Vagus Nerve Stimulation for the Treatment of Heart Failure: The INOVATE-HF Trial.

BACKGROUND: Heart failure (HF) is increasing in prevalence and is a major cause of morbidity and mortality despite advances in medical and device therapy. Autonomic imbalance, with excess sympathetic activation and decreased vagal tone, is an integral component of the pathophysiology of HF. OBJECTIVES: The INOVATE-HF (Increase of Vagal Tone in Heart Failure) trial assessed the safety and efficacy of vagal nerve stimulation (VNS) among patients with HF and a reduced ejection fraction. METHODS: INOVATE-HF was a multinational, randomized trial involving 85 centers including patients with chronic HF, New York Heart Association functional class III symptoms and ejection fraction ≤40%. Patients were assigned to device implantation to provide VNS (active) or continued medical therapy (control) in a 3:2 ratio. The primary efficacy endpoint was composite of death from any cause or first event for worsening HF. RESULTS: Patients (n = 707) were randomized and followed up for a mean of 16 months. The primary efficacy outcome occurred in 132 of 436 patients in the VNS group, compared to 70 of 271 in the control group (30.3% vs. 25.8%; hazard ratio: 1.14; 95% confidence interval: 0.86 to 1.53; p = 0.37). During the trial, the estimated annual mortality rates were 9.3% and 7.1%, respectively (p = 0.19). Quality of life, New York Heart Association functional class, and 6-min walking distance were favorably affected by VNS (p < 0.05), but left ventricular end-systolic volume index was not different (p = 0.49). CONCLUSIONS: VNS does not reduce the rate of death or HF events in chronic HF patients. (INcrease Of VAgal TonE in CHF [INOVATE-HF]; NCT01303718).

First experience with a novel robotic remote catheter system: Amigo™ mapping trial.

INTRODUCTION: Amigo™ (Catheter Robotics, Inc., Mount Olive, NJ) remote catheter system (RCS) was designed to provide a simple and relatively inexpensive system for remote catheter manipulation. The purpose of this study was to evaluate the performance and safety of Amigo in mapping the right side of the heart. METHODS AND RESULTS: This non-randomized, prospective clinical trial was conducted at 13 sites (NCT: #01139814). Using the controller, a mapping catheter was moved to eight pre-specified locations in a specific sequence: right ventricular apex, mid-right ventricular septum, right ventricular outflow tract, His-bundle position, coronary sinus ostium, high right atrium, lateral tricuspid annulus, and low lateral right atrium. The pre-specified efficacy endpoint was to achieve 80 % successful navigation to all locations. Time to each location, location accuracy, and quality of contact were confirmed by imaging and specific criteria for electrograms and pacing thresholds. In 181 patients, a total of 1,396 of 1,448 (96 %) locations were successfully mapped with all protocol criteria met (one-sided p value < 0.0001). The median time to move the catheter to a new location was 24 s. The Amigo-related major complication rate was 0 % which was significantly less than the predefined endpoint of 4 % (one-sided p = 0.003). CONCLUSION: We found the Amigo RCS to be safe and effective for positioning a mapping catheter at sites within the right atrium and ventricle.

Subgroup analysis of a randomized controlled trial evaluating the safety and efficacy of cardiac contractility modulation in advanced heart failure.

BACKGROUND: Cardiac contractility modulation (CCM) signals are nonexcitatory electrical signals delivered during the absolute refractory period intended to improve contraction. We previously tested the safety and efficacy of CCM in 428 NYHA functional class III/IV heart failure patients with EF ≤35% and narrow QRS randomized to optimal medical treatment (OMT) plus CCM (n = 215) versus OMT alone (n = 213) and found no significant effect on ventilatory anaerobic threshold (VAT), the study's primary end point. In the present analysis, we sought to identify if there was a subgroup of patients who showed a response to CCM. METHODS AND RESULTS: The protocol specified that multiregression analysis would be used to determine if baseline EF, NYHA functional class, pVO(2), or etiology of heart failure influenced the impact of CCM on AT. Etiology and baseline pVO(2) did not affect efficacy. However, baseline NYHA functional class III and EF ≥25% were significant predictors of increased efficacy. In this subgroup (comprising 97 OMT and 109 CCM patients, ∼48% of the entire population) VAT increased by 0.10 ± 2.36 in CCM versus -0.54 ± 1.83 mL kg(-1) min(-1) in OMT (P = .03) and pVO(2) increased by 0.34 ± 3.11 in CCM versus -0.97 ± 2.31 (P = .001) at 24 weeks compared with baseline; 44% of CCM versus 23% of OMT subjects showed improvement of ≥1 class in NYHA functional class (P = .002), and 59% of CCM versus 42% of OMT subjects showed a ≥10-point reduction in Minnesota Living with Heart Failure Questionnaire (P = .01). All of these findings were similar to those seen at 50 weeks. CONCLUSIONS: The results of this retrospective hypothesis-generating analysis indicate that CCM significantly improves objective parameters of exercise tolerance in a subgroup of patients characterized by normal QRS duration, NYHA functional class III symptoms, and EF >25%.

Noninvasive measurement of cardiac performance in recovery from exercise in heart failure patients.

OBJECTIVE: To examine the association between cardiac performance during recovery and the severity of heart failure, as determined by clinical and cardiopulmonary exercise test responses. METHODS: As part of a retrospective cohort study, 46 heart failure patients and 13 normal subjects underwent cardiopulmonary exercise testing while cardiac output was measured using a noninvasive device. Cardiac output in recovery was expressed as the slope of a single exponential relationship between cardiac output and time; the recovery-time constant was assessed in relation to indices of cardiac function, along with clinical, functional, and cardiopulmonary exercise responses. RESULTS: The recovery time constant was delayed in patients with heart failure compared with normal subjects (296.7 ± 238 vs. 110.1 ±27 seconds, p <0.01), and the slope of the decline of cardiac output in recovery was steeper in normal subjects compared with heart failure patients (p<0.001). The slope of the decline in cardiac output recovery was inversely related to peak VO(2) (r = -0.72, p<0.001) and directly related to the VE/VCO(2) slope (r = 0.57, p,0.001). Heart failure patients with abnormal recovery time constants had lower peak VO(2), lower VO(2) at the ventilatory threshold, lower peak cardiac output, and a heightened VE/VCO(2) slope during exercise. CONCLUSIONS: Impaired cardiac output recovery kinetics can identify heart failure patients with more severe disease, lower exercise capacity, and inefficient ventilation. Estimating cardiac output in recovery from exercise may provide added insight into the cardiovascular status of patients with heart failure.

A randomized controlled trial evaluating the safety and efficacy of cardiac contractility modulation in advanced heart failure.

BACKGROUND: Cardiac contractility modulation (CCM) delivers nonexcitatory electrical signals to the heart during the absolute refractory period intended to improve contraction. METHODS: We tested CCM in 428 New York Heart Association class III or IV, narrow QRS heart failure patients with ejection fraction (EF) ≤ 35% randomized to optimal medical therapy (OMT) plus CCM (n = 215) versus OMT alone (n = 213). Efficacy was assessed by ventilatory anaerobic threshold (VAT), primary end point, peak Vo2 (pVo2), and Minnesota Living with Heart Failure Questionnaire (MLWFQ) at 6 months. The primary safety end point was a test of noninferiority between groups at 12 months for the composite of all-cause mortality and hospitalizations (12.5% allowable delta). RESULTS: The groups were comparable for age (58 ± 13 vs 59 ± 12 years), EF (26% ± 7% vs 26% ± 7%), pVo2 (14.7 ± 2.9 vs 14.8 ± 3.2 mL kg⁻¹ min⁻¹), and other characteristics. While VAT did not improve at 6 months, CCM significantly improved pVo2 and MLWHFQ (by 0.65 mL kg⁻¹ min⁻¹ [P = .024] and -9.7 points [P < .0001], respectively) over OMT. Forty-eight percent of OMT and 52% of CCM patients experienced a safety end point, which satisfied the noniferiority criterion (P = .03). Post hoc, hypothesis-generating analysis identified a subgroup (characterized by baseline EF ≥ 25% and New York Heart Association class III symptoms) in which all parameters were improved by CCM. CONCLUSIONS: In the overall target population, CCM did not improve VAT (the primary end point) but did improve pVo2 and MLWHFQ. Cardiac contractility modulation did not have an adverse affect on hospitalizations or mortality within the prespecified boundaries. Further study is required to clarify the role of CCM as a treatment for medically refractory heart failure.

Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a randomised controlled trial.

BACKGROUND: Results of previous studies support the hypothesis that implantable haemodynamic monitoring systems might reduce rates of hospitalisation in patients with heart failure. We undertook a single-blind trial to assess this approach. METHODS: Patients with New York Heart Association (NYHA) class III heart failure, irrespective of the left ventricular ejection fraction, and a previous hospital admission for heart failure were enrolled in 64 centres in the USA. They were randomly assigned by use of a centralised electronic system to management with a wireless implantable haemodynamic monitoring (W-IHM) system (treatment group) or to a control group for at least 6 months. Only patients were masked to their assignment group. In the treatment group, clinicians used daily measurement of pulmonary artery pressures in addition to standard of care versus standard of care alone in the control group. The primary efficacy endpoint was the rate of heart-failure-related hospitalisations at 6 months. The safety endpoints assessed at 6 months were freedom from device-related or system-related complications (DSRC) and freedom from pressure-sensor failures. All analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00531661. FINDINGS: In 6 months, 83 heart-failure-related hospitalisations were reported in the treatment group (n=270) compared with 120 in the control group (n=280; rate 0·31 vs 0·44, hazard ratio [HR] 0·70, 95% CI 0·60-0·84, p<0·0001). During the entire follow-up (mean 15 months [SD 7]), the treatment group had a 39% reduction in heart-failure-related hospitalisation compared with the control group (153 vs 253, HR 0·64, 95% CI 0·55-0·75; p<0·0001). Eight patients had DSRC and overall freedom from DSRC was 98·6% (97·3-99·4) compared with a prespecified performance criterion of 80% (p<0·0001); and overall freedom from pressure-sensor failures was 100% (99·3-100·0). INTERPRETATION: Our results are consistent with, and extend, previous findings by definitively showing a significant and large reduction in hospitalisation for patients with NYHA class III heart failure who were managed with a wireless implantable haemodynamic monitoring system. The addition of information about pulmonary artery pressure to clinical signs and symptoms allows for improved heart failure management. FUNDING: CardioMEMS.

Noninvasive measurement of cardiac performance in recovery from exercise in heart failure patients

OBJECTIVE: To examine the association between cardiac performance during recovery and the severity of heart failure, as determined by clinical and cardiopulmonary exercise test responses. METHODS: As part of a retrospective cohort study, 46 heart failure patients and 13 normal subjects underwent cardiopulmonary exercise testing while cardiac output was measured using a noninvasive device. Cardiac output in recovery was expressed as the slope of a single exponential relationship between cardiac output and time; the recovery-time constant was assessed in relation to indices of cardiac function, along with clinical, functional, and cardiopulmonary exercise responses. RESULTS: The recovery time constant was delayed in patients with heart failure compared with normal subjects (296.7 + 238 vs. 110.1 +27 seconds, p <0.01), and the slope of the decline of cardiac output in recovery was steeper in normal subjects compared with heart failure patients (p,0.001). The slope of the decline in cardiac output recovery was inversely related to peak VO2 (r = -0.72, p<0.001) and directly related to the VE/VCO2 slope (r = 0.57, p,0.001). Heart failure patients with abnormal recovery time constants had lower peak VO2, lower VO2 at the ventilatory threshold, lower peak cardiac output, and a heightened VE/VCO2 slope during exercise. CONCLUSIONS: Impaired cardiac output recovery kinetics can identify heart failure patients with more severe disease, lower exercise capacity, and inefficient ventilation. Estimating cardiac output in recovery from exercise may provide added insight into the cardiovascular status of patients with heart failure.

End-tidal CO2 pressure and cardiac performance during exercise in heart failure.

INTRODUCTION: In patients with heart failure (HF), end-tidal CO2 pressure (PetCO2) is related to ventricular function at rest and has been shown to predict prognosis. However, little is known about the association between ventricular performance and PetCO2 responses to exercise. METHODS: Forty-eight patients with HF and 13 normal subjects underwent cardiopulmonary exercise testing (CPX), while cardiac output and other hemodynamic measurements at rest and during exercise were obtained using a novel, noninvasive, bioreactance device based on assessment of relative phase shifts of electric currents injected across the thorax, heart rate, and ventricular ejection time. CPX responses and indices of cardiac performance were compared between normal subjects and HF patients achieving above and below a PetCO2 of 36 mm Hg at the ventilatory threshold (PetCO2@VT). RESULTS: HF patients with an abnormal PetCO2@VT (<36 mm Hg) had a lower exercise capacity, a lower .VO2@VT, a higher .V_E/.VCO2 slope, and lower oxygen uptake efficiency slope (OUES) values compared with normal subjects and patients achieving a normal PetCO2@VT. Patients with reduced PetCO2@VT had lower peak cardiac output responses to exercise (20.0 +/- 10, 17.8 +/- 6, and 13.7 +/- 7 L x min for normal subjects and HF patients with normal and abnormal PetCO2 responses to exercise, respectively, P = 0.04). PetCO2@VT was inversely related to the .V_E/.VCO2 slope (r = -0.78, P < 0.001) and directly related to the OUES (r = 0.55, P < 0.001). CONCLUSION: Reduced PetCO2 reflects impairments in the functional, ventilatory, and cardiac performance response to exercise in patients with HF. PetCO2 can supplement other clinical and CPX indices in the functional and prognostic evaluation of patients with HF.

Quantification of the impaired cardiac output response to exercise in heart failure: application of a non-invasive device.

An impaired cardiac output (CO) response to exercise is a hallmark of chronic heart failure (CHF), and the degree to which CO is impaired is related to the severity of CHF and prognosis. However, practical methods for obtaining cardiac output during exercise are lacking, and what constitutes and impaired response is unclear. Forty six CHF patients and 13 normal subjects underwent cardiopulmonary exercise testing (CPX) while CO and other hemodynamic measurements at rest and during exercise were obtained using a novel, non-invasive, bioreactance device based on assessment of relative phase shifts of electric currents injected across the thorax, heart rate and ventricular ejection time. An abnormal cardiac output response to exercise was defined as achieving ≤ 95% of the confidence limits of the slope of the relationship between CO and oxygen uptake (VO2). An impaired CO slope identified patients with more severe CHF as evidenced by a lower peak VO2, lower peak CO, heightened VE/VCO2 slope, and lower oxygen uptake efficiency slope. CO can be estimated during exercise using a novel bioreactance technique; patients with an impaired response to exercise exhibit reduced exercise capacity and inefficient ventilation typical of more severe CHF. Non- invasive measurement of cardiac performance in response to exercise provides a simple method of identifying patients with more severe CHF and may complement the CPX in identifying CHF patients at high risk. Key pointsNon-invasive measurement of cardiac output during exercise is feasible in patients with heart failure.Impairment in the CO response to exercise identifies heart failure patients with more severe disease, lower exercise capacity and inefficient ventilation.Non-invasive measurement of cardiac performance during exercise has potentially important applications for the functional and prognostic assessment of patients with heart failure.

Cardiac output and cardiopulmonary responses to exercise in heart failure: application of a new bio-reactance device.

BACKGROUND: Cardiopulmonary exercise testing (CPX) is widely used to evaluate heart failure (HF) patients, but lacks information about ventricular performance. There is a need for a noninvasive cardiac output (CO) measurement. METHODS AND RESULTS: Twenty-three HF patients and 13 normals underwent CPX and CO measurements with a new, noninvasive, bioreactance technology based on assessment of relative phase shifts (d phi/d t) of electric currents injected across the thorax, heart rate, and ventricular ejection time. CO and oxygen uptake (VO2) closely paralleled each another during exercise, and peak CO was strongly correlated with peak VO2 (r = 0.73, P < .001). The relationships between peak VO2 and peak cardiac index (CI) were similar for directly measured CI (r = 0.61) and noninvasive CI (r = 0.61). The CO-VO2 relationship was also similar between the current study and previous studies from the literature, as evidenced by a similar line of best fit and 95% confidence limits. Maximal CO was significantly related to indices of ventilatory efficiency, including the VE/VCO2 slope (r = -0.47, P < .01), and the oxygen uptake efficiency slope (r = 0.67, P < .01). CONCLUSION: Noninvasive measurement of CO during exercise using a novel bioreactance-based device has potentially important applications as a simple, inexpensive tool to supplement the clinical evaluation of patients with HF.

Nonexcitatory, cardiac contractility modulation electrical impulses: feasibility study for advanced heart failure in patients with normal QRS duration.

BACKGROUND: Cardiac contractility modulation signals are associated with acutely improved hemodynamics, but chronic clinical impact is not defined. OBJECTIVES: The purpose of this randomized, double-blind, pilot study was to determine the feasibility of safely and effectively delivering cardiac contractility modulation signals in patients with heart failure. METHODS: Forty-nine subjects with ejection fraction <35%, normal QRS duration (105 +/- 15 ms), and New York Heart Association (NYHA) class III or IV heart failure despite medical therapy received a cardiac contractility modulation pulse generator. Patients were randomized to have their devices programmed to deliver cardiac contractility modulation signals (n = 25, treatment group) or to remain off (n = 24, control group) for 6 months. Evaluations included NYHA class, 6-minute walk, cardiopulmonary stress test, Minnesota Living with Heart Failure Questionnaire, and Holter monitoring. RESULTS: Although most baseline features were balanced between groups, ejection fraction (31.4% +/- 7.4% vs 24.9% +/- 6.5%, P = .003), end-diastolic dimension (52.1 +/- 21.4 mm vs 62.5 +/- 6.2 mm, P = .01), peak VO(2) (16.0 +/- 2.9 mL O(2)/kg/min vs 14.3 +/- 2.8 mL O(2)/kg/min, P = .02), and anaerobic threshold (12.3 +/- 2.5 mL O(2)/kg/min vs 10.6 +/- 2.4 mL O(2)/kg/min, P = .01) were worse in the treatment group than in the control group. Nevertheless, one death occurred in the control group, and more patients in the treatment group were free of hospitalization for any cause at 6 months (84% vs 62%). No change in ectopy was observed. Compared with baseline, 6-minute walk (13.4 m), peak VO(2) (0.2 mL O(2)/kg/min), and anaerobic threshold (0.8 mL O(2)/kg/min) increased more in the treatment group than in control. None of these differences were statistically significant (small sample size). NYHA and Minnesota Living with Heart Failure Questionnaire changed similarly in the two groups. CONCLUSION: Despite a sicker population in the treatment group, no specific safety concerns emerged with chronic cardiac contractility modulation signal administration. Further study is required to definitively define the safety and efficacy of cardiac contractility modulation signals.