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Maria Rosa Costanzo,1 Shahrokh Javaheri,2,3 Piotr Ponikowski,4 Olaf Oldenburg,5 Ralph Augostini,3 Lee R Goldberg,6 Christoph Stellbrink,7 Henrik Fox,8 Alan R Schwartz,6 Sanjaya Gupta,9 Scott McKane,10 Timothy E Meyer,10 William T Abraham3 for the remedē®System Pivotal Trial Study Group1Advocate Heart Institute, Naperville, IL, USA; 2Bethesda North Hospital, Cincinnati, OH, USA; 3The Ohio State University, Columbus, OH, USA; 4Department of Heart Diseases, Medical University, Military Hospital, Wroclaw, Poland; 5Ludgerus-Kliniken Münster, Clemens Hospital, Münster, Germany; 6University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; 7Bielefeld Medical Center, Bielefeld, Germany; 8Clinic for General and Interventional Cardiology Angiology, Herz- und Diabeteszentrum NRW, Ruhr-Universität Bochum, Bad Oeynhausen, Germany; 9University of Missouri-Kansas City School of Medicine, Saint Luke’s Mid-America Heart Institute, Kansas City, MO, USA; 10Respicardia, Inc., Minnetonka, MN, USACorrespondence: Maria Rosa CostanzoAdvocate Heart Institute, Naperville, IL, 60566, USAEmail mariarosa.costanzo@aah.orgBackground: The remedē System Pivotal Trial was a prospective, multi-center, randomized trial demonstrating transvenous phrenic nerve stimulation (TPNS) therapy is safe and effectively treats central sleep apnea (CSA) and improves sleep architecture and daytime sleepiness. Subsequently, the remedē System was approved by FDA in 2017. As a condition of approval, the Post Approval Study (PAS) collected clinical evidence regarding long-term safety and effectiveness in adults with moderate to severe CSA through five years post implant.Methods: Patients remaining in the Pivotal Trial at the time of FDA approval were invited to enroll in the PAS and consented to undergo sleep studies (scored by a central laboratory), complete the Epworth Sleepiness Scale (ESS) questionnaire to assess daytime sleepiness, and safety assessment. All subjects (treatment and former control group) receiving active therapy were pooled; data from both trials were combined for analysis.Results: Fifty-three of the original 151 Pivotal Trial patients consented to participate in the PAS and 52 completed the 5-year visit. Following TPNS therapy, the apnea-hypopnea index (AHI), central-apnea index (CAI), arousal index, oxygen desaturation index, and sleep architecture showed sustained improvements. Comparing 5 years to baseline, AHI and CAI decreased significantly (AHI baseline median 46 events/hour vs 17 at 5 years; CAI baseline median 23 events/hour vs 1 at 5 years), though residual hypopneas were present. In parallel, the arousal index, oxygen desaturation index and sleep architecture improved. The ESS improved by a statistically significant median reduction of 3 points at 5 years. Serious adverse events related to implant procedure, device or delivered therapy were reported by 14% of patients which include 16 (9%) patients who underwent a pulse generator reposition or lead revision (primarily in the first year). None of the events caused long-term harm. No unanticipated adverse device effects or related deaths occurred through 5 years.Conclusion: Long-term TPNS safely improves CSA, sleep architecture and daytime sleepiness through 5 years post implant.Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT01816776.Keywords: central sleep apnea, phrenic nerve stimulation

Heart failure (HF) is a global phenomenon, and the overall incidence and prevalence of the condition are steadily increasing. Medical therapies have proven efficacious, but only a small number of pharmacological options are in development. When patients cease to respond adequately to optimal medical therapy, cardiac resynchronization therapy has been shown to improve symptoms, reduce hospitalizations, promote reverse remodelling, and decrease mortality. However, challenges remain in identifying the ideal recipients for this therapy. The field of mechanical circulatory support has seen immense growth since the early 2000s, and left ventricular assist devices (LVADs) have transitioned over the past decade from large, pulsatile devices to smaller, more-compact, continuous-flow devices. Infections and haematological issues are still important areas that need to be addressed. Whereas LVADs were once approved only for 'bridge to transplantation', these devices are now used as destination therapy for critically ill patients with HF, allowing these individuals to return to the community. A host of novel strategies, including cardiac contractility modulation, implantable haemodynamic-monitoring devices, and phrenic and vagus nerve stimulation, are under investigation and might have an impact on the future care of patients with chronic HF. [ABSTRACT FROM AUTHOR]

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%. [ABSTRACT FROM AUTHOR]

BACKGROUND: Intrathoracic impedance fluid monitoring has been shown to predict worsening congestive heart failure (CHF) in patients with implantable devices. We developed and externally validated a modified algorithm to identify worsening heart failure (HF) by using intrathoracic impedance. METHODS AND RESULTS: The modified algorithm was developed by using published data from 81 CHF subjects averaging 259 days of follow-up. Device-measured daily impedance was input to both the existing and the modified intrathoracic impedance fluid monitoring algorithms to determine a reference impedance and a fluid index (FI). Separate validation sets included 326 cardiac resynchronization therapy device (CRT-D) patients with an average 333 days of follow-up (group 1) and 104 CRT-D/implantable cardioverter/defibrillator (ICD) patients followed for an average of 520 days (group 2). Clinicians and patients in group 2 were blinded to impedance and FI data. HF events included adjudicated HF hospitalizations or emergency room visits. Sensitivity was defined as the percentage of HF events preceded by FI exceeding the predefined threshold (60 -d) within the last 2 weeks. Unexplained detections were FI threshold crossing events not followed by a HF event within 2 weeks. The modified algorithm significantly decreased unexplained detections by 30% (P = .01; GEE) in the development set, 30% (P < .001) in the group 1 validation set, and 43% (P < .001) in group 2. Sensitivity did not change significantly in any group. Simulated monthly review of FI threshold crossings identified subjects at significantly greater risk of worsening HF within the next 30 days. CONCLUSIONS: A modified intrathoracic impedance based fluid detection algorithm lowered the number of unexplained FI threshold crossings and identified patients at significantly increased immediate risk of worsening HF. [ABSTRACT FROM AUTHOR]

Background: Cardiac resynchronization therapy (CRT) decreases mortality, improves functional status, and induces reverse left ventricular (LV) remodeling in selected populations. However, the effect of CRT on ventricular arrhythmias is controversial. This is particularly important among patients with mild heart failure (HF), in whom sudden death is a leading cause of mortality.Objective: This study sought to assess the impact of CRT on ventricular arrhythmias in mild HF.Methods: The REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction (REVERSE) study is a multicenter randomized, double-blind trial of CRT among patients with mild systolic HF. The time to first appropriate, treated ventricular tachycardia/ventricular fibrillation (VT/VF) episode or spontaneous sustained VT in cardiac resynchronization therapy plus defibrillation device (CRT-D) patients was compared between groups, as were predictors of VT/VF.Results: The study randomized 508 patients who received CRT-D devices. There were no significant demographic differences between groups. There were no differences in VT/VF episodes or VT storm between groups. Specifically, in the CRT ON group, the estimated event rate was 18.7% at 2 years, compared with 21.9% in the CRT OFF group (hazard ratio 1.05, P = .84). However, among CRT ON patients, those with reverse remodeling had a reduced incidence of VT/VF compared with those without remodeling (5.6% vs. 16.3%, hazard ratio 0.31, P = .001).Conclusion: CRT for up to 2 years does not impact VT/VF in mild HF despite marked clinical and remodeling effects of pacing. This neutral effect may be attributable to competing antiarrhythmic effects of reverse remodeling and proarrhythmic effect of pacing.Clinical Trial Registration: http://www.clinicaltrials.gov/ct2/show/NCT00271154. [ABSTRACT FROM AUTHOR]

BACKGROUND: The purpose of this study was to develop an automated surveillance system, using pressure-based hemodynamic factors that would detect which patients were making the transition from compensated to decompensated heart failure before they developed worsening symptoms and required acute medical care. METHODS AND RESULTS: Intracardiac pressures in 274 patients with heart failure were measured using an implantable hemodynamic monitor (IHM) and were analyzed in a retrospective manner. An automated pressure change detection (PCD) algorithm was developed using the cumulative sum method. The performance characteristics of the PCD algorithm were defined in all patients who developed a heart failure-related event (HFRE); patients without HFRE served as controls. Optimal PCD threshold values were chosen using a receiver operator curve analysis. Each of the pressures measured with the IHM were evaluated using the PCD analysis. All had sensitivities >=80% and false-positive rates <4.7/patient-year; however, estimated pulmonary artery diastolic pressure (ePAD) had the best performance. An ePAD based on the optimized PCD threshold of 6.0 yielded a sensitivity of 83% and a false-positive rate of 4.1/patient-year for detecting patients making the transition from compensated to decompensated heart failure. These performance characteristics were not significantly different for patients with an ejection fraction > vs. <50%, estimated glomerular filtration rate > vs. <60 mL/min/1.73 m(2), or age > vs. <60 years. CONCLUSIONS: The automated PCD algorithm had high sensitivity and acceptable false-positive rates in detecting the development of decompensated heart failure before the patient developed worsening symptoms and required acute medical care. These data support the development of a prospective study to examine the utility of adding an automated PCD algorithm to IHM-based management strategies to prevent decompensated heart failure. [ABSTRACT FROM AUTHOR]

BACKGROUND: The purpose of this study was to determine which pressure-based hemodynamic factor was most closely associated with the transition from chronic compensated to acute decompensated heart failure. METHODS AND RESULTS: Intracardiac pressures were retrospectively examined in 274 heart failure patients using an implantable hemodynamic monitor. The relationship between the development of a heart failure-related event (HFRE) and 3 pressure variables were analyzed: peak estimated pulmonary artery diastolic pressure (ePAD) at the time of an HFRE, change in ePAD from baseline to peak pressure, and the product of ePAD pressure and time (PxT) calculated as the area under the pressure-versus-time curve from baseline to peak pressure. Patients without an HFRE served as control subjects. Peak ePAD and change in ePAD were not closely associated with the development of an HFRE. In patients with an HFRE, PxT was 221 ± 130 mm Hg·days with only 4% of the PxT values <60 mm Hg·days. In contrast, in patients without an HFRE, the PxT was 5 ± 23 with only 4% of the PxT values >60 mm Hg·days. CONCLUSIONS: The product of small increases in pressure that occur over an extended period of time (PxT) is the pressure-based hemodynamic factor most closely associated with the transition to acute decompensated heart failure. [ABSTRACT FROM AUTHOR]

Background: Decompensated heart failure (HF) is associated with unacceptable morbidity and mortality risks. Recent implantable technology advancements allow frequent filling pressure monitoring and provide insight into HF pathophysiology and a new tool for HF management.Methods: The CHAMPION trial is a prospective, multicenter, randomized, single-blind clinical trial testing the hypothesis that HF management guided by frequently assessed pulmonary artery pressures is superior to traditional methods. A total of 550 subjects with New York Heart Association (NYHA) functional class III HF were enrolled at 64 sites in the United States. All subjects received the CardioMEMS HF sensor as a permanent pulmonary artery implant and were randomized to the treatment or the control group before discharge. The treatment group received traditional HF management guided by hemodynamic information from the sensor. The control group received traditional HF disease management. Safety endpoints include freedom from device/system-related complications and freedom from HF sensor failure at 6 months. The efficacy endpoint is a reduction in the rate of HF-related hospitalizations in the treatment group versus the control group at 6 months.Conclusions: The CHAMPION trial will investigate the safety and clinical efficacy of the CardioMEMS hemodynamic monitoring system and may establish this management strategy as a new paradigm for the medical management of patients with symptomatic HF. [ABSTRACT FROM AUTHOR]

Background: Clinical trialists involved in projects aimed at assessing the impact of a device or therapy on exercise capacity must select an end point that can detect a therapy-derived change and do so in a manner that is both sensitive to the change and valid. Using baseline data from the Prospective Evaluation of Elastic Restraint to Lessen the Effects of Heart Failure (PEERLESS-HF) trial, we describe the coefficient of variation (CV) for peak oxygen uptake (Vo2) and other parameters measured during a cardiopulmonary exercise (CPX) test.Methods: Prior to conducting CPX testing, a CPX core laboratory conducted training with testing staff at each site, and a standardized quality assurance protocol was completed. During screening, subjects performed two symptom-limited CPX tests (CPX-0 and CPX-1) within 14 days.Results: The CVs for peak Vo2, ventilatory efficiency, and ventilatory-derived anaerobic threshold were 5.9%, 4.8%, and 6.8%, respectively. During CPX-0, the percentage of subjects with a respiratory exchange ratio (RER) < 1.05 who increased their peak Vo2 by ≥ 6% during CPX-1 was 47%, compared with 12% of subjects also with an RER < 1.05 who experienced a decrease in peak Vo2 ≥ 6%.Conclusions: In a multisite clinical trial setting, we showed that the achieved test-retest reproducibility for peak Vo2 can be acceptable, as evidenced by a CV at 5.9%. Until more data are available to identify patients who may demonstrate greater test-retest variance and to avoid repeat testing in all subjects at baseline, clinical trialists might consider repeating tests when RER < 1.05.Trial Registration: clinicaltrials.gov; Identifier: NCT00382863. [ABSTRACT FROM AUTHOR]

Background: Treatment of obstructive sleep apnea (OSA) in outpatients with systolic heart failure improves cardiac function. We evaluated the impact of immediate inpatient diagnosis and treatment of OSA in hospitalized patients with acutely decompensated heart failure (ADHF) on in-hospital cardiac outcomes.Methods: A pilot randomized controlled trial was conducted in an academic heart hospital. Patients with ADHF underwent an attended in-hospital sleep study within 2 days of hospital admission to establish the diagnosis of sleep-disordered breathing. The participants were 46 consecutive patients with ADHF who had OSA (apnea-hypopnea index [AHI], >or= 15 events per hour). Participants were randomly assigned to either the intervention arm (n = 23), with in-hospital treatment of OSA using auto-adjusting positive airway pressure along with standard treatment of ADHF, or to the control arm (n = 23), in which they received only standard treatment for ADHF. The primary outcome was the change in left ventricular ejection fraction (LVEF) 3 nights postrandomization.Results: The change in LVEF from baseline to 3 days postrandomization in the intervention arm was significantly superior to that of the control group. The difference in LVEF improvement was 4.6% (p = 0.03). LVEF increased in the intervention group by 4.5% (SE, 1.7%). The LVEF change in the control arm was--0.3% (SE, 1.5%). The difference in LVEF improvement between the two groups persisted after adjustment for baseline LVEF, type of cardiomyopathy, BMI, AHI, and sex.Conclusions: An approach of early identification and in-hospital treatment of OSA in patients with ADHF is feasible and resulted in improvement in systolic function. The impact of this approach on out-of-hospital outcomes requires further investigation.Trial Registration: ClinicalTrials.gov Identifier: NCT00701038. [ABSTRACT FROM AUTHOR]

Background: Most patients hospitalized for acute heart failure syndromes (AHFS) carry a diagnosis of coronary artery disease (CAD), but coronary angiography is infrequently performed. This purpose of this study was to determine the influence of coronary angiography on use of therapeutics and early postdischarge outcomes in patients with AHFS. Methods: The Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure program enrolled 48,612 patients admitted with AHFS at 259 academic and community hospitals throughout the United States Inhospital treatments and outcomes were tracked in all patients and postdischarge outcomes in a prespecified 10% sample. Outcome data were prospectively collected and analyzed according to whether coronary angiography was performed during the index hospitalization and whether a patient had CAD. Results: Overall, 8.7% of all patients underwent inhospital angiography. Among patients with CAD who underwent angiography, 27.5% underwent inhospital myocardial revascularization. At the time of discharge, patients with CAD who underwent angiography were significantly more likely to be receiving aspirin (68.9% vs 50.3%, P < .0001), statins (56.6% vs 40.6%, P < .0001), beta-blockers (78.6% vs 67.5%, P < .0001), and angiotensin-converting enzyme inhibitors (64.9% vs 51.5%, P < .0001). In patients with AHFS and CAD, the use of inhospital angiography was associated with significantly lower mortality and rehospitalization risk in the first 60 to 90 days post hospital discharge after adjustment for multiple comorbidities and patient factors: mortality (HR 0.31 [95% CI 0.14-0.70], P = .004) and death or rehospitalization (OR 0.65 [95% CI 0.50-0.86], P = .003). There were no significant differences in any of these outcomes in patients with AHFS and a nonischemic etiology based the performance of inhospital angiography. Conclusions: The performance of inhospital angiography on patients with AHFS and CAD is associated with an increased use of aspirin, statins, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors and myocardial revascularization. This corresponded with significantly lower rates of death, rehospitalization, and death or rehospitalization at 60 to 90 days post discharge. [ABSTRACT FROM AUTHOR]

Background: Obstructive sleep apnea (OSA) is prevalent in patients with heart failure. Treatment with continuous positive airway pressure (CPAP) improves systolic function in patients with heart failure. Bilevel positive airway pressure (PAP) is another treatment modality for OSA. The intermediate-term effect of bilevel PAP on left ventricular ejection fraction (LVEF) in patients with stable heart failure and OSA has not been compared to the effect of CPAP.Methods: In this pilot randomized controlled trial, patients with stable systolic dysfunction and newly diagnosed OSA (n = 24) were randomized to receive either CPAP or bilevel PAP. Titration was done in the sleep laboratory using a CPAP-based algorithm. Primary outcome was the improvement in LVEF after 3 months of treatment. Other measurements included 6-min walk test, Epworth sleepiness scale score, and the Minnesota Living With Heart Failure questionnaire.Results: Bilevel PAP increased LVEF 7.9% (LVEF percentage scale) more than CPAP (95% confidence interval [CI], 2.3 to 13.4; p = 0.01). In the bilevel PAP group, LVEF increased 8.5% (95% CI, 3.7 to 13.4; p = 0.002). In the CPAP group, LVEF did not change significantly (0.5%; 95% CI, - 2.7 to 3.7; p = 0.7). The difference in LVEF improvement between the two groups was still significant after adjustment for adherence, level of treatment positive pressure, body mass index, and severity of OSA.Conclusion: This pilot randomized controlled trial suggests that bilevel PAP is superior to CPAP in improving LVEF in patients with systolic dysfunction and OSA. Larger trials are required to evaluate the mechanism behind this effect. [ABSTRACT FROM AUTHOR]

Background: Renal dysfunction is an important independent prognostic factor in heart failure (HF). Cardiac resynchronization therapy (CRT) improves functional status and left ventricular (LV) function in HF patients with ventricular dyssynchrony, but the impact of CRT on renal function is less defined. We hypothesized that CRT would improve glomerular filtration rate as estimated by the abbreviated Modification of Diet in Renal Disease equation (eGFR).Methods and Results: The Multicenter InSync Randomized Clinical Evaluation (MIRACLE) study evaluated CRT in HF patients with NYHA Class III-IV, ejection fraction or=130 ms. Patients were evaluated before and 6 months after randomization to control (n = 225) or CRT (n = 228). Patients were categorized according to their baseline eGFR: >or=90 (category A), 60 Conclusions: CRT increased eGFR and reduced blood urea nitrogen in HF patients with moderately reduced baseline eGFR. By improving cardiac function, CRT can indirectly improve renal function, underscoring the importance of cardiorenal interaction and providing another mechanism for the beneficial effects of CRT. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The objective was to investigate whether increasing health heterogeneity during the middle years is attributed, at least in part, to the influence of varying levels of, and changes in, work control of the current midlife cohort. METHOD: The study used four waves of data collected from 372 employed rural women and 320 employed men of the midlife cohort during a 10-year period. Variables included self-reported work control, stressful nonwork life events, and mental and physical health. The analyses used latent growth curve modeling. RESULTS: The results partially supported the hypothesized pathways. For middle-aged men, work control directly influences health outcomes, whereas for middle-aged women work control indirectly influences health outcomes through the occurrence of stressful life events. DISCUSSION: Through understanding these processes, work can be better designed to promote positive health outcomes, minimize negative health outcomes, and allow for better formulation and more effective implementation of health promotional programs. [ABSTRACT FROM AUTHOR]