronic, open-loop ART continued to be well-tolerated in patients with HFrEF. The open label, randomized, controlled, ANTHEM-HFrEF Pivotal Study is currently underway to further evaluate ART in patients with advanced HF.
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Insuficiencia Cardíaca , Estudios de Seguimiento , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/terapia , Humanos , Proyectos Piloto , Volumen Sistólico , Resultado del Tratamiento , Función Ventricular IzquierdaRESUMEN
BACKGROUND: Recent heart failure studies have associated lower baseline natriuretic peptide levels with improved morbidity/mortality outcomes during pharmaceutical treatment, and better clinical outcomes during neuromodulation (NM) with carotid nerve plexus stimulation for HFrEF when NT-proBNP < 1600 pg/ml. Whether baseline NT-proBNP is associated with HFrEF responsiveness to NM using vagus nerve stimulation (VNS) has not been examined. Hence, we evaluated the interaction of baseline NT-proBNP with changes in symptoms and function that occurred during chronic VNS in the ANTHEM-HF study. METHODS: A repeated measures, generalized-estimating, equations model evaluated the relationship of baseline NT-proBNP values above and below 1600 pg/ml to symptomatic and functional responses in ANTHEM-HF. RESULTS: Median (interquartile range; maximum) NT-proBNP was 868 (322, 1875; 14,656) pg/ml (N = 58). Heart rate (HR), HR variability (SDNN), 6-minute walk distance, MLWHF mean score, and NYHA improved significantly, independent of baseline NT-proBNP. While there was a statistical interaction between baseline NT-proBNP and better LVEF improvement during VNS, LVEF improved overall in the study cohort (N = 60; 32 ± 7 to 37 ± 10%; p = 0.0042), and in those patients whose baseline NT-proBNP was below the median baseline NT-proBNP value (n = 29; 36 ± 6 to 42 ± 10%; p < 0.0025)] or above this value (n = 29; 29 ± 7 to 32 ± 9%; p < 0.05). CONCLUSIONS: In ANTHEM-HF, overall symptomatic and functional improvement during chronic VNS was independent of baseline NTproBNP. These are preliminary and hypothesis-generating findings, and the reason for a differing interaction between baseline NT-proBNP and response to CNPS and VNS remains unclear. It is anticipated that the ongoing ANTHEM-HFrEF Pivotal Study of VNS will provide additional insight.
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AIMS: Clinical studies of vagal nerve stimulation (VNS) for heart failure with reduced ejection fraction have had mixed results to date. We sought to compare VNS delivery and associated changes in symptoms and function in autonomic regulation therapy via left or right cervical vagus nerve stimulation in patients with chronic heart failure (ANTHEM-HF), increase of vagal tone in heart failure (INOVATE-HF), and neural cardiac therapy for heart failure (NECTAR-HF) for hypothesis generation. METHODS AND RESULTS: Descriptive statistics were used to analyse data from the public domain for differences in proportions using Pearson's chi-square test, differences in mean values using Student's unpaired t-test, and differences in changes of mean values using two-sample t-tests. Guideline-directed medical therapy recommendations were similar across studies. Fewer patients were in New York Heart Association 3, and baseline heart rate (HR) was higher in ANTHEM-HF. In INOVATE-HF, VNS was aimed at peripheral neural targets, using closed-loop delivery that required synchronization of VNS to R-wave sensing by an intracardiac lead. Pulse frequency was low (1-2 Hz) because of a timing schedule allowing ≤3 pulses of VNS following at most 25% of detected R waves. NECTAR-HF and ANTHEM-HF used open-loop VNS delivery (i.e. independent of any external signal) aimed at both central and peripheral targets. In NECTAR-HF, VNS delivery at 20 Hz caused off-target effects that limited VNS up-titration in a majority of patients. In ANTHEM-HF, VNS delivery at 10 Hz allowed up-titration until changes in HR dynamics were confirmed. Six months after VNS titration, significant improvements in both HR and HR variability occurred only in ANTHEM-HF. When ANTHEM-HF and NECTAR-HF were compared, greater improvements from baseline were observed in ANTHEM-HF in standard deviation in normal-to-normal R-R intervals (94 ± 26 to 111 ± 50 vs. 146 ± 48 to 130 ± 52 ms; P < 0.001), left ventricular ejection fraction (32 ± 7 to 37 ± 0.4 vs. 31 ± 6 to 33 ± 6; P < 0.05), and Minnesota Living with Heart Failure mean score (40 ± 14 to 21 ± 10 vs. 44 ± 22 to 36 ± 21; P < 0.002). When compared with INOVATE-HF, greater improvement in 6-min walk distance was observed in ANTHEM-HF (287 ± 66 to 346 ± 78 vs. 304 ± 111 to 334 ± 111 m; P < 0.04). CONCLUSIONS: In this post-hoc analysis, differences in patient demographics were seen and may have caused the differential responses in symptoms and function observed in association with VNS. Major differences in technology platforms, neural targets, VNS delivery, and HR and HR variability responses could have also potentially played a very important role. Further study is underway in a randomized controlled trial with these considerations in mind.
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Insuficiencia Cardíaca , Estimulación del Nervio Vago , Anciano , Antagonistas de Receptores de Angiotensina , Inhibidores de la Enzima Convertidora de Angiotensina , Femenino , Insuficiencia Cardíaca/terapia , Humanos , Masculino , Persona de Mediana Edad , Néctar de las Plantas , Volumen Sistólico , Resultado del Tratamiento , Función Ventricular IzquierdaRESUMEN
AIMS: Clinical trials of new heart failure (HF) therapies administer guideline-directed medical therapy (GDMT) as background pharmacologic treatment (BPT). In the ANTHEM-HF Pilot Study, addition of autonomic regulation therapy to GDMT significantly improved left ventricular function, New York Heart Association (NYHA) class, 6 min walk distance, and quality of life in patients with HF with reduced ejection fraction (HFrEF). A post hoc analysis was performed to compare BPT in ANTHEM-HF with two other trials of novel HF therapies: the PARADIGM-HF study of sacubitril-valsartan and the SHIFT study of ivadrabine. All three studies evaluated patients with HFrEF, and the recommendations for use of GDMT were similar. A left ventricular ejection fraction ≤40% was required for entry into ANTHEM-HF and PARADIGM-HF and ≤35% for SHIFT. NYHA 2 or 3 symptoms were required for entry into ANTHEM-HF, and patients with predominantly NYHA 2 or 3 symptoms were enrolled in PARADIGM-HF and SHIFT. METHODS AND RESULTS: Data on BPT were obtained from peer-reviewed publications and the public domain. Pearson's χ2 test was used to evaluate differences in proportions, and Student's unpaired t-test was used to evaluate differences in mean values. The minimum period of stable GDMT required before randomization was longer in ANTHEM-HF: 3 months vs. 1 month in PARADIGM-HF and SHIFT, respectively. When compared with PARADIGM-HF and SHIFT, more patients in ANTHEM-HF received beta-blockers (100% vs. 93% and 89%, P < 0.04 and P < 0.007) and mineralocorticoid receptor antagonists (75% vs. 55% and 61%, P < 0.002 and P < 0.03). More patients in PARADIGM-HF received an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker than in ANTHEM-HF or SHIFT (100% vs. 85%, P < 0.0001, and 100% vs. 91%, P < 0.001), which was related to PARADIGM's design. When beta-blocker doses in ANTHEM-HF and SHIFT were compared, significantly fewer patients in ANTHEM-HF received doses ≥100% of target (10% vs. 23%, P < 0.02), and fewer patients tended to receive doses ≥50% of target (17% vs. 26%, P = 0.11). When ANTHEM-HF and PARADIGM-HF were compared, more patients in ANTHEM-HF tended to receive doses ≥100% of target (10% vs. 7%, P = 0.36), and fewer patients tended to receive doses ≥50% of target (17% vs. 20%, P = 0.56). CONCLUSIONS: Background treatment with GDMT in ANTHEM-HF compared favourably with that in two other contemporary trials of new HF therapies. The minimum period of stable GDMT required before randomization was longer, and GDMT remained unchanged for the study's duration. These findings serve to further support the potential role of autonomic regulation therapy as an adjunct to GDMT for patients with HFrEF.
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Sistema Nervioso Autónomo/efectos de los fármacos , Insuficiencia Cardíaca/tratamiento farmacológico , Guías de Práctica Clínica como Asunto/normas , Función Ventricular Izquierda/efectos de los fármacos , Antagonistas Adrenérgicos beta/farmacología , Antagonistas Adrenérgicos beta/uso terapéutico , Adulto , Anciano , Aminobutiratos/farmacología , Aminobutiratos/uso terapéutico , Antagonistas de Receptores de Angiotensina/farmacología , Antagonistas de Receptores de Angiotensina/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Sistema Nervioso Autónomo/fisiopatología , Compuestos de Bifenilo , Fármacos Cardiovasculares/farmacología , Fármacos Cardiovasculares/uso terapéutico , Combinación de Medicamentos , Femenino , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/psicología , Humanos , Ivabradina/farmacología , Ivabradina/uso terapéutico , Masculino , Persona de Mediana Edad , Antagonistas de Receptores de Mineralocorticoides/farmacología , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Calidad de Vida , Volumen Sistólico/efectos de los fármacos , Volumen Sistólico/fisiología , Tetrazoles/farmacología , Tetrazoles/uso terapéutico , Resultado del Tratamiento , Estimulación del Nervio Vago/métodos , Valsartán , Función Ventricular Izquierda/fisiología , Prueba de Paso/métodos , Prueba de Paso/estadística & datos numéricosRESUMEN
BACKGROUND: 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. METHODS: The Autonomic Neural Regulation Therapy to Enhance Myocardial Function in Patients with Heart Failure and Preserved Ejection Fraction (ANTHEM-HFpEF) study is designed to evaluate the feasibility, tolerability, and safety of ART using right cervical VNS in patients with chronic, stable HFpEF and HFmrEF. Patients with symptomatic HF and HFpEF or HFmrEF fulfilling the enrolment criteria will receive chronic ART with a subcutaneous VNS system attached to the right cervical vagus nerve. Safety parameters will be continuously monitored, and cardiac function and HF symptoms will be assessed every 3 months during a post-titration follow-up period of at least 12 months. CONCLUSIONS: The ANTHEM-HFpEF study is likely to provide valuable information intended to expand our understanding of the potential role of ART in patients with chronic symptomatic HFpEF and HFmrEF.
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Insuficiencia Cardíaca/terapia , Volumen Sistólico/fisiología , Estimulación del Nervio Vago/métodos , Función Ventricular Izquierda/fisiología , Anciano , Anciano de 80 o más Años , Estudios de Factibilidad , Femenino , Estudios de Seguimiento , Insuficiencia Cardíaca/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Resultado del TratamientoRESUMEN
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.
Asunto(s)
Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/terapia , Frecuencia Cardíaca/fisiología , Estimulación del Nervio Vago , Sistema Nervioso Autónomo/fisiopatología , Electrocardiografía , Femenino , Determinación de la Frecuencia Cardíaca , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Resultado del TratamientoRESUMEN
BACKGROUND: 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. METHODS: A new measure involving quantification of intrinsic HRR was developed for 24-hr ambulatory ECG (AECG) recordings based on spontaneous heart rate changes observed during daily activity in patients with symptomatic heart failure and reduced ejection fraction. Intrinsic HRR values were compared in 21 patients enrolled in the ANTHEM-HF study (NCT01823887) before and after 12 months of chronic ART (10 Hz, 250 µs pulse width, 18% duty cycle, maximum tolerable current amplitude after 10 weeks of titration) and to values from normal subjects (PhysioNet database, n = 54). RESULTS: With chronic ART, average intrinsic HRR was improved as indicated by a shortening of the rate-recovery time constant by 8.9% (from 12.3 ± 0.1 at baseline to 11.2 ± 0.1 s, p < .0001) among patients receiving high-intensity stimuli (≥2 mA). In addition, mean heart rate decreased by 8.5 bpm (from 75.9 ± 2.6 to 67.4 ± 2.9 bpm, p = .005) and left ventricular ejection fraction (LVEF) increased by 4.7% (from 32.6 ± 2.0% to 37.3 ± 1.9%, p < .005). CONCLUSION: Using a new technique adapted for 24-hr AECG recordings, intrinsic HRR was found to be impaired in patients with symptomatic HF compared to normal subjects. Chronic ART significantly improved intrinsic HRR, indicating an improvement in autonomic function.
Asunto(s)
Sistema Nervioso Autónomo/fisiopatología , Electrocardiografía Ambulatoria/métodos , Prueba de Esfuerzo/métodos , Insuficiencia Cardíaca/fisiopatología , Frecuencia Cardíaca/fisiología , Estimulación del Nervio Vago/métodos , Adulto , Anciano , Electrocardiografía Ambulatoria/estadística & datos numéricos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
BACKGROUND: 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. METHODS AND RESULTS: We evaluated acute effects of VNS on R-R-interval dynamics during the VNS titration period in patients (n = 59) enrolled in ANTHEM-HF trial by quantifying effects during continuous cyclic VNS (14-seconds on-time, 66-seconds off-time) adjusted to the maximum tolerable dose without excessive (<4 bpm) bradycardia during the 10-week titration period. VNS elicited an immediate change in heart rate that was correlated to VNS current amplitude, pulse width, and frequency. Heart rate decreased more in the 28 patients with right-sided stimulation (-2.22 ± 0.13 bpm) than in the 31 patients with left-sided stimulation (-0.60 ± 0.08 bpm, P < 0.001). The linear correlation between stimulus intensity and lengthening of the R-R interval was stronger among the 28 patients with right-sided VNS implantation (r = 0.88, P < 0.0001) than among the 31 patients with left-sided VNS implantation (r = 0.49, P < 0.002). In all patients, the heart rate change elicited by VNS was significantly greater than the change during the same timing intervals in 10 randomly selected patients without stimulation (+0.08 ± 0.06 bpm, P < 0.001). CONCLUSION: Instantaneous heart rate change during therapeutic levels of VNS in patients with heart failure indicates consistent modulation of the autonomic nervous system for both left- and right-sided stimulation.