Purpose Little is known about sex differences in the treatment of central sleep apnea (CSA). Our post hoc analysis of the rem edē 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 rem edē 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.

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 remedē 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 remedē System Therapy (rēST) Study is a prospective non-randomized multicenter international study evaluating long-term safety and effectiveness of the remedē 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.

BACKGROUND: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.

Introduction Central sleep apnea (CSA) and heart failure (HF) often present with similar symptoms. Treatment of CSA primarily focuses on management of CSA-related symptoms such as frequent night-time awakenings or arousals, daytime sleepiness and reduced quality of life (QoL). Transvenous phrenic nerve stimulation (TPNS) has demonstrated improvements in sleep metrics and patient reported outcomes (PROs). Hypothethis To identify symptoms experienced by patients with HF and CSA and determine what types of improvements occur in the most symptomatic patients using TPNS. Methods Post-hoc analysis of baseline and 12-month data collected from patients (N = 75) with HF and moderate to severe CSA from the remedē System Pivotal Trial. Responses to questions pertaining to PROs (Epworth Sleepiness Scale [ESS] and Minnesota Living with Heart Failure Questionnaire [MLHFQ]) and clinical symptoms were analyzed to assess impact of TPNS therapy. Results Baseline clinical symptoms including nocturia (72%), reduced exercise capacity (61%), fatigue or weakness (69%), daytime sleepiness (77%), difficulty falling or staying asleep (52%), snoring (56%) and insomnia/fragmented sleep (51%) were reported by over half of the patients. By 12 months, 24%, 41%, 44%, 45%, 51%, 60% and 66% of the patients, respectively, no longer reported these specific clinical symptoms. On the baseline ESS, > = 50% of patients with HF reported moderate to high (2-3 on the scale) chance of dozing while sitting and reading (55%), watching television (56%) and lying down to rest in the afternoon (68%). For these patients with > = moderate at baseline, 71%, 52% and 35%, respectively, improved to less than moderate chance at 12 months. On the MLHFQ, 6/21 questions had > = 50% of subjects report that HF prevented them from living as they wanted moderately to very much (3-5 on the scale). Following 12 months of TPNS therapy, 33% to 71% of subjects improved from > = moderate at baseline to below moderate (Figure). NYHA functional class improved or remained stable in 89% (67/75) of subjects. Conclusion In the most symptomatic patients with CSA and HF, TPNS may improve symptoms and QoL, specifically related to sleep, sleepiness and fatigue. Heart failure patients with these symptoms may benefit from screening and subsequent treatment of CSA with TPNS.

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 remedē 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.

Introduction Central sleep apnea (CSA) has been associated with a poor prognosis in patients with heart failure (HF). CSA in HF is associated with fatigue, daytime sleepiness, higher rates of HF-related readmission within 6 months and. Treatment of CSA using transvenous phrenic nerve stimulation (TPNS) with the remedē system has been shown to be safe and effective through 36 months of therapy in those with moderate-to-severe CSA with underlying HF, demonstrating improvement in sleep metrics, daytime sleepiness and quality of life regardless of HF. The aim of this analysis was to evaluate clinically relevant echocardiographic changes seen in patients within all HF subtypes. Hypothesis We hypothesized no adverse change on echocardiography would occur with CSA therapy. Methods Patients with CSA and HF who participated in the remedē system Pivotal trial were implanted with the remedē system with therapy activation 1-month post-implant in the treatment group and 6-months post-implant in the control group. The groups were then pooled for analysis based on months of active therapy. Echocardiography was performed at 6, 12, and 18 months with attention to the right ventricular end-diastolic diameter (RVEDD), tricuspid annular planar systolic excursion (TAPSE) and right ventricular (RV) ejection time. Subjects with permanent atrial fibrillation were excluded. Results Based on pooled data, there was no clinically meaningful change from baseline in RVEDD, TAPSE and RV ejection time in any of the EF subgroups (HFrEF [EF<40%], HFmrEF [EF40-50%] and HFpEF [EF ≥ 50%]) at 6, 12, and 18 months (see Table 1). Conclusions This is the first analysis of echocardiographic changes among HF patients with CSA across the EF spectrum receiving TPNS. In concert with prior data, no adverse structural consequences were observed in these echocardiographic parameters of TPNS. These data reveal that transvenous stimulation of the phrenic nerve in patients with HF and CSA may be a therapeutic option for patients regardless of EF.

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.

Introduction Central sleep apnea is a frequent finding in heart failure (HF) and is being increasingly reported in heart failure patients with preserved ejection fraction (HFpEF). Mechanisms of CSA occurrence in those with HFpEF may be similar to CSA in HF with reduced ejection fraction (HFrEF). While treatment of CSA in HFrEF has been reported to be safe and associated with improved sleep metrics, long-term follow-up in patients with moderately reduced ejection fraction (HFmrEF - EF 40-50%) or HFpEF (EF > 50%) and CSA is not well understood. The aim of this analysis was to evaluate changes in LVEF and natriuretic peptides in patients with HFmrEF or HFpEF and CSA following transvenous phrenic nerve stimulation (TPNS). Hypothesis We hypothesized no meaningful reduction in LVEF or increase in natriuretic peptides would be observed. Methods Patients who participated in the remedē system Pivotal trial had TPNS activated 1-month post-implant in the treatment group and 6-months post-implant in the control group. The groups were then pooled for post hoc analysis based on months of active therapy. Echocardiography was performed at 6, 12, and 18 months with attention to EF%, particularly in those without permanent atrial fibrillation, as well as measurement of BNP or NT-pro-BNP at those time points. Results : The HFmrEF group had a median EF of 49.5% [interquartile range (IQR) - 47.0, 53.0] (n=10) at 18 months with a paired change from baseline of 5.0% [2.0, 8.0] (p = 0.031). The HFpEF group had an EF of 56.0% [54.0, 58.0] (n = 10) at 18 months with a paired change from baseline of 1.5% [0.0, 4.0] (p = 0.086). Based on pooled data there was no clinically meaningful change in BNP or NT-pro-BNP over the course of 18 months of active therapy (Table 1). Conclusions This analysis shows no clinically meaningful change in EF based on echocardiographic changes and no clinically meaningful changes in natriuretic peptides following TPNS activation in patients with HFmrEF or HFpEF. Future studies in this patient population should be considered.

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.

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.

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.

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. (C) 2017 Heart Rhythm Society. All rights reserved.

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.

Although cardiac resynchronization therapy (CRT) may reduce functional mitral regurgitation (MR) in some patients with heart failure and reduced ejection fraction, the role of optimization of lead position on MR reduction is unclear. In this substudy, the authors found that longer LV electric delay at the LV stimulation site was associated with greater MR reduction and reverse remodeling after CRT. These findings suggest that optimization of LV lead placement may contribute to reduction in MR after CRT. BACKGROUND: Mitral regurgitation (MR) is associated with worse survival in those undergoing cardiac resynchronization therapy (CRT). Left ventricular (LV) lead position in CRT may ameliorate mechanisms of MR. We examine the association between a longer LV electric delay (QLV) at the LV stimulation site and MR reduction after CRT. METHODS AND RESULTS: QLV was assessed retrospectively in 426 patients enrolled in the SMART-AV study (SmartDelay Determined AV Optimization: A Comparison to Other AV Delay Methods Used in CRT). QLV CONCLUSIONS: The study provides the first high-resolution landscape on neonatal cardiac lncRNAs and reveals their potential interaction with mRNA transcriptome during cardiac maturation. Ppp1r1b-lncRNA was identified as a regulator of Tcap expression, with dynamic interaction in postnatal cardiac development and congenital heart defects. There is limited understanding of the transcriptome changes in neonatal heart chambers during maturation of the heart, particularly the coordinated regulation of long noncoding RNAs (lncRNAs) and messenger RNA (mRNA). This study provides a high-resolution landscape on neonatal mouse cardiac lncRNAs and identifies a potential interaction with mRNA transcriptome during cardiac maturation. Moreover, a specific interaction between Ppp1r1b-lncRNA and its corresponding gene partner Tcap provided a molecular signature that differentiated congenital heart defect phenotypes. These results highlight the potential power of transcriptomics to identify molecular mechanisms involved in perinatal circulatory transition in heart and the discovery of potential diagnostic and therapeutic targets for congenital heart defects. BACKGROUND: Recent reports have suggested that long-term, intensive physical training may be associated with adverse cardiovascular effects, including the development of myocardial fibrosis. However, the dose– response association of different levels of lifelong physical activity on myocardial fibrosis has not been evaluated. Previous studies suggest long-term physical training is associated with the development of myocardial fibrosis in middle-aged athletes. This current study evaluated 92 seniors, categorized by their histories of committed exercise, who underwent cardiac MRI and late gadolinium enhancement assessment of fibrosis. The results suggest that consistent and increasing physical activity was not associated the prevalence of myocardial fibrosis, supporting the need for the evaluation of individualized exercise dosages and level evaluation. and 2-SS in percutaneous coronary intervention for unprotected distal left main disease may be summarized by the high incidence of TLR, mainly because of restenosis at the ostial left circumflex artery in the 2-SS group. Bifurcation lesions remain challenging for unprotected percutaneous coronary intervention (PCI) in the left main coronary artery, even in the drug-eluting stent (DES) era. This observational study compares clinical outcomes of a 1-stent strategy and a 2-stent strategy for these complex lesions. The 2-stent strategy was associated with a higher risk of side-branch restenosis, but no difference in major adverse events. These results support a selective 2-stent strategy when necessary in patients with unprotected distal left main disease. validated bootstrapped C risk predictive 30-day all-cause readmission prediction, the machine LR C statistics, 0.628 and C statistic by 24.9% LR C statistic 0.678 and 0.543, 30-day all-cause readmission, readmission the and deciles of predicted with random and 26.2%, respectively) a much wider separation This study compares newer machine learning methods with more traditional statistical techniques to develop prediction models for readmissions in heart failure–a topic that is important for policymakers and providers. Though machine learning methods require further optimization and development, the results of this study highlight limitations of standard statistical methods and show improvements in discrimination and a range of prediction metrics with machine learning techniques. BACKGROUND: Sleep-disordered breathing (SDB) is common in patients with heart failure (HF), and hypoxia and hypercapnia episodes activate chemoreceptors stimulating autonomic reflex responses. We tested the hypothesis that muscle vasoconstriction and muscle sympathetic nerve activity (MSNA) in response to hypoxia and hypercapnia would be more pronounced in patients with HF and SDB than in patients with HF without SDB (NoSBD). METHODS AND RESULTS: Ninety consecutive patients with HF, New York Heart Association functional class II–III, and left ventricular ejection fraction ≤ 40% were screened for the study. Forty-one patients were enrolled: NoSDB (n=13, 46 [39–53] years) and SDB (n=28, 57 [54–61] years). SDB was characterized by apnea–hypopnea index ≥ 15 events per hour (polysomnography). Peripheral (10% O2 and 90% N2, with CO2 titrated) and central (7% CO2 and 93% O2) chemoreceptors were stimulated for 3 minutes. Forearm and calf blood flow were evaluated by venous occlusion plethysmography, MSNA by microneurography, and blood pressure by beat-to-beat noninvasive technique. Baseline forearm blood flow, forearm vascular conductance, calf blood flow, and calf vascular conductance were similar between groups. MSNA was higher in the SDB group. During hypoxia, the vascular responses (forearm blood flow, forearm vascular conductance, calf blood flow, and calf vascular conductance) were significantly lower in the SDB group compared with the NoSDB group ( P <0.01 to all comparisons). Similarly, during hypercapnia, the vascular responses (forearm blood flow, forearm vascular conductance, calf blood flow, and calf vascular conductance) were significantly lower in the SDB group compared with the NoSDB group ( P <0.001 to all comparisons). MSNA were higher in response to hypoxia ( P =0.024) and tended to be higher to hypercapnia ( P =0.066) in the SDB group. CONCLUSIONS: Patients with HF and SDB have more severe muscle vasoconstriction during hypoxia and hypercapnia than HF patients without SDB, which seems to be associated with endothelial dysfunction and, in part, increased MSNA response. This study tested muscle vasoconstriction and muscle sympathetic nerve activity in response to hypoxia and hypercapnia in patients with heart failure (HF) and sleep-disordered breathing (SDB) and in patients with HF and without SDB. The authors report that more severe muscle vasoconstriction and sympathetic nerve activation was reported in HF patients with SDB during peripheral and central chemoreceptor stimulation. These results suggest mechanisms by which SDB may contribute to increased morbidity and mortality in patients with HF as opposed to HF patients without SDB.

Background— Mitral regurgitation (MR) is associated with worse survival in those undergoing cardiac resynchronization therapy (CRT). Left ventricular (LV) lead position in CRT may ameliorate mechanisms of MR. We examine the association between a longer LV electric delay (QLV) at the LV stimulation site and MR reduction after CRT. Methods and Results— QLV was assessed retrospectively in 426 patients enrolled in the SMART-AV study (SmartDelay Determined AV Optimization: A Comparison to Other AV Delay Methods Used in CRT). QLV was defined as the time from QRS onset to the first large peak of the LV electrogram. Linear regression and logistic regression were used to assess the association between baseline QLV and MR reduction at 6 months (absolute change in vena contracta width and odds of ≥1 grade reduction in MR). At baseline, there was no difference in MR grade, LV dyssynchrony, or LV volumes in those with QLV above versus below the median (95 ms). After multivariable adjustment, increasing QLV was an independent predictor of MR reduction at 6 months as reflected by an increased odds of MR response (odds ratio: 1.13 [1.03–1.25]/10 ms increase QLV; P =0.02) and a decrease in vena contracta width ( P <0.001). At 3 months, longer QLV (≥median) was associated with significant decrease in LV end-systolic volume (ΔLV end-systolic volume −28.2±38.9 versus −4.9±33.8 mL, P <0.001). Adjustment for 3-month ΔLV end-systolic volume attenuated the association between QLV and 6-month MR reduction. Conclusions— In patients undergoing CRT, longer QLV was an independent predictor of MR reduction at 6 months and associated with interval 3-month LV reverse remodeling. These findings provide a mechanistic basis for using an electric-targeting LV lead strategy at the time of CRT implant.

Introduction: Left ventricular (LV) delay, as measured by the QLV interval, at the LV pacing site predicts a number of outcomes with CRT including the magnitude of reverse remodeling. It also ident...

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.

BACKGROUND Cardiac resynchronization therapy (CRT) reduces mortality and morbidity in selected heart failure patients. However, not all patients respond to CRT.OBJECTIVE We hypothesized that a novel measure of electrical dyssynchrony, sum absolute QRST integral (SAI QRST), predicts CRT response independent of QRS duration and morphology.METHODS We retrospectively analyzed baseline 121ead electrocardiograms of SmartDelay Determined AV Optimization: A comparison to other AV delay methods used in cardiac resynchronization therapy (SMART-AV) trial study participants (N = 234; mean age 67 years; 163 (70%) men; 140 (60%) ischemic cardiomyopathy; mean left ventricular ejection fraction 25%; mean QRS duration 152 ms; 179 (77%) had left bundle branch block). Baseline pre-implant electrocardiograms were digitized, transformed into orthogonal XYZ, and analyzed automatically by customized MATLAB software. SAI QRST was measured as an averaged arithmetic sum of absolute areas under the QRST curve. Patients were followed prospectively 6 months after CRT-defibrillator implantation. Patients with a decrease in left ventricular end-systolic volume >15 mL after 6 months of CRT were considered responders. The logistic regression model was adjusted for age, sex, bundle branch block morphology, left ventricular ejection fraction, cardiomyopathy type, and (IRS duration.RESULTS Patients with the high mean SAI QRST (third tertile) had 2.5 times greater odds of response than those with the low mean SAI QRST (first tertile: odds ratio [OR] 2.5; 95% confidence interval [CI] 1.3-5.0; P =.010) and 1.9 times greater than the lower 2 tertiles combined (OR 1.9; 950/0 CI 1.1-3.5; P =.03). Adjustment for renal function (OR 2.33; 950/0 CI 1.32-4.11; P =.003) and left ventricular lead position in right anterior oblique and left anterior oblique views (OR 1.7; 950/0 CI 0.9-3.2; P =.087) did not attenuate association of SAI QRST with outcome.CONCLUSION High SAI QRST independently predicts CRT response in the SMART-AV study.

Background: Early identification of a favorable cardiac resynchronization therapy (CRT) response holds great clinical import. These studies often utilized a single biomarker or were performed at one point in time. The present study utilized an innovative approach whereby a panel of biomarkers were quantified in patients prior to CRT implant (Baseline) and then at 3 and 6 months post-CRT in a robust group of patients whereby CRT response had also been pre-specified. Methods/Results: Plasma was collected from patients (SMART-AV trial), and a positive CRT response was pre-specified as a ≥15 mL reduction in LV end-systolic volume at 6 months post-CRT (Responders:n=390/Non-Responders:n=388). Through initial cohort testing and multivariate modeling, serial measures of a 12 biomarker cassette was selected using high sensitivity multiplex profiling, which consisted of C-reactive protein, soluble glycoprotein 130, soluble interleukin-2 receptor, soluble tumor necrosis factor receptor-II, interferon gamma, N-terminal brain natriuretic peptide (NT-proBNP), soluble suppressor of tumorgenicity-2 (sST-2), matrix metalloproteinases-2 and -9 (MMP-2, MMP-9), and tissue inhibitors of MMP (TIMP-1, -2, -4). Analysis of variance (ANOVA) for repeated measures identified that NT-proBNP, sST-2, and MMP-2 changed across time following CRT (by ANOVA, p Conclusion: The unique findings from this study identified that time dependent changes in a specific biomarker signature occur early in those patients likely to respond favorably to CRT, and as such, may be of potential utility for point of care testing and integration into the CRT evaluation algorithm.