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Background: Left ventricular assist device (LVAD) use remains uncommon in advanced heart failure (HF) patients not dependent on inotropes., Objectives: Before considering a randomized trial comparing a strategy of earlier use of LVAD to continued medical therapy, a better understanding is needed of the clinical trajectory of ambulatory patients with advanced systolic HF on optimal guideline-directed medical therapy (GDMT)., Methods: REVIVAL enrolled 400 patients with advanced ambulatory systolic HF, ≥1 HF mortality risk marker (≥2 HF hospitalizations past year; or HF hospitalization and high natriuretic peptide; or no HF hospitalizations but low peak oxygen consumption, 6-minute walk, serum sodium, HF survival score or Seattle HF model predicted survival), and no LVAD contraindication at 21 LVAD centers from July 2015 to June 2016. Patients were followed for 2 years or until a primary outcome (death, durable ventricular assist device, or urgent transplant). Clinical outcomes and health-related quality of life were evaluated., Results: Mean baseline left ventricular ejection fraction was 21%, median 6-minute walk was 341 m, and 92% were Interagency Registry for Mechanically Assisted Circulatory Support profiles 5 to 7. Adherence to GDMT and electrical device therapies was robust. Composite primary outcome occurred in 22% and 37% at 1 and 2 years, with death alone in 8% and 16%, respectively. Patients surviving for 2 years maintained GDMT intensity and had no decline in health-related quality of life., Conclusion: Structured, serial follow-up at programs with expertise in caring for advanced ambulatory systolic HF patients facilitates triage for advanced therapies. Better strategies are still needed to avoid deaths in a small but significant group of patients who die without advanced therapies. REVIVAL patients not selected for VAD or transplant have robust survival and patient-reported outcomes, which challenges advocacy for earlier VAD implantation. (Registry Evaluation of Vital Information for VADs in Ambulatory Life [REVIVAL]; NCT01369407)., Competing Interests: Funding Support and Author Disclosures Supported by funding from the National Institutes of Health, National Heart, Lung, and Blood Institute (contract number HHSN268201100026C) for REVIVAL and the National Center for Advancing Translational Sciences (grant numbers UL1TR002240 and UM1TR004404) for the Michigan Institute for Clinical and Health Research. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services. Dr Aaronson has received research support from Medtronic, Abbott, Bioventrix, Amgen; has held ownership interest in Procyrion; and has served as a consultant/on the Advisory Board for Medtronic and Procyrion; at the time of submission of this manuscript, he does not have industry research funding, ownership interests, or ongoing consulting relationships. Dr Stewart has served as a consultant for Abbott and Procyrion. Dr Cascino has received research support from Johnson & Johnson and has served as a consultant for Merck & Co. Dr Stehlik has received honoraria from Medtronic; has served as a consultant for Medtronic, TransMedics, and Natera; and has received research support from Natera and Merck. Dr Lala has received honoraria from Zoll. Dr Pagani has served as a scientific advisor (without compensation) for Abbott, CH Biomedical, FineHeart, and Medtronic; has served as a medical monitor (without compensation) for Abiomed; and has received salary support from Blue Shield of Michigan. Dr Mann has served as a consultant/on the Advisory Board for Novartis and Bristol Myers Squibb. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. All rights reserved.)

Background: Impaired daytime vigilance is an important consequence of OSA, but several studies have reported no association between objective measurements of vigilance and the apnea-hypopnea index (AHI). Notably, the AHI does not quantify the degree of flow limitation, that is, the extent to which ventilation fails to meet intended ventilation (ventilatory drive)., Research Question: Is flow limitation during sleep associated with daytime vigilance in OSA?, Study Design and Methods: Nine hundred ninety-eight participants with suspected OSA completed a 10-min psychomotor vigilance task (PVT) before same-night in-laboratory polysomnography. Flow limitation frequency (percent of flow-limited breaths) during sleep was quantified using airflow shapes (eg, fluttering and scooping) from nasal pressure airflow. Multivariable regression assessed the association between flow limitation frequency and the number of lapses (response times > 500 ms, primary outcome), adjusting for age, sex, BMI, total sleep time, depression, and smoking status., Results: Increased flow limitation frequency was associated with decreased vigilance: a 1-SD (35.3%) increase was associated with 2.1 additional PVT lapses (95% CI, 0.7-3.7; P = .003). This magnitude was similar to that for age, where a 1-SD increase (13.5 years) was associated with 1.9 additional lapses. Results were similar after adjusting for AHI, hypoxemia severity, and arousal severity. The AHI was not associated with PVT lapses (P = .20). In secondary exploratory analysis, flow limitation frequency was associated with mean response speed (P = .012), median response time (P = .029), fastest 10% response time (P = .041), slowest 10% response time (P = .018), and slowest 10% response speed (P = .005)., Interpretation: Increased flow limitation during sleep was associated with decreased daytime vigilance in individuals with suspected OSA, independent of the AHI. Flow limitation may complement standard clinical metrics in identifying individuals whose vigilance impairment most likely is explained by OSA., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: J. T. has received royalties related to Bittium BrainStatus EEG outside the submitted work. S. A. S. has received personal fees as a consultant for Nox Medical, Merck, Apnimed, Respicardia, Inspire Medical Systems, Eli Lilly, LinguaFlex, and Forepont outside the submitted work; receives grant support from Apnimed, Prosomnus, and Dynaflex for unrelated studies; and holds patents on phenotyping from wearable technology and sleep apnea pharmacotherapy through his institution’s Innovation department. His industry interactions are managed by Brigham and Women’s Hospital and Mass General Brigham in accordance with their conflict of interest policies. P. I. T. has received honoraria from the University of Sydney, the University of Adelaide, and Flinders University outside the submitted work. Outside the submitted work, A. A. has received a grant from Somnifix; consulting fees from Apnimed, Somnifix, LinguaFlex, Respicardia, Eli Lilly, and Inspire; honoraria from the American Academy of Orofacial Pain for a lecture; honoraria from University of Alberta for a grant review; equipment loaned from Philips Respironics; and has a patent pending for phenotyping sleep apnea using wearables. None declared (E. S., T. L., S. K., T. G., D. L. M., B. D.)., (Copyright © 2023 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: CPAP delivered via an oronasal mask is associated with lower adherence, higher residual apnea-hypopnea index (AHI), and increased CPAP therapeutic pressure compared with nasal masks. However, the mechanisms underlying the increased pressure requirements are not well understood., Research Question: How do oronasal masks affect upper airway anatomy and collapsibility?, Study Design and Methods: Fourteen patients with OSA underwent a sleep study with both a nasal and oronasal mask, each for one-half of the night (order randomized). CPAP was manually titrated to determine therapeutic pressure. Upper airway collapsibility was assessed using the pharyngeal critical closing pressure (P crit ) technique. Cine MRI was done to dynamically assess the cross-sectional area of the retroglossal and retropalatal airway throughout the respiratory cycle with each mask interface. Scans were repeated at 4 cm H 2 O and at the nasal and oronasal therapeutic pressures., Results: The oronasal mask was associated with higher therapeutic pressure requirements (ΔM ± SEM; +2.6 ± 0.5; P < .001) and higher P crit (+2.4 ± 0.5 cm H 2 O; P = .001) compared with the nasal mask. The change in therapeutic pressure between masks was strongly correlated with the change in P crit (r 2  = 0.73; P = .003). Increasing CPAP increased both the retroglossal and retropalatal airway dimensions across both masks. After controlling for pressure and breath phase, the retropalatal cross-sectional area was moderately larger when using a nasal vs an oronasal mask (+17.2 mm 2 ; 95% CI, 6.2-28.2, P < .001) while nasal breathing., Interpretation: Oronasal masks are associated with a more collapsible airway than nasal masks, which likely contributes to the need for a higher therapeutic pressure., (Copyright © 2023 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: The LIFE (LCZ696 In Hospitalized Advanced Heart FailurE) trial, which evaluated sacubitril/valsartan in patients with advanced heart failure (HF) with reduced ejection fraction and recent New York Heart Association functional class IV symptomatology, did not require tolerance to a renin angiotensin system antagonist before initiating sacubitril/valsartan, thus affording an opportunity to study the tolerability of sacubitril/valsartan in advanced HF with reduced ejection fraction., Objectives: The goal of this analysis of the LIFE trial is to characterize the tolerability of initiating sacubitril/valsartan in patients with chronic advanced HF with reduced ejection fraction., Methods: In the LIFE trial, 445 subjects with advanced HF entered an unblinded run-in period of 3-7 days with sacubitril/valsartan 24/26 mg twice a day. The authors compared characteristics of subjects completing and failing run-in, performed multivariable analysis of clinical parameters associated with run-in failure, and developed a predictive model for short-term intolerance to sacubitril/valsartan., Results: Of 445 subjects entering run-in, 73 (18%) were intolerant of sacubitril/valsartan. Reasons for intolerance included systolic blood pressure <90 mm Hg (59%), symptoms of hypotension/dizziness with systolic blood pressure >90 mm Hg (19%), and renal dysfunction (creatinine >2.0 mg/dL) (12%). Multivariable predictors of intolerance included lower mean arterial pressure, lower serum chloride, presence of an implantable cardioverter-defibrillator and/or cardiac resynchronization device, moderate or greater mitral regurgitation, nonuse of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker at the screening visit, and use of insulin at screening. Subjects with 4 or more predictors had a 48.9% probability of sacubitril/valsartan intolerance., Conclusions: Intolerance to low doses of sacubitril/valsartan is common in patients with advanced chronic HF with reduced ejection fraction and may be predicted by the presence of certain risk factors. (EntrestoTM [LCZ696] in Advanced Heart Failure [LIFE Study] [HFN-LIFE] NCT02816736)., Competing Interests: Funding Support and Author Disclosures Research reported in this publication was supported by the NHLBI of the NIH under award number U10 HL084904 (for the Coordinating Center) and award numbers U10 HL110297, U10 HL110342, U10 HL110309, U10 HL110262, U10 HL110338, U10 HL110312, U10 HL110302, U10 HL110336, and U10 HL110337 (for the Regional Clinical Centers). The NHLBI contributed to the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript; and the decision to submit the manuscript for publication. Novartis Pharmaceutical Corporation provided study drug and partial funding through its investigator-initiated trial program CLCZ696BUS04T, but did not contribute to the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript; and the decision to submit the manuscript for publication. Neither the NHLBI nor Novartis Pharmaceutical Corporation were involved in manuscript submission. Dr Mann serves on the steering committee for the PARADISE-MI trial for Novartis; and is a member of the Scientific Advisory Board for MyoKardia. Dr Anstrom has received research support from the National Institutes of Health (NIH), Merck, Bayer, and PCORI. Dr Starling serves on the steering committee for the PARAGLIDE trial sponsored by Novartis. Dr Desvigne-Nickens is an employee of the NHLBI; and is a consultant for Novartis. Dr Hernandez has received research grants and consulting fees from AstraZeneca, Amgen, Bayer, Merck, and Novartis. Dr Braunwald has received research support through his institution from AstraZeneca, Daiichi-Sankyo, Merck, and Novartis; and is a consultant for Amgen, Boehringer Ingelheim/Lilly, Cardurion, MyoKardia, Novo-Nordisk, and Verve. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. All rights reserved.)

Introduction: Patients with ambulatory advanced heart failure (HF) are increasingly considered for durable mechanical circulatory support (MCS) and heart transplantation and their effective triage requires careful assessment of the clinical trajectory., Methods: REVIVAL, a prospective, observational study, enrolled 400 ambulatory advanced HF patients from 21 MCS/transplant centers in 2015-2016. Study design included a clinical re-assessment of Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile within 120 days after enrollment. The prognostic impact of a worsening INTERMACS Profile assigned by the treating physician was assessed at 1 year after the Early Relook., Results: Early Relook was done in 325 of 400 patients (81%), of whom 24% had a worsened INTERMACS Profile, associated with longer HF history and worse baseline INTERMACS profile, but no difference in baseline LVEF (median 0.20), 6-minute walk, quality of life, or other baseline parameters. Early worsening predicted higher rate of the combined primary endpoint of death, urgent MCS, or urgent transplant by 1 year after Early Relook, (28% vs 15%), with hazard ratio 2.2 (95% CI 1.2- 3.8; p = .006) even after adjusting for baseline INTERMACS Profile and Seattle HF Model score. Deterioration to urgent MCS occurred in 14% vs 5% (p = .006) during the year after Early Relook., Conclusions: Early Relook identifies worsening of INTERMACS Profile in a significant population of ambulatory advanced HF, who had worse outcomes over the subsequent year. Early reassessment of ambulatory advanced HF patients should be performed to better define the trajectory of illness and inform triage to advanced therapies., Competing Interests: Disclosure P.S. reports the following grant support: American Heart Association/Enduring Hearts Scientist Development Grant, Merck, Haemonetrics, and Medtronic. Consulting: NuPulse CV and Ortho Clinical Diagnostics. K.D.A. reports the following related to the submitted work: the National Institutes of Health/National Heart, Lung, and Blood Institute (contract) and outside the submitted work: Medtronic (research support and consultant [Independent Physician Quality Panel member]), Abbott (research support), Procyrion (consultant), NuPulseCV (consultant), Bioventrix (research support). M.K., A.V.A., S.P., J.T., N.A.G., G.A.E., J.S., M.P., J.D.E., J.T.B., W.T.P., T.M.C., N.J., L.W.S., D.L.M., G.C.S., M.Y., B.R., and S.K have no conflicts of interest to disclose., (Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Patients with OSA can have the majority of their respiratory events in rapid eye movement (REM) sleep or in non-rapid eye movement (NREM) sleep. No previous studies have linked the different physiologic conditions in REM and NREM sleep to the common polysomnographic patterns seen in everyday clinical practice, namely REM predominant OSA (REM OSA ) and NREM predominant OSA (NREM OSA )., Research Question: (1) How does OSA physiologic condition change with sleep stage in patients with NREM OSA and REM OSA ? (2) Do patients with NREM OSA and REM OSA have different underlying OSA pathophysiologic conditions?, Study Design and Methods: We recruited patients with three polysomnographic patterns. (1) REM OSA : twice as many respiratory events in REM sleep, (2) NREM OSA : twice as many events in NREM sleep, and (3) uniform OSA: equal number of events in NREM/REM sleep. We deployed a noninvasive phenotyping method to determine OSA endotype traits (Vpassive, Vactive, loop gain, arousal threshold) in NREM sleep, REM sleep, and total night sleep in each group of patients (NREM OSA , REM OSA , uniform OSA)., Results: Patients with NREM OSA have significantly worse ventilatory control stability in NREM sleep compared with REM sleep (loop gain, 0.546 [0.456,0.717] in NREM vs 0.365 [0.238,0.459] in REM sleep; P = .0026). Patients with REM OSA displayed a significantly more collapsible airway (ie, lower Vpassive) in REM compared with NREM sleep (98.4 [97.3,99.2] %Veupnea in NREM vs 95.9 [86.4,98.9] %Veupnea in REM sleep; P < .0001). The major between-group difference across the whole night was a significantly higher loop gain in the NREM OSA group (0.561 [0.429,0.675]) compared with the REM OSA group (0.459 [0.388,0.539]; P = .0033)., Interpretation: This study is the first to link long-recognized polysomnographic patterns of OSA to underlying physiologic differences. Patients with NREM OSA have a higher loop gain in NREM sleep; patients with REM OSA have a worsening of Vpassive in REM sleep., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Objectives: This study sought to determine cardiopulmonary exercise (CPX) predictors of the combined outcome of durable mechanical circulatory support (MCS), transplantation, or death at 1 year among patients with ambulatory advanced heart failure (HF)., Background: Optimal CPX predictors of outcomes in contemporary ambulatory advanced HF patients are unclear., Methods: REVIVAL (Registry Evaluation of Vital Information for ventricular assist devices [VADs] in Ambulatory Life) enrolled 400 systolic HF patients, INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) profiles 4-7. CPX was performed by 273 subjects 2 ± 1 months after study enrollment. Discriminative power of maximal (peak oxygen consumption [peak VO 2 ]; VO 2 pulse, circulatory power [CP]; peak systolic blood pressure • peak VO 2 ], peak end-tidal pressure CO 2 [PEtCO 2 ], and peak Borg scale score) and submaximal CPX parameters (ventilatory efficiency [VE/VCO 2 slope]; VO 2 at anaerobic threshold [VO 2 AT]; and oxygen uptake efficiency slope [OUES]) to predict the composite outcome were assessed by univariate and multivariate Cox regression and Harrell's concordance statistic., Results: At 1 year, there were 39 events (6 transplants, 15 deaths, 18 MCS implantations). Peak VO 2 , VO 2 AT, OUES, peak PEtCO 2 , and CP were higher in the no-event group (all p < 0.001), whereas VE/VCO 2 slope was lower (p < 0.0001); respiratory exchange ratio was not different. CP (hazard ratio [HR]: 0.89; p = 0.001), VE/VCO 2 slope (HR: 1.05; p = 0.001), and peak Borg scale score (HR: 1.20; p = 0.005) were significant predictors on multivariate analysis (model C-statistic: 0.80)., Conclusions: Among patients with ambulatory advanced HF, the strongest maximal and submaximal CPX predictor of MCS implantation, transplantation, or death at 1 year were CP and VE/VCO 2, respectively. The patient-reported measure of exercise effort (Borg scale score) contributed substantially to the prediction of outcomes, a surprising and novel finding that warrants further investigation. (Registry Evaluation of Vital Information for VADs in Ambulatory Life [REVIVAL]; NCT01369407)., Competing Interests: Funding support and Author Disclosures Supported by U.S. National Institutes of Health, National Heart, Lung, and Blood Institute (NHLBI) contract HHSN268201100026C, and National Center for Advancing Translational Sciences grant UL1TR002240. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health, or the US Department of Health and Human Services. Dr. Lanfear has received research grants from NHLBI (R01HL132154), Amgen, Bayer, and Janssen; and is a consultant for Amgen, Janssen, Ortho Diagnostics, and Novartis. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The PARADIGM-HF (Prospective Comparison of Angiotensin II Receptor Blocker Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial reported that sacubitril/valsartan (S/V), an angiotensin receptor-neprilysin inhibitor, significantly reduced mortality and heart failure (HF) hospitalization in HF patients with a reduced ejection fraction (HFrEF). However, fewer than 1% of patients in the PARADIGM-HF study had New York Heart Association (NYHA) functional class IV symptoms. Accordingly, data that informed the use of S/V among patients with advanced HF were limited. The LIFE (LCZ696 in Hospitalized Advanced Heart Failure) study was a 24-week prospective, multicenter, double-blinded, double-dummy, active comparator trial that compared the safety, efficacy, and tolerability of S/V with those of valsartan in patients with advanced HFrEF. The trial planned to randomize 400 patients ≥18 years of age with advanced HF, defined as an EF ≤35%, New York Heart Association functional class IV symptoms, elevated natriuretic peptide concentration (B-type natriuretic peptide [BNP] ≥250 pg/ml or N-terminal pro-B-type natriuretic peptide [NT-proBNP] ≥800 pg/ml), and ≥1 objective finding of advanced HF. Following a 3- to 7-day open label run-in period with S/V (24 mg/26 mg twice daily), patients were randomized 1:1 to S/V titrated to 97 mg/103 mg twice daily versus 160 mg of V twice daily. The primary endpoint was the proportional change from baseline in the area under the curve for NT-proBNP levels measured through week 24. Secondary and tertiary endpoints included clinical outcomes and safety and tolerability. Because of the COVID-19 pandemic, enrollment in the LIFE trial was stopped prematurely to ensure patient safety and data integrity. The primary analysis consists of the first 335 randomized patients whose clinical follow-up examination results were not severely impacted by COVID-19. (Entresto [LCZ696] in Advanced Heart Failure [LIFE STUDY] [HFN-LIFE]; NCT02816736)., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Introduction: Improved understanding of the clinical course of ambulatory advanced chronic systolic heart failure may improve the provision of appropriate care and is central to the design of clinical trials in this population., Methods: Twenty-one implanting ventricular assist device (VAD) centers enrolled 400 subjects in the Registry Evaluation of Vital Information for VADs in Ambulatory Life (REVIVAL), a prospective, observational study in ambulatory, chronic, advanced systolic heart failure, designed to identify a cohort with an approximately 25% 1-year risk of the primary composite outcome of death, urgent transplant, or durable mechanical circulatory support. Inclusion criteria utilized only information collected during routine clinical care. Exclusion criteria identified patients with contraindications to VAD. Study inclusion required at least 1 of 10 high-risk criteria derived from established hospitalization and non-hospitalization markers of increased mortality risk. We evaluated the test performance characteristics of the high-risk criteria., Results: Data on 373 subjects evaluable for the primary composite outcome at the 1-year visit are presented. Baseline data were consistent with a less advanced cohort than Medical Arm for Mechanically Assisted Circulatory Support or Risk Assessment (MedaMACS) and Comparative Effectiveness of Left Ventricular Assist Device and Medical Management in Ambulatory Heart Failure Patients (ROADMAP). Freedom from the primary composite outcome was 75.9%. Non-hospitalization inclusion criteria identified 89% of patients with events., Conclusions: Using routinely obtained clinical information for enrollment, REVIVAL successfully recruited an ambulatory chronic systolic heart failure cohort with an approximately 25% annual risk of the primary composite outcome. Information from this registry will be relevant to the planning of future trials of earlier VAD use and of other interventions in this population., (Copyright © 2019 International Society for Heart and Lung Transplantation. All rights reserved.)

Objectives: This study sought to characterize cognitive decline (CD) over time and its predictors in patients with systolic heart failure (HF)., Background: Despite the high prevalence of CD and its impact on mortality, predictors of CD in HF have not been established., Methods: This study investigated CD in the WARCEF (Warfarin versus Aspirin in Reduced Ejection Fraction) trial, which performed yearly Mini-Mental State Examinations (MMSE) (higher scores indicate better cognitive function; e.g., normal score: 24 or higher). A longitudinal time-varying analysis was performed among pertinent covariates, including baseline MMSE and MMSE scores during follow-up, analyzed both as a continuous variable and a 2-point decrease. To account for a loss to follow-up, data at the baseline and at the 12-month visit were analyzed separately (sensitivity analysis)., Results: A total of 1,846 patients were included. In linear regression, MMSE decrease was independently associated with higher baseline MMSE score (p < 0.0001), older age (p < 0.0001), nonwhite race/ethnicity (p < 0.0001), and lower education (p < 0.0001). In logistic regression, CD was independently associated with higher baseline MMSE scores (odds ratio [OR]: 1.13; 95% confidence interval [CI]: 1.07 to 1.20]; p < 0.001), older age (OR: 1.37; 95% CI: 1.24 to 1.50; p < 0.001), nonwhite race/ethnicity (OR: 2.32; 95% CI: 1.72 to 3.13 for black; OR: 1.94; 95% CI: 1.40 to 2.69 for Hispanic vs. white; p < 0.001), lower education (p < 0.001), and New York Heart Association functional class II or higher (p = 0.03). Warfarin and other medications were not associated with CD. Similar trends were seen in the sensitivity analysis (n = 1,439)., Conclusions: CD in HF is predicted by baseline cognitive status, demographic variables, and NYHA functional class. The possibility of intervening on some of its predictors suggests the need for the frequent assessment of cognitive function in patients with HF. (Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction [WARCEF]; NCT00041938)., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study sought to explore clinical characteristics and outcomes in women and men with ambulatory advanced heart failure (HF)., Background: Women have been underrepresented in studies of advanced HF and have an increased mortality on the transplant waiting list and early after mechanical circulatory support (MCS). An increased understanding of the differential burden of HF between women and men is required to inform the use of mechanical circulatory support in ambulatory advanced HF patients., Methods: REVIVAL (Registry Evaluation for Vital Information on Ventricular Assist Devices in Ambulatory Life) is a prospective, observational study of 400 outpatients with chronic systolic HF, New York Heart Association functional class II to IV, and 1 additional high-risk feature. Clinical characteristics, quality of life, and functional capacity were compared between women and men, as was a primary composite endpoint of death, durable MCS, or urgent heart transplantation at 1 year., Results: REVIVAL enrolled 99 women (25% of the cohort) who had similar age, ejection fraction, INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) profiles, medication use, and willingness to consider MCS as the men enrolled; however, women reported significantly greater limitations in quality of life with respect to physical limitation, reduced 6-min walk distance, and more frequent symptoms of depression. Nevertheless, 1-year combined risk of death, durable MCS, or urgent transplantation did not differ between women and men (24% vs. 22%; p = 0.94)., Conclusions: This study represents the largest report to date of women with ambulatory advanced HF receiving contemporary therapies. Systematic elicitation of patient-reported outcome measures uncovered an added burden of HF in women and may be an appropriate target of augmented support and intervention., (Copyright © 2019 American College of Cardiology Foundation. All rights reserved.)

Objectives: This study sought to confirm a subgroup analysis of the prior FIX-HF-5 (Evaluate Safety and Efficacy of the OPTIMIZER System in Subjects With Moderate-to-Severe Heart Failure) study showing that cardiac contractility modulation (CCM) improved exercise tolerance (ET) and quality of life in patients with ejection fractions between 25% and 45%., Background: CCM therapy for New York Heart Association (NYHA) functional class III and IV heart failure (HF) patients consists of nonexcitatory electrical signals delivered to the heart during the absolute refractory period., Methods: A total of 160 patients with NYHA functional class III or IV symptoms, QRS duration <130 ms, and ejection fraction ≥25% and ≤45% were randomized to continued medical therapy (control, n = 86) or CCM (treatment, n = 74, unblinded) for 24 weeks. Peak Vo 2 (primary endpoint), Minnesota Living With Heart Failure questionnaire, NYHA functional class, and 6-min hall walk were measured at baseline and at 12 and 24 weeks. Bayesian repeated measures linear modeling was used for the primary endpoint analysis with 30% borrowing from the FIX-HF-5 subgroup. Safety was assessed by the percentage of patients free of device-related adverse events with a pre-specified lower bound of 70%., Results: The difference in peak Vo 2 between groups was 0.84 (95% Bayesian credible interval: 0.123 to 1.552) ml O 2 /kg/min, satisfying the primary endpoint. Minnesota Living With Heart Failure questionnaire (p < 0.001), NYHA functional class (p < 0.001), and 6-min hall walk (p = 0.02) were all better in the treatment versus control group. There were 7 device-related events, yielding a lower bound of 80% of patients free of events, satisfying the primary safety endpoint. The composite of cardiovascular death and HF hospitalizations was reduced from 10.8% to 2.9% (p = 0.048)., Conclusions: CCM is safe, improves exercise tolerance and quality of life in the specified group of HF patients, and leads to fewer HF hospitalizations. (Evaluate Safety and Efficacy of the OPTIMIZER System in Subjects With Moderate-to-Severe Heart Failure; NCT01381172)., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Diagnosis, prognosis, treatment, and development of new therapies for diseases or syndromes depend on a reliable means of identifying phenotypes associated with distinct predictive probabilities for these various objectives. Left ventricular ejection fraction (LVEF) provides the current basis for combined functional and structural phenotyping in heart failure by classifying patients as those with heart failure with reduced ejection fraction (HFrEF) and those with heart failure with preserved ejection fraction (HFpEF). Recently the utility of LVEF as the major phenotypic determinant of heart failure has been challenged based on its load dependency and measurement variability. We review the history of the development and adoption of LVEF as a critical measurement of LV function and structure and demonstrate that, in chronic heart failure, load dependency is not an important practical issue, and we provide hemodynamic and molecular biomarker evidence that LVEF is superior or equal to more unwieldy methods of identifying phenotypes of ventricular remodeling. We conclude that, because it reliably measures both left ventricular function and structure, LVEF remains the best current method of assessing pathologic remodeling in heart failure in both individual clinical and multicenter group settings. Because of the present and future importance of left ventricular phenotyping in heart failure, LVEF should be measured by using the most accurate technology and methodologic refinements available, and improved characterization methods should continue to be sought., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to determine whether aspirin increases heart failure (HF) hospitalization or death in patients with HF with reduced ejection fraction receiving an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB)., Background: Because of its cyclooxygenase inhibiting properties, aspirin has been postulated to increase HF events in patients treated with ACE inhibitors or ARBs. However, no large randomized trial has addressed the clinical relevance of this issue., Methods: We compared aspirin and warfarin for HF events (hospitalization, death, or both) in the 2,305 patients enrolled in the WARCEF (Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction) trial (98.6% on ACE inhibitor or ARB treatment), using conventional Cox models for time to first event (489 events). In addition, to examine multiple HF hospitalizations, we used 2 extended Cox models, a conditional model and a total time marginal model, in time to recurrent event analyses (1,078 events)., Results: After adjustment for baseline covariates, aspirin- and warfarin-treated patients did not differ in time to first HF event (adjusted hazard ratio: 0.87; 95% confidence interval: 0.72 to 1.04; p = 0.117) or first hospitalization alone (adjusted hazard ratio: 0.88; 95% confidence interval: 0.73 to 1.06; p = 0.168). The extended Cox models also found no significant differences in all HF events or in HF hospitalizations alone after adjustment for covariates., Conclusions: Among patients with HF with reduced ejection fraction in the WARCEF trial, there was no significant difference in risk of HF events between the aspirin and warfarin-treated patients. (Warfarin Versus Aspirin in Reduced Cardiac Ejection Fraction trial [WARCEF]; NCT00041938)., (Copyright © 2017 American College of Cardiology Foundation. All rights reserved.)

The incentives for sport organizations to identify talented athletes from a young age continue to grow, yet effective talent identification remains a challenging task. This opinion paper examines recent advances in talent identification, focusing in particular on the emergence of new approaches that may offer promise to identify talent (e.g., small-sided games, genetic testing, and advanced statistical analyses). We appraise new multi-disciplinary and large-scale population studies of talent identification, provide a consideration of the most recent psychological predictors of performance, examine the emergence of new approaches that strive to diminish biases in talent identification, and look at the rise in interest in talent identification in Paralympic sport., (Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.)

Objectives: This study sought to assess the performance of the HeartMate Risk Score (HMRS) in a large multicenter cohort, with a focus on its performance as a function of disease severity., Background: The HMRS has been proposed as a simple tool for risk stratification of LVAD recipients, but subsequent studies have challenged its validity., Methods: We performed a retrospective, longitudinal, comparative study using the INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) database. The HMRS was calculated for each patient and its association with mortality was assessed using Cox models, including a pre-specified interaction by INTERMACS profile groups (1 vs. 2 vs. 3 vs 4+)., Results: Among 10,847 patients with a mean age of 57.0 ± 12.9 years, 78.9 % were male; and 14.1%, 37.4%, 30.4%, and 18.2% were in INTERMACS profile groups 1, 2, 3, and ≥4, respectively. The HMRS showed moderate discrimination for both short-term (90-day, C-index 0.62) and long-term (2-years, C-index 0.60) mortality, with no significant difference between axial and centrifugal devices. Patients in the highest HMRS group had a relative risk of 90-day mortality 2.8 times greater than those in the lowest HMRS group (13.0% vs. 4.7%; p < 0.001). Importantly, the relative risks of higher HMRS scores were similar across INTERMACS profile groups, with subgroups of patients in INTERMACS profile 1 and 2 having comparable or lower mortality than some in INTERMACS profile 4+., Conclusions: The HMRS is a valid means of risk-stratifying patients across all INTERMACS profiles and may be superior to traditional INTERMACS classification. Risk stratification with the HMRS showed that patients within each INTERMACS profile groups have a wide spectrum of mortality risk and low INTERMACS profiles should therefore not be considered a contraindication to mechanical support., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Patients with systolic heart failure (HF) are at increased risk of both ischemic stroke and death. Currently, no risk scores are available to identify HF patients at high risk of stroke or death. The Warfarin vs. Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial studied 2305 HF patients, in sinus rhythm, followed for up to 6 years (3.5±1.5 years). This trial showed no overall difference in those treated with warfarin vs aspirin with regard to death or stroke. The present study develops the first prognostic model to identify patients at higher risk of stroke or death based on their overall risk profile., Methods and Results: A scoring algorithm using 8 readily obtainable clinical characteristics as predictors, age, gender, hemoglobin, blood urea nitrogen, ejection fraction, diastolic blood pressure, diabetes status, and prior stroke or transient ischemic attack (C-index=0.65, 95% CI: 0.613-0.681), was developed. It was validated internally using a bootstrap method. In predicting 1-year survival for death alone, our 8-predictor model had an AUC of 0.63 (95% CI: 0.579-0.678) while the 14-predictor Seattle model had an AUC of 0.72. The Seattle model did not report stroke., Conclusions: This novel prognostic model predicts the overall risk of ischemic stroke or death for HF patients. This model compares favorably for death with the Seattle model and has the added utility of including stroke as an endpoint. Use of this model will help identify those patients in need of more intensive monitoring and therapy and may help identify appropriate populations for trials of new therapies., Clinical Trial Registration: http://www.Clinicatrials.govNCT00041938., (Copyright © 2015 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Objectives: The primary objective of the study was a change in left ventricular end-systolic volume index (LVESVi) from baseline to 6 months of spinal cord stimulation (SCS) therapy in the treatment arm compared to the control arm as measured by echocardiography. Secondary objectives were changes in peak oxygen uptake and N-terminal pro-B-type natriuretic peptide (NT-proBNP) between the treatment arm and control arm from baseline through 6 months., Background: Abnormal neurohormonal activation is often responsible for progression of heart failure (HF). Treatment has often included drug therapy to modulate the neurohormonal axis. The purpose of the DEFEAT-HF (Determining the Feasibility of Spinal Cord Neuromodulation for the Treatment of Chronic Heart Failure) clinical study was to evaluate whether direct modulation of the nervous system through SCS improved HF metrics, including heart size, biomarkers, functional capacity, and symptoms., Methods: The DEFEAT-HF study was a prospective, multicenter randomized (3:2), parallel, single-blind, controlled study to investigate whether SCS was a feasible therapy for the treatment of systolic HF for patients with New York Heart Association functional class III HF, left ventricular ejection fraction (LVEF) ≤35%, QRS duration <120 ms, and left ventricular end-diastolic dimension ≥55 mm. The primary objective of the DEFEAT-HF study was to evaluate the reduction in LVESVi after 6 months of SCS therapy in the treatment arm compared to the control arm., Results: In total, 81 patients were enrolled, with 66 successfully randomized and implanted with the SCS device system. Seventy-six percent (50 of 66) had an implantable cardioverter-defibrillator at the baseline visit. Among randomized patients, the mean age was 61 years, 79% were male, mean LVEF was 27%, and mean QRS duration was 105 ms. The change in LVESVi over 6 months was not significantly different between randomization arms (SCS OFF: -2.2 [95% confidence interval: -9.1 to 4.6] vs., Scs on: 2.1 [95% confidence interval: -2.7 to 6.9]; p = 0.30). Analyses of secondary endpoints for the study were also not significantly different., Conclusions: The present study does not provide evidence to support a meaningful change in clinical outcomes for HF patients receiving SCS. (Determining the Feasibility of Spinal Cord Neuromodulation for the Treatment of Chronic Heart Failure [DEFEAT-HF]; NCT01112579)., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: A tissue engineering approach to augment the left ventricular wall has been suggested as a means to treat patients with advanced heart failure. This study evaluated the safety and feasibility of Algisyl-LVR™ as a method of left ventricular augmentation in patients with dilated cardiomyopathy undergoing open-heart surgery., Methods and Results: Eleven male patients (aged 44 to 74years) with advanced heart failure (NYHA class 3 or 4), a left ventricular ejection fraction (LVEF) of <40% and requiring conventional heart surgery received Algisyl-LVR delivered into the LV myocardial free wall. Serial echocardiography, assessment of NYHA class, Kansas City Cardiomyopathy Questionnaire (KCCQ) and 24-hour Holter monitoring were obtained at baseline, days 3 and 8 (for echocardiography and Holter monitoring), and at 3, 6, 12, 18 and 24months. A total of 9 (81.8%) patients completed 24months of follow-up. Two patients withdrew consent after day 8 and at the 3month visit. Operative mortality was 0% (n=10 with 30day follow-up). There were no adverse events attributed to Algisyl-LVR. Mean LVEF improved from 27.1 (±7.3) % at screening to a mean LVEF of 34.8 (±18.6) % 24months post-discharge. Improvements of NYHA class were corroborated with improvements in KCCQ summary scores. Holter monitor data showed a significant decrease in the episodes of nonsustained ventricular tachycardia following administration of Algisyl-LVR., Conclusions: Administration of Algisyl-LVR to patients with advanced HF at the time of cardiac surgery is feasible and safe; warranting continued development of Algisyl-LVR as a potential therapy in patients with advanced HF., (Copyright © 2015. Published by Elsevier Ireland Ltd.)

Objectives: This study evaluated the Heartmate Risk Score (HMRS) and its potential benefits in clinical practice., Background: The HMRS has been shown to correlate with mortality in the cohort of patients enrolled in the Heartmate II trials, but its validity in unselected, "real world" populations remains unclear., Methods: This study identified a cohort of 269 consecutive patients who received a Heartmate II left ventricular assist device at our institution, the Barnes-Jewish Hospital in St. Louis, Missouri, between June 2005 and June 2013. Ninety-day and 2-year mortality rates, as well as frequency of several morbid events, were compared by retrospectively assigned HMRS category groups. The analysis was repeated within the subgroup of INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) class 1 patients., Results: Receiver operating curve analysis showed that the HMRS correlated with 90-day mortality with an area under the curve of 0.70. Stratification in low, mid, and high HMRS groups identified patients with increasing hazard of 90-day mortality, increasing long-term mortality, increasing rate of gastrointestinal bleeding events, and increasing median number of days spent in the hospital in the first year post implant. Within INTERMACS class 1 patients, those in the highest HMRS group were found to have a relative risk of 90-day mortality 5.7 times higher than those in the lowest HMRS group (39.1% vs. 6.9%, p = 0.029)., Conclusions: HMRS is a valid clinical tool to stratify risk of morbidity and mortality after implant of Heartmate II devices in unselected patients and can be used to predict short-term mortality risk in INTERMACS class 1 patients., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Introduction: Anaplastic lymphoma kinase (ALK) fusion is the most common mechanism for overexpression and activation in non-small-cell lung carcinoma. Several fusion partners of ALK have been reported, including echinoderm microtubule-associated protein-like 4, TRK-fused gene, kinesin family member 5B, kinesin light chain 1 (KLC1), protein tyrosine phosphatase and nonreceptor type 3, and huntingtin interacting protein 1 (HIP1)., Methods and Results: A 60-year-old Korean man had a lung mass which was a poorly differentiated adenocarcinoma with ALK overexpression. By using an Anchored Multiplex polymerase chain reaction assay and sequencing, we found that tumor had a novel translocated promoter region (TPR)-ALK fusion. The fusion transcript was generated from an intact, in-frame fusion of TPR exon 15 and ALK exon 20 (t(1;2)(q31.1;p23)). The TPR-ALK fusion encodes a predicted protein of 1192 amino acids with a coiled-coil domain encoded by the 5'-2 of the TPR and juxtamembrane and kinase domains encoded by the 3'-end of the ALK., Conclusions: The novel fusion gene and its protein TRP-ALK, harboring coiled-coil and kinase domains, could possess transforming potential and responses to treatment with ALK inhibitors. This case is the first report of TPR-ALK fusion transcript in clinical tumor samples and could provide a novel diagnostic and therapeutic candidate target for patients with cancer, including non-small-cell lung carcinoma.

Objectives: The aim of this study was to characterize levels of serum biomarkers in patients with severe refractory cardiogenic shock (SRCS) and to document temporal changes in these levels during restoration of circulation., Background: Patients with SRCS have been challenging to study because of their rapidly changing clinical condition while undergoing multiple simultaneous interventions., Methods: Twenty-one patients with SRCS received circulatory support via a percutaneously implanted ventricular assist device (PVAD). Serum samples obtained prior to PVAD support initiation, at 24 h of PVAD support, and at 7 days of PVAD support were assayed for B-type natriuretic peptide (BNP), high-sensitivity C-reactive protein (hsCRP), soluble tumor necrosis factor receptor-1 (sTNFR1), soluble Fas (sFas), soluble Fas ligand (sFasL), endothelin-1, and procollagen III N-terminal peptide (PIIINP). Baseline biomarker levels were qualitatively compared to reference values; levels at 24 h of PVAD support and at 7 days of PVAD support were compared to baseline using 2-tailed Wilcoxon matched pair signed rank tests with Bonferroni correction for multiple comparisons., Results: These patients with SRCS had elevated serum levels of BNP, hsCRP, sTNFR1, endothelin-1, and PIIINP. Ventricular unloading and restoration of circulation via PVAD support in patients with SRCS were associated with reductions in serum BNP, sFas, and endothelin-1 levels and increases in serum sFasL and PIIINP levels., Conclusions: This study characterizes several important baseline serum biomarker levels in patients with SRCS and introduces a novel PVAD-based protocol with the potential to "reverse"-model the pathophysiology of cardiogenic shock., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The incorporation of complex medical device technologies into clinical practice is governed by critical oversight of the United States Food and Drug Administration. This regulatory process requires a judicious balance between assuring safety and efficacy, while providing efficient review to facilitate access to innovative therapies. Recent contrasting views of the regulatory process have emphasized the difficulties in obtaining an optimal balance. Mechanical circulatory support has evolved to become an important therapy for patients who have advanced heart failure with the advent of more durable, implantable ventricular assist devices. The regulatory oversight of these new technologies has been difficult owing to the complexities of these devices, associated adverse event profile, and severity of illness of the intended patient population. Maintaining a regulatory environment to foster efficient introduction of safe and effective technologies is critical to the success of ventricular assist device therapy and the health of patients with advanced heart failure. Physicians representing key surgical and cardiology societies, and representatives from the Food and Drug Administration, National Heart Lung, and Blood Institute, Centers for Medicare and Medicaid Services, Inter-agency Registry of Mechanically Assisted Circulatory Support, and industry partners gathered to discuss relevant issues regarding the current regulatory environment assessing ventricular assist devices. The goal of the meeting was to explore innovative ways to foster the introduction of technologically advanced, safe, and effective ventricular assist devices. The following summary reflects opinions and conclusions endorsed by The Society of Thoracic Surgeons, American Association for Thoracic Surgery, American Heart Association, Heart Failure Society of America, International Society for Heart and Lung Transplantation, and Interagency Registry of Mechanically Assisted Circulatory Support., (Copyright © 2012. Published by Elsevier Inc.)

The incorporation of complex medical device technologies into clinical practice is governed by critical oversight of the US Food and Drug Administration. This regulatory process requires a judicious balance between assuring safety and efficacy, while providing efficient review to facilitate access to innovative therapies. Recent contrasting views of the regulatory process have emphasized the difficulties in obtaining an optimal balance. Mechanical circulatory support has evolved to become an important therapy for patients who have advanced heart failure with the advent of more durable, implantable ventricular assist devices. The regulatory oversight of these new technologies has been difficult owing to the complexities of these devices, associated adverse event profile, and severity of illness of the intended patient population. Maintaining a regulatory environment to foster efficient introduction of safe and effective technologies is critical to the success of ventricular assist device therapy and the health of patients with advanced heart failure. Physicians representing key surgical and cardiology societies, and representatives from the Food and Drug Administration, National Heart Lung, and Blood Institute, Centers for Medicare and Medicaid Services, Interagency Registry of Mechanically Assisted Circulatory Support, and industry partners gathered to discuss relevant issues regarding the current regulatory environment assessing ventricular assist devices. The goal of the meeting was to explore innovative ways to foster the introduction of technologically advanced, safe, and effective ventricular assist devices. The following summary reflects opinions and conclusions endorsed by The Society of Thoracic Surgeons, American Association for Thoracic Surgery, American Heart Association, Heart Failure Society of America, International Society for Heart and Lung Transplantation, and Interagency Registry of Mechanically Assisted Circulatory Support., (Copyright © 2012 The Society of Thoracic Surgeons, American Heart Association, Inc, and International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

The incorporation of complex medical device technologies into clinical practice is governed by critical oversight of the US Food and Drug Administration. This regulatory process requires a judicious balance between assuring safety and efficacy, while providing efficient review to facilitate access to innovative therapies. Recent contrasting views of the regulatory process have emphasized the difficulties in obtaining an optimal balance. Mechanical circulatory support has evolved to become an important therapy for patients with advanced heart failure with the advent of more durable, implantable ventricular assist devices. The regulatory oversight of these new technologies has been difficult owing to the complexities of these devices, associated adverse event profile, and severity of illness of the intended patient population. Maintaining a regulatory environment to foster efficient introduction of safe and effective technologies is critical to the success of ventricular assist device therapy and the health of patients with advanced heart failure. Physicians representing key surgical and cardiology societies, and representatives from the Food and Drug Administration, National Heart Lung, and Blood Institute, Centers for Medicare and Medicaid Services, Interagency Registry of Mechanically Assisted Circulatory Support, and industry partners gathered to discuss relevant issues regarding the current regulatory environment assessing ventricular assist devices. The goal of the meeting was to explore innovative ways to foster the introduction of technologically advanced, safe, and effective ventricular assist devices. The following summary reflects opinions and conclusions endorsed by The Society of Thoracic Surgeons, American Association for Thoracic Surgery, American Heart Association, Heart Failure Society of America, International Society for Heart and Lung Transplantation, and the Interagency Registry of Mechanically Assisted Circulatory Support., (Copyright © 2012 The Society of Thoracic Surgeons, American Heart Association, Inc, and International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Chronic heart failure continues to impose a substantial health-care burden, despite recent treatment advances. The key pathophysiological process that ultimately leads to chronic heart failure is cardiac remodelling in response to chronic disease stresses. Here, we review recent advances in our understanding of molecular and cellular mechanisms that play a part in the complex remodelling process, with a focus on key molecules and pathways that might be suitable targets for therapeutic manipulation. Such pathways include those that regulate cardiac myocyte hypertrophy, calcium homoeostasis, energetics, and cell survival, and processes that take place outside the cardiac myocyte--eg, in the myocardial vasculature and extracellular matrix. We also discuss major gaps in our current understanding, take a critical look at conventional approaches to target discovery that have been used to date, and consider new investigational avenues that might accelerate clinically relevant discovery., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Digoxin has been shown to reduce heart failure (HF) hospitalizations with no overall effect on mortality in HF patients. We used cluster analysis to delineate the clinical characteristics of HF patients in whom digoxin therapy was associated with improved or worsened clinical outcomes., Methods: The Digitalis Investigation Group (DIG) database was partitioned into 20 clusters. Multivariate Cox regression analyses was used, to identify clusters in which digoxin was associated with either an increase (Mortality(dig)HR>1), decrease (Mortality(dig)HR<1), or no association with all cause mortality (Mortality(dig)HR-NS); and separately, with an increase (HFA(dig)HR>1), decrease (HFA(dig)HR<1), or no association (HFA(dig)HR-NS) with HF admissions (HFA)., Results: We identified 938 patients in the Mortality(dig)HR>1 group, 6818 patients in the Mortality(dig)HR-NS group, and none in Mortality(dig)HR<1 group. The Mortality(dig)HR>1 group had a higher prevalence of females, diabetes mellitus, hypertension, higher age, systolic blood pressure (SBP), heart rate and ejection fraction (EF), compared to the Mortality(dig)HR-NS group. Similarly, 6325 patients clustered in the HFA(dig)HR<1 group, 1431 patients in the HFA(dig)HR-NS group, and none in the HFA(dig)HR>1 group. The HFA(dig)HR-NS group had a higher prevalence of females and hypertension, higher SBP, body mass index and EF; and lower prevalence of peripheral edema and third heart sound, compared with the HFA(dig)HR<1 group., Conclusion: Thus, the baseline characteristics of patients who did not have reduction in HF hospitalization or who had increased mortality were very similar and included females with hypertension, higher EF and higher SBP. Thus, use of digoxin in patients with this profile may need to be avoided., (Published by Elsevier Ireland Ltd.)

Background: Continuous-flow left ventricular assist devices (LVAD) are increasingly being used in patients with end-stage heart failure and have largely replaced older generation pulsatile devices. While significant rates of infection have been reported in patients with pulsatile device support, incidence and outcomes of this complication for the continuous-flow device patients remain unknown., Methods: Between June 2005 and August 2009, 81 patients were implanted with continuous-flow LVADs at Washington University School of Medicine either as bridge to transplantation or as destination therapy. Outcomes of this study included incidence of postimplantation infection, types of infection, microbiologic profile, and association of postimplantation infections with clinical endpoints., Results: Forty-two patients (51.9%) had at least one type of infection on continuous-flow LVAD support with a mean follow-up period of 9.2 ± 9.2 months. Patients who had an infection on LVAD support had a significantly prolonged hospital stay (37.9 ± 32.0 versus 20.7 ± 23.0 days, p = 0.008) and a trend toward increased mortality (33.1% versus 18.7% at 2 years, respectively, log rank p = 0.102) compared with patients who did not. Subgroup analysis revealed that postimplantation sepsis was significantly associated with increased mortality in the continuous-flow LVAD cohort (61.9% versus 18.0% at 2 years, respectively, in septic and nonseptic patients, log rank p = 0.001). The majority of the sepsis cases occurred before hospital discharge, whereas most of the device related infections occurred after discharge. Resistant Staphylococcus and Pseudomonas species were the most common pathogens leading to device- and nondevice-related local infections. Development of driveline or pocket infection had no effect on survival in patients with continuous-flow assist device support (p = 0.193)., Conclusions: Even though better clinical outcomes have been achieved with the newer generation continuous-flow devices, infection complications-in particular sepsis-are still a major risk for patients with continuous-flow LVAD implantation. Prevention strategies with aggressive medical and surgical management of infections may increase survival and decrease morbidity among continuous-flow LVAD patients., (Copyright © 2010 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Activation of the renin-angiotensin system (RAS) plays an important role in the pathogenesis of heart failure. Thus, strategies for the treatment of heart failure have focused on agents that block the RAS. More recently, the role of angiotensin receptor blockers (ARBs) in heart failure therapy has been better defined. This article examines the rationale and role of ARBs in the treatment of patients with heart failure on the basis of evidence from clinical trials.

Background: The objective of this study was to assess the long-term effects of the CorCap Cardiac Support Device (CSD; Acorn Cardiovascular, Inc, St. Paul, MN) on left ventricular (LV) structure and function in patients with heart failure. Cardiac support devices, which reduce LV wall stress, have been shown to promote reverse remodeling in three different experimental models of heart failure. However, long-term effects in patients with heart failure have not been reported., Methods: We enrolled 300 patients with heart failure in the Acorn Randomized Trial, as previously reported (Ann Thorac Surg 2007;84:1226-35). Echocardiograms were obtained every six months until the last patient was followed for one year, and then annually thereafter. Standard measurements of LV volumes, ejection fraction, and sphericity index were made by a Core laboratory at the Mayo Clinic who were blinded to treatment assignment., Results: Patients treated with the CorCap Cardiac Support Device had significant reductions in LV end diastolic volume (average difference 18.8 mL; p = 0.005) and LV end systolic volume (average difference 15.6 mL; p = 0.013) compared with the control group. Sphericity index was significantly increased in the treatment group (average difference 0.045 units; p = 0.018). These changes were maintained over three years of follow-up. The improvements in LV size and shape were observed when the CorCap was implanted concomitantly with mitral value surgery or by itself., Conclusions: These results demonstrate that the CorCap Cardiac Support Device has a long-term beneficial impact on LV size and shape in patients with heart failure.

Background: Left ventricular (LV) remodeling is related to adverse outcomes in heart failure. The CorCap Cardiac Support Device (CSD; Acorn Cardiovascular, Inc, St. Paul, MN) is an implantable device that attenuates LV remodeling., Methods: The Acorn trial assessed the safety and efficacy of the CSD in 300 heart failure patients. Patients needing mitral surgery (n = 193) were randomized to mitral surgery alone or mitral surgery plus CSD. Patients who did not need mitral surgery (n = 107) were randomized to medical therapy or medical therapy plus CSD. The primary endpoint was a clinical composite based on changes in patient vital status, the need for major cardiac procedures for worsening heart failure, and a change in New York Heart Association (NYHA) class., Results: The proportional odds ratio for the primary endpoint favored treatment with the CSD (1.73 confidence interval [CI]: 1.07 to 2.79; p = 0.024). The CSD-treated patients received significantly (p = 0.01) fewer cardiac procedures indicative of worsening heart failure and had an improvement in New York Heart Association class (p = 0.049). There was no significant difference in survival between groups (p = 0.85). Treatment with the CSD led to a decrease in LV end-diastolic (p = 0.009) and end-systolic volumes (p = 0.017), an increase in the LV sphericity index (p = 0.026), an improvement in the Minnesota Living with Heart Failure score (p = 0.04), and the Short Form-36 Questionnaire (p = 0.015). There was no evidence for a significant difference (p = 0.43) in serious adverse events between the treatment and control groups., Conclusions: The results of the Acorn trial support the hypothesis that preventing LV remodeling with a CSD favorably impacts the untoward natural history of heart failure.

Objectives: Patients with heart failure have increased circulating levels of tumor necrosis factor (TNF) and TNF receptors. It is not known whether TNF, which is known to blunt beta-adrenergic responsiveness in experimental models, contributes to the loss of heart rate variability in patients with heart failure. Therefore, we examined heart rate variability in relation to circulating levels of TNF, TNF receptors, and norepinephrine in patients with heart failure and in control subjects., Methods: Heart rate variability was obtained from 24-h ambulatory ECG recordings in age-matched control subjects (n = 10) and patients with mild (n = 15) to moderate (n = 14) heart failure. Plasma levels of TNF and soluble type 1 and 2 TNF receptors were measured by enzyme-linked immunoassay; plasma norepinephrine levels were measured by high-performance liquid chromatography., Results: There was a significant inverse linear correlation between increased circulating levels of TNF, TNF receptors, and norepinephrine for time-domain and frequency-domain indexes of heart rate variability among patients with heart failure and control subjects. Multiple stepwise linear regression analysis showed that TNF was a stronger independent predictor of frequency-domain indexes of heart rate variability than norepinephrine., Conclusions: TNF is an independent predictor of depressed heart rate variability in patients with heart failure. Insofar as TNF blunts beta-adrenergic signaling, this study suggests the possibility that overexpression of TNF and subsequent loss of beta-adrenergic responsiveness contributes to the decrease in heart rate variability observed in heart failure.

Study Objectives: Proinflammatory cytokines may contribute to disease progression in heart failure by virtue of the direct toxic effects that these molecules exert on the heart and the circulation. Accordingly, there is interest in developing therapeutic agents with anticytokine properties that might be used as adjunctive therapy to modulate proinflammatory cytokine levels in patients with heart failure. Previous experimental studies suggested that vesnarinone has potent anticytokine properties in vitro. Therefore, we examined the effects of vesnarinone on circulating levels of cytokines and cytokine receptors in a large-scale, multicenter, clinical trial of patients with moderate-to-advanced heart failure: the Vesnarinone Trial (VEST)., Methods: Circulating levels of tumor necrosis factor (TNF)-alpha, soluble TNF-receptor type 1, soluble TNF-receptor type 2, as well as interleukin (IL)-6 and soluble IL-6 receptor (sIL-6R) were measured on plasma samples by enzyme-linked immunosorbent assay at baseline and at 24 weeks in patients who were receiving placebo (n = 352), 30 mg of vesnarinone (n = 367), and 60 mg of vesnarinone (n = 327)., Results: Treatment with 30 mg and 60 mg of vesnarinone had no effect on circulating levels of cytokines or cytokine receptors in patients with advanced heart failure over a 24-week period., Conclusions: In contrast to the potent anticytokine effects observed with vesnarinone in experimental studies in vitro, the results of this clinical study suggest that vesnarinone does not have any measurable anticytokine effects in vivo in patients with moderate-to-advanced heart failure.

Background: Plasma levels of proinflammatory cytokines, including tumor necrosis factor (TNF)-alpha and interleukin (IL)-6, are elevated in patients with congestive heart failure (CHF). Recent studies suggest that the failing human heart is a source of proinflammatory cytokines in the end-stage failing heart. However, the relevance of plasma levels to those of the myocardium remains undefined. We sought to compare cytokine expression in early and end-stage CHF, and to evaluate the correlation of tissue expression to plasma levels., Methods: Two patient populations were studied: patients with recent-onset CHF, all with symptoms less than 6 months (n = 17, duration of symptoms 2.1 +/- 1.6 months, range of New York Heart Association (NYHA) 1 to 3), and end-stage heart-failure patients (n = 7) who underwent left-ventricular assist-device (LVAD) implantation (Duration of symptoms 47.1 +/- 28.0 months, all NYHA class 4). Plasma levels of TNF-alpha and IL-6 proteins were evaluated by an Enzyme-Linked Immuno-Sorbent Assay (ELISA), while myocardial levels of cytokine transcripts were assessed by ribonuclease (Rnase) protection assay., Results: In patients with end-stage heart failure, TNF-alpha and IL-6 were increased in the plasma as well as in the myocardium (plasma: TNF-alpha = 7.7 +/- 2.3 pg/ml, IL-6 = 45.0 +/- 47.1 pg/ml; myocardium: TNF-alpha = 0.31 +/- 0.15% of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) expression, IL-6 = 1.56 +/- 1.54% ). In contrast, despite elevated plasma levels of TNF-alpha and IL-6, the myocardium of patients with the recent onset of symptoms demonstrated minimal expression of TNF-alpha and IL-6 messenger ribonucleic acid (mRNA) (plasma: TNF-alpha = 4.3 +/- 1.7 pg/ml, IL-6 = 3.3 +/- 1.8 pg/ml; myocardium: TNF-alpha = 0.13 +/- 0. 04%, IL-6 = 0.02 +/- 0.04%). Plasma levels of TNF-alpha were significantly correlated with those in the myocardium when both populations were combined. (r = 0.69, p < 0.001)., Conclusions: Cytokines are expressed in the myocardium in end-stage heart failure to a much greater degree than in patients with the recent-onset of symptoms. This suggests that induction of cytokines in the myocardium is a relatively late event in the pathogenesis of CHF. Furthermore, plasma levels of TNF-alpha correlates with mRNA expression in the myocardium and thus may serve as an appropriate marker of myocardial cytokine activation. Whether the production of cytokines in the failing human heart precedes the elevation of cytokines in the plasma remains undefined. Therefore, we studied expression of TNF-alpha and IL-6 in the myocardium as well as in the plasma in patients with early and end-stage CHF. The results have demonstrated that cytokines are expressed in the myocardium in end-stage heart failure to a much greater degree than in patients with the recent onset of symptoms. This suggests that induction of cytokines in the myocardium is a relatively late event in the pathogenesis of CHF.

The relationship between SR Ca2+ ATPase (SERCA) activities, cell calcium level, SR calcium store and cell cycle events is not clearly understood. We studied SERCA overexpression in Cos cells using an adenovirus vector. Twofold increases in SERCA mRNA and in protein were correlated with a 2.3-fold and a 1.6-fold paralleled increase in SR calcium pump activity (R = 0.97 and R = 0.99 respectively). Dose-related apoptotic cell death was associated with SERCA overexpression (R = 0.92). When serum was reduced to 4%, cell apoptosis further increased from 20.7 +/- 4.8% to 47.5 +/- 12.9% (M+/-SD; P<0.05; n=3). Flow cytometry identified cell cycle arrest at the G2/M phase. The interleukin-1 converting enzyme (ICE) inhibitor z-VAD-fmk reduced apoptosis for low-, medium- and high-expressing constructs, whereas the CPP-32 inhibitor z-DEVD-fmk had no effect. Flow cytometry using Fluo-3 and Fura-Red revealed a 1.5-fold higher basal calcium and a 10-fold SR calcium overload. ICE inhibitor z-VAD-fmk did not alter calcium loading. An epitope-tagged SERCA mutant, which has no intrinsic Ca2+-pump activities, had a much smaller effect on the SR calcium. These findings suggest that SERCA2A overexpression has an intrinsic role in altering cell-cycle progression, augmenting cellular and SR calcium loading, and precipitating ICE protease-mediated apoptosis; this represents as a novel model for primary SR calcium overload and associated cell apoptosis.

Despite repeated attempts to develop a unifying hypothesis that explains the clinical syndrome of heart failure, no single conceptual paradigm has withstood the test of time. In this regard, recent studies have shown that a class of biologically active molecules, generically referred to as cytokines, are overexposed in heart failure. This article will review recent clinical and experimental material that suggest proinflammatory (stress activated) cytokines such as tumor necrosis factor-alpha (TFN-alpha), interleukin-1 (IL-1), and interleukin-6 (IL-6) may play a role in the pathogenesis of congestive heart failure. The scope of this article includes an overview of the biology of cytokines in the heart, as well as review of the clinical studies that have documented elevated levels of cytokines and cytokine receptors in patients with heart failure.

The incidence and severity of catheter-induced tricuspid regurgitation has not been studied extensively. Given the frequency with which right heart catheters are employed to measure cardiac output, it is important to know whether the severity of catheter-induced tricuspid regurgitation is sufficient to invalidate the measurement of thermodilution cardiac output. Accordingly, the purpose of the present prospective study was to determine the incidence and severity of catheter-induced tricuspid regurgitation in 25 men (mean age, 58.1 +/- 1.4 years) using Doppler ultrasound. The tricuspid valve was interrogated from two orthogonal views using pulsed-wave and color flow Doppler, either in the presence or absence of a 7-French catheter across the tricuspid valve. The severity of catheter-induced tricuspid regurgitation was graded semiquantitatively using a validated scoring system. Pulsed-wave Doppler studies showed that the incidence of catheter-induced tricuspid regurgitation was 48 percent, and that the average tricuspid regurgitation score increased from 0.41 +/- 0.16 to 0.61 +/- 0.17 (p less than 0.01). Color flow Doppler studies showed similar findings. Further, the incidence of catheter-induced tricuspid regurgitation was not related to the patient's underlying hemodynamic status or right ventricular geometry. In conclusion, this study shows for the first time that the quantitative extent of catheter-induced tricuspid regurgitation is small, and is therefore unlikely to be important clinically, particularly with regard to the assessment of thermodilution cardiac output.