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Background/aim: The study aims to describe the role of diabetes in patients with heart failure., Methods: In all, 1052 chronic heart failure patients were included in the FARmacology and NeuroHumoral Activation (FAR NHL) multicenter prospective registry. They had ejection fraction below 50% and were on stable medication for at least 1 month., Results: More than one-third (38.9%) of the patients had diabetes mellitus (DM). Diabetic patients (N = 409) were older (median 67 vs. 64, p < 0.001), had higher body mass index (BMI) (30 vs. 28 kg/m 2 , p < 0.001), much more frequently had ischemic heart disease (71 vs. 47%, p < 0.001), hypertension (80 vs. 67%, p < 0.001), dyslipidemia (89 vs. 69%, p < 0.001), worse renal function (estimated glomerular filtration rate [eGFR] median 63 vs. 73 mL/min/1.73 m 2 , p < 0.001), and higher N-terminal pro-brain natriuretic peptide (NT-proBNP) (median 681 vs. 463 pg/mL, p = 0.003). All-cause death, left ventricle assist device implantation, and orthotopic heart transplantation were set as the combined primary end point, which was present in 15.5% (163 patients) within the 2-year follow-up. In the 2-year follow-up, 81.0% of patients with diabetes survived without a primary end point, while 85.4% of the patients without diabetes survived, the difference being on the verge of statistical significance (p = 0.089). DM is a statistically significant predictor of NT-proBNP value in univariate analysis, but it is not an independent predictor in a multivariate analysis. When the NT-proBNP level was high, the presence of DM did not influence the prognosis., Conclusion: The combination of diabetes and NT-proBNP levels may better stratify the prognosis of patients with chronic heart failure., (© 2024 The Author(s). Journal of Diabetes published by Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Background: Physical activity is pivotal in managing heart failure with reduced ejection fraction, and walking integrated into daily life is an especially suitable form of physical activity. This study aimed to determine whether a 6-month lifestyle walking intervention combining self-monitoring and regular telephone counseling improves functional capacity assessed by the 6-minute walk test (6MWT) in patients with stable heart failure with reduced ejection fraction compared with usual care., Methods: The WATCHFUL trial (Pedometer-Based Walking Intervention in Patients With Chronic Heart Failure With Reduced Ejection Fraction) was a 6-month multicenter, parallel-group randomized controlled trial recruiting patients with heart failure with reduced ejection fraction from 6 cardiovascular centers in the Czech Republic. Eligible participants were ≥18 years of age, had left ventricular ejection fraction <40%, and had New York Heart Association class II or III symptoms on guidelines-recommended medication. Individuals exceeding 450 meters on the baseline 6MWT were excluded. Patients in the intervention group were equipped with a Garmin vívofit activity tracker and received monthly telephone counseling from research nurses who encouraged them to use behavior change techniques such as self-monitoring, goal-setting, and action planning to increase their daily step count. The patients in the control group continued usual care. The primary outcome was the between-group difference in the distance walked during the 6MWT at 6 months. Secondary outcomes included daily step count and minutes of moderate to vigorous physical activity as measured by the hip-worn Actigraph wGT3X-BT accelerometer, NT-proBNP (N-terminal pro-B-type natriuretic peptide) and high-sensitivity C-reactive protein biomarkers, ejection fraction, anthropometric measures, depression score, self-efficacy, quality of life, and survival risk score. The primary analysis was conducted by intention to treat., Results: Of 218 screened patients, 202 were randomized (mean age, 65 years; 22.8% female; 90.6% New York Heart Association class II; median left ventricular ejection fraction, 32.5%; median 6MWT, 385 meters; average 5071 steps/day; average 10.9 minutes of moderate to vigorous physical activity per day). At 6 months, no between-group differences were detected in the 6MWT (mean 7.4 meters [95% CI, -8.0 to 22.7]; P =0.345, n=186). The intervention group increased their average daily step count by 1420 (95% CI, 749 to 2091) and daily minutes of moderate to vigorous physical activity by 8.2 (95% CI, 3.0 to 13.3) over the control group. No between-group differences were detected for any other secondary outcomes., Conclusions: Whereas the lifestyle intervention in patients with heart failure with reduced ejection fraction improved daily steps by about 25%, it failed to demonstrate a corresponding improvement in functional capacity. Further research is needed to understand the lack of association between increased physical activity and functional outcomes., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03041610., Competing Interests: Disclosures Dr Belohlavek reports receiving lecture honoraria and participation on advisory boards for Novartis, Boehringer Ingelheim, and AstraZeneca. Dr Linhart reports receiving lecture honoraria and participation on advisory boards for Novartis, Boehringer Ingelheim, and AstraZeneca. Dr Vesely reports receiving lecture honoraria and participation on advisory boards for Novartis, Boehringer Ingelheim, and AstraZeneca. Dr Svobodova reports receiving lecture honoraria from Novartis, Boehringer Ingelheim, and AstraZeneca and participation on an advisory board for Boehringer Ingelheim. Dr Pelouch reports receiving lecture honoraria from Novartis, Boehringer Ingelheim, and AstraZeneca. The other investigators report no conflicts of interest.

Background: Physical activity is an effective management strategy for heart failure with reduced ejection fraction, but patients' compliance is challenging. Walking is a suitable form of physical activity due to its convenience and sustainability, and it can potentially improve functional capacity in heart failure patients., Objectives: The WATCHFUL trial aims to determine whether a pedometer-based walking intervention combined with face-to-face sessions and regular telephone contact improves functional capacity in heart failure patients., Methods: The WATCHFUL trial is a 6-month multicenter, parallel-group, randomized, controlled, superiority trial with a 6-month follow-up. A total of 202 patients were recruited for the trial. The primary analysis will evaluate the change in distance walked during the 6-min walk test from baseline to 6 months based on the intention-to-treat population; the analysis will be performed using a linear mixed-effect model adjusted for baseline values. Missing data will be imputed using multiple imputations, and the impact of missing data will be assessed using a sensitivity analysis. Adverse events are monitored and recorded throughout the trial period., Discussion: The trial has been designed as a pragmatic trial with a scalable intervention that could be easily translated into routine clinical care. The trial has been affected by the COVID-19 pandemic, which slowed patients' recruitment and impacted their physical activity patterns., Conclusions: The present publication provides details of the planned statistical analyses for the WATCHFUL trial to reduce the risks of reporting bias and erroneous data-driven results., Trial Registration: ClinicalTrials.gov (identifier: NCT03041610, registered: 3/2/2017)., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Cardiopulmonary exercise testing parameters including ventilatory efficiency (V E /VCO 2 slope) are used for risk assessment of lung resection candidates. However, many patients are unable or unwilling to undergo exercise. V E /VCO 2 slope is closely related to the partial pressure of end-tidal carbon dioxide (P ET CO 2 ). We hypothesized P ET CO 2 at rest predicts postoperative pulmonary complications., Methods: Consecutive lung resection candidates were included in this prospective multicenter study. Postoperative respiratory complications were assessed from the first 30 postoperative days or from the hospital stay. Student t test or Mann-Whitney U test was used for comparison. Multivariate stepwise logistic regression analysis was used to analyze association with the development of postoperative pulmonary complications. The De Long test was used to compare area under the curve (AUC). Data are summarized as median (interquartile range)., Results: Three hundred fifty-three patients were analyzed, of which 59 (17%) developed postoperative pulmonary complications. P ET CO 2 at rest was significantly lower (27 [24-30] vs 29 [26-32] mm Hg; P < .01) and V E /VCO 2 slope during exercise significantly higher (35 [30-40] vs 29 [25-33]; P < .01) in patients who developed postoperative pulmonary complications. Both rest P ET CO 2 with odds ratio 0.90 (95% confidence interval [CI] 0.83-0.97); P = .01 and V E /VCO 2 slope with odds ratio 1.10 (95% CI 1.05-1.16); P < .01 were independently associated with postoperative pulmonary complications by multivariate stepwise logistic regression analysis. There was no significant difference between AUC of both models (rest P ET CO 2 : AUC = 0.79 (95% CI 0.74-0.85); V E /VCO 2 slope: AUC = 0.81 (95% CI 0.75-0.86); P = .48)., Conclusions: P ET CO 2 at rest has similar prognostic utility as V E /VCO 2 slope, suggesting rest P ET CO 2 may be used for postoperative pulmonary complications prediction in lung resection candidates., (Copyright © 2023 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

The term 'mechanosensation' describes the capacity of cells to translate mechanical stimuli into the coordinated regulation of intracellular signals, cellular function, gene expression and epigenetic programming. This capacity is related not only to the sensitivity of the cells to tissue motion, but also to the decryption of tissue geometric arrangement and mechanical properties. The cardiac stroma, composed of fibroblasts, has been historically considered a mechanically passive component of the heart. However, the latest research suggests that the mechanical functions of these cells are an active and necessary component of the developmental biology programme of the heart that is involved in myocardial growth and homeostasis, and a crucial determinant of cardiac repair and disease. In this Review, we discuss the general concept of cell mechanosensation and force generation as potent regulators in heart development and pathology, and describe the integration of mechanical and biohumoral pathways predisposing the heart to fibrosis and failure. Next, we address the use of 3D culture systems to integrate tissue mechanics to mimic cardiac remodelling. Finally, we highlight the potential of mechanotherapeutic strategies, including pharmacological treatment and device-mediated left ventricular unloading, to reverse remodelling in the failing heart., (© 2022. Springer Nature Limited.)

Aims: The management of congestion is one of the key treatment targets in heart failure. Assessing congestion is, however, difficult. The purpose of this study was to investigate the safety and dynamic response of a novel, passive, inferior vena cava (IVC) sensor in a chronic ovine model., Methods and Results: A total of 20 sheep divided into three groups were studied in acute and chronic in vivo settings. Group I and Group II included 14 sheep in total with 12 sheep receiving the sensor and two sheep receiving a control device (IVC filter). Group III included an additional six animals for studying responses to volume challenges via infusion of blood and saline solutions. Deployment was 100% successful with all devices implanted; performing as expected with no device-related complications and signals were received at all observations. At similar volume states no significant differences in IVC area normalized to absolute area range were measured (55 ± 17% on day 0 and 62 ± 12% on day 120, p = 0.51). Chronically, the sensors were completely integrated with a thin, reendothelialized neointima with no loss of sensitivity to infused volume. Normalized IVC area changed significantly from 25 ± 17% to 43 ± 11% (p = 0.007) with 300 ml infused. In contrast, right atrial pressure required 1200 ml of infused volume prior to a statistically significant change from 3.1 ± 2.6 mmHg to 7.5 ± 2.0 mmHg (p = 0.02)., Conclusion: In conclusion, IVC area can be measured remotely in real-time using a safe, accurate, wireless, and chronic implantable sensor promising to detect congestion with higher sensitivity than filling pressures., (© 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Electromechanical coupling in patients receiving cardiac resynchronization therapy (CRT) is not fully understood. Our aim was to determine the best combination of electrical and mechanical substrates associated with effective CRT., Methods and Results: Sixty-two patients were prospectively enrolled from two centres. Patients underwent 12-lead electrocardiogram (ECG), cardiovascular magnetic resonance (CMR), echocardiography, and anatomo-electromechanical mapping (AEMM). Remodelling was measured as the end-systolic volume (ΔESV) decrease at 6 months. CRT was defined effective with ΔESV ≤ -15%. QRS duration (QRSd) was measured from ECG. Area strain was obtained from AEMM and used to derive systolic stretch index (SSI) and total left-ventricular mechanical time. Total left-ventricular activation time (TLVAT) and transeptal time (TST) were derived from AEMM and ECG. Scar was measured from CMR. Significant correlations were observed between ΔESV and TST [rho = 0.42; responder: 50 (20-58) vs. non-responder: 33 (8-44) ms], TLVAT [-0.68; 81 (73-97) vs. 112 (96-127) ms], scar [-0.27; 0.0 (0.0-1.2) vs. 8.7 (0.0-19.1)%], and SSI [0.41; 10.7 (7.1-16.8) vs. 4.2 (2.9-5.5)], but not QRSd [-0.13; 155 (140-176) vs. 167 (155-177) ms]. TLVAT and SSI were highly accurate in identifying CRT response [area under the curve (AUC) > 0.80], followed by scar (AUC > 0.70). Total left-ventricular activation time (odds ratio = 0.91), scar (0.94), and SSI (1.29) were independent factors associated with effective CRT. Subjects with SSI >7.9% and TLVAT <91 ms all responded to CRT with a median ΔESV ≈ -50%, while low SSI and prolonged TLVAT were more common in non-responders (ΔESV ≈ -5%)., Conclusion: Electromechanical measurements are better associated with CRT response than conventional ECG variables. The absence of scar combined with high SSI and low TLVAT ensures effectiveness of CRT., Competing Interests: Conflict of interest: F.M. reports intellectual property with Biosense Webster. A.A. is a consultant to Boston Scientific, Backbeat, Biosense Webster, Cardiac, Corvia, Daiichi Sankyo, Medtronic, Merit, Microport CRM, Philips, and V-Wave; he received speakers’ fee from Daiichi Sankyo, Boston Scientific, Biosense Webster, Medtronic, Microport CRM, and Philips; he participated in clinical trials sponsored by Boston Scientific, Medtronic, Microport CRM, and Zoll Medical; he reports intellectual properties with Boston Scientific, Biosense Webster, and Microport CRM. F.W.P. has received research grants from Medtronic, Abbott, Microport CRM, Biotronik, and Biosense Webster and speakers fee from Medtronic, Abbott, and Microport CRM. He reports intellectual property with Boston Scientific, Medtronic, and Biosense Webster. K.S.G. received speakers’ fee from Medtronic and participated in clinical trials sponsored by Medtronic and Abbott. W.W. received lecture honorarium from the Biosense Webster. All other authors do not have disclosures., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Introduction: Ventilatory efficiency (VE/VCO2 slope) has been shown superior to peak oxygen consumption (VO2) for prediction of post-operative pulmonary complications in patients undergoing thoracotomy. VE/VCO2 slope is determined by ventilatory drive and ventilation/perfusion mismatch whereas VO2 is related to cardiac output and arteriovenous oxygen difference. We hypothesized pre-operative VO2 predicts post-operative cardiovascular complications in patients undergoing lung resection., Methods: Lung resection candidates from a published study were evaluated by post-hoc analysis. All of the patients underwent preoperative cardiopulmonary exercise testing. Post-operative cardiovascular complications were assessed during the first 30 post-operative days or hospital stay. One-way analysis of variance or the Kruskal-Wallis test, and multivariate logistic regression were used for statistical analysis and data summarized as median (IQR)., Results: Of 353 subjects, 30 (9%) developed pulmonary complications only (excluded from further analysis), while 78 subjects (22%) developed cardiovascular complications and were divided into two groups for analysis: cardiovascular only (n = 49) and cardiovascular with pulmonary complications (n = 29). Compared to patients without complications (n = 245), peak VO2 was significantly lower in the cardiovascular with pulmonary complications group [19.9 ml/kg/min (16.5-25) vs. 16.3 ml/kg/min (15-20.3); P<0.01] but not in the cardiovascular only complications group [19.9 ml/kg/min (16.5-25) vs 19.0 ml/kg/min (16-23.1); P = 0.18]. In contrast, VE/VCO2 slope was significantly higher in both cardiovascular only [29 (25-33) vs. 31 (27-37); P = 0.05] and cardiovascular with pulmonary complication groups [29 (25-33) vs. 37 (34-42); P<0.01)]. Logistic regression analysis showed VE/VCO2 slope [OR = 1.06; 95%CI (1.01-1.11); P = 0.01; AUC = 0.74], but not peak VO2 to be independently associated with post-operative cardiovascular complications., Conclusion: VE/VCO2 slope is superior to peak VO2 for prediction of post-operative cardiovascular complications in lung resection candidates., Competing Interests: The authors have declared that no competing interests exist.

Background: Primary preventive implantation of implantable defibrillator (ICD) is according to current guidelines indicated in patients with heart failure NYHA (New York Heart Association) class II/III and LVEF <35%. Thanks to advances in heart failure pharmacotherapy, a decrease in mortality could render a benefit of ICD insufficient to justify its implantation in some patients., Methods: Study design: multicenter, prospective, randomized, controlled trial evaluating the benefit of implantation of Cardiac Resynchronization and Defibrillator Therapy (CRT-D) or CRT Alone (CRT-P) in non-ischemic patients with reduced left ventricle ejection fraction (LVEF) and optimal pharmacotherapy without significant mid-wall myocardial fibrosis detected by cardiac magnetic resonance (CMR). The primary end-point: Re-hospitalization for heart failure, ventricular tachycardia, major adverse cardiac events (MACE). The secondary end-points: Sudden cardiac death, cardiovascular death, resuscitated cardiac arrest or sustained ventricular tachycardia, device-related complications, and change in quality of life. Course of the study: After a pharmacotherapy is optimized and significant mid-wall myocardial fibrosis excluded, patients will be randomized 1:1 to CRT-P or CRT-D implantation., Discussion: If our hypothesis is confirmed, this could provide evidence for the management of these patients with a significant impact on common daily praxis and health care expenditures., Clinicaltrials: gov, NCT04139460., Competing Interests: The authors report no conflicts of interest in this work.

The sodium-glucose cotransporter 2 inhibitor empagliflozin reduces the risk of cardiovascular death or heart failure hospitalization in patients with chronic heart failure, but whether empagliflozin also improves clinical outcomes when initiated in patients who are hospitalized for acute heart failure is unknown. In this double-blind trial (EMPULSE; NCT04157751 ), 530 patients with a primary diagnosis of acute de novo or decompensated chronic heart failure regardless of left ventricular ejection fraction were randomly assigned to receive empagliflozin 10 mg once daily or placebo. Patients were randomized in-hospital when clinically stable (median time from hospital admission to randomization, 3 days) and were treated for up to 90 days. The primary outcome of the trial was clinical benefit, defined as a hierarchical composite of death from any cause, number of heart failure events and time to first heart failure event, or a 5 point or greater difference in change from baseline in the Kansas City Cardiomyopathy Questionnaire Total Symptom Score at 90 days, as assessed using a win ratio. More patients treated with empagliflozin had clinical benefit compared with placebo (stratified win ratio, 1.36; 95% confidence interval, 1.09-1.68; P = 0.0054), meeting the primary endpoint. Clinical benefit was observed for both acute de novo and decompensated chronic heart failure and was observed regardless of ejection fraction or the presence or absence of diabetes. Empagliflozin was well tolerated; serious adverse events were reported in 32.3% and 43.6% of the empagliflozin- and placebo-treated patients, respectively. These findings indicate that initiation of empagliflozin in patients hospitalized for acute heart failure is well tolerated and results in significant clinical benefit in the 90 days after starting treatment., (© 2022. The Author(s).)

Background and Objective: Short- and long-term mortality following ischemic stroke (IS) and their predictors have not been defined in the Czech population, and studies on long-term mortality are largely missing for the populations of Central Europe., Methods: Using the National Register of Hospitalized Patients and the Czech National Mortality Registry, we analyzed data on 1-month, 1-year, and 3-year all-cause mortality for patients admitted with IS to any of the 4 hospitals with a certified stroke unit in Brno, Czech Republic, in 2011. We reviewed discharge summaries and recorded potential factors impacting mortality after the index stroke event. Using univariate and multivariable analyses, we identified predictors of mortality at all 3 time points., Results: In our multivariable model, statin use (odds ratio [OR] 0.095, p < 0.0001), age at stroke (OR 1.03, p = 0.0445), and admission National Institutes of Health Stroke Scale (NIHSS) score (OR 1.16, p < 0.0001) predicted 1-month mortality, while statin use (OR 0.43, p = 0.0004), history of cardiac failure (OR 2.17, p = 0.0137), age at stroke (OR 1.07, p < 0.0001), and admission NIHSS score (OR 1.14, p < 0.0001) predicted 1-year mortality. Statin use (OR 0.54, p = 0.0051), history of cardiac failure (OR 2.13, p = 0.0206), age at stroke (OR 1.07, p < 0.0001), and admission NIHSS score (OR 1.11, p < 0.0001) also predicted 3-year mortality., Conclusions: Our study is the first to report data on short- and long-term mortality rates and their predictors in patients hospitalized with IS in the Czech population. Our results indicate that mortality rates and predictors of mortality are consistent with those reported in studies from other populations throughout the world., (© 2021 The Author(s). Published by S. Karger AG, Basel.)

Background: The identification of high-risk heart failure (HF) patients makes it possible to intensify their treatment. Our aim was to determine the prognostic value of a newly developed, high-sensitivity troponin I assay (Atellica®, Siemens Healthcare Diagnostics) for patients with HF with reduced ejection fraction (HFrEF; LVEF < 40%) and HF with mid-range EF (HFmrEF) (LVEF 40%-49%)., Methods and Results: A total of 520 patients with HFrEF and HFmrEF were enrolled in this study. Two-year all-cause mortality, heart transplantation, and/or left ventricular assist device implantation were defined as the primary endpoints (EP). A logistic regression analysis was used for the identification of predictors and development of multivariable models. The EP occurred in 14% of the patients, and these patients had higher NT-proBNP (1,950 vs. 518 ng/l; p < 0.001) and hs-cTnI (34 vs. 17 ng/l, p < 0.001) levels. C-statistics demonstrated that the optimal cut-off value for the hs-cTnI level was 17 ng/l (AUC 0.658, p < 0.001). Described by the AUC, the discriminatory power of the multivariable model (NYHA > II, NT-proBNP, hs-cTnI and urea) was 0.823 (p < 0.001). Including heart failure hospitalization as the component of the combined secondary endpoint leads to a diminished predictive power of increased hs-cTnI., Conclusion: hs-cTnI levels ≥ 17 ng/l represent an independent increased risk of an adverse prognosis for patients with HFrEF and HFmrEF. Determining a patient's hs-cTnI level adds prognostic value to NT-proBNP and clinical parameters., Competing Interests: The authors have declared that no competing interests exist.

Background: The latest European heart failure guidelines define patients as those with reduced (HFrEF), mid-range, and preserved (HFpEF) left ventricular ejection fraction (LVEF; <40%, 40%-49%, and ≥50%, respectively). We investigated the causes of rehospitalizations/deaths in our institution's heart failure patients and focused on differences in the clinical presentation, risk profile, and long-term outcomes between the HFrEF and HFpEF groups in a real-life scenario., Methods and Results: We followed 1274 patients discharged from heart failure hospitalization in 2 centres. The mean patient age was 75.9 years, and men and women were represented equally. During the minimal follow-up of 2 years, 57% of patients were hospitalised for any cause, 24.9% for decompensated heart failure, and 43.3% for any cardiovascular cause. A total of 36.1% of patients died, either with prior (11.8%) or without prior (24.3%) heart failure rehospitalization. Heart failure was also the most frequent cause of cardiovascular hospitalization, followed by gastrointestinal problems, infections, and tumours for noncardiovascular hospitalizations. Patients with HFrEF had different baseline characteristics and risk profiles, experienced more hospitalizations for acute heart failure (28.6% vs 20.2%, P=0.012), and had higher cardiovascular mortality (82.4% vs 63.5%, P<0.001) when compared with HFpEF patients. Overall mortality and rehospitalization rates were similar., Conclusion: Within 2 years, half of the patients died and/or were hospitalised for acute decompensation of heart failure, and only one-third of the patients survived without any hospitalization. HFrEF and HFpEF patients were confirmed to be different entities with diverse characteristics, risk profiles, and cardiovascular event rates.

Rationale: Cardiac ECM (extracellular matrix) comprises a dynamic molecular network providing structural support to heart tissue function. Understanding the impact of ECM remodeling on cardiac cells during heart failure (HF) is essential to prevent adverse ventricular remodeling and restore organ functionality in affected patients., Objectives: We aimed to (1) identify consistent modifications to cardiac ECM structure and mechanics that contribute to HF and (2) determine the underlying molecular mechanisms., Methods and Results: We first performed decellularization of human and murine ECM (decellularized ECM) and then analyzed the pathological changes occurring in decellularized ECM during HF by atomic force microscopy, 2-photon microscopy, high-resolution 3-dimensional image analysis, and computational fluid dynamics simulation. We then performed molecular and functional assays in patient-derived cardiac fibroblasts based on YAP (yes-associated protein)-transcriptional enhanced associate domain (TEAD) mechanosensing activity and collagen contraction assays. The analysis of HF decellularized ECM resulting from ischemic or dilated cardiomyopathy, as well as from mouse infarcted tissue, identified a common pattern of modifications in their 3-dimensional topography. As compared with healthy heart, HF ECM exhibited aligned, flat, and compact fiber bundles, with reduced elasticity and organizational complexity. At the molecular level, RNA sequencing of HF cardiac fibroblasts highlighted the overrepresentation of dysregulated genes involved in ECM organization, or being connected to TGFβ1 (transforming growth factor β1), interleukin-1, TNF-α, and BDNF signaling pathways. Functional tests performed on HF cardiac fibroblasts pointed at mechanosensor YAP as a key player in ECM remodeling in the diseased heart via transcriptional activation of focal adhesion assembly. Finally, in vitro experiments clarified pathological cardiac ECM prevents cell homing, thus providing further hints to identify a possible window of action for cell therapy in cardiac diseases., Conclusions: Our multiparametric approach has highlighted repercussions of ECM remodeling on cell homing, cardiac fibroblast activation, and focal adhesion protein expression via hyperactivated YAP signaling during HF.

Aims: EMPEROR-Preserved is an ongoing trial evaluating the effect of empagliflozin in patients with heart failure with preserved ejection fraction (HFpEF). This report describes the baseline characteristics of the EMPEROR-Preserved cohort and compares them with patients enrolled in prior HFpEF trials., Methods and Results: EMPEROR-Preserved is a phase III randomized, international, double-blind, parallel-group, placebo-controlled trial in which 5988 symptomatic HFpEF patients [left ventricular ejection fraction (LVEF) >40%] with and without type 2 diabetes mellitus (T2DM) have been enrolled. Patients were required to have elevated N-terminal pro B-type natriuretic peptide (NT-proBNP) concentrations (i.e. >300 pg/mL in patients without and >900 pg/mL in patients with atrial fibrillation) along with evidence of structural changes in the heart or documented history of heart failure hospitalization. Among patients enrolled from various regions (45% Europe, 11% Asia, 25% Latin America, 12% North America), the mean age was 72 ± 9 years, 45% were women. Almost all patients had New York Heart Association class II or III symptoms (99.6%), and 23% had prior heart failure hospitalization within 12 months. Thirty-three percent of the patients had baseline LVEF of 41-50%. The mean LVEF (54 ± 9%) was slightly lower while the median NT-proBNP [974 (499-1731) pg/mL] was higher compared with previous HFpEF trials. Presence of comorbidities such as diabetes (49%) and chronic kidney disease (50%) were common. The majority of the patients were on angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor-neprilysin inhibitors (80%) and beta-blockers (86%), and 37% of patients were on mineralocorticoid receptor antagonists., Conclusion: When compared with prior trials in HFpEF, the EMPEROR-Preserved cohort has a somewhat higher burden of comorbidities, lower LVEF, higher median NT-proBNP and greater use of mineralocorticoid receptor antagonists at baseline. Results of the EMPEROR-Preserved trial will be available in 2021., (© 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is being tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF) trial. Here we describe the baseline characteristics of participants in GALACTIC-HF and how these compare with other contemporary trials., Methods and Results: Adults with established HFrEF, New York Heart Association (NYHA) functional class ≥II, ejection fraction ≤35%, elevated natriuretic peptides and either current hospitalization for heart failure or history of hospitalization/emergency department visit for heart failure within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic-guided dosing: 25, 37.5, or 50 mg bid). A total of 8256 patients [male (79%), non-white (22%), mean age 65 years] were enrolled with a mean ejection fraction 27%, ischaemic aetiology in 54%, NYHA class II 53% and III/IV 47%, and median N-terminal pro-B-type natriuretic peptide 1971 pg/mL. Heart failure therapies at baseline were among the most effectively employed in contemporary heart failure trials. GALACTIC-HF randomized patients representative of recent heart failure registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure <100 mmHg (n = 1127), estimated glomerular filtration rate <30 mL/min/1.73 m 2 (n = 528), and treated with sacubitril/valsartan at baseline (n = 1594)., Conclusions: GALACTIC-HF enrolled a well-treated, high-risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation., (© 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure in patients regardless of the presence or absence of diabetes. More evidence is needed regarding the effects of these drugs in patients across the broad spectrum of heart failure, including those with a markedly reduced ejection fraction., Methods: In this double-blind trial, we randomly assigned 3730 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less to receive empagliflozin (10 mg once daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of cardiovascular death or hospitalization for worsening heart failure., Results: During a median of 16 months, a primary outcome event occurred in 361 of 1863 patients (19.4%) in the empagliflozin group and in 462 of 1867 patients (24.7%) in the placebo group (hazard ratio for cardiovascular death or hospitalization for heart failure, 0.75; 95% confidence interval [CI], 0.65 to 0.86; P<0.001). The effect of empagliflozin on the primary outcome was consistent in patients regardless of the presence or absence of diabetes. The total number of hospitalizations for heart failure was lower in the empagliflozin group than in the placebo group (hazard ratio, 0.70; 95% CI, 0.58 to 0.85; P<0.001). The annual rate of decline in the estimated glomerular filtration rate was slower in the empagliflozin group than in the placebo group (-0.55 vs. -2.28 ml per minute per 1.73 m 2 of body-surface area per year, P<0.001), and empagliflozin-treated patients had a lower risk of serious renal outcomes. Uncomplicated genital tract infection was reported more frequently with empagliflozin., Conclusions: Among patients receiving recommended therapy for heart failure, those in the empagliflozin group had a lower risk of cardiovascular death or hospitalization for heart failure than those in the placebo group, regardless of the presence or absence of diabetes. (Funded by Boehringer Ingelheim and Eli Lilly; EMPEROR-Reduced ClinicalTrials.gov number, NCT03057977.)., (Copyright © 2020 Massachusetts Medical Society.)

Aims: A reduction of habitual physical activity due to prolonged COVID-19 quarantine can have serious consequences for patients with cardiovascular diseases, such as heart failure. This study aimed to explore the effect of COVID-19 nationwide quarantine on accelerometer-assessed physical activity of heart failure patients., Methods and Results: We analysed the daily number of steps in 26 heart failure patients during a 6-week period that included 3 weeks immediately preceding the onset of the quarantine and the first 3 weeks of the quarantine. The daily number of steps was assessed using a wrist-worn accelerometer worn by the patients as part of an ongoing randomized controlled trial. Multilevel modelling was used to explore the effect of the quarantine on the daily step count adjusted for weather conditions. As compared with the 3 weeks before the onset of the quarantine, the step count was significantly lower during each of the first 3 weeks of the quarantine (P < 0.05). When the daily step count was averaged across the 3 weeks before and during the quarantine, the decrease amounted to 1134 (SE 189) steps per day (P < 0.001), which translated to a 16.2% decrease., Conclusions: The introduction of the nationwide quarantine due to COVID-19 had a detrimental effect on the level of habitual physical activity in heart failure patients, leading to an abrupt decrease of daily step count that lasted for at least the 3-week study period. Staying active and maintaining sufficient levels of physical activity during the COVID-19 pandemic are essential despite the unfavourable circumstances of quarantine., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Aims: Danon disease (DD) is a rare X-linked disorder caused by mutations in the lysosomal-associated membrane protein type 2 gene (LAMP2). DD is difficult to distinguish from other causes of dilated or hypertrophic cardiomyopathy (HCM) in female patients. As DD female patients regularly progress into advanced heart failure (AHF) aged 20-40 years, their early identification is critical to improve patient survival and facilitate genetic counselling. In this study, we evaluated the prevalence of DD among female patients with non-ischemic cardiomyopathy, who reached AHF and were younger than 40 years., Methods and Results: The study cohort comprised 60 female patients: 47 (78%) heart transplant recipients, 2 (3%) patients treated with ventricular assist device, and 11 (18%) patients undergoing pre-transplant assessment. Aetiology of the cardiomyopathy was known in 15 patients (including two DD patients). LAMP2 expression in peripheral white blood cells (WBC) was tested by flow cytometry (FC) in the remaining 45 female patients. Whole exome sequencing was used as an alternative independent testing method to FC. Five additional female DD patients (two with different novel LAMP2 mutations) were identified by FC. The total prevalence of DD in this cohort was 12%. HCM phenotype (57% vs. 9%, * P = 0.022) and delta waves identified by electrocardiography (43% vs. 0%, ** P = 0.002) were significantly more frequent in DD female patients., Conclusions: Danon disease is an underdiagnosed cause of AHF in young female patients. LAMP2 expression testing in peripheral WBCs by FC can be used as an effective screening/diagnostic tool to identify DD in this patient population., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Background: Exercise oscillatory ventilation (EOV) is a consequence of ventilatory control system instability and is commonly observed in patients with advanced heart failure (HF); it is associated with adverse prognosis. The goal of this study was to evaluate the effects of cardiac resynchronization therapy (CRT) on oscillatory ventilation as quantified by a proposed EOV score., Methods and Results: Consecutive patients with HF (N = 35) who underwent clinically indicated CRT, cardiopulmonary exercise testing and carbon dioxide (CO 2 ) chemosensitivity by rebreathe before and 4-6 months after CRT were included in this post hoc analysis. With CRT, EOV scores improved in 22 patients (63%). In these patients, left ventricular ejection fraction, left atrial volume, brain natriuretic peptide concentration, and CO 2 chemosensitivity significantly improved after CRT (P < 0.05). Furthermore, minute ventilation per unit CO 2 production significantly decreased, and end-tidal CO 2 increased at rest and at peak exercise post-CRT. Multiple regression analysis showed only the change of CO 2 chemosensitivity to be significantly associated with the improvement of the EOV score (b = 0.64; F = 11.3; P = 0.004). In the group without EOV score improvement (n = 13), though left ventricular ejection fraction significantly increased with CRT (P = 0.015), no significant changes in ventilation or gas exchange were observed., Conclusion: The EOV score was mitigated by CRT and was associated with decreased CO 2 chemosensitivity., (Copyright © 2020. Published by Elsevier Inc.)

Background: Heart rate (HR) at admission in patients with acute heart failure (AHF) has been shown to be an important risk marker of in-hospital mortality. However, its relation with mid and long-term prognosis as well as the impact of Ejection Fraction (EF) is unknown. Our objective was to study the relationship between long-term survival and HR at admission depending on EF in a cohort of patients hospitalized for AHF., Methods: We analyzed the data of 2335 patients in sinus rhythm hospitalized for AHF from AHEAD registry. Patients with cardiogenic shock and AHF from surgical or non-cardiac etiology were excluded., Results: Survival rates at 6 and 12 months were 84.8% and 78% respectively. Increased age, decreased diastolic BP, lack of PCI during hospitalization, increased creatinine level and increased HR (with different cut-offs according to EF categories) were found as predictors whatever the EF at 6 and 12 months. Optimal prognostic cut-offs of heart rate were identified for Heart Failure with reduced EF at 100 bpm, for Heart Failure with mid-range EF at 90 bpm and for Heart Failure with preserved EF at 80 bpm for both 6 and 12 months., Conclusion: Our study suggests that HR at admission appears to be an independent prognostic parameter in AHF patients in sinus rhythm irrespective of EF and can be used to classify patients according to the severity of the disease., Competing Interests: Declaration of conflict of interest The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. BT and FF are employees of Institut de Recherches Internationales Servier (IRIS). All authors declare no potential conflict of interest related to this article., (Copyright © 2020 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

B-type natriuretic peptide (BNP) exhibits roles in natriuresis and diuresis, making it an ideal drug that may aid in diuresing a fluid-overloaded patient with poor or worsening renal function. Several randomized clinical trials have tested the hypothesis that infusions of pharmacological doses of BNP to acute heart failure (HF) patients may enhance decongestion and preserve renal function in this clinical setting. Unfortunately, none of these have demonstrated beneficial outcomes. The current challenge for BNP research in acute HF lies in addressing a failure of concept and a reluctance to abandon an ineffective research model. Future success will necessitate a detailed understanding of the mechanism of action of BNP, as well as better integration of basic and clinical science., (© 2020 John Wiley & Sons Australia, Ltd.)

Aims: The aim of this study was to determine the relationship between electrical and mechanical activation in heart failure (HF) patients and whether electromechanical coupling is affected by scar., Methods and Results: Seventy HF patients referred for cardiac resynchronization therapy or biological therapy underwent endocardial anatomo-electromechanical mapping (AEMM) and delayed-enhancement magnetic resonance (CMR) scans. Area strain and activation times were derived from AEMM data, allowing to correlate mechanical and electrical activation in time and space with unprecedented accuracy. Special attention was paid to the effect of presence of CMR-evidenced scar. Patients were divided into a scar (n = 43) and a non-scar group (n-27). Correlation between time of electrical and mechanical activation was stronger in the non-scar compared to the scar group [R = 0.84 (0.72-0.89) vs. 0.74 (0.52-0.88), respectively; P = 0.01]. The overlap between latest electrical and mechanical activation areas was larger in the absence than in presence of scar [72% (54-81) vs. 56% (36-73), respectively; P = 0.02], with smaller distance between the centroids of the two regions [10.7 (4.9-17.4) vs. 20.3 (6.9-29.4) % of left ventricular radius, P = 0.02]., Conclusion: Scar decreases the association between electrical and mechanical activation, even when scar is remote from late activated regions., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Aims: Recent data from national registries suggest that acute heart failure (AHF) outcomes might vary in men and women, however, it is not known whether this observation is universal. The aim of this study was to evaluate the association of biological sex and 1-year all-cause mortality in patients with AHF in various regions of the world., Methods and Results: We analysed several AHF cohorts including GREAT registry (22 523 patients, mostly from Europe and Asia) and OPTIMIZE-HF (26 376 patients from the USA). Clinical characteristics and medication use at discharge were collected. Hazard ratios (HRs) for 1-year mortality according to biological sex were calculated using a Cox proportional hazards regression model with adjustment for baseline characteristics (e.g. age, comorbidities, clinical and laboratory parameters at admission, left ventricular ejection fraction). In the GREAT registry, women had a lower risk of death in the year following AHF [HR 0.86 (0.79-0.94), P < 0.001 after adjustment]. This was mostly driven by northeast Asia [n = 9135, HR 0.76 (0.67-0.87), P < 0.001], while no significant differences were seen in other countries. In the OPTIMIZE-HF registry, women also had a lower risk of 1-year death [HR 0.93 (0.89-0.97), P < 0.001]. In the GREAT registry, women were less often prescribed with a combination of angiotensin-converting enzyme inhibitors and beta-blockers at discharge (50% vs. 57%, P = 0.001)., Conclusion: Globally women with AHF have a lower 1-year mortality and less evidenced-based treatment than men. Differences among countries need further investigation. Our findings merit consideration when designing future global clinical trials in AHF., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Background: Beta-blockers are one of the most important classes of cardiovascular agents and have been considered a cornerstone therapy in heart diseases, such as heart failure (HF) and atrial fibrillation (AF). Among different beta-blockers, metoprolol is a selective beta1-adrenergic antagonist, which has been extensively used since the 1970s., Areas of Uncertainty: Although current guidelines include recommendations for the use of controlled-release metoprolol succinate in specific HF and AF indications, and despite extensive clinical experience with metoprolol, comparative evidence on the use of metoprolol succinate compared with other beta-blockers in these indications is limited., Data Sources: We systematically reviewed the data from head-to-head studies directly comparing this compound with other beta-blockers in the treatment of HF or AF. Only clinical trials and observational studies were considered; no other limits were applied. The quality and relevance of retrieved articles were reviewed., Results: A total of 18 articles of the 353 articles identified were selected for inclusion; 12 HF articles and 6 for AF. Additional references were identified from the bibliographies of retrieved articles. The studies show that oral prophylaxis with an appropriate dose of metoprolol may reduce new incidents of AF in high-risk patients. Furthermore, metoprolol succinate is associated with significant mortality and morbidity benefits in the treatment of HF., Conclusions: Despite the introduction of newer beta-blockers with differing clinical characteristics since its introduction, metoprolol succinate remains a useful drug in both HF and AF.

Introduction: The present study introduces a new ultra-high-frequency 14-lead electrocardiogram technique (UHF-ECG) for mapping ventricular depolarization patterns and calculation of novel dyssynchrony parameters that may improve the selection of patients and application of cardiac resynchronization therapy (CRT)., Methods: Components of the ECG in sixteen frequency bands within the 150 to 1000 Hz range were used to create ventricular depolarization maps. The maximum time difference between the UHF QRS complex centers of mass of leads V1 to V8 was defined as ventricular electrical dyssynchrony (e-DYS), and the duration at 50% of peak voltage amplitude in each lead was defined as the duration of local depolarization (Vd). Proof of principle measurements was performed in seven patients with left (left bundle branch block) and four patients with right bundle branch block (right bundle branch block) before and during CRT using biventricular and His-bundle pacing., Results: The acquired activation maps reflect the activation sequence under the tested conditions. e-DYS decreased considerably more than QRS duration, during both biventricular pacing (-50% vs -8%) and His-bundle pacing (-77% vs -13%). While biventricular pacing slightly increased Vd, His-bundle pacing reduced Vd significantly (+11% vs -36%), indicating the contribution of the fast conduction system. Optimization of biventricular pacing by adjusting VV-interval showed a decrease of e-DYS from 102 to 36 ms with only a small Vd increase and QRS duration decrease., Conclusions: The UHF-ECG technique provides novel information about electrical activation of the ventricles from a standard ECG electrode setup, potentially improving the selection of patients for CRT and application of CRT., (© 2019 Wiley Periodicals, Inc.)

Background: Serelaxin is a recombinant form of human relaxin-2, a vasodilator hormone that contributes to cardiovascular and renal adaptations during pregnancy. Previous studies have suggested that treatment with serelaxin may result in relief of symptoms and in better outcomes in patients with acute heart failure., Methods: In this multicenter, double-blind, placebo-controlled, event-driven trial, we enrolled patients who were hospitalized for acute heart failure and had dyspnea, vascular congestion on chest radiography, increased plasma concentrations of natriuretic peptides, mild-to-moderate renal insufficiency, and a systolic blood pressure of at least 125 mm Hg, and we randomly assigned them within 16 hours after presentation to receive either a 48-hour intravenous infusion of serelaxin (30 μg per kilogram of body weight per day) or placebo, in addition to standard care. The two primary end points were death from cardiovascular causes at 180 days and worsening heart failure at 5 days., Results: A total of 6545 patients were included in the intention-to-treat analysis. At day 180, death from cardiovascular causes had occurred in 285 of the 3274 patients (8.7%) in the serelaxin group and in 290 of the 3271 patients (8.9%) in the placebo group (hazard ratio, 0.98; 95% confidence interval [CI], 0.83 to 1.15; P = 0.77). At day 5, worsening heart failure had occurred in 227 patients (6.9%) in the serelaxin group and in 252 (7.7%) in the placebo group (hazard ratio, 0.89; 95% CI, 0.75 to 1.07; P = 0.19). There were no significant differences between the groups in the incidence of death from any cause at 180 days, the incidence of death from cardiovascular causes or rehospitalization for heart failure or renal failure at 180 days, or the length of the index hospital stay. The incidence of adverse events was similar in the two groups., Conclusions: In this trial involving patients who were hospitalized for acute heart failure, an infusion of serelaxin did not result in a lower incidence of death from cardiovascular causes at 180 days or worsening heart failure at 5 days than placebo. (Funded by Novartis Pharma; RELAX-AHF-2 ClinicalTrials.gov number, NCT01870778.)., (Copyright © 2019 Massachusetts Medical Society.)

Background: Hyperuricemia is associated with a poorer prognosis in heart failure (HF) patients. Benefits of hyperuricemia treatment with allopurinol have not yet been confirmed in clinical practice. The aim of our work was to assess the benefit of allopurinol treatment in a large cohort of HF patients., Methods: The prospective acute heart failure registry (AHEAD) was used to select 3160 hospitalized patients with a known level of uric acid (UA) who were discharged in a stable condition. Hyperuricemia was defined as UA ≥500 μmoL/L and/or allopurinol treatment at admission. The patients were classified into three groups: without hyperuricemia, with treated hyperuricemia, and with untreated hyperuricemia at discharge. Two- and five-year all-cause mortality were defined as endpoints. Patients without hyperuricemia, unlike those with hyperuricemia, had a higher left ventricular ejection fraction, a better renal function, and higher hemoglobin levels, had less frequently diabetes mellitus and atrial fibrillation, and showed better tolerance to treatment with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and/or beta-blockers., Results: In a primary analysis, the patients without hyperuricemia had the highest survival rate. After using the propensity score to set up comparable groups, the patients without hyperuricemia had a similar 5-year survival rate as those with untreated hyperuricemia (42.0% vs 39.7%, P = 0.362) whereas those with treated hyperuricemia had a poorer prognosis (32.4% survival rate, P = 0.006 vs non-hyperuricemia group and P = 0.073 vs untreated group)., Conclusion: Hyperuricemia was associated with an unfavorable cardiovascular risk profile in HF patients. Treatment with low doses of allopurinol did not improve the prognosis of HF patients., (© 2019 The Authors. Clinical Cardiology published by Wiley Periodicals, Inc.)

The heart and lungs are intimately linked. Hence, impaired function of one organ may lead to changes in the other. Accordingly, heart failure is associated with airway obstruction, loss of lung volume, impaired gas exchange, and abnormal ventilatory control. Cardiopulmonary exercise testing is an excellent tool for evaluation of gas exchange and ventilatory control. Indeed, many parameters routinely measured during cardiopulmonary exercise testing, including the level of minute ventilation per unit of carbon dioxide production and the presence of exercise oscillatory ventilation, have been found to be strongly associated with prognosis in patients with heart failure., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: Measurement of ventilatory efficiency, defined as minute ventilation per unit carbon dioxide production (VE/VCO2), by cardiopulmonary exercise testing (CPET) has been proposed as a screen for hyperventilation syndrome (HVS). However, increased VE/VCO2 may be associated with other disorders which need to be distinguished from HVS. A more specific marker of HVS by CPET would be clinically useful. We hypothesized ventilatory control during exercise is abnormal in patients with HVS., Methods: Patients who underwent CPET from years 2015 through 2017 were retrospectively identified and formed the study group. HVS was defined as dyspnea with respiratory alkalosis (pH >7.45) at peak exercise with absence of acute or chronic respiratory, heart or psychiatric disease. Healthy patients were selected as controls. For comparison the Student t-test or Mann-Whitney U test were used. Data are summarized as mean ± SD or median (IQR); p<0.05 was considered significant., Results: Twenty-nine patients with HVS were identified and 29 control subjects were selected. At rest, end-tidal carbon dioxide (PETCO2) was 27 mmHg (25-30) for HVS patients vs. 30 mmHg (28-32); in controls (p = 0.05). At peak exercise PETCO2 was also significantly lower (27 ± 4 mmHg vs. 35 ± 4 mmHg; p<0.01) and VE/VCO2 higher ((38 (35-43) vs. 31 (27-34); p<0.01)) in patients with HVS. In contrast to controls, there were minimal changes of PETCO2 (0.50 ± 5.26 mmHg vs. 6.2 ± 4.6 mmHg; p<0.01) and VE/VCO2 ((0.17 (-4.24-6.02) vs. -6.6 (-11.4-(-2.8)); p<0.01)) during exercise in patients with HVS. The absence of VE/VCO2 and PETCO2 change during exercise was specific for HVS (83% and 93%, respectively)., Conclusion: Absence of VE/VCO2 and PETCO2 change during exercise may identify patients with HVS., Competing Interests: The authors have declared that no competing interests exist.

Background: According to guidelines, the prognosis of patients with chronic heart failure can be predicted by determining the levels of natriuretic peptides, the NYHA classification and comorbidities. The aim our work was to develop a prognostic score in chronic heart failure patients that would take account of patients' comorbidities, NYHA and NT-proBNP levels., Methods and Results: A total of 1,088 patients with chronic heart failure with reduced ejection fraction (HFrEF) (LVEF<40%) and mid-range EF (HFmrEF) (LVEF 40-49%) were enrolled consecutively. Two-year all-cause mortality, heart transplantation and/or LVAD implantation were defined as the primary endpoint (EP). The occurrence of EP was 14.9% and grew with higher NYHA, namely 4.9% (NYHA I), 11.4% (NYHA II) and 27.8% (NYHA III-IV) (p<0.001). The occurrence of EP was 3%, 10% and 15-37% in patients with NT-proBNP levels ≤125 ng/L, 126-1000 ng/L and >1000 ng/L respectively. Discrimination abilities of NYHA and NT-proBNP were AUC 0.670 (p<0.001) and AUC 0.722 (p<0.001) respectively. The predictive value of the developed clinical model, which took account of older age, advanced heart failure (NYHA III+IV), anaemia, hyponatraemia, hyperuricaemia and being on a higher dose of furosemide (>40 mg daily) (AUC 0.773; p<0.001) was increased by adding the NT-proBNP level (AUC 0.790)., Conclusion: The use of prediction models in patients with chronic heart failure, namely those taking account of natriuretic peptides, should become a standard in routine clinical practice. It might contribute to a better identification of a high-risk group of patients in which more intense treatment needs to be considered, such as heart transplantation or LVAD implantation., Competing Interests: The authors have declared that no competing interests exist.

Physiologically, leptin concentration is controlled by circadian rhythm. However, in critically ill patients, circadian rhythm is disrupted. Thus we hypothesized that circadian leptin concentration changes are not preserved in critically ill patients. Ten consecutive critically ill heart failure patients with the clinical indication for mechanical ventilation and sedation were included into our study. Plasma leptin concentration was measured every 4 h during the first day (0-24 h) and during the third day (48-72 h) after admission. During the first day, there were significant leptin concentration changes (ANOVA, p<0.05), characterized by an increase in concentration by 44 % (16-58 %); p=0.02 around noon (10 am-2 pm) and then a decrease in concentration by 7 % (1-27 %); p=0.04 in the morning (2 am-6 am). In contrast, there was no significant change in leptin concentration during the third day after admission (ANOVA, p=0.79). Based on our preliminary results, we concluded that in critically ill heart failure patients, the circadian rhythm of plasma leptin concentration seems to be preserved during the first but not during the third day after admission.

Background: Although cardiac resynchronization therapy (CRT) is beneficial in heart failure patients with left bundle branch block, 30% of these patients do not respond to the therapy. Identifying these patients before implantation of the device is one of the current challenges in clinical cardiology., Methods: We verified the diagnostic contribution and an optimized computerized approach to measuring ventricular electrical activation delay (VED) from body surface 12-lead ECGs. We applied the method to ECGs acquired before implantation (baseline) in the MADIT-CRT trial (Multicenter Automatic Defibrillator Implantation-Cardiac Resynchronization Therapy). VED values were dichotomized using its quartiles, and we tested the association of VED values with the MADIT-CRT primary end point of heart failure or death. Multivariate Cox proportional models were used to estimate the risk of study end points. In addition, the association between VED values and hemodynamic changes after CRT-D implantation was examined using 1-year follow-up echocardiograms., Results: Our results showed that left bundle branch block patients with baseline VED <31.2 ms had a 35% risk of MADIT-CRT end points, whereas patients with VED ≥31.2 ms had a 14% risk ( P <0.001). The hazard ratio for predicting primary end points in patients with low VED was 2.34 (95% confidence interval, 1.53-3.57; P <0.001). Higher VED values were also associated with beneficial hemodynamic changes. These strong VED associations were not found in the right bundle branch block and intraventricular conduction delay cohorts of the MADIT-CRT trial., Conclusions: Left bundle branch block patients with a high baseline VED value benefited most from CRT, whereas left bundle branch block patients with low VED did not show CRT benefits., (© 2018 The Authors.)

Low leptin concentration has been shown to be associated with central sleep apnea in heart failure patients. We hypothesized that low leptin concentration predicts central sleep apnea. Consecutive ambulatory New York Heart Association (NYHA) classes I-IV heart failure patients were studied prospectively, including measurement of serum leptin, echocardiography and polysomnography. Sleep apnea was defined by type (central/mixed/obstructive) and by apnea-hypopnea index ≥5 by polysomnography. Subjects were divided into four groups by polysomnography: (1) central sleep apnea, (2) mixed apnea, (3) no apnea and (4) obstructive sleep apnea. Fifty-six subjects were included. Eighteen subjects were diagnosed with central sleep apnea, 15 with mixed apnea, 12 with obstructive apnea and 11 with no sleep apnea. Leptin concentration was significantly lower in central sleep apnea compared to obstructive apnea (8 ± 10.7 ng mL -1 versus 19.7 ± 14.7 ng mL -1 , P ˂ 0.01) or no sleep apnea (8 ± 10.7 ng mL -1 versus 17.1 ± 8.4 ng mL -1 , P ˂ 0.01). Logistic regression showed leptin to be associated independently with central sleep apnea [odds ratio (OR): 0.19; 95% confidence interval (CI): 0.06-0.62; area under the curve (AUC): 0.80, P < 0.01]. For the detection of central sleep apnea, a cut-off value for leptin concentration 5 ng mL -1 yielded a sensitivity of 50% and specificity of 89%. In conclusion, a low leptin concentration may have utility for the screening of heart failure patients for central sleep apnea., (© 2017 European Sleep Research Society.)

Background: The interaction between chronic medications on admission and the association between serum potassium level and outcome in patients with acute heart failure (AHF) are unknown., Methods: Observational intercontinental study of patients admitted with AHF. 15954 patients were included from 12 cohorts in 4 continents. Main outcome was 90-day mortality. Clinical presentation (medication use, hemodynamics, comorbidities), demographic, echocardiographic, and biochemical data on admission were recorded prospectively in each cohort, with prospective adjudication of outcomes., Results: Positive and negative linear relationships between 90-day mortality and sK+ above 4.5 mmol/L (hyperkalemia) and below 3.5 mmol/L (hypo-kalemia) were observed. Hazard ratio for death was 1.46 [1.34-1.58] for hyperkalemia and 1.22 [1.06-1.40] for hypokalemia. In a fully adjusted model, only hyperkalemia remained associated with mortality (HR 1.03 [1.02-1.04] for each 0.1 mmol/l change of sK+ above 4.5 mmol/L). Interaction tests revealed that the association between hyperkalemia and outcome was significantly affected by chronic medications. The association between hyperkalemia and mortality was absent for patients treated with beta blockers and in those with preserved renal function., Conclusions: In patients with AHF, sK+ > 4.5 mmol/L appears to be associated with 90-day mortality. B-blockers have potentially a protective effect in the setting of hyperkalemia.

Heart failure with preserved ejection fraction (HFpEF) is a serious clinical disease. The pathophysiology of HFpEF is complex, and specific diagnostic criteria have evolved over time. Limited data are available on the quantification of diastolic function using two-dimensional real-time echocardiography, and a simple parameter has not yet been established. The aim of this work is to evaluate new echocardiographic parameters-the diastolic wall strain of the posterior wall (DWS PW) and the vortex formation time (VFT). Echocardiographic data from 111 subjects with exertional dyspnea and normal left ejection fraction (Group A) and 20 healthy volunteers (Group B) were retrospectively evaluated. In addition to the standard parameters used in the diagnosis of HFpEF, DWS PW and VFT were assessed in all patients. HFpEF was diagnosed in 38 patients with dyspnea (Group A1). The remaining 73 patients did not meet the established criteria for a positive diagnosis of HFpEF (Group A2). We discovered that both observed parameters were significantly lower in patients with HFpEF than in other groups. Multivariate analysis revealed that both DWS PW and VFT independently predicted the presence of HFpEF. DWS PW and VFT are simple parameters in the evaluation of diastolic function and may play a potential role as a part of an integrated approach to the assessment of HFpEF.

Background: Altered mental status is among the signs of hypoperfusion in cardiogenic shock, the most severe form of acute heart failure. The aim of this study was to investigate the prevalence of altered mental status, to identify factors associating with it, and to assess the prognostic significance of altered mental status in cardiogenic shock., Methods: Mental status was assessed at presentation of shock in 215 adult cardiogenic shock patients in a multinational, prospective, observational study. Clinical picture, biochemical variables, and short-term mortality were compared between patients presenting with altered and normal mental status., Results: Altered mental status was detected in 147 (68%) patients, whereas 68 (32%) patients had normal mental status. Patients with altered mental status were older (68 vs. 64 years, p=0.04) and more likely to have an acute coronary syndrome than those with normal mental status (85% vs. 74%, p=0.04). Altered mental status was associated with lower systolic blood pressure (76 vs. 80 mmHg, p=0.03) and lower arterial pH (7.27 vs. 7.35, p<0.001) as well as higher levels of blood lactate (3.4 vs. 2.3 mmol/l, p<0.001) and blood glucose (11.4 vs. 9.0 mmol/l, p=0.01). Low arterial pH (adjusted odds ratio 1.6 (1.1-2.2), p=0.02) was the only factor independently associated with altered mental status. Ninety-day mortality was significantly higher (51% vs. 22%, p<0.001) among patients with altered mental status., Conclusions: Altered mental status is a common clinical sign of systemic hypoperfusion in cardiogenic shock and is associated with poor outcome. It is also associated with several biochemical findings that reflect inadequate tissue perfusion, of which low arterial pH is independently associated with altered mental status.

Aims: Heart failure oral therapies (HFOTs), including beta-blockers (BB), renin-angiotensin system inhibitors (RASi) and mineralocorticoid receptor antagonists, administered before hospital discharge after acute heart failure (AHF) might improve outcome. However, concerns have been raised because early administration of HFOTs may worsen patient's condition. We hypothesized that HFOTs at hospital discharge might be associated with better post-discharge survival., Methods and Results: The study population was composed of 19 980 AHF patients from the GREAT registry. The primary and secondary outcomes were 90-day and 1-year all-cause mortality, respectively. Survival was estimated with univariate and covariate-adjusted Cox proportional hazards regression models for the whole population and after propensity-score matching. HFOTs at discharge were consistently associated with no excess mortality in the unadjusted and adjusted analyses of the whole and matched cohorts. In the matched cohort, BB and RASi at discharge were associated with lower 90-day mortality risks compared to the respective untreated groups [hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.46-0.69; and HR 0.53, 95% CI 0.42-0.66, respectively]. The favourable associations of BB and RASi at discharge with 90-day mortality were present in many subgroups including patients with reduced or preserved left ventricular ejection fraction and persisted up to 1 year after discharge. The combination of RASi and BB was associated with an even lower risk of death than RASi or BB alone., Conclusions: Administration of HFOTs at hospital discharge is associated with better survival of AHF patients., (© 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.)

Background/aims: The rate of incidence and prevalence of acute kidney injury is increasing due to an increased number of patients with heart failure. Therefore it is very pertinent to early detect the level of renal injuries and to make necessary heart failure predictions. Thus the aim of this study is to determine renal functions and prognosis stratification in chronic heart failure patients and importance of Neutrophil Gelatinase-Associated Lipocalin (NGAL), an early diagnostic marker of acute kidney injury, as well as stratification of cardiovascular risk in heart failure patients., Methods: Data including age, gender, comorbidities and medical history of outpatients and hospitalized patients from Farmacology and NeuroHumoraL activation (FAR NHL) multicenter prospective registry comprising three Cardiological Centers in the Czech Republic were collected between 1st October 2014 and 30th November 2015. One-year follow-up data were collected in November 2016 in such a way that all patients had at least one-year data from the time of recruitment, but up to two years to the time of follow-up. One-year data were used for the whole set of patients while data up to 24 months were used with Kaplan-Meier's survival curves to analyse the patients' survival data. Blood samples were collected from the patients and basic parameters were evaluated in order to analyse Neutrophil gelatinase-associated lipocalin (NGAL) and plasma levels of N-terminal pro-brain natriuretic peptide (NT-ProBNP) using Lipocalin-2/NGAL Human ELISA kit (Bio Vendor, Czechia) and the Cobas E411 NT-proBNP Immunoassay kit (Roche Diagnostics, Indianapolis, IN, USA) respectively. Statistical analysis was further carried out to explain the level of significance of the evaluated parameters using Spearman Correlation, Mann Whitney or Kruskal-Wallis test and log-rank test., Results: Out of 547 patients from Farmacology and NeuroHumoraL activation (FAR NHL) multicenter prospective registry with available data on hospitalizations, mortality, biomarkers and one-year follow-up that were recorded, there were 439 males (80.3%) with a median age of 66 years. At least one-month stable patients with left ventricle ejection fraction (LV EF) under 50% were recorded. The etiology of heart failure was ischemic heart disease in 54%, dilated cardiomyopathy in 40% and others in 6%. 69% patients were in New York Heart Association functional class II. There were 76 events (13.9%; all-cause mortality, acute heart failure hospitalization, left ventricle assist device implantation and orthotopic heart transplant) in the first 365 days of follow-up. The area under the receiver operating characteristic curve was higher for NT-proBNP (0.77) than the creatinine (0.57), NGAL (0.55) or creatinine clearance (0.54). In multivariable analyses, NT-proBNP (P= 0.001) and NGAL (P = 0.004) were significant predictors of events. Subjects with NT-proBNP and NGAL above the cut off value (NT-proBNP 1,121 pg/ml, NGAL 80 ng/ml) survived without any event in 55.7%, subjects with NT-proBNP and NGAL under the cut off value survived without any event in 90.5%, after two years (P = 0.001)., Conclusion: The findings of the study showed that NGAL associated with NT-proBNP was a stronger predictor of the primary endpoint than NGAL or NT-proBNP alone. The level of NGAL was rising in hypertension, ischemia, anemia, hypoalbuminemia, diabetes or arrhythmias., (© 2018 The Author(s). Published by S. Karger AG, Basel.)

Background: Regular physical activity is recommended for patients with chronic heart failure to improve their functional capacity, and walking is a popular, effective, and safe form of physical activity. Pedometers have shown potential to increase the amount of walking across a range of chronic diseases, but it is unknown whether a pedometer-based intervention improves functional capacity and neurohumoral modulation in heart failure patients., Methods: Two multicenter randomized controlled trials will be conducted in parallel: one in patients with chronic heart failure with reduced ejection fraction (HFrEF), the other in patients with chronic heart failure with preserved ejection fraction (HFpEF). Each trial will consist of a 6-month intervention with an assessment at baseline, at 3 months, at the end of the intervention, and 6 months after completing the intervention. Each trial will aim to include a total of 200 physically inactive participants with chronic heart failure who will be randomly assigned to intervention or control arms. The 6-month intervention will consist of an individualized pedometer-based walking program with weekly step goals, behavioral face-to-face sessions with a physician, and regular telephone calls with a research nurse. The intervention will be based on effective behavioral principles (goal setting, self-monitoring, personalized feedback). The primary outcome is the change in 6-min walk distance at the end of the 6-month intervention. Secondary outcomes include changes in serum biomarkers levels, pulmonary congestion assessed by ultrasound, average daily step count measured by accelerometry, anthropometric measures, symptoms of depression, health-related quality of life, self-efficacy, and MAGGIC risk score., Discussion: To our knowledge, these are the first studies to evaluate a pedometer-based walking intervention in patients with chronic heart failure with either reduced or preserved ejection fraction. The studies will contribute to a better understanding of physical activity promotion in heart failure patients to inform future physical activity recommendations and heart failure guidelines. Trial registration The trials are registered in ClinicalTrials.gov, identifiers: NCT03041610, registered 29 January 2017 (HFrEF), NCT03041376, registered 1 February 2017 (HFpEF).

Background: Leptin modulates ventilation and circulating levels are higher in normal women than men., Objectives: The aim of this study was to compare exercise ventilation and gas exchange in men and women with heart failure (HF) and their relation to circulating leptin concentration., Methods: Consecutive HF patients were studied by cardiopulmonary exercise testing and assay of circulating leptin concentration., Results: Fifty-seven men and 20 women were similar with respect to age, BMI, NYHA class, left ventricular ejection fraction, and peak oxygen consumption (all p > 0.05). Leptin concentration was lower (10.3 ± 10 vs. 25.3 ± 16 ng/mL; p < 0.01) and peak exercise ventilatory efficiency (V E /VCO 2 ) was higher (43 ± 10 vs. 36 ± 5; p < 0.01) in men. Leptin concentration was associated with peak exercise V E /VCO 2 (b = -0.35; F = 5.6; p = 0.02)., Conclusion: Men have significantly lower circulating leptin concentration and increased ventilatory drive during exercise than women with comparable HF. In men with HF, lower leptin concentration may account for an increased ventilatory drive., (Copyright © 2017. Published by Elsevier Inc.)

Background: Afterload reduction is a cornerstone in the management of patients with heart failure (HF) and reduced ejection fraction. However, arterial load and the effect of HF therapies on afterload might vary between individuals. Tailoring vasoactive medicines to patients with HF based upon better understanding of arterial afterload may enable better individualization of therapy., Methods and Results: Subjects with HF and reduced ejection fraction underwent aggressive titration of vasoactive HF therapies with assessment of central aortic waveforms analyzed using pulse wave, wave separation, and arterial reservoir models. Clinical response to treatment was assessed using the 6-minute walk test distance, which increased in 25 subjects and decreased or remained unchanged in 13. Subjects with improvement on therapy displayed higher aortic pressure wave pulsatility (central pulse pressure [PP], reflected pressure wave, and reservoir pressure) at study entry compared with subjects without improvement (all P<0.05). Parameters derived by the arterial analysis methods were strongly correlated with one another and displayed similar ability to predict improvement. Aortic pressure pulsatility significantly decreased in subjects with functional improvement, whereas no change was observed in patients without functional improvement (P for interaction <0.05). These differences in arterial load at baseline and on therapy were not apparent from conventional brachial artery cuff pressure assessments., Conclusions: Increased aortic pressure wave pulsatility and greater decrease in pulsatility on treatment are associated with functional improvement in patients with HF and reduced ejection fraction receiving aggressive vasodilator titration. These differences are not identifiable using brachial cuff pressures. Central aortic waveform analysis may enable better individualization of vasoactive therapies in chronic HF and reduced ejection fraction., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00588692., Competing Interests: Disclosures: The data from this study was obtained in an investigator-initiated trial funded by AtCor Medical. The authors have no conflicts to disclose., (© 2017 American Heart Association, Inc.)

Aims: Several clinical conditions may precipitate acute heart failure (AHF) and influence clinical outcome. In this study we hypothesized that precipitating factors are independently associated with 90-day risk of death in AHF., Methods and Results: The study population consisted of 15 828 AHF patients from Europe and Asia. The primary outcome was 90-day all-cause mortality according to identified precipitating factors of AHF [acute coronary syndrome (ACS), infection, atrial fibrillation (AF), hypertension, and non-compliance]. Mortality at 90 days was 15.8%. AHF precipitated by ACS or by infection showed increased 90-day risk of death compared with AHF without identified precipitants [hazard ratio (HR) 1.69, 95% confidence interval (CI) 1.44-1.97, P < 0.001; and HR 1.51, 95% CI 1.18-1.92, P = 0.001), while AHF precipitated by AF showed lower 90-day risk of death (HR 0.56, 95% CI 0.42-0.75, P < 0.001), after multivariable adjustment. The risk of death in AHF precipitated by ACS was the highest during the first week after admission, while in AHF precipitated by infection the risk of death had a delayed peak at week 3. In AHF precipitated by AF, a trend toward reduced risk of death during the first weeks was shown. At weeks 5-6, AHF precipitated by ACS, infection, or AF showed similar risk of death to that of AHF without identified precipitants., Conclusions: Precipitating factors are independently associated with 90-day mortality in AHF. AHF precipitated by ACS or infection is independently associated with higher, while AHF precipitated by AF is associated with lower 90-day risk of death., (© 2016 The Authors. European Journal of Heart Failure © 2016 European Society of Cardiology.)

Background: Impaired contractility is a feature of heart failure with reduced ejection fraction. We assessed the pharmacokinetics and effects on cardiac function and structure of the cardiac myosin activator, omecamtiv mecarbil., Methods: In this randomised, double-blind study, done at 87 sites in 13 countries, we recruited patients with stable, symptomatic chronic heart failure and left ventricular ejection fraction 40% or lower. Patients were randomly assigned equally, via an interactive web response system, to receive 25 mg oral omecamtiv mecarbil twice daily (fixed-dose group), 25 mg twice daily titrated to 50 mg twice daily guided by pharmacokinetics (pharmacokinetic-titration group), or placebo for 20 weeks. We assessed the maximum concentration of omecamtiv mecarbil in plasma (primary endpoint) and changes in cardiac function and ventricular diameters. This trial is registered with ClinicalTrials.gov, number NCT01786512., Findings: From March 17, 2014, to March 5, 2015, we enrolled 150 patients in the fixed-dose omecamtiv mecarbil group and 149 in the pharmacokinetic-titration and placebo groups. Mean maximum concentration of omecamtiv mecarbil at 12 weeks was 200 (SD 71) ng/mL in the fixed-dose group and 318 (129) ng/mL in the pharmacokinetic-titration group. For the pharmacokinetic-titration group versus placebo group at 20 weeks, least square mean differences were as follows: systolic ejection time 25 ms (95% CI 18-32, p<0·0001), stroke volume 3·6 mL (0·5-6·7, p=0·0217), left ventricular end-systolic diameter -1·8 mm (-2·9 to -0·6, p=0·0027), left ventricular end-diastolic diameter -1·3 mm, (-2·3 to 0·3, p=0·0128), heart rate -3·0 beats per min (-5·1 to -0·8, p=0·0070), and N-terminal pro B-type natriuretic peptide concentration in plasma -970 pg/mL (-1672 to -268, p=0·0069). The frequency of adverse clinical events did not differ between groups., Interpretation: Omecamtiv mecarbil dosing guided by pharmacokinetics achieved plasma concentrations associated with improved cardiac function and decreased ventricular diameter., Funding: Amgen., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Aims: To compare the differences between patients with inflammatory cardiomyopathy (ICM) with and without improvement in left ventricular (LV) systolic function and to identify the relevant predictors of LV improvement., Patients and Methods: The study included 63 patients with biopsy-proven ICM and heart failure symptoms of at least NYHA II, symptom duration ≤ 6 months, LV ejection fraction (LVEF) ≤ 40% assessed by echocardiography and presence of >14 mononuclear leukocytes (LCA+ cells)/mm 2 in biopsy samples. Patients were evaluated at baseline and after 6 months., Results: In the group with LVEF improvement of ≥ 10% (I+ group, n = 41), LVEF increased from 24 ± 7% to 47 ± 8% (P < 0.001). In 22 patients (group I-), there was no or minimal LVEF increase (< 10%). In the I+ group, there were more LCA+ cells/mm 2 at baseline (25.1 ± 16.5 vs. 18.5 ± 4.4 cells/mm 2 ; P = 0.032) and a more significant decrease in LCA+ cells in the follow-up (reduction of 13.6 ± 14.3 cells/mm 2 vs. 5.0 ± 7.7 cells/mm 2 in the I- group; P = 0.009). The univariate logistic regression showed a possible association of number of LCA+ cells, LV end-diastolic diameter and N-terminal fragment of pro-brain natriuretic peptide (NTproBNP) value with LVEF improvement. In the multivariate analysis, only NTproBNP at diagnosis was confirmed as an independent predictor of LVEF improvement (OR=1.2; 1.003 to 1.394; P = 0.046)., Conclusion: The LV systolic function improvement was observed in 65% of the patients. In these patients, the number of inflammatory cells at baseline was higher and decreased more but the higher baseline NTproBNP value was the only independent predictor of LVEF improvement.

Background: Continuous blood flow could have deleterious effects on endothelium and vascular health. This could have serious consequences in patients with heart failure treated with continuous flow left ventricular assist devices (LVAD). Therefore, we studied effect of LVAD on three circulating vascular biomarkers: stem cells (SC), endothelial progenitor cells (EPC) and microparticles (MP)., Methods: In 23 patients (5 women) with end-stage heart failure, SC, EPC and MP were measured before, and 3 and 6months after implantation of LVAD (HeartMate II). SC were defined using determination of surface antigen expression as mononuclear CD34+/CD45low+ cells and EPC as mononuclear CD34+/CD45low+/KDR+ cells. MP concentrations were determined by ELISA method., Results: Three months after LVAD implantation numbers of SC and EPC significantly decreased (p=0.01 and p=0.001, respectively). On the contrary, between 3rd and 6th month after implantation they significantly increased (p=0.006 and p=0.003, respectively).MP did not change significantly during the study despite exerting similar trend as SC and EPC., Conclusions: Observed biphasic changes of SC and EPC might reflect two processes. First, shortly after LVAD implantation, improved tissue perfusion could lead to decrease in ischemic stimuli and ensuing decrease of SC and EPC. Second, continuous flow between 3rd and 6th month produced by LVAD could lead to increase of SC and EPC through activation of endothelium. This explanation could be supported also by similar trend in the changes of concentrations of MP., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Congestive heart failure (HF) remains a serious burden in the Western World. Despite advances in pharmacotherapy and resynchronization, many patients have progression to end-stage HF. These patients may be candidates for heart transplant or left ventricular assist device (LVAD) therapy. Heart transplants are limited by organ shortages and in some cases by patient comorbidities; therefore, LVAD therapy is emerging as a strategy of bridge to transplant or as a destination therapy in patients ineligible for transplant. Patients initially ineligible for a transplant may, in certain cases, become eligible for transplant after physiologic improvement with LVAD therapy, and a small number of patients with an LVAD may have sufficient recovery of myocardial function to allow device explantation. This clinically oriented review will describe (1) the most frequently used pump types and aspects of the continuous-flow physiology and (2) the clinical indications for and the shift toward the use of LVADs in less sick patients with HF. Additionally, we review complications of LVAD therapy and project future directions in this field. We referred to the Interagency Registry for Mechanically Assisted Circulatory Support, landmark trials, and results from recently published studies as major sources in obtaining recent outcomes, and we searched for related published literature via PubMed. This review focuses primarily on clinical practice for primary care physicians and non-HF cardiologists in the United States., (Copyright © 2016 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Background: Blood-based biomarkers have a prognostic value in patients with myocardial infarction. The aim of our prospective observational cohort study was to evaluate the prognostic value of biomarkers of different pathophysiological pathways for the occurrence of 1-year all-cause mortality and hospitalisation due to acute heart failure., Methods and Results: In 593 patients with ST-segment elevation MI (STEMI) treated by primary PCI, biomarkers were evaluated at 24h after MI onset. A minimum of three-year follow-up was achieved in all patients. The combination of 1-year all-cause mortality and hospitalisation due to heart failure was the primary endpoint. A cohort for validation of our combined GRACE-natriuretic peptide (NP) score included 667 STEMI patients. The primary endpoint was reached in 9.3% of patients. Among 21 biomarkers, only B-type natriuretic peptide (BNP), NT-proBNP, superoxide dismutase and nitrite/nitrate, added to clinical GRACE score led to a significant increase in the area under the curve of C statistics, in comparison to GRACE alone (tested by Delong's test). Continuous net reclassification improvement and integrated discrimination index demonstrated an improved reclassification and discrimination of the GRACE model for SOD, BNP and NT-proBNP, and improved reclassification for nitrite/nitrate. Consistent results for this new combined prognostic model GRACE-NP were found also for a validation cohort., Conclusions: The levels of NP have an additional value to the prognostic properties of the GRACE score for the prediction of the combined endpoint of one-year mortality or hospitalisation for AHF. Nitrite/nitrate and SOD are strong prognostic factors, even on top of the GRACE score., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Patients with myocarditis and left ventricular (LV) dysfunction may improve after standard heart failure therapy. This improvement seems to be related to retreat of myocardial inflammation. The aim of the present study was to assess changes in clinical, echocardiographic and some laboratory parameters and to correlate them with changes in the number of inflammatory infiltrating cells in endomyocardial biopsy (EMB) samples during the 6-month follow-up, and to define predictors of LV function improvement among baseline parameters. Forty patients with biopsy-proven myocarditis and impaired LV function (LV ejection fraction-LVEF <40 %) with heart failure symptoms ≤ 6 months were evaluated. Myocarditis was defined as the presence of >14 mononuclear leukocytes/mm(2) and/or >7 T-lymphocytes/mm(2) in the baseline EMB. The EMB, echocardiography and clinical evaluation were repeated after 6 months of standard heart failure therapy. LVEF improved on average from 25 ± 9 to 42 ± 12 % (p < 0.001); LV end-systolic volume and LV end-diastolic volume (LVEDV) decreased from 158 ± 61 to 111 ± 58 ml and from 211 ± 69 to 178 ± 63 ml (both p < 0.001). NYHA class decreased from 2.6 ± 0.5 to 1.6 ± 0.6 (p < 0.001) and NTproBNP from 2892 ± 3227 to 851 ± 1835 µg/ml (p < 0.001). A decrease in the number of infiltrating leukocytes (CD45+/LCA+) from 23 ± 15 to 13 ± 8 cells/mm(2) and in the number of infiltrating T lymphocytes (CD3+) from 7 ± 5 to 4 ± 3 cells/mm(2) (both p < 0.001) was observed. The decline in the number of infiltrating CD45+ cells significantly correlated with the change in LVEF (R = -0.43; p = 0.006), LVEDV (R = 0.39; p = 0.012), NYHA classification (R = 0.35; p = 0.025), and NTproBNP (R = 0.33; p = 0.045). The decrease in the number of CD3+ cells correlated with the change of systolic and diastolic diameters of the left ventricle (R = -0.33; p = 0.038 and R = -0.45; p = 0.003) and with the change in LVEDV (R = -0.43; p = 0.006). Tricuspid annular plane systolic excursion (TAPSE) (OR 0.61; p = 0.005) and early transmitral diastolic flow velocity (E wave) (OR 0.89; p = 0.002) were identified as predictors of LVEF improvement. Improvements in clinical status, LV function and NTproBNP levels correlated with decrease in the number of infiltrating inflammatory cells. TAPSE and E wave velocity were significant predictors of improvement in multivariate regression. Our observations suggest that contemporary guidelines-based therapy of heart failure is an effective treatment option in patients with recent onset biopsy-proven inflammatory cardiomyopathy.