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

Abstract Aims Inflammation has emerged as a potential key pathophysiological mechanism in heart failure (HF) in general and acute HF (AHF) specifically, with inflammatory biomarkers shown to be highly predictive of adverse outcomes in these patients. The CORTAHF study builds on both these data and the fact that steroid burst therapy has been shown to be effective in the treatment of respiratory diseases and COVID‐19. Our hypothesis is that in patients with AHF and elevated C‐reactive protein (CRP) levels without symptoms or signs of infection, a 7‐day course of steroid therapy will lead to reduced inflammation and short‐term improvement in quality of life and a reduced risk of worsening HF (WHF) events. Methods and results The study, which is currently ongoing, will include 100 patients with AHF ages 18–85, regardless of ejection fraction, screened within 12 h of presentation. Patients will be included who have NT‐proBNP > 1500 pg/mL and CRP > 20 mg/L at screening. Exclusion criteria include haemodynamic instability and symptoms and signs of infection. After signed consent, eligible patients will be randomized according to a central randomization scheme stratified by centre 1:1 to either treatment once daily for 7 days with 40 mg prednisone orally or to standard care. Patients will be assessed at study day 2, day 4 or at discharge if earlier, and at days 7 and 31 at the hospital; and at day 91 through a telephone follow‐up. The primary endpoint is the change in CRP level from baseline to day 7, estimated from a mixed model for repeated measures (MMRM) including all measured timepoints, in patients without a major protocol violation. Secondary endpoints include the time to the first event of WHF adverse event, readmission for HF, or death through day 91; and changes to day 7 in EQ‐5D visual analogue scale score and utility index. Additional clinical and laboratory measures will be assessed. Conclusions The results of the study will add to the knowledge of the role of inflammation in AHF and potentially inform the design of larger studies with possibly longer duration of anti‐inflammatory therapies in AHF.

Abstract Aims We aim to identify the most accurate marker for early prediction of poor diuretic response in acute heart failure (AHF) patients with signs of congestion requiring intravenous diuretic treatment. Methods In this single‐centre, prospective observational study, AHF patients with signs of congestion received a standardized intravenous furosemide dose (1 mg/kg of body weight; 40 mg in bolus and remaining dose in 2 h continuous infusion). Subsequently, we assessed spot urine composition at 2 h post‐administration, comparing it with total urine output at 6 h. Various potential urine markers were analysed for predicting urine output using receiver operating characteristic (ROC) curves and logistic regression models. We investigated guideline‐recommended markers, including spot urine sodium (UNa+) and its cut‐off, and introduced the UNa+/UCr (urine creatinine concentration) ratio adjusting UNa+ for urine dilution. Results Out of 111 patients (85% males, 66.4 ± 13.9 years old, NTproBNP 7290 [4493–14 582] pg/ml), there were 18 (16%) with a poor diuretic response (cumulative urine output

Abstract Despite improvements over recent years, morbidity and mortality associated with heart failure (HF) are higher in countries in the Central and Eastern Europe and Baltic region than in Western Europe. With the goal of improving the standard of HF care and patient outcomes in the Central and Eastern Europe and Baltic region, this review aimed to identify the main barriers to optimal HF care and potential areas for improvement. This information was used to suggest methods to improve HF management and decrease the burden of HF in the region that can be implemented at the national and regional levels. We performed a literature search to collect information about HF epidemiology in 11 countries in the region (Bulgaria, Croatia, Czechia, Estonia, Hungary, Latvia, Lithuania, Poland, Romania, Serbia, and Slovenia). The prevalence of HF in the region was 1.6–4.7%, and incidence was 3.1–6.0 per 1000 person‐years. Owing to the scarcity of published data on HF management in these countries, we also collected insights on local HF care and management practices via two surveys of 11 HF experts representing the 11 countries. Based on the combined results of the literature review and surveys, we created national HF care and management profiles for each country and developed a common patient pathway for HF for the region. We identified five main barriers to optimal HF care: (i) lack of epidemiological data, (ii) low awareness of HF, (iii) lack of national HF strategies, (iv) infrastructure and system gaps, and (v) poor access to novel HF treatments. To overcome these barriers, we propose the following routes to improvement: (i) establish regional and national prospective HF registries for the systematic collection of epidemiological data; (ii) establish education campaigns for the public, patients, caregivers, and healthcare professionals; (iii) establish formal HF strategies to set clear and measurable policy goals and support budget planning; (iv) improve access to quality‐of‐care centres, multidisciplinary care teams, diagnostic tests, and telemedicine/telemonitoring; and (v) establish national treatment monitoring programmes to develop policies that ensure that adequate proportions of healthcare budgets are reserved for novel therapies. These routes to improvement represent a first step towards improving outcomes in patients with HF in the Central and Eastern Europe and Baltic region by decreasing disparities in HF care within the region and between the region and Western Europe.

Abstract In our retrospective study, we aimed to investigate the relationship between urinary chloride (uCl−) and selected clinical and laboratory biomarkers, renal function, and patient outcomes in the acute heart failure (AHF) population. We divided 248 adult patients (≥ 18 years) with AHF into two groups: low uCl− (

Abstract Heart failure (HF) poses a significant challenge, often leading to frequent hospitalizations and compromised quality of life. Continuous pulmonary artery pressure (PAP) monitoring offers a surrogate for congestion status in ambulatory HF care. This meta-analysis examines the efficacy of PAP monitoring devices (CardioMEMS and Chronicle) in preventing adverse outcomes in HF patients, addressing gaps in prior randomized controlled trials (RCTs). Five RCTs (2572 participants) were systematically reviewed. PAP monitoring significantly reduced HF-related hospitalizations (RR 0.72 [95% CI 0.6–0.87], p = 0.0006) and HF events (RR 0.86 [95% CI 0.75–0.99], p = 0.03), with no impact on all-cause or cardiovascular mortality. Subgroup analyses highlighted the significance of CardioMEMS and blinded studies. Meta-regression indicated a correlation between prolonged follow-up and increased reduction in HF hospitalizations. The risk of bias was generally high, with evidence certainty ranging from low to moderate. PAP monitoring devices exhibit promise in diminishing HF hospitalizations and events, especially in CardioMEMS and blinded studies. However, their influence on mortality remains inconclusive. Further research, considering diverse patient populations and intervention strategies with extended follow-up, is crucial for elucidating the optimal role of PAP monitoring in HF management.

IntroductionThe growing population of heart failure (HF) patients places a burden on the healthcare system. Patient-centered outcomes such as health-related quality of life (HRQoL) and self-care behaviors are key elements of modern HF management programs. Thus, optimized strategies to improve these outcomes are sought.PurposeTo assess the effects of a new model of medical telecare on HRQoL and self-care in patients with HF (the AMULET study).MethodsThe study was prospective, randomized, open-label, and controlled with two parallel groups: telecare and standard care. In the telecare group, HF nurses performed patient clinical assessments with telemedical support by a cardiologist and provided education focused on the prevention of HF exacerbation. In the standard care group, patients were followed according to standard practices in the existing healthcare system. At the baseline and at 12 months, HRQoL was assessed using the Short Form 36 (SF-36) questionnaire and the Minnesota Living with Heart Failure Questionnaire (MLwHF). The level of self-care was assessed with the 12-item standardized European Heart Failure Self-care Behavior Scale (EHFScBS-12).ResultsIn the overall study group, 79% of the subjects were male, the mean age was 67 ± 14 years, and 59% of the subjects were older than 65 years of age. The majority of the subjects (70%) had a left ventricular ejection fraction below 40%. After 12 months, statistically significant increases in physical component of the SF-36 (43.3 vs. 47.4 for telecare vs. 43.4 vs. 46.6 for standard care) and mental component of SF-36 (58.4 vs. 62 for telecare vs. 60.4 vs. 64.2 for standard care) were noted, with no intergroup differences. However, patients receiving telecare showed improvement in specific domains, such as physical functioning, role-physical, bodily pain, vitality, social functioning, role-emotional, and mental health. There was a significant decrease in MLwHF (29 vs. 35.0; lower is better) at follow-up for both groups. Telecare patients had a statistically significant decrease in EHFScBS-12 (lower is better) at 12 months.ConclusionAMULET outpatient telecare, which is based on nurse-led non-invasive assessments supported by specialist teleconsultations, improved the HRQoL and self-care of HF patients after an episode of acute HF.

Abstract Background Frailty is a severe, common co‐morbidity associated with heart failure (HF) with preserved ejection fraction (HFpEF). The impact of frailty on HFpEF outcomes may affect treatment choices in HFpEF. The impact of frailty on HFpEF patients and any impact on the clinical benefits of sodium glucose co‐transporter 2 (SGLT2) inhibition in HFpEF have been described in only a limited number of trials. Whether the SGLT2 inhibitor empagliflozin would improve or worsen frailty status when given to HFpEF patients is also not known. The aims of this study were, therefore, to evaluate, in HFpEF patients enrolled in the EMPEROR‐Preserved trial (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction), the impact of frailty on clinical outcomes, and on the effects of empagliflozin, as well as the effect of empagliflozin on frailty status during treatment period. Methods We calculated a cumulative deficit‐derived frailty index (FI) using 44 variables including clinical, laboratory and quality of life parameters recorded in EMPEROR‐Preserved. Patients were classified into four groups: non‐frail (FI

Abstract The decongestion ability in response to diuretic treatment plays a crucial role in the treatment of acute heart failure. This effectiveness is evaluated through the assessment of sodium concentration and urine volume, which are also treatment goals themselves. However, the bidirectional interconnection between these factors remains not fully understood. The objective of this study is to provide mechanistic insights into the correlation between spot urine sodium concentrations (UNa+) and urine dilution. This aims to better understand of the decongestive abilities in acute heart failure (AHF). The study was single-center, prospective, conducted on a group of 50 AHF patients. Each participant received a standardized furosemide dose of 1 mg per kg of body weight. Hourly diuresis was measured in the first 6 h of the study, and urine composition was assessed at predefined timepoints. The study group presented the exponential (rather than linear) pattern of relationship between UNa+ and 6-h urine volume, whereas relationship between eGFR and 6-h urine volume was linear (r = 0.61, p

Sodium-glucose co-transporter 2 (SGLT2) inhibitors have recently been recommended as a foundational therapy for patients with heart failure (HF) and reduced ejection fraction (HFrEF) because of their favourable effects on mortality, clinical events and quality of life. While clinical practice guidelines have recommended dapagliflozin or empagliflozin in all patients with HFrEF, or sotagliflozin in those with HFrEF and concomitant diabetes, the timing and practical integration of these drugs in clinical practice is less well defined. We propose that these drugs are candidates for early, upfront administration to patients with newly diagnosed HFrEF and for patients hospitalized with HF. Growing evidence has established early benefits, with clinically meaningful reductions in clinical events that reach statistical significance within days to weeks, following dapagliflozin, empagliflozin or, in diabetic patients, sotagliflozin initiation. Secondly, although major clinical trials have tested these drugs in patients already receiving background HF therapy, secondary analyses showed that their efficacy is independent of that. Third, SGLT2 inhibitors are generally safe and well tolerated, with clinical trial data reporting minimal effects on blood pressure, glycaemia-related adverse events, and no excess in acute kidney injury. Rather, they exert renal protective effects and reduce risk of hyperkalaemia, properties that favour initiation, tolerance and persistence of renin-angiotensin system inhibitors and mineralocorticoid receptor antagonists. This review supports the early initiation of dapagliflozin and empagliflozin (or sotagliflozin limited to patients with diabetes) to rapidly improve clinical outcome and quality of life of HFrEF patients.

Abstract The COVID-19 pandemic has had a significant impact on global public health, with long-term consequences that are still largely unknown. This study aimed to assess the data regarding acute cardiovascular hospital admissions in five European centers before and during the pandemic. A multicenter, multinational observational registry was created, comparing admissions to the emergency departments during a 3-months period in 2020 (during the pandemic) with the corresponding period in 2019 (pre-pandemic). Data on patient demographics, COVID-19 test results, primary diagnosis, comorbidities, heart failure profile, medication use, and laboratory results were collected. A total of 8778 patients were included in the analysis, with 4447 patients in 2019 and 4331 patients in 2020. The results showed significant differences in the distribution of cardiovascular diseases between the two years. The frequency of pulmonary embolism (PE) increased in 2020 compared to 2019, while acute heart failure (AHF) and other cardiovascular diseases decreased. The odds of PE incidence among hospitalized patients in 2020 were 1.316-fold greater than in 2019. The incidence of AHF was 50.83% less likely to be observed in 2020, and the odds for other cardiovascular diseases increased by 17.42% between the 2 years. Regarding acute coronary syndrome (ACS), the distribution of its types differed between 2019 and 2020, with an increase in the odds of ST-segment elevation myocardial infarction (STEMI) in 2020. Stratification based on sex revealed further insights. Among men, the incidence of AHF decreased in 2020, while other cardiovascular diseases increased. In women, only the incidence of STEMI showed a significant increase. When analyzing the influence of SARS-CoV-2 infection, COVID-positive patients had a higher incidence of PE compared to COVID-negative patients. COVID-positive patients with ACS also exhibited symptoms of heart failure more frequently than COVID-negative patients. These findings provide valuable information on the impact of the COVID-19 pandemic on acute cardiovascular hospital admissions. The increased incidence of PE and changes in the distribution of other cardiovascular diseases highlight the importance of monitoring and managing cardiovascular health during and post pandemic period. The differences observed between sexes emphasize the need for further research to understand potential sex-specific effects of COVID-19 on cardiovascular outcomes.

Abstract Background In AFFIRM-AHF, treatment of iron deficiency with intravenous ferric carboxymaltose (FCM) reduced the risk of heart failure (HF) hospitalization and improved quality of life (QoL) vs placebo in patients stabilized following an acute HF (AHF) episode, with no effect on cardiovascular (CV) death. Diabetes and iron deficiency frequently accompany AHF. This post hoc analysis explored the effects of diabetes on outcomes in AFFIRM-AHF patients. Methods Patients were stratified by diabetes yes/no at baseline. The effects of FCM vs placebo on primary (total HF hospitalizations and CV death) and secondary (total CV hospitalizations and CV death; CV death; total HF hospitalizations; time to first HF hospitalization or CV death; and days lost due to HF hospitalizations or CV death) endpoints at Week 52 and change vs baseline in disease-specific QoL (12-item Kansas City Cardiomyopathy Questionnaire [KCCQ-12]) at Week 24 were assessed by subgroup. For each endpoint, the interaction between diabetes status and treatment outcome was explored. Results Of 1108 AFFIRM-AHF patients, 475 (FCM: 231; placebo: 244) had diabetes and 633 (FCM: 327; placebo: 306) did not have diabetes. Patients with diabetes were more commonly male (61.5% vs 50.9%), with a higher frequency of ischemic HF etiology (57.9% vs 39.0%), prior HF history (77.7% vs 66.5%), and comorbidities (including previous myocardial infarction [49.3% vs 32.9%] and chronic kidney disease [51.4% vs 32.4%]) than those without diabetes. The annualized event rate/100 patient-years with FCM vs placebo for the primary endpoint was 66.9 vs 80.9 in patients with diabetes (rate ratio [RR]: 0.83, 95% CI 0.58–1.81) and 51.3 vs 66.9 in patients without diabetes (RR: 0.77, 95% CI 0.55–1.07), with no significant interaction between diabetes status and treatment effect (pinteraction = 0.76). Similar findings were observed for secondary outcomes. Change from baseline in KCCQ-12 overall summary score was numerically greater with FCM vs placebo at almost all time points in both subgroups, with no interaction between diabetes and treatment effect at Week 24. Conclusions The clinical and QoL benefits observed with intravenous FCM in patients with iron deficiency following stabilization from an AHF episode are independent of diabetes status. Trial registration Clinicaltrials.gov, NCT02937454 (registered 10.18.2016).

The co-occurrence of cancer and heart failure (HF) represents a significant clinical drawback as each disease interferes with the treatment of the other. In addition to shared risk factors, a growing body of experimental and clinical evidence reveals numerous commonalities in the biology underlying both pathologies. Inflammation emerges as a common hallmark for both diseases as it contributes to the initiation and progression of both HF and cancer. Under stress, malignant and cardiac cells change their metabolic preferences to survive, which makes these metabolic derangements a great basis to develop intersection strategies and therapies to combat both diseases. Furthermore, genetic predisposition and clonal haematopoiesis are common drivers for both conditions and they hold great clinical relevance in the context of personalized medicine. Additionally, altered angiogenesis is a common hallmark for failing hearts and tumours and represents a promising substrate to target in both diseases. Cardiac cells and malignant cells interact with their surrounding environment called stroma. This interaction mediates the progression of the two pathologies and understanding the structure and function of each stromal component may pave the way for innovative therapeutic strategies and improved outcomes in patients. The interdisciplinary collaboration between cardiologists and oncologists is essential to establish unified guidelines. To this aim, pre-clinical models that mimic the human situation, where both pathologies coexist, are needed to understand all the aspects of the bidirectional relationship between cancer and HF. Finally, adequately powered clinical studies, including patients from all ages, and men and women, with proper adjudication of both cancer and cardiovascular endpoints, are essential to accurately study these two pathologies at the same time.

Objective This study aimed to assess the prognostic significance of residual (discharge) dyspnoea in acute heart failure (AHF) patients.Design Single-centre, prospective observational study.Setting Patients hospitalised for decompensated AHF in a single cardiology centre, in Poland.Participants All patients (n=202) who survived the hospitalisation with the primary diagnosis of AHF and were discharged from the hospital.Primary and secondary outcome measures 1-year all-cause mortality; and the composite endpoint of 1-year all-cause mortality and rehospitalisation for the HF (whichever occurred first).Results On admission, 159 (78.7%) AHF patients presented dyspnoea at rest, while residual resting dyspnoea at discharge was present in 16 patients (7.9%). There were 48 (24%) patients with moderate/severe exertional dyspnoea at discharge. In the multivariable model, the resting dyspnoea at discharge was related to a higher risk of both 1-year mortality and composite outcome, with HR (95% CI) 8.0 (3.7 to 17.3) and 5.1 (2.6 to 10.2), respectively, both p

ABSTRACT Acute heart failure is a common and increasingly prevalent condition, affecting >10 million people annually. For those patients who survive to discharge, early readmissions and death rates are >30% everywhere on the planet, making it a malignant condition. Beyond these adverse outcomes, it represents one of the largest drivers of health care costs globally. Studies in the past 2 years have demonstrated that we can induce remissions in this malignant process if therapy is instituted rapidly, at the first acute heart failure episode, using full doses of all available effective medications. Multiple studies have demonstrated that this goal can be achieved safely and effectively. Now the urgent call is for all stakeholders, patients, physicians, payers, politicians, and the public at large to come together to address the gaps in implementation and enable health care providers to induce durable remissions in patients with acute heart failure.

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has important implications for the safety of participants in clinical trials and the research staff caring for them and, consequently, for the trials themselves. Patients with heart failure may be at greater risk of infection with COVID-19 and the consequences might also be more serious, but they are also at risk of adverse outcomes if their clinical care is compromised. As physicians and clinical trialists, it is our responsibility to ensure safe and effective care is delivered to trial participants without affecting the integrity of the trial. The social contract with our patients demands no less. Many regulatory authorities from different world regions have issued guidance statements regarding the conduct of clinical trials during this COVID-19 crisis. However, international trials may benefit from expert guidance from a global panel of experts to supplement local advice and regulations, thereby enhancing the safety of participants and the integrity of the trial. Accordingly, the Heart Failure Association of the European Society of Cardiology on 21 and 22 March 2020 conducted web-based meetings with expert clinical trialists in Europe, North America, South America, Australia, and Asia. The main objectives of this Expert Position Paper are to highlight the challenges that this pandemic poses for the conduct of clinical trials in heart failure and to offer advice on how they might be overcome, with some practical examples. While this panel of experts are focused on heart failure clinical trials, these discussions and recommendations may apply to clinical trials in other therapeutic areas.

ObjectivesThis study sought to characterize cognitive decline (CD) over time and its predictors in patients with systolic heart failure (HF).BackgroundDespite the high prevalence of CD and its impact on mortality, predictors of CD in HF have not been established.MethodsThis study investigated CD in the WARCEF (Warfarin versus Aspirin in Reduced Ejection Fraction) trial, which performed yearly Mini-Mental State Examinations (MMSE) (higher scores indicate better cognitive function; e.g., normal score: 24 or higher). A longitudinal time-varying analysis was performed among pertinent covariates, including baseline MMSE and MMSE scores during follow-up, analyzed both as a continuous variable and a 2-point decrease. To account for a loss to follow-up, data at the baseline and at the 12-month visit were analyzed separately (sensitivity analysis).ResultsA total of 1,846 patients were included. In linear regression, MMSE decrease was independently associated with higher baseline MMSE score (p

AimsEpisodes of acute heart failure (AHF) may lead to end-organ dysfunction. In this post hoc analysis of the Relaxin in Acute Heart Failure trial, we used the MELD-XI (Model of End-Stage Liver Dysfunction) score to examine hepatorenal dysfunction in patients with AHF.Methods and resultsOn admission, the MELD-XI score was elevated (abnormal) in 918 (82%) patients, with 638 (57%) having isolated renal dysfunction (creatinine > 1 mg/dL), 73 (6.5%) isolated liver dysfunction (bilirubin > 1 mg/dL), and 207 (18.5%) coexisting dysfunction of the kidneys and the liver (both creatinine and bilirubin > 1 mg/dL). The percentage of patients with elevated MELD-XI score remained constant through a 60 day follow-up, as we observed a gradual decrease of liver dysfunction prevalence, counterbalanced by an increase in renal dysfunction. Serelaxin treatment was associated with a lower MELD-XI score on Day 2 and Day 5 (both P

Abstract Aims Treatment response to vericiguat, based on baseline N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) subgroups specified in the protocol, was evaluated in the heart failure (HF) VICTORIA trial population by post hoc analysis of combined lower three quartiles [Q1–Q3] vs. the upper quartile [Q4]. Methods and results VICTORIA participants with available baseline NT‐proBNP levels (n = 4805; 95.1% of total) were included. Compared with patients in Q1–Q3 (NT‐proBNP: Q1, ≤1556 pg/mL; Q2, >1556–2816 pg/mL; and Q3, >2816–5314 pg/mL), patients in Q4 (NT‐proBNP: >5314 pg/mL) were older (69.2 ± 12.0 vs. 66.6 ± 12.1 years), had lower mean ejection fraction (27.2 ± 8.3% vs. 29.5 ± 8.2%; P

Abstract Aims Insulin like growth factor binding protein 7 (IGFBP7) is a marker of senescence secretome and a novel biomarker in patients with heart failure (HF). We evaluated the prognostic value of IGFBP7 in patients with heart failure and examined associations to uncover potential new pathophysiological pathways related to increased plasma IGFBP7 concentrations. Methods and results We have measured plasma IGFBP7 concentrations in 2250 subjects with new‐onset or worsening heart failure (BIOSTAT‐CHF cohort). Higher IGFBP7 plasma concentrations were found in older subjects, those with worse kidney function, history of atrial fibrillation, and diabetes mellitus type 2, and in subjects with higher number of HF hospitalizations. Higher IGFBP7 levels also correlate with the levels of several circulating biomarkers, including higher NT‐proBNP, hsTnT, and urea levels. Cox regression analyses showed that higher plasma IGFBP7 concentrations were strongly associated with increased risk of all three main endpoints (hospitalization, all‐cause mortality, and combined hospitalization and mortality) (HR 1.75, 95% CI 1.25–2.46; HR 1.71, 95% CI 1.39–2.11; and HR 1.44, 95% CI 1.23–1.70, respectively). IGFBP7 remained a significant predictor of these endpoints in patients with both reduced and preserved ejection fraction. Likelihood ratio test showed significant improvement of all three risk prediction models, after adding IGFBP7 (P

Abstract The aim of this research was to examine the prevalence of hyperventilation (defined by pCO2 value) among acute heart failure (AHF) patients and to link it with potential triggers and prognosis. All patients underwent dyspnea severity assessment and capillary blood examination on hospital admission and during hospitalization. Out of 241 AHF patients, 57(24%) were assigned to low pCO2 group (pCO2 ≤ 30 mmHg) and 184 (76%) to normal pCO2 group (pCO2 > 30 mmHg). Low pCO2 group had significantly lower HCO3 - (22.3 ± 3.4 vs 24.7 ± 2.9 mmol/L, p

Introduction: The most common side effect of ticagrelor is dyspnea, which leads to premature withdrawal of this life-saving medication in 6.5% of patients. Increased chemoreceptors’ sensitivity was suggested as a possible pathophysiological explanation of this phenomenon; however, the link between oversensitization of peripheral and/or central chemosensory areas and ticagrelor intake has not been conclusively proved.Methods: We measured peripheral chemoreceptors’ sensitivity using hypoxic ventilatory response (HVR), central chemoreceptors’ sensitivity using hypercapnic hyperoxic ventilatory response (HCVR), and dyspnea severity before and 4 ± 1 weeks following ticagrelor initiation in 11 subjects with chronic coronary syndrome undergoing percutaneous coronary intervention (PCI). The same tests were performed in 11 age-, sex-, and BMI-matched patients treated with clopidogrel. The study is registered at ClinicalTrials.com at NCT05080478.Results: Ticagrelor significantly increased both HVR (0.52 ± 0.46 vs. 0.84 ± 0.69 L min-1 %−1; p < 0.01) and HCVR (1.05 ± 0.64 vs. 1.75 ± 1.04 L min−1 mmHg−1; p < 0.01). The absolute change in HVR correlated with the change in HCVR. Clopidogrel administration did not significantly influence HVR (0.63 ± 0.32 vs. 0.58 ± 0.33 L min-1%−1; p = 0.53) and HCVR (1.22 ± 0.67 vs. 1.2 ± 0.64 L min−1 mmHg−1; p = 0.79). Drug-related dyspnea was reported by three subjects in the ticagrelor group and by none in the clopidogrel group. These patients were characterized by either high baseline HVR and HCVR or excessive increase in HVR following ticagrelor initiation.Discussion: Ticagrelor, contrary to clopidogrel, sensitizes both peripheral and central facets of chemodetection. Two potential mechanisms of ticagrelor-induced dyspnea have been identified: 1) high baseline HVR and HCVR or 2) excessive increase in HVR or HVR and HCVR. Whether other patterns of changes in chemosensitivities play a role in the pathogenesis of this phenomenon needs to be further investigated.

AimsThere is debate on whether the beneficial effect of implantable cardioverter-defibrillators (ICDs) is attenuated in patients with non-ischaemic cardiomyopathy (NICM). We assess whether any ICD benefit differs between patients with NICM and those with ischaemic cardiomyopathy (ICM), using data from the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial.Methods and resultsWe performed a post hoc analysis using WARCEF (N = 2293; ICM, n = 991 vs. NICM, n = 1302), where participants received optimal medical treatment. We developed stratified propensity scores for having an ICD at baseline using 41 demographic and clinical variables and created 1:2 propensity-matched cohorts separately for ICM patients with ICD (N = 223 with ICD; N = 446 matched) and NICM patients (N = 195 with ICD; N = 390 matched). We constructed a Cox proportional hazards model to assess the effect of ICD status on mortality for patients with ICM and those with NICM and tested the interaction between ICD status and aetiology of heart failure. During mean follow-up of 3.5 ± 1.8 years, 527 patients died. The presence of ICD was associated with a lower risk of all-cause death among those with ICM (hazard ratio: 0.640; 95% confidence interval: 0.448 to 0.915; P = 0.015) but not among those with NICM (hazard ratio: 0.984; 95% confidence interval: 0.641 to 1.509; P = 0.941). There was weak evidence of interaction between ICD status and the aetiology of heart failure (P = 0.131).ConclusionsThe presence of ICD is associated with a survival benefit in patients with ICM but not in those with NICM.

Abstract Background A higher protein intake has been associated with a higher muscle mass and lower mortality rates in the general population, but data about protein intake and survival in patients with heart failure (HF) are lacking. Methods We studied the prevalence, predictors, and clinical outcome of estimated protein intake in 2516 patients from the BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT‐CHF) index cohort. Protein intake was calculated in spot urine samples using a validated formula [13.9 + 0.907 * body mass index (BMI) (kg/m2) + 0.0305 * urinary urea nitrogen level (mg/dL)]. Association with mortality was assessed using multivariable Cox regression models. All findings were validated in an independent cohort. Results We included 2282 HF patients (mean age 68 ± 12 years and 27% female). Lower estimated protein intake in HF patients was associated with a lower BMI, but with more signs of congestion. Mortality rate in the lowest quartile was 32%, compared with 18% in the highest quartile (P

IntroductionThe research examines the relationship between marathon performance and muscle stiffness changes from pre to marathon in recreational runners aged 50+ years.MethodsThirty-one male long-distance runners aged 50–73 years participated in the experiment. The muscle stiffness of quadriceps and calves was measured in two independent sessions: the day before the marathon and 30 min after the completed marathon run using a Myoton device.Results and DiscussionThe 42.195-km run was completed in 4.30,05 h ± 35.12 min, which indicates an intensity of 79.3% ± 7.1% of HRmax. The long-term, low-intensity running exercise (marathon) in older recreational runners and the low level of HRmax and VO2max showed no statistically significant changes in muscle stiffness (quadriceps and calves). There was reduced muscle stiffness (p = 0.016), but only in the triceps of the calf in the dominant (left) leg. Moreover, to optimally evaluate the marathon and adequately prepare for the performance training program, we need to consider the direct and indirect analyses of the running economy, running technique, and HRmax and VO2max variables. These variables significantly affect marathon exercise.

Background Outcomes and treatment effects of therapy may vary according to the cause of heart failure (HF). Methods and Results In this post hoc analysis of the EMPEROR‐Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction) trial, the effect of empagliflozin on cardiovascular and renal outcomes was assessed according to the cause of HF. The cause of HF was investigator reported and stratified as ischemic or nonischemic. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% CIs. Of the 3730 patients enrolled, 1929 (51.7%) had ischemic cause. In the placebo arm, patients with ischemic cause of HF did not have a significantly higher risk of cardiovascular mortality (HR, 1.21 [95% CI, 0.90–1.63]) and hospitalization for HF (HR, 0.90 [95% CI, 0.72–1.12]) compared with nonischemic cause. Empagliflozin compared with placebo significantly reduced the risk of cardiovascular death or hospitalization for HF in patients with ischemic and nonischemic cause (HR, 0.82 [95% CI, 0.68–0.99] for ischemic and HR, 0.67 [95% CI, 0.55–0.82] for nonischemic cause; P interaction=0.15). The benefit of empagliflozin on HF hospitalization, the renal composite end point, estimated glomerular filtration slope changes, and health status scores were also consistent in both groups without treatment by cause modification. Conclusions Empagliflozin offers cardiovascular and renal benefits in patients with heart failure with reduced ejection fraction regardless of the cause of HF. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03057977.

AimsLeft atrium (LA) dilation is associated with adverse cardiovascular (CV) outcomes. Blood stasis, thrombus formation and atrial fibrillation may occur, especially in heart failure (HF) patients. It is not known whether preventive antithrombotic treatment may decrease the incidence of CV events in HF patients with LA enlargement. We investigated the relationship between LA enlargement and CV outcomes in HF patients and the effect of different antithrombotic treatments.Methods and resultsTwo-dimensional echocardiography with LA volume index (LAVi) measurement was performed in 1148 patients with systolic HF from the Warfarin versus Aspirin in Reduced Ejection Fraction (WARCEF) trial. Patients were randomized to warfarin or aspirin and followed for 3.4 ± 1.7 years. While the primary aim of the trial was a composite of ischaemic stroke, death, and intracerebral haemorrhage, the present report focuses on the individual CV events, whose incidence was compared across different LAVi and treatment subgroups. After adjustment for demographics and clinical covariates, moderate or severe LA enlargement was significantly associated with total death (hazard ratio 1.6 and 2.7, respectively), CV death (HR 1.7 and 3.3), and HF hospitalization (HR 2.3 and 2.6) but not myocardial infarction (HR 1.0 and 1.4) or ischaemic stroke (1.1 and 1.5). The increased risk was observed in both patients treated with warfarin or aspirin. In warfarin-treated patients, a time in therapeutic range >60% was associated with lower event rates, and an interaction between LAVi and time in therapeutic range was observed for death (P = 0.034).ConclusionsIn patients with systolic HF, moderate or severe LA enlargement is associated with death and HF hospitalization despite treatment with antithrombotic medications. The possibility that achieving a more consistent therapeutic level of anticoagulation may decrease the risk of death requires further investigation.

Previous studies in patients with atrial fibrillation showed that a history of heart failure (HF) could negatively impact anticoagulation quality, as measured by the average time in therapeutic range (TTR). Whether additional markers of HF severity are associated with TTR has not been investigated thoroughly. We aimed to examine the potential role of HF severity in the quality of warfarin control in patients with HF with reduced ejection fraction. Data from the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction Trial were used to investigate the association between TTR and HF severity. Multivariable logistic regression models were used to examine the association of markers of HF severity, including New York Heart Association (NYHA) class, Minnesota Living with HF (MLWHF) score, and frequency of HF hospitalization, with TTR ≥70% (high TTR). We included 1,067 participants (high TTR, N = 413; low TTR, N = 654) in the analysis. In unadjusted analysis, patients with a high TTR were older and less likely to have had strokes or receive other antiplatelet agents. Those patients also had lower NYHA class, better MLWHF scores, greater 6-minute walk distance, and lower frequency of HF hospitalizations. Multivariable analysis showed that NYHA class III and/or IV (Odds ratio [OR] 0.68 [95% confidence intervals [CIs] 0.49 to 0.94]), each 10-point increase in MLWHF score (i.e., worse health-related quality of life) (OR 0.92 [0.86 to 0.99]), and higher number of HF hospitalization per year (OR0.45 [0.30 to 0.67]) were associated with decreased likelihood of having high TTR. In HF patients with systolic dysfunction, NYHA class III and/or IV, poor health-related quality of life, and a higher rate of HF hospitalization were independently associated with suboptimal quality of warfarin anticoagulation control. These results affirm the need to assess the new approaches, such as direct oral anticoagulants, to prevent thromboembolism in this patient population.

Abstract Peripheral chemoreceptors’ (PCh) hyperactivity increases sympathetic tone. An augmented acute ventilatory response to hypoxia, being a marker of PCh oversensitivity, was also identified as a marker of poor prognosis in HF. However, not much is known about the tonic (chronic) influence of PCh on cardio-respiratory parameters. In our study 30 HF patients and 30 healthy individuals were exposed to 100% oxygen for 1 min during which minute ventilation and hemodynamic parameters were non-invasively recorded. Systemic vascular resistance (SVR) and mean arterial pressure (MAP) responses to acute hyperoxia differed substantially between HF and control. In HF hyperoxia caused a significant drop in SVR in early stages with subsequent normalization, while increase in SVR was observed in controls. MAP increased in controls, but remained unchanged in HF. Bilateral carotid bodies excision performed in two HF subjects changed the response to hyperoxia towards the course seen in healthy individuals. These differences may be explained by the domination of early vascular reaction to hyperoxia in HF by vasodilation due to the inhibition of augmented tonic activity of PCh. Otherwise, in healthy subjects the vasoconstrictive action of oxygen remains unopposed. The magnitude of SVR change during acute hyperoxia may be used as a novel method for tonic PCh activity assessment.

Pathomechanisms responsible for recovery from acute myocarditis (MCD) or progression to non-ischemic cardiomyopathy have not been comprehensively investigated. Iron, positioned at the crossroads of inflammation and the energy metabolism of cardiomyocytes, may contribute to the pathophysiology of inflammatory myocardial disease. The aim of this study was to evaluate whether systemic iron parameters are related to myocardial dysfunction in MCD patients. We prospectively enrolled 42 consecutive patients hospitalized for MCD. Their iron status and their clinical, laboratory, and echocardiographic indices were assessed during hospitalization and during ambulatory visits six weeks after discharge. A control group comprising healthy volunteers was recruited. The MCD patients had higher serum ferritin and hepcidin and lower serum iron concentration and transferrin saturation (TSAT) than the healthy controls (all p < 0.01). Six weeks after discharge, the iron status of the MCD patients was already comparable to that of the control group. During hospitalization, lower serum iron and TSAT correlated with higher NT-proBNP (both p < 0.05). In-hospital lower serum iron and TSAT correlated with both a lower left ventricular ejection fraction (LVEF) and worse left ventricular global longitudinal strain at follow-up visits (all p < 0.05). In conclusion, in patients with acute MCD, iron status is altered and normalizes within six weeks. Low serum iron and TSAT are related to greater in-hospital neurohormonal activation and subtle persistent left ventricular dysfunction.

Abstract Aims Heart failure (HF) is characterized by high mortality and hospital readmission rates. Limited access to cardiologists restricts the application of guideline‐directed, patient‐tailored medical therapy. Some telemedicine solutions and novel non‐invasive diagnostic tools may facilitate real‐time detection of early HF decompensation symptoms, prompt initiation of appropriate treatment, and optimal management of medical resources. We describe the rationale and design of the AMULET trial, which investigates the effect of comprehensive outpatient intervention, based on individualized haemodynamic assessment and teleconsultations, on cardiovascular mortality and unplanned hospitalizations in HF patients. Methods and results The AMULET trial is a multicentre, prospective, randomized, open‐label, and controlled parallel group trial (ClinicalTrials.gov Identifier: NCT03476590). Six hundred and five eligible patients with HF (left ventricular ejection fraction ≤49%, at least one hospitalization due to acute HF decompensation within 6 months prior to enrolment) were randomly assigned in a 1:1 ratio to either an intervention group or a standard care group. The planned follow‐up is 12 months. The AMULET interventions are performed in ambulatory care points operated by nurses, with the remote support of cardiologists. The comprehensive clinical evaluation comprises measurements of heart rate, blood pressure, body mass, thoracic fluid content, and total body water. A recommendation support module based on these objective parameters is implemented in remote therapeutic decision‐making. The primary complex endpoints are cardiovascular mortality and unplanned HF hospitalization. Conclusions The AMULET trial will provide a prospective assessment of the effect of comprehensive ambulatory intervention, based on telemedicine and haemodynamically guided therapy, on mortality and readmissions in HF patients.

Abstract Heart failure (HF) does not occur in a vacuum and is commonly defined and exacerbated by its co‐morbid conditions. Neurohormonal imbalance and systemic inflammation are some of the key pathomechanisms of HF but also commonly encountered co‐morbidities such as arterial hypertension, diabetes mellitus, cachexia, obesity and sleep‐disordered breathing. A cornerstone of HF management is neurohormonal blockade, which in HF with reduced ejection fraction has been tied to a reduction in morbidity and mortality. Pharmacological treatment effective in patients with HF with reduced ejection fraction did not show substantial effects in HF with preserved ejection fraction. Here, we review novel device‐based therapies using neuromodulation of extra‐cardiac targets to treat cardiometabolic disease.

Abstract Aims Most studies examined spot urine sodium's (sUNa+) prognostic utility during the early phase of acute heart failure (AHF) hospitalization. In AHF, sodium excretion is related to clinical status; therefore, we investigated the differences in the prognostic information of spot UNa+ throughout the course of hospitalization for AHF (admission vs. discharge). Methods and results The study population were AHF patients (n = 172), who survived the index hospitalization. We compared the relationship between early (on admission, at 24 and 48 h) and discharge sUNa+ measurements with post‐discharge study endpoints: composite of 1 year all‐cause mortality and AHF rehospitalization (with time to first event analysis) as well as with each event in separation. There were 49 (28.5%) deaths, 40 (23.3%) AHF rehospitalizations, while the composite endpoint occurred in 69 (40.1%) during 1 year follow‐up. The sUNa+ had prognostic significance for the composite endpoint when assessed on admission, at 24 and at 48 h: hazard ratios (HRs) with 95% confidence intervals (CIs) (per 10 mmol/L) were 0.88 (0.82–0.94); 0.87 (0.81–0.91); 0.90 (0.84–0.96), all P

AimsCurrently, no acute heart failure (AHF) therapy definitively improves outcomes. Reducing morbidity and mortality from acute heart failure (AHF) remains an unmet need. TRV027 is a novel 'biased' ligand of the angiotensin II type 1 receptor (AT1R), selectively antagonizing the negative effects of angiotensin II, while preserving the potential pro-contractility effects of AT1R stimulation. BLAST-AHF was designed to determine the safety, efficacy, and optimal dose of TRV027 to advance into future studies.Methods and resultsBLAST-AHF was a multi-centre, international, randomized, double-blind, placebo-controlled, parallel group, phase IIb dose-ranging study, enrolling patients with AHF into 4 groups: placebo, 1, 5, or 25 mg/h of TRV027. Treatment was by IV infusion for 48-96 h. The primary composite endpoint was comprised of the following: (i) time from baseline to death through day 30, (ii) time from baseline to heart failure re-hospitalization through day 30, (iii) the first assessment time point following worsening heart failure through day 5, (iv) change in dyspnea visual analogue scale (VAS) score calculated as the area under the curve (AUC) representing the change from baseline over time from baseline through day 5, and (v) length of initial hospital stay (in days) from baseline. Analyses were by modified intention-to-treat. Overall, 621 patients were enrolled. After 254 patients, a pre-specified interim analysis resulted in several protocol changes, including a lower blood pressure inclusion criterion as well as a new allocation scheme of 2:1:2:1, overweighting both placebo, and the 5 mg/h dose. TRV027 did not confer any benefit over placebo at any dose with regards to the primary composite endpoint or any of the individual components. There were no significant safety issues with TRV027.ConclusionIn this phase IIb dose-ranging AHF study, TRV027 did not improve clinical status through 30-day follow-up compared with placebo.