Analysis by sex of safety and effectiveness of transvenous phrenic nerve stimulation.

PURPOSE: Little is known about sex differences in the treatment of central sleep apnea (CSA). Our post hoc analysis of the remede System Pivotal Trial aimed to determine sex-specific differences in the safety and effectiveness of treating moderate to severe CSA in adults with transvenous phrenic nerve stimulation (TPNS). METHODS: Men and women enrolled in the remede System Pivotal Trial were included in this post hoc analysis of the effect of TPNS on polysomnographic measures, Epworth Sleepiness Scale, and patient global assessment for quality of life. RESULTS: Women (n = 16) experienced improvement in CSA metrics that were comparable to the benefits experienced by men (n = 135), with central apneas being practically eliminated post TPNS. Women experienced improvement in sleep quality and architecture that was comparable to men post TPNS. While women had lower baseline apnea hypopnea index than men, their quality of life was worse at baseline. Additionally, women reported a 25-percentage point greater improvement in quality of life compared to men after 12 months of TPNS therapy. TPNS was found to be safe in women, with no related serious adverse events through 12 months post-implant, while men had a low rate of 10%. CONCLUSION: Although women had less prevalent and less severe CSA than men, they were more likely to report reduced quality of life. Transvenous phrenic nerve stimulation may be a safe and effective tool in the treatment of moderate to severe CSA in women. Larger studies of women with CSA are needed to confirm our findings. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01816776; March 22, 2013.

Plasma galectin-3 and heart failure outcomes in MADIT-CRT (multicenter automatic defibrillator implantation trial with cardiac resynchronization therapy).

BACKGROUND: Elevated circulating levels of the protein galectin-3, a mediator of fibrogenesis, have previously been associated with adverse outcomes in heart failure (HF) patients and appear to modify response to certain pharmacologic therapies. This study investigated the relationship between galectin-3 level and clinical outcomes in HF patients randomized to implantable cardioverter defibrillator (ICD-only) or cardiac resynchronization therapy (CRT-D). METHODS AND RESULTS: Plasma galectin-3 concentrations were measured in 654 New York Heart Association functional class I/II patients participating in the MADIT-CRT trial. A heterogeneity of response was detected between pre-implantation galectin-3 and randomization group (CRT-D or ICD-only) on the primary MADIT-CRT trial end point of nonfatal HF event or death (P = .045). Among patients with baseline galectin-3 levels in the top quartile of the distribution, CRT-D was associated with a 65% reduction in risk of the primary end point (hazard ratio [HR] 0.35, 95% confidence interval [CI] 0.19-0.67), whereas among patients with lower baseline galectin-3 values CRT-D was associated with a 25% decrease in risk (HR 0.75, 95% CI. 0.51-1.11). Baseline galectin-3 level also was observed to be an independent predictor of the primary end point (multivariable adjusted HR per log unit increase: 1.55; 95% CI 1.01-2.38; P = .043). CONCLUSIONS: Elevated galectin-3 was found to be an independent predictor of adverse HF outcome in patients with mildly symptomatic HF. A significant interaction of device randomization group with pre-implantation galectin-3 level was detected, with HF patients with the highest baseline galectin-3 levels deriving a disproportionately larger benefit from CRT-D.

The relationship between ventricular electrical delay and left ventricular remodelling with cardiac resynchronization therapy.

AIMS: The aim of the present study was to evaluate the relationship between left ventricular (LV) electrical delay, as measured by the QLV interval, and outcomes in a prospectively designed substudy of the SMART-AV Trial. METHODS AND RESULTS: This was a multicentre study of patients with advanced heart failure undergoing cardiac resynchronization therapy (CRT) defibrillator implantation. In 426 subjects, QLV was measured as the interval from the onset of the QRS from the surface ECG to the first large peak of the LV electrogram. Left ventricular volumes were measured by echocardiography at baseline and after 6 months of CRT by a blinded core laboratory. Quality of life (QOL) was assessed by a standardized questionnaire. When separated by quartiles based on QLV duration, reverse remodelling response rates (>15% reduction in LV end systolic volume) increased progressively from 38.7 to 68.4% and QOL response rate (>10 points reduction) increased from 50 to 72%. Patients in the highest quartile of QLV had a 3.21-fold increase (1.58-6.50, P = 0.001) in their odds of a reverse remodelling response after correcting for QRS duration, bundle branch block type, and clinical characteristics by multivariate logistic regression analysis. CONCLUSION: Electrical dyssynchrony, as measured by QLV, was strongly and independently associated with reverse remodelling and QOL with CRT. Acute measurements of QLV may be useful to guide LV lead placement.

Design of the remede System Therapy (reST) study: A prospective non-randomized post-market study collecting clinical data on safety and effectiveness of the remede system for the treatment of central sleep apnea.

BACKGROUND: Central sleep apnea (CSA) is a disorder defined by lack of respiratory drive from the brain stem on breathing efforts. There is a lack of established therapies for CSA and most available therapies are limited by poor patient adherence, limited randomized controlled studies, and potentially adverse cardiovascular effects. The remede System (ZOLL Respicardia, Inc., Minnetonka, Minnesota) uses transvenous phrenic nerve stimulation to stimulate the diaphragm, thereby restoring a more normal breathing pattern throughout the sleep period. METHODS: The remede System Therapy (reST) Study is a prospective non-randomized multicenter international study evaluating long-term safety and effectiveness of the remede System in the post-market setting. Up to 500 adult patients with moderate to severe CSA will be enrolled and followed up to 5 years at approximately 50 sites in the United States and Europe. Safety objectives include evaluation of adverse events related to the implant procedure, device or delivered therapy, death, and hospitalizations. Effectiveness endpoints include assessment of changes in sleep-disordered breathing metrics from polysomnograms and home sleep tests, changes in daytime sleepiness using the Epworth Sleepiness Scale, and changes in QoL using the PROMIS-29 and Patient Global Assessment questionnaires. The subgroup of patients with heart failure will undergo additional assessments including echocardiography to assess cardiac reverse remodeling, 6-min walk distance, QoL assessment by Kansas City Cardiomyopathy Questionnaire and measurement of biomarkers. CONCLUSION: This will be the largest prospective study evaluating long-term safety and effectiveness of transvenous phrenic nerve stimulation for the treatment of moderate to severe CSA in adult patients.

Long-term outcome after ICD and CRT implantation and influence of remote device follow-up: the ALTITUDE survival study.

BACKGROUND: Outcome data for patients receiving implantable cardioverter-defibrillator (ICD) and cardiac resynchronization therapy-defibrillator (CRT-D) devices treated outside of clinical trials are lacking. No clinical trial has evaluated mortality after device implantation or after shock therapy in large numbers of patients with implanted devices that regularly transmit device data over a network. METHODS AND RESULTS: Survival status in patients implanted with ICD and CRT devices across the United States from a single manufacturer was assessed. Outcomes were compared between patients followed in device clinic settings and those who regularly transmit remote data collected from the device an average of 4 times monthly. Shock delivery and electrogram analysis could be ascertained from patients followed on the network, enabling survival after ICD shock to be evaluated. One- and 5-year survival rates in 185,778 patients after ICD implantation were 92% and 68% and were 88% and 54% for CRT-D device recipients. In 8228 patients implanted with CRT-only devices, survival was 82% and 48% at 1 and 5 years, respectively. For the 69,556 ICD and CRT-D patients receiving remote follow-up on the network, 1- and 5-year survival rates were higher compared with those in the 116,222 patients who received device follow-up in device clinics only (50% reduction; P<0.0001). There were no differences between patients followed on or off the remote network for the characteristics of age, gender, implanted device year or type, and economic or educational status. Shock therapy was associated with subsequent mortality risk for both ICD and CRT-D recipients. CONCLUSIONS: Survival after ICD and CRT-D implantation in patients treated in naturalistic practice compares favorably with survival rates observed in clinical trials. Remote follow-up of device data is associated with excellent survival, but arrhythmias that result in device therapy in this population are associated with a higher mortality risk compared with patients who do not require shock therapy.

Primary results from the SmartDelay determined AV optimization: a comparison to other AV delay methods used in cardiac resynchronization therapy (SMART-AV) trial: a randomized trial comparing empirical, echocardiography-guided, and algorithmic atrioventricular delay programming in cardiac resynchronization therapy.

BACKGROUND: one variable that may influence cardiac resynchronization therapy response is the programmed atrioventricular (AV) delay. The SmartDelay determined av optimization: a comparison to other AV delay methods used in cardiac resynchronization therapy (SMART-AV) trial prospectively randomized patients to a fixed empirical AV delay (120 milliseconds), echocardiographically optimized AV delay, or AV delay optimized with SmartDelay, an electrogram-based algorithm. METHODS AND RESULTS: a total of 1014 patients (68% men; mean age, 66 ± 11 years; mean left ventricular ejection fraction, 25 ± 7%) who met enrollment criteria received a cardiac resynchronization therapy defibrillator, and 980 patients were randomized in a 1:1:1 ratio. All patients were programmed (DDD-60 or DDDR-60) and evaluated after implantation and 3 and 6 months later. The primary end point was left ventricular end-systolic volume. Secondary end points included New York Heart Association class, quality-of-life score, 6-minute walk distance, left ventricular end-diastolic volume, and left ventricular ejection fraction. The medians (quartiles 1 and 3) for change in left ventricular end-systolic volume at 6 months for the SmartDelay, echocardiography, and fixed arms were -21 mL (-45 and 6 mL), -19 mL (-45 and 6 mL), and -15 mL (-41 and 6 mL), respectively. No difference in improvement in left ventricular end-systolic volume at 6 months was observed between the SmartDelay and echocardiography arms (P=0.52) or the SmartDelay and fixed arms (P=0.66). Secondary end points, including structural (left ventricular end-diastolic volume and left ventricular ejection fraction) and functional (6-minute walk, quality of life, and New York Heart Association classification) measures, were not significantly different between arms. CONCLUSIONS: neither SmartDelay nor echocardiography was superior to a fixed AV delay of 120 milliseconds. The routine use of AV optimization techniques assessed in this trial is not warranted. However, these data do not exclude possible utility in selected patients who do not respond to cardiac resynchronization therapy.

Improving Nocturnal Hypoxemic Burden with Transvenous Phrenic Nerve Stimulation for the Treatment of Central Sleep Apnea.

Nocturnal hypoxemic burden is established as a robust prognostic metric of sleep-disordered breathing (SDB) to predict mortality and treating hypoxemic burden may improve prognosis. The aim of this study was to evaluate improvements in nocturnal hypoxemic burden using transvenous phrenic nerve stimulation (TPNS) to treat patients with central sleep apnea (CSA). The remede System Pivotal Trial population was examined for nocturnal hypoxemic burden. The minutes of sleep with oxygen saturation < 90% significantly improved in Treatment compared with control (p < .001), with the median improving from 33 min at baseline to 14 min at 6 months. Statistically significant improvements were also observed for average oxygen saturation and lowest oxygen saturation. Hypoxemic burden has been demonstrated to be more predictive for mortality than apnea-hypopnea index (AHI) and should be considered a key metric for therapies used to treat CSA. Transvenous phrenic nerve stimulation is capable of delivering meaningful improvements in nocturnal hypoxemic burden. There is increasing interest in endpoints other than apnea-hypopnea index in sleep-disordered breathing. Nocturnal hypoxemia burden may be more predictive for mortality than apnea-hypopnea index in patients with poor cardiac function. Transvenous phrenic nerve stimulation is capable of improving nocturnal hypoxemic burden. Graphical Abstract.

Transvenous Phrenic Nerve Stimulation for Treatment of Central Sleep Apnea: Five-Year Safety and Efficacy Outcomes.

BACKGROUND: The remede 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 remede 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.

SmartDelay determined AV optimization: a comparison of AV delay methods used in cardiac resynchronization therapy (SMART-AV): rationale and design.

BACKGROUND: The clinical benefit of cardiac resynchronization therapy (CRT) for patients with moderate-to-severely symptomatic heart failure, left ventricular systolic dysfunction, and ventricular conduction delay is established. However, some patients do not demonstrate clinical improvement following CRT. It is unclear whether systematic optimization of the programmed atrioventricular (AV) delay improves the rate of clinical response. METHODS: SMART-AV is a randomized, multicenter, double-blinded, three-armed trial that will investigate the effects of optimizing AV delay timing in heart failure patients receiving CRT + defibrillator (CRT-D) therapy. A minimum of 950 patients will be randomized in a 1:1:1 ratio using randomly permuted blocks within each center programmed to either DDD or DDDR with a lower rate of 60. The study will include echocardiographic measurements of volumes and function [e.g., left ventricular end-systolic volume (LVESV)], biochemical measurements of plasma biomarker profiles, and functional measurements (e.g., 6-minute hall walk) in CRT-D patients who are enrolled and randomized to fixed AV delay (i.e., 120 ms), AV delay determined by electrogram-based SmartDelay, or an AV delay determined by echocardiography (i.e., mitral inflow). Patients will be evaluated prior to initiation of CRT, 3 and 6 months post-implant. The primary endpoint is the relative change in LVESV at 6 months between the groups. Patient enrollment commenced in May 2008 and the study is registered at clinicaltrials.gov. CONCLUSION: SMART-AV is a randomized, clinical trial designed to evaluate three different methods of AV delay optimization to determine whether systematic AV optimization is beneficial for patients receiving CRT for 6 months post-implant.

Transvenous phrenic nerve stimulation for central sleep apnea is safe and effective in patients with concomitant cardiac devices.

BACKGROUND: Central sleep apnea is common in heart failure patients. Transvenous phrenic nerve stimulation (TPNS) requires placing a lead to stimulate the phrenic nerve and activate the diaphragm. Data are lacking concerning the safety and efficacy of TPNS in patients with concomitant cardiovascular implantable electronic devices (CIEDs). OBJECTIVE: To report the safety and efficacy of TPNS in patients with concomitant CIEDs. METHODS: In the remede System Pivotal Trial, 151 patients underwent TPNS device implant. This analysis compared patients with concomitant CIEDs to those without with respect to safety, implant metrics, and efficacy of TPNS. Safety was assessed using incidence of adverse events and device-device interactions. A detailed interaction protocol was followed. Implant metrics included overall TPNS implantation success. Efficacy endpoints included changes in the apnea-hypopnea index (AHI) and quality of life. RESULTS: Of 151 patients, 64 (42%) had a concomitant CIED. There were no significant differences between the groups with respect to safety. There were 4 CIED oversensing events in 3 patients leading to 1 inappropriate defibrillator shock and delivery of antitachycardia pacing. There was no difference in efficacy between the CIED and non-CIED subgroups receiving TPNS, with both having similar percentages of patients who achieved ≥50% reduction in AHI and quality-of-life improvement. CONCLUSION: Concomitant CIED and TPNS therapy is safe. The presence of a concomitant CIED did not seem to impact implant metrics, implantation success, and TPNS efficacy. A detailed interaction protocol should be followed to minimize the incidence of device-device interaction.

Predictors of early mortality in implantable cardioverter-defibrillator recipients.

AIMS: Multiple trials have shown that implantable cardioverter defibrillators (ICDs) prolong survival in secondary and primary prevention populations. However, in spite of the efficacy of these devices in terminating life-threatening arrhythmias, total mortality remains high. METHODS AND RESULTS: We evaluated 1703 patients (mean age: 67 +/- 12 years, 82% male) with conventional ICD indications, who were enrolled and followed between 2001 and 2004 at 128 US centres. Patients were followed for up to a year, and vital status was obtained for 1655 patients (97%, median follow-up: 377 days). There were 183 deaths within 1 year of ICD implantation (1-year mortality rate: 16%). Predictors of mortality included a history of atrial fibrillation (AF, P < 0.0001), diabetes (P = 0.0001), failure to use cholesterol-lowering medications (P < 0.001), use of digitalis and derivatives (P < 0.0001), use of diuretics (P < 0.0001), low body mass index (BMI, P < 0.0001), increasing age (P < 0.0001), low left ventricular ejection fraction (P < 0.0001), low activity hours (P < 0.0001), elevated resting heart rate (P = 0.014), low mean arterial pressure (MAP, P = 0.007), and poor functional status (New York Heart Association class, P < 0.0001). In multivariate modelling, AF (P < or = 0.001), diabetes (P = 0.004), BMI (P = 0.001), MAP (P = 0.040), and functional class (P = 0.006) predicted mortality. CONCLUSION: In this population undergoing ICD implantation, poor functional status, low MAP, diabetes, low BMI, and AF were strongly associated with death within a year.

Long-term efficacy and safety of phrenic nerve stimulation for the treatment of central sleep apnea.

STUDY OBJECTIVE: To evaluate long-term efficacy and safety of phrenic nerve stimulation (PNS) in patients with moderate-to-severe central sleep apnea (CSA) through 3 years of therapy. METHODS: Patients in the remede System Pivotal Trial were observed every 3 months after implant until US Food and Drug Administration approval. At the time of approval and study closure, all patients completed 24 months of follow-up; 33 patients had not reached the 36-month visit. Sleep metrics (polysomnography) and echocardiographic parameters are reported at baseline, 12, 18, and 24 months, in addition to available 36-month sleep results from polygraphy. Safety was assessed through 36 months; however, analysis focused through 24 months and available 36-month results are provided. RESULTS: Patients were assessed at 24 (n = 109) and 36 (n = 60) months. Baseline characteristics included mean age 64 years, 91% male, and mean apnea-hypopnea index 47 events per hour. Sleep metrics (apnea-hypopnea index (AHI), central apnea index, arousal index, oxygen desaturation index, rapid eye movement sleep) remained improved through 24 and 36 months with continuous use of PNS therapy. At least 60% of patients in the treatment group achieved at least 50% reduction in AHI through 24 months. Serious adverse events (SAEs) related to the remede System implant procedure, device, or therapy through 24 months were reported by 10% of patients, no unanticipated adverse device effects or deaths, and all events resolved. No additional related SAEs were reported between 24 and 36 months. CONCLUSION: These data suggest beneficial effects of long-term PNS in patients with CSA appear to sustain through 36 months with no new safety concerns. TRIAL REGISTRATION: NCT01816776.

Development of a biomarker panel to predict cardiac resynchronization therapy response: Results from the SMART-AV trial.

BACKGROUND: Predicting a favorable cardiac resynchronization therapy (CRT) response holds great clinical importance. OBJECTIVE: The purpose of this study was to examine proteins from broad biological pathways and develop a prediction tool for response to CRT. METHODS: Plasma was collected from patients before CRT (SMART-AV [SmartDelay Determined AV Optimization: A Comparison to Other AV Delay Methods Used in Cardiac Resynchronization Therapy] trial). A CRT response was prespecified as a ≥15-mL reduction in left ventricular end-systolic volume at 6 months, which resulted in a binary CRT response (responders 52%, nonresponders 48%; n = 758). RESULTS: Candidate proteins (n = 74) were evaluated from the inflammatory, signaling, and structural domains, which yielded 12 candidate biomarkers, but only a subset of these demonstrated predictive value for CRT response: soluble suppressor of tumorgenicity-2, soluble tumor necrosis factor receptor-II, matrix metalloproteinase-2, and C-reactive protein. These biomarkers were used in a composite categorical scoring algorithm (Biomarker CRT Score), which identified patients with a high/low probability of a response to CRT (P <.001) when adjusted for a number of clinical covariates. For example, a Biomarker CRT Score of 0 yielded 5 times higher odds of a response to CRT compared to a Biomarker CRT Score of 4 (P <.001). The Biomarker CRT Score demonstrated additive predictive value when considered against a composite of clinical variables. CONCLUSION: These unique findings demonstrate that developing a biomarker panel for predicting individual response to CRT is feasible and holds potential for point-of-care testing and integration into evaluation algorithms for patients presenting for CRT.

A blended sensor restores chronotropic response more favorably than an accelerometer alone in pacemaker patients: the LIFE study results.

BACKGROUND: Adaptive rate sensors used in permanent pacemakers incorporate an accelerometer (XL) to increase heart rate with activity. Limited data exists regarding the relative benefit of a blended sensor (BS) (XL and minute ventilation) versus XL alone in restoring chronotropic response (CR) in chronotropically incompetent (CI) patients. METHODS: One thousand five hundred thirty-eight patients from the limiting chronotropic incompetence for pacemaker recipients (LIFE) study were implanted with a pacemaker and 1,256 patients had data collected at 1 month. Patients performed a treadmill test 1-month postimplant while programmed in nonrate responsive mode (DDD-60) to determine CI. Only patients who completed at least three exercise stages and achieved a peak perceived exertion >or=16 were included in the analyses. The metabolic chronotropic relationship (MCR) slope was used to evaluate CR in 547 patients. Patients were randomized to XL or BS with a conservative fixed rate response factor (XL = 8, MV = 4). CI patients performed a follow-up 6-month treadmill test. RESULTS: CI prevalence in this patient population (n = 547) was 34%. No differences in baseline characteristics existed between groups. Although both groups showed significant within-group improvements in MCR slope from 1 to 6 months (both P < 0.001), the BS group had a significantly higher MCR slope at 6 months compared to the XL group (P = 0.011). Improvement in quality of life (QOL) did not differ between groups. CONCLUSIONS: In this general pacemaker population with CI, a BS programmed empirically restores CR more favorably than an XL sensor programmed nominally. Further studies are needed to determine if individual sensor optimization would lead to improvement in functional capacity, higher MCR slopes, and QOL.

Effect of Interventricular Electrical Delay on Atrioventricular Optimization for Cardiac Resynchronization Therapy.

BACKGROUND: Routine atrioventricular optimization (AVO) has not been shown to improve outcomes with cardiac resynchronization therapy (CRT). However, more recently subgroup analyses of multicenter CRT trials have identified electrocardiographic or lead positions associated with benefit from AVO. Therefore, the purpose of this analysis was to evaluate whether interventricular electrical delay modifies the impact of AVO on reverse remodeling with CRT. METHODS: This substudy of the SMART-AV trial (SMARTDELAY Determined AV Optimization) included 275 subjects who were randomized to either an electrogram-based AVO (SmartDelay) or nominal atrioventricular delay (120 ms). Interventricular delay was defined as the time between the peaks of the right ventricular (RV) and left ventricular (LV) electrograms (RV-LV duration). CRT response was defined prospectively as a >15% reduction in LV end-systolic volume from implant to 6 months. RESULTS: The cohort was 68% men, with a mean age of 65±11 years and LV ejection fraction of 28±8%. Longer RV-LV durations were significantly associated with CRT response ( P<0.01) for the entire cohort. Moreover, the benefit of AVO increased as RV-LV duration prolonged. At the longest quartile, there was a 4.26× greater odds of a remodeling response compared with nominal atrioventricular delays ( P=0.010). CONCLUSIONS: Baseline interventricular delay predicted CRT response. At long RV-LV durations, AVO can increase the likelihood of reverse remodeling with CRT. AVO and LV lead location optimized to maximize interventricular delay may work synergistically to increase CRT response. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00874445.

Long-term low-calorie low-protein vegan diet and endurance exercise are associated with low cardiometabolic risk.

BACKGROUND: Western diets, which typically contain large amounts of energy-dense processed foods, together with a sedentary lifestyle are associated with increased cardiometabolic risk. We evaluated the long-term effects of consuming a low-calorie low-protein vegan diet or performing regular endurance exercise on cardiometabolic risk factors. METHODS: In this cross-sectional study, cardiometabolic risk factors were evaluated in 21 sedentary subjects, who had been on a low-calorie low-protein raw vegan diet for 4.4 +/- 2.8 years, (mean age, 53.1 +/- 11 yrs), 21 body mass index (BMI)-matched endurance runners consuming Western diets, and 21 age- and gender-matched sedentary subjects, consuming Western diets. RESULTS: BMI was lower in the low-calorie low-protein vegan diet (21.3 +/- 3.1 kg/m(2)) and endurance runner (21.1 +/- 1.6 kg/m(2)) groups than in the sedentary Western diet group (26.5 +/- 2.7 kg/m(2)) (p < 0.005). Plasma concentrations of lipids, lipoproteins, glucose, insulin, C-reactive protein, blood pressure (BP), and carotid artery intima-media thickness were lower in the low-calorie low-protein vegan diet and runner groups than in the Western diet group (all p < 0.05). Both systolic and diastolic BP were lower in the low-calorie low-protein vegan diet group (104 +/- 15 and 62 +/- 11 mm Hg) than in BMI-matched endurance runners (122 +/- 13 and 72 +/- 9 mmHg) and Western diet group (132 +/- 14 and 79 +/- 8 mm Hg) (p < 0.001); BP values were directly associated with sodium intake and inversely associated with potassium and fiber intake. CONCLUSIONS: Long-term consumption of a low-calorie low-protein vegan diet or regular endurance exercise training is associated with low cardiometabolic risk. Moreover, our data suggest that specific components of a low-calorie low-protein vegan diet provide additional beneficial effects on blood pressure.

The burden of proof: The current state of atrial fibrillation prevention and treatment trials.

Atrial fibrillation (AF) is an age-related arrhythmia of enormous socioeconomic significance. In recent years, our understanding of the basic mechanisms that initiate and perpetuate AF has evolved rapidly, catheter ablation of AF has progressed from concept to reality, and recent studies suggest lifestyle modification may help prevent AF recurrence. Emerging developments in genetics, imaging, and informatics also present new opportunities for personalized care. However, considerable challenges remain. These include a paucity of studies examining AF prevention, modest efficacy of existing antiarrhythmic therapies, diverse ablation technologies and practice, and limited evidence to guide management of high-risk patients with multiple comorbidities. Studies examining the long-term effects of AF catheter ablation on morbidity and mortality outcomes are not yet completed. In many ways, further progress in the field is heavily contingent on the feasibility, capacity, and efficiency of clinical trials to incorporate the rapidly evolving knowledge base and to provide substantive evidence for novel AF therapeutic strategies. This review outlines the current state of AF prevention and treatment trials, including the foreseeable challenges, as discussed by a unique forum of clinical trialists, scientists, and regulatory representatives in a session endorsed by the Heart Rhythm Society at the 12th Global CardioVascular Clinical Trialists Forum in Washington, DC, December 3-5, 2015.

Soluble ST2 and Risk of Arrhythmias, Heart Failure, or Death in Patients with Mildly Symptomatic Heart Failure: Results from MADIT-CRT.

Soluble ST2 is an established biomarker of heart failure (HF) progression. Data about its prognostic implications in patients with mildly symptomatic HF eligible to receive cardiac resynchronization therapy defibrillators (CRT-D) are limited. In a cohort of 684 patients enrolled in Multicenter Automated Defibrillator Implantation Trial (MADIT)-CRT, levels of soluble ST2 (sST2) were serially assessed at baseline and 1 year (n = 410). In multivariable-adjusted models, elevated baseline sST2 was associated with an increased risk of death, death or HF, and death or ventricular arrhythmia (VA) even when adjusting for baseline brain natriuretic protein (BNP) levels. In addition, patients with lower baseline sST2 levels had greater risk reduction with CRT-D (p = 0.006). Serial assessment revealed increased risk of VA and death or VA (HR per 10 % increase in sST2 1.11 (1.04-1.20), p = 0.004). Among patients with mildly symptomatic HF and eligibility for CRT-D, baseline and serial assessments sST2 may provide important information for risk stratification.

Interventricular Electrical Delay Is Predictive of Response to Cardiac Resynchronization Therapy.

OBJECTIVES: This study was conceived to evaluate the relationship between interventricular electrical delay, as measured by the right ventricle-left ventricle (RV-LV) interval, and outcomes in a prospectively designed substudy of the SMART-AV (SMARTDELAY determined AV Optimization) trial. BACKGROUND: Despite the well-documented benefit of cardiac resynchronization therapy (CRT), the nonresponder rate remains an important clinical problem. Implanting LV leads by traditional anatomic criteria has limited impact on outcomes. However, pacing at sites with late electrical activation improves CRT response rates. Thus, we hypothesized that interventricular electrical delay is associated with improved CRT outcomes. METHODS: This was a multicenter study of patients with advanced heart failure undergoing CRT implantation. In 419 subjects, the unpaced RV-LV interval was measured in sinus rhythm. LV volumes and ejection fraction were measured by echocardiography at baseline and after 6 months of CRT by a blinded core laboratory. Quality of life (QOL) was assessed by a standardized questionnaire. RESULTS: When separated by quartiles based on interventricular delay, the magnitudes of LV volumes, ejection fraction and the QOL measure increased significantly with prolongation of RV-LV delay (p < 0.05). The LV end-systolic volume response rate increased progressively from 30% to 75% (p < 0.001), and the QOL response rate increased from 50% to 65% (p = 0.08). Patients in the highest quartile of RV-LV had a 5.98-fold increase (p < 0.001) in their odds of a reverse remodeling response, with female sex, ischemic etiology, and baseline LV end-systolic volume being the other independent predictors of response. CONCLUSIONS: Baseline interventricular delay is a potent independent predictor of remodeling and QOL responses with CRT.