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Background: Fluid overload (FO) subjects patients with severe aortic stenosis (AS) to increased risk for heart failure and death after valve replacement and can be objectively quantified using bioimpedance spectroscopy (BIS)., Objectives: The authors hypothesized that in AS patients with concomitant FO, BIS-guided decongestion could improve prognosis and quality of life following transcatheter aortic valve replacement (TAVR)., Methods: This randomized, controlled trial enrolled 232 patients with severe AS scheduled for TAVR. FO was defined using a portable whole-body BIS device according to previously established cutoffs (≥1.0 L and/or ≥7%). Patients with FO (n = 111) were randomly assigned 1:1 to receive BIS-guided decongestion (n = 55) or decongestion by clinical judgment alone (n = 56) following TAVR. Patients without FO (n = 121) served as a control cohort. The primary endpoint was the composite of hospitalization for heart failure and/or all-cause death at 12 months. The secondary endpoint was the change from baseline to 12 months in the Kansas City Cardiomyopathy Questionnaire., Results: The occurrence of the primary endpoint at 12 months was significantly lower in the BIS-guided vs the non-BIS-guided decongestion group (7/55 [12.7%, all deaths] vs 18/56 [32.1%, 9 hospitalizations for heart failure and 9 deaths]; HR: 0.36; 95% CI: 0.15-0.87; absolute risk reduction = -19.4%). Outcomes in the BIS-guided decongestion group were identical to the euvolemic control group (log-rank test, P = 0.7). BIS-guided decongestion was also associated with a higher increase in the Kansas City Cardiomyopathy Questionnaire score from baseline compared to non-BIS-guided decongestion (P = 0.001)., Conclusions: In patients with severe AS and concomitant FO, quantitatively guided decongestive treatment and associated intensified management post-TAVR was associated with improved outcomes and quality of life compared to decongestion by clinical judgment alone. (Management of Fluid Overload in Patients Scheduled for Transcatheter Aortic Valve Replacement [EASE-TAVR]; NCT04556123)., Competing Interests: Funding Support and Author Disclosures This study was supported by the Austrian Society of Cardiology. Dr Dannenberg has received consulting fees from Abbott; and has received educational grants from Edwards Lifesciences. Dr Kammerlander has received speaker fees from Bayer and Boehringer Ingelheim; has received advisory board honoraria from Boehringer Ingelheim; and has received research grants from Pfizer. Dr Hengstenberg has received proctoring/speaker fees from Boston Scientific and Edwards Lifesciences; and has received institutional research grants from Abbott, Boston Scientific, Edwards Lifesciences, and Medtronic). Dr Mascherbauer has received proctor fees from Abbott and Edwards Lifesciences; has received consulting fees from Boston Scientific, Edwards Lifesciences, and Shockwave Medical; and has received educational grants from Abbott, Boston Scientific, and Edwards Lifesciences. Dr Nitsche has received speaker fees/institutional research grants from Pfizer; and has received advisory board honoraria from Prothena). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: Regulation of the renin-angiotensin system (RAS) in heart failure (HF) with reduced ejection fraction (HFrEF) still raises questions, as a large proportion of patients show normal renin levels despite manifest disease. Experimental venous congestion results in reduced renal perfusion pressure and stimulates renin secretion. We hypothesized that excess renin levels are mainly a result of right ventricular failure as a sequalae of left ventricular dysfunction. The study aimed to link right ventricular function (RVF) with renin levels and to investigate further contributors to excess RAS activation., Methods and Results: Three hundred thirty-two chronic HFrEF patients undergoing routine ambulatory care were consecutively enrolled in a prospective, registry-based, observational study. Laboratory parameters, including cardiac-specific markers renin, aldosterone, and N-terminal pro-brain natriuretic peptide (NT-proBNP), echocardiographic examination (n = 247), and right heart catheterization (n = 85), were documented. The relationship between renin and its respective parameters was analysed. Renin concentration was not associated with the New York Heart Association class or NT-proBNP. Systolic blood pressure, systemic vascular resistance, serum sodium, aldosterone, and lactate dehydrogenase were associated with increased renin levels (P < 0.035 for all). Renin levels similarly increased with worsening of RVF parameters such as fractional area change, tricuspid annular plane systolic excursion, tissue Doppler imaging, and inferior vena cava diameter (P < 0.011 for all), but not with pulmonary pressure. Excess renin levels were observed when worsening RVF was combined with reduced renal perfusion {625 μIU/mL [interquartile range (IQR): 182-1761] vs. 67 μIU/mL [IQR: 16-231], P < 0.001}, which was associated with worse survival., Conclusions: While unrelated to classical indices of HF severity, circulating renin levels increase with the worsening of RVF, especially in the combined presence of forward and backward failure. This might explain normal renin levels in HFrEF patients but also excess renin levels in poor haemodynamic conditions., (© 2024 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Cognitive impairment is prevalent in patients with heart failure with reduced ejection fraction (HFrEF), affecting self-care and outcomes. Novel blood-based biomarkers have emerged as potential diagnostic tools for neurodegeneration., Objectives: This study aimed to assess neurodegeneration in HFrEF by measuring neurofilament light chain (NfL), total tau (t-tau), amyloid beta 40 (Aβ40), and amyloid beta 42 (Aβ42) in a large, well-characterized cohort., Methods: The study included 470 patients with HFrEF from a biobank-linked prospective registry at the Medical University of Vienna. High-sensitivity single-molecule assays were used for measurement. Unplanned heart failure (HF) hospitalization and all-cause death were recorded as outcome parameters., Results: All markers, but not the Aβ42:Aβ40 ratio, correlated with HF severity, ie, N-terminal pro-B-type natriuretic peptide and NYHA functional class, and comorbidity burden and were significantly associated with all-cause death and HF hospitalization (crude HR: all-cause death: NfL: 4.44 [95% CI: 3.02-6.53], t-tau: 5.04 [95% CI: 2.97-8.58], Aβ40: 3.90 [95% CI: 2.27-6.72], and Aβ42: 5.14 [95% CI: 2.84-9.32]; HF hospitalization: NfL: 2.48 [95% CI: 1.60-3.85], t-tau: 3.44 [95% CI: 1.95-6.04], Aβ40: 3.13 [95% CI: 1.84-5.34], and Aβ42: 3.48 [95% CI: 1.93-6.27]; P < 0.001 for all). These associations remained statistically significant after multivariate adjustment including N-terminal pro-B-type natriuretic peptide. The discriminatory accuracy of NfL in predicting all-cause mortality was comparable to the well-established risk marker N-terminal pro-B-type natriuretic peptide (C-index: 0.70 vs 0.72; P = 0.225), whereas the C-indices of t-tau, Aβ40, Aβ42, and the Aβ42:Aβ40 ratio were significantly lower (P < 0.05 for all)., Conclusions: Neurodegeneration is directly interwoven with the progression of HF. Biomarkers of neurodegeneration, particularly NfL, may help identify patients potentially profiting from a comprehensive neurological work-up. Further research is necessary to test whether early diagnosis or optimized HFrEF treatment can preserve cognitive function., Competing Interests: Funding Support and Author Disclosures This project was funded by an unrestricted grant of the Austrian Cardiac Society (Österreichische Kardiologische Gesellschaft). The authors have reported that they have no relationships relevant to the contents of this paper to declare., (Copyright © 2024. Published by Elsevier Inc.)

Aims: Transcatheter aortic valve replacement (TAVR) revolutionized the therapy of severe aortic stenosis (AS) with rising numbers. Mixed aortic valve disease (MAVD) treated by TAVR is gaining more interest, as those patients represent a more complex cohort as compared with isolated AS. However, concerning long-term outcome for this cohort only, limited data are available. The aim of the study is to assess the prevalence of MAVD in TAVR patients, investigate its association with paravalvular regurgitation (PVR), and analyse its impact on long-term mortality after TAVR., Methods and Results: We conducted a registry-based cohort study using the Vienna TAVR registry, enrolling patients who underwent TAVR at Medical University of Vienna between January 2007 and May 2020 with available transthoracic echocardiography before and after TAVR (n = 880). Data analysis included PVR incidence and long-term survival outcomes. A total of 647 (73.52%) out of 880 patients had ≥ mild aortic regurgitation next to severe AS. MAVD was associated with PVR compared with isolated AS with an odds ratio of 2.06, 95% confidence interval (CI): 1.51-2.81 (P = <0.001). More than mild PVR after TAVR (n = 168 out of 880: 19.09%) was related to higher mortality compared with the absence of PVR with a hazard ratio (HR) of 1.33, 95% CI: 1.05- 1.67 (P = 0.016). MAVD patients developing ≥ mild PVR after TAVR were also associated with higher mortality compared with the absence of PVR with an HR of 1.30 and 95% CI: 1.04-1.62 (P = 0.022)., Conclusion: MAVD is prevalent among TAVR patients and presents unique challenges, with increased PVR risk and worse outcomes compared with isolated AS. Long-term survival for MAVD patients, not limited to those developing PVR post-TAVR, is compromised. Earlier intervention before the occurrence of structural myocardial damage or surgical valve replacement might be a potential workaround to improve outcomes., Competing Interests: Conflict of interest: M.A. is a proctor/consultant/speaker (Edwards, Abbott, Medtronic, Boston, AbbVie, Zoll) and received institutional research grants (Edwards, Abbott, Medtronic, LSI). All other authors have no relationships relevant to the contents of this article to disclose., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: CILP-1 regulates myocardial fibrotic response and remodeling and was reported to indicate right ventricular dysfunction (RVD) in pulmonary hypertension (PH) and heart failure (HF). This study examines CILP-1 as a potential biomarker for RVD and prognosis in heart failure with reduced ejection fraction (HFrEF) patients on guideline-directed medical therapy., Methods: CILP-1 levels were measured in 610 HFrEF patients from a prospective registry with biobanking (2016-2022). Correlations with echocardiographic and hemodynamic data and its association with RVD and prognosis were analyzed., Results: The median age was 62 years (Q1-Q3: 52-72), 77.7% of patients were male, and the median NT-proBNP was 1810 pg/mL (Q1-Q3: 712-3962). CILP-1 levels increased with HF severity, as indicated by NT-proBNP and NYHA class ( p < 0.0001, for both). CILP-1 showed a weak-moderate direct association with increased left ventricular filling pressures and its sequalae, i.e., backward failure (LA diameter r s = 0.15, p = 0.001; sPAP r s = 0.28, p = 0.010; RVF r s = 0.218, p < 0.0001), but not with cardiac index (CI) and systemic vascular resistance (SVR). CILP-1 trended as a risk factor for all-cause mortality (crude HR for 500 pg/mL increase: 1.03 (95%CI: 1.00-1.06), p = 0.053) but lost significance when it was adjusted for NT-proBNP (adj. HR: 1.00 (95%CI: 1.00-1.00), p = 0.770). No association with cardiovascular hospitalization was observed., Conclusions: CILP-1 correlates with HFrEF severity and may indicate an elevated risk for all-cause mortality, though it is not independent from NT-proBNP. Increased CILP-1 is associated with backward failure and RVD rather than forward failure. Whether CILP-1 release in this context is based on elevated pulmonary pressures or is specific to RVD needs to be further investigated.

Introduction: The renin-angiotensin system (RAS) is the main target of neurohumoral therapy in heart failure with reduced ejection fraction (HFrEF) effectively reducing mortality. Reasonably, renin might serve as a biomarker for risk prediction and therapy response. Renin indeed bears some additional value to clinical risk models, albeit the effect is not pronounced. Whether assessing renin trajectories can overcome the weaknesses of single renin measurements has not been reported., Methods: A total of 505 patients with stable HFrEF were enrolled prospectively and followed through routine clinical visits. Active plasma renin concentration was documented up to 5 years. Changes in renin were analyzed throughout the disease course, and survival was compared for different renin trajectories within the first year., Results: Baseline renin levels were not related to all-cause mortality (crude HR for an increase of 100  μ iE/ml: 1.01 (95% CI: 0.99-1.02), p = 0.414) but associated with unplanned HF hospitalizations (crude HR: 1.01 (95% CI: 1.00-1.02), p = 0.015). Renin increased during the disease course from baseline to 1-year and 2-year FUP (122.7 vs. 185.6  μ IU/ml, p = 0.039, and 122.7 vs. 258.5  μ IU/ml, p = 0.001). Both survival and unplanned HF hospitalization rates were comparable for different renin trajectories at 1-year FUP ( p = 0.546, p = 0.357)., Conclusions: Intriguingly, renin is not a good biomarker to indicate prognosis in HF, while renin trajectories over a 1-year period do not have an additional value. Rapid physiologic plasma renin variations, but also opposing effects of angiotensinogen-derived metabolites under presence of RAS blockade, might obscure the predictive ability of renin., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2023 Emilie Han et al.)

Background: Right ventricular-to-pulmonary artery (RV-PA) coupling has recently been shown to be associated with outcome in valvular heart disease. However, longitudinal data on RV dysfunction and reverse cardiac remodeling in patients following transcatheter edge-to-edge mitral valve repair (M-TEER) are scarce., Methods: Consecutive patients with primary as well as secondary mitral regurgitation (MR) were prospectively enrolled and had comprehensive echocardiographic and invasive hemodynamic assessment at baseline. Kaplan-Meier estimates and multivariable Cox-regression analyses were performed, using a composite endpoint of heart failure hospitalization and death., Results: Between April 2018 and January 2021, 156 patients (median 78 y/o, 55% female, EuroSCORE II: 6.9%) underwent M-TEER. On presentation, 64% showed impaired RV-PA coupling defined as tricuspid annular plane systolic excursion to pulmonary artery systolic pressure (TAPSE/PASP) ratio < 0.36. Event-free survival rates at 2 years were significantly lower among patients with impaired coupling (57 vs. 82%, p < 0.001), both in patients with primary (64 vs. 91%, p = 0.009) and secondary MR (54 vs. 76%, p = 0.026). On multivariable Cox-regression analyses adjusted for baseline, imaging, hemodynamic, and procedural data, TAPSE/PASP ratio < 0.36 was independently associated with outcome (adj.HR 2.74, 95% CI 1.17-6.43, p = 0.021). At 1-year follow-up, RV-PA coupling improved (TAPSE: ∆ + 3 mm, PASP: ∆ - 10 mmHg, p for both < 0.001), alongside with a reduction in tricuspid regurgitation (TR) severity (grade ≥ II: 77-54%, p < 0.001)., Conclusions: TAPSE/PASP ratio was associated with outcome in patients undergoing M-TEER for primary as well as secondary MR. RV-PA coupling, alongside with TR severity, improved after M-TEER and might thus provide prognostic information in addition to established markers of poor outcome., (© 2023. The Author(s).)

Aims: Heart failure with preserved ejection fraction (HFpEF) is a condition that commonly coexists with type 2 diabetes mellitus (T2DM) and obesity. Whether the obesity-related survival benefit generally observed in HFpEF extends to individuals with concomitant T2DM is unclear. This study sought to examine the prognostic role of overweight and obesity in a large cohort of HFpEF with and without T2DM., Methods and Results: This large-scale cohort study included patients with HFpEF enrolled between 2010 and 2020. The relationship between body mass index (BMI), T2DM, and survival was assessed. A total of 6744 individuals with HFpEF were included, of which 1702 (25%) had T2DM. Patients with T2DM had higher BMI values (29.4 kg/m2 vs. 27.1 kg/m2, P < 0.001), higher N-terminal pro-brain natriuretic peptide values (864 mg/dL vs. 724 mg/dL, P < 0.001), and a higher prevalence of numerous risk factors/comorbidities than those without T2DM. During a median follow-up time of 47 months (Q1-Q3: 20-80), 2014 (30%) patients died. Patients with T2DM had a higher incidence of fatal events compared with those without T2DM, with a mortality rate of 39.2% and 26.7%, respectively (P < 0.001). In the overall cohort, using the BMI category 22.5-24.9 kg/m2 as the reference group, the unadjusted hazard ratio (HR) for all-cause death was increased in patients with BMI <22.5 kg/m2 [HR: 1.27 (confidence interval 1.09-1.48), P = 0.003] and decreased in BMI categories ≥25 kg/m2. After multivariate adjustment, BMI remained significantly inversely associated with survival in non-T2DM, whereas survival was unaltered at a wide range of BMI in patients with T2DM., Conclusion: Among the various phenotypes of HFpEF, the T2DM phenotype is specifically associated with a greater disease burden. Higher BMI is linked to improved survival in HFpEF overall, while this effect neutralises in patients with concomitant T2DM. Advising BMI-based weight targets and weight loss may be pursued with different intensity in the management of HFpEF, particularly in the presence of T2DM., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aim: Tricuspid regurgitation secondary to heart failure (HF) is common with considerable impact on survival and hospitalization rates. Currently, insights into epidemiology, impact, and treatment of secondary tricuspid regurgitation (sTR) across the entire HF spectrum are lacking, yet are necessary for healthcare decision-making., Methods and Results: This population-based study included data from 13 469 patients with HF and sTR from the Viennese community over a 10-year period. The primary outcome was long-term mortality. Overall, HF with preserved ejection fraction was the most frequent (57%, n = 7733) HF subtype and the burden of comorbidities was high. Severe sTR was present in 1514 patients (11%), most common among patients with HF with reduced ejection fraction (20%, n = 496). Mortality of patients with sTR was higher than expected survival of sex- and age-matched community and independent of HF subtype (moderate sTR: hazard ratio [HR] 6.32, 95% confidence interval [CI] 5.88-6.80, p < 0.001; severe sTR: HR 9.04; 95% CI 8.27-9.87, p < 0.001). In comparison to HF and no/mild sTR patients, mortality increased for moderate sTR (HR 1.58, 95% CI 1.48-1.69, p < 0.001) and for severe sTR (HR 2.19, 95% CI 2.01-2.38, p < 0.001). This effect prevailed after multivariate adjustment and was similar across all HF subtypes. In subgroup analysis, severe sTR mortality risk was more pronounced in younger patients (<70 years). Moderate and severe sTR were rarely treated (3%, n = 147), despite availability of state-of-the-art facilities and universal health care., Conclusion: Secondary tricuspid regurgitation is frequent, increasing with age and associated with excess mortality independent of HF subtype. Nevertheless, sTR is rarely treated surgically or percutaneously. With the projected increase in HF prevalence and population ageing, the data suggest a major burden for healthcare systems that needs to be adequately addressed. Low-risk transcatheter treatment options may provide a suitable alternative., (© 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Mitral- and tricuspid regurgitation are associated with significant morbidity and mortality and are increasingly treated interventionally. CardioMEMS is a transcutaneously implanted pressure sensor placed in the pulmonary artery that allows invasive measurement of pulmonary artery pressure and cardiac output., Methods: This proof-of-concept study aimed to observe hemodynamic changes as determined by CardioMEMS after transcatheter atrioventricular valve interventions, assess the additional value of CardioMEMS on top of echocardiography, and investigate a potential effect of CardioMEMS on outcome. Patients treated with transcatheter mitral- or tricuspid valve interventions (mitral: TMVR, tricuspid: TTVR) or bicaval valve implantation (bi-CAVI) were recruited. All patients were followed for 12 months., Results: Thirty-six patients were included (4 with CardioMEMS, 32 controls). Patients with CardioMEMS were monitored prior to intervention and 3-12 months thereafter (one received TMVR, one bi-CAVI, one both TMVR and TTVR, and one isolated TTVR). CardioMEMS group: In both patients with TMVR and in the patient with bi-CAVI, mean pulmonary artery pressures decreased (all p < .001) and cardiac output increased significantly (both TMVR p < .001 and bi-CAVI p = .006) while functional parameters, echocardiography, and NT-proBNP were difficult to interpret, unreliable, or both. Changes after TTVR remained inconclusive., Conclusion: Invasive monitoring using CardioMEMS provides important information after mitral- and tricuspid valve interventions. Such data pave the way for a deeper understanding of the prerequisites for optimal patient selection and management for catheter-based interventions., (© 2023 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

Aims: Bioprosthetic valve dysfunction (BVD) is a major concern regarding transcatheter aortic valve implantation (TAVI) durability. We aimed to assess incidence, correlates, causes, and outcome of early to mid-term BVD after TAVI in relation to patient's life expectancy., Methods and Results: Consecutive TAVI recipients (2007-20) with a follow-up ≥1 year were prospectively included. BVD and bioprosthetic valve failure (BVF) were assessed according to Valve-Academic-Research-Consortium-3. BVD/BVF and all-cause death served as endpoints. Average life expectancy was calculated from National Open Health Data and patients were stratified according to tertiles (1st: <6.85 years, 2nd: 6.85-9.7 years, 3rd: >9.7 years). Of 1047 patients (81.6 ± 6.8 years old, EuroSCORE II 4.5 ± 2.5), ≥2 follow ups were available from 622 (serial echo cohort). After a median echo follow up of 12.2 months, incidence rates of BVD/BVF were 8.4% (95% confidence interval 6.7-10.3), and 3.5% (2.5-4.9) per valve-year, respectively, without differences between life expectancy tertiles. The incidence of BVD was two-fold higher within the first year of implant (9.9% per valve-year) vs. beyond (4.8% per valve-year). Valve-in-valve procedure and residual stenosis, but not age/life expectancy predisposed for BVD. BVD/BVF were independently associated with outcome for patients in the first [adjusted hazard ratio (AHR) 1.72 (1.06-2.88)/2.97 (1.72-6.22)] and second [AHR 1.96 (1.02-3.73)/2.31 (1.00-5.30)], but not the third tertile of life expectancy (P = n.s.)., Conclusions: In this large prospective observational cohort, early to mid-term BVD after TAVI occurred at the same rate across the spectrum of life expectancy and was associated with increased mortality in patients with short but not in those with the longest life expectancy., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Aims: Secondary tricuspid regurgitation (sTR) is the most frequent valvular heart disease and has a significant impact on mortality. A high burden of comorbidities often worsens the already dismal prognosis of sTR, while tricuspid interventions remain underused and initiated too late. The aim was to examine the most powerful predictors of all-cause mortality in moderate and severe sTR using machine learning techniques and to provide a streamlined approach to risk-stratification using readily available clinical, echocardiographic and laboratory parameters., Methods and Results: This large-scale, long-term observational study included 3359 moderate and 1509 severe sTR patients encompassing the entire heart failure spectrum (preserved, mid-range and reduced ejection fraction). A random survival forest was applied to investigate the most important predictors and group patients according to their number of adverse features.The identified predictors and thresholds, that were associated with significantly worse mortality were lower glomerular filtration rate (<60 mL/min/1.73m2), higher NT-proBNP, increased high sensitivity C-reactive protein, serum albumin < 40 g/L and hemoglobin < 13 g/dL. Additionally, grouping patients according to the number of adverse features yielded important prognostic information, as patients with 4 or 5 adverse features had a fourfold risk increase in moderate sTR [4.81(3.56-6.50) HR 95%CI, P < 0.001] and fivefold risk increase in severe sTR [5.33 (3.28-8.66) HR 95%CI, P < 0.001]., Conclusion: This study presents a streamlined, machine learning-derived and internally validated approach to risk-stratification in patients with moderate and severe sTR, that adds important prognostic information to aid clinical-decision-making., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Secondary, or functional, mitral regurgitation (FMR) was recently recognized as a separate clinical entity, complicating heart failure with reduced ejection fraction (HFrEF) and entailing particularly poor outcome. Currently, there is a lack of targeted therapies for FMR due to the fact that pathomechanisms leading to FMR progression are incompletely understood. In this study, we sought to perform metabolomic profiling of HFrEF patients with severe FMR, comparing results to patients with no or mild FMR., Methods and Results: Targeted plasma metabolomics and untargeted eicosanoid analyses were performed in samples drawn from HFrEF patients (n = 80) on optimal guideline-directed medical therapy. Specifically, 17 eicosanoids and 188 metabolites were analysed. Forty-seven patients (58.8%) had severe FMR, and 33 patients (41.2%) had no or non-severe FMR. Comparison of eicosanoid levels between groups, accounting for age, body mass index, and sex, revealed significant up-regulation of six eicosanoids (11,12-EET, 13(R)-HODE, 12(S)-HETE, 8,9-DiHETrE, metPGJ2, and 20-HDoHE) in severe FMR patients. Metabolites did not differ significantly. In patients with severe FMR, but not in those without severe FMR, levels of 8,9-DiHETrE above a cut-off specified by receiver-operating characteristic analysis independently predicted all-cause mortality after a median follow-up of 43 [interquartile range 38, 48] months [hazard ratio 12.488 (95% confidence interval 3.835-40.666), P < 0.0001]., Conclusions: We report the up-regulation of various eicosanoids in patients with severe FMR, with 8,9-DiHETrE appearing to predict mortality. Our observations may serve as a nucleus for further investigations into the causes and consequences of metabolic derangements in this important valvular abnormality., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Secondary mitral regurgitation (sMR) in the setting of heart failure (HF) has considerable impact on quality of life, HF rehospitalizations, and mortality. Identification of high-risk cohorts is essential to understand disease trajectories and for risk stratification., Objectives: This study aimed to provide a structured decision tree-like approach to risk stratification in patients with severe sMR and HF., Methods: This observational study included 1,317 patients with severe sMR from the entire HF spectrum. Clinical, echocardiographic, and laboratory data were extracted for all patients. The primary end point was all-cause mortality. Survival tree analysis, a supervised learning technique, was applied to identify patient subgroups at risk of mortality and further stratified by HF subtype (preserved, mildly reduced, and reduced ejection fraction)., Results: Using supervised learning (survival tree method), 8 distinct subgroups were identified that differed significantly in long-term survival. Subgroup 7, characterized by younger age (≤66 years), higher hemoglobin (>12.7 g/dL), and higher albumin levels (>40.6 g/L) had the best survival. In contrast, subgroup 5 displayed a 20-fold risk of mortality (hazard ratio: 20.38 [95% CI: 10.78-38.52]); P  < 0.001 and had older age (>68 years), low serum albumin (≤40.6 g/L), and higher NT-proBNP levels (≥9,750 pg/mL). Unique subgroups were further identified for each type of HF subtypes., Conclusions: Supervised machine learning reveals heterogeneity in the sMR risk spectrum, highlighting the clinical variability in the population. A decision tree-like model can help identify differences in outcomes among subgroups and can help provide tailored risk stratification., Competing Interests: This work was supported by a grant of the 10.13039/501100002428Austrian Science Fund (FWF – identification number: KLI-818B). The authors have reported that they have no relationships relevant to the contents of this paper to disclose.PERSPECTIVESCOMPETENCY IN PATIENT CARE AND PROCEDURAL SKILLS: In patients with severe sMR and HF, a heterogenous risk spectrum was identified by supervised learning techniques. Patients with younger age, better renal function, and higher hemoglobin values had the most favorable survival, whereas older patients with low serum albumin and higher NT-proBNP values experience a 20-fold risk increase in mortality. TRANSLATIONAL OUTLOOK: Further studies are needed to refine the therapeutic management for sMR in every HF subtype, taking into account the complex underlying heterogeneity in this population., (© 2022 The Authors.)

Background: Dual pathology of severe aortic stenosis (AS) and transthyretin cardiac amyloidosis (ATTR) is increasingly recognized. Evolution of symptoms, biomarkers, and myocardial mechanics in AS-ATTR following valve replacement is unknown. We aimed to characterize reverse remodeling in AS-ATTR and compared with lone AS., Methods: Consecutive patients referred for transcatheter aortic valve replacement (TAVR) underwent ATTR screening by blinded 99mTc-DPD bone scintigraphy (Perugini Grade-0 negative, 1-3 increasingly positive) before intervention. ATTR was diagnosed by DPD and absence of monoclonal protein. Reverse remodeling was assessed by comprehensive evaluation before TAVR and at 1 year., Results: One hundred twenty patients (81.8±6.3 years, 51.7% male, 95 lone AS, 25 AS-ATTR) with complete follow-up were studied. At 12 months (interquartile range, 7-17) after TAVR, both groups experienced significant symptomatic improvement by New York Heart Association functional class (both P <0.001). Yet, AS-ATTR remained more symptomatic (New York Heart Association ≥III: 36.0% versus 13.8; P =0.01) with higher residual NT-proBNP (N-terminal pro-brain natriuretic peptide) levels ( P <0.001). Remodeling by echocardiography showed left ventricular mass regression only for lone AS ( P =0.002) but not AS-ATTR ( P =0.5). Global longitudinal strains improved similarly in both groups. Conversely, improvement of regional longitudinal strain showed a base-to-apex gradient in AS-ATTR, whereas all but apical segments improved in lone AS. This led to the development of an apical sparing pattern in AS-ATTR only after TAVR., Conclusions: Patterns of reverse remodeling differ from lone AS to AS-ATTR, with both groups experiencing symptomatic improvement by TAVR. After AS treatment, AS-ATTR transfers into a lone ATTR cardiomyopathy phenotype.

Introduction: Severe tricuspid regurgitation (TR) is a common condition promoting right heart failure and is associated with a poor long-term prognosis. Transcatheter tricuspid valve repair (TTVR) emerged as a low-risk alternative to surgical repair techniques. However, patient selection remains controversial, particularly regarding the benefits of TTVR in patients with pulmonary hypertension (PH)., Aim: We aimed to investigate the impact of preprocedural invasive hemodynamic assessment and procedural success on right ventricular (RV) remodeling and outcome., Methods: All patients undergoing TTVR with a TR reduction of ≥1 grade without precapillary or combined PH [mean pulmonary artery pressure (mPAP) ≥25 mmHg, mean pulmonary artery Wedge pressure ≤ 15 mmHg, pulmonary vascular resistance ≥3 Wood units] were assigned to the responder group. All patients with a TR reduction of ≥1 grade and precapillary or combined PH were classified as non-responders. Patients with a TR reduction ≥2 grade were directly classified as responders, and patients without TR reduction were directly assigned as non-responders., Results: A total of 107 patients were enrolled, 75 were classified as responders and 32 as non-responders. We observed evidence of significant RV reverse remodeling in responders with a decrease in RV diameters (-2.9 mm, p = 0.001) at a mean follow-up of 229 days (±219 SD) after TTVR. RV function improved in responders [fractional area change (FAC) + 5.7%, p < 0.001, RV free wall strain +3.9%, p = 0.006], but interestingly further deteriorated in non-responders (FAC -4.5%, p = 0.003, RV free wall strain -3.9%, p = 0.007). Non-responders had more persistent symptoms than responders (NYHA ≥3, 72% vs. 11% at follow-up). Subsequently, non-response was associated with a poor long-term prognosis in terms of death, heart failure (HF) hospitalization, and re-intervention after 2 years (freedom of death, HF hospitalization, and reintervention at 2 years: 16% vs. 78%, log-rank: p < 0.001)., Conclusion: Hemodynamic assessment before TTVR and procedural success are significant factors for patient prognosis. The hemodynamic profiling prior to intervention is an essential component in patient selection for TTVR. The window for edge-to-edge TTVR might be limited, but timely intervention is an important factor for a better outcome and successful right ventricular reverse remodeling., Competing Interests: VD received consulting fees from Abbott, and educational grants from Edwards Lifesciences. JM received proctor fees from Abbott, consulting fees from Edwards Lifesciences, Boston Scientific, Shockwave Medical, and educational grants from Edwards Lifesciences. CH received proctor fees from Edwards Lifesciences and Boston Scientific, Educational grants from Abbott, Edwards Lifesciences, Boston Scientific, and Medtronic. MA received proctor/speaker/consulting fees from Abbott, Edwards, and Medtronic and institutional research funding (Edwards, Abbott, Medtronic, LSI). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Dannenberg, Koschutnik, Donà, Nitsche, Mascherbauer, Heitzinger, Halavina, Kammerlander, Spinka, Winter, Andreas, Mach, Schneider, Bartunek, Bartko, Hengstenberg, Mascherbauer and Goliasch.)

Background: High body mass index (BMI) is paradoxically associated with better outcome in patients with heart failure (HF). The effects of malnutrition on this phenomenon across the whole spectrum of HF have not yet been studied., Methods: In this observational study, patients were classified by guideline diagnostic criteria to one of three heart failure subtypes: reduced (HFrEF), mildy reduced (HFmrEF), and preserved ejection fraction (HFpEF). Data were retrieved from the Viennese-community healthcare provider network between 2010 and 2020. The relationship between BMI, nutritional status reflected by the prognostic nutritional index (PNI), and survival was assessed. Patients were classified by the presence (PNI < 45) or absence (PNI ≥ 45) of malnutrition., Results: Of the 11 995 patients enrolled, 6916 (58%) were classified as HFpEF, 2809 (23%) HFmrEF, and 2270 HFrEF (19%). Median age was 70 years (IQR 61-77), and 67% of patients were men. During a median follow-up time of 44 months (IQR 19-76), 3718 (31%) of patients died. After adjustment for potential confounders, BMI per IQR increase was independently associated with better survival (adj. hazard ratio [HR]: 0.91 [CI 0.86-0.97], P = 0.005), this association remained significant after additional adjustment for HF type (adj. HR: 0.92 [CI 0.86-0.98], P = 0.011). PNI was available in 10 005 patients and lowest in HFrEF patients. PNI was independently associated with improved survival (adj. HR: 0.96 [CI 0.95-0.97], P < 0.001); additional adjustment for HF type yielded similar results (adj. HR: 0.96 [CI 0.96-0.97], P < 0.001). Although obese patients experienced a 30% risk reduction, malnutrition at least doubled the risk for death with 1.8- to 2.5-fold higher hazards for patients with poor nutritional status compared with normal weight well-nourished patients., Conclusions: The obesity paradox seems to be an inherent characteristic of HF regardless of phenotype and nutritional status. Yet malnutrition significantly changes trajectory of outcome with regard to BMI alone: obese patients with malnutrition have a considerably worse outcome compared with their well-nourished counterparts, outweighing protective effects of high BMI alone. In this context, routine recommendation towards weight loss in patients with obesity and HF should generally be made with caution and focus should be shifted on nutritional status., (© 2022 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Background: Guideline-directed medical therapy (GDMT) is the recommended initial treatment for secondary mitral regurgitation (SMR), however, supported by only little comprehensive evidence. This study, therefore, sought to assess the effect of GDMT titration on SMR and to identify specific substance combinations able to reduce SMR severity., Methods and Results: We included 261 patients who completed two visits with an echocardiographic exam available within 1 month at each visit. After comprehensively defining GDMT titration as well as SMR reduction, logistic regression analysis was applied in order to assess the effects of overall GDMT titration and specific substance combinations on SMR severity. SMR severity improved by at least 1° in 39.3% of patients with subsequent titration of GDMT and was accompanied by reverse remodelling and clinical improvement. The effects of GDMT titration were significantly associated with SMR reduction (adj. odds ratio 2.91, 95% confidence interval 1.34-6.32, P = 0.007). Moreover, angiotensin receptor/neprilysin inhibitor (ARNi) as well as the combined dosage effects of (i) renin-angiotensin system inhibitors (RASi) and mineralocorticoid-receptor antagonists (MRA), (ii) beta-blockers (BB) and MRA, as well as (iii) RASi, BB, and MRA were all significantly associated with SMR improvement (P < 0.044 for all)., Conclusion: The present study provides comprehensive evidence for the effectiveness of contemporary GDMT to specifically improve SMR. Our data indicate that GDMT titration conveys a three-fold increased chance of reducing SMR severity. Moreover, the dosage effects of ARNi, as well as the combination of RASi and MRA, BB and MRA, and all three substances in the aggregate are able to significantly improve SMR., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Neutrophils are critically involved in the immune response. Inflammatory stimuli alter the expression status of their surface molecule toolset, while inflammation-stimulated granulopoiesis might also influence their maturation status. Data on neutrophil status in heart failure with reduced ejection fraction (HFrEF) are scarce. The present study aims to evaluate the role of neutrophil CD11b, CD66b and CD64 expression in HFrEF., Methods: A total of 135 HFrEF patients and 43 controls were recruited. Mean fluorescence intensity of the activation/maturation markers CD11b, CD66b and CD64 was measured on neutrophils by flow cytometry. CD10 (neprilysin) expression was simultaneously determined., Results: Neutrophil CD64 expression was higher in HFrEF compared with controls, while CD11b/CD66b levels were similar. Neutrophil CD11b and CD66b showed a significant direct correlation to neutrophil CD10 expression (rs = 0.573, p < 0.001 and rs = 0.184, p = 0.033). Neutrophil CD11b and CD66b correlated inversely with heart failure severity reflected by NT-proBNP and NYHA class (NT-proBNP: rs = -0.243, p = 0.005 and rs = -0.250, p = 0.004; NYHA class: p = 0.032 and p = 0.055), whereas no association for CD64 could be found. Outcome analysis did not reveal a significant association between the expression of CD11b, CD66b and CD64 and all-cause mortality ( p = ns)., Conclusions: The results underline the potential role of neutrophils in HFrEF disease pathophysiology and risk stratification and should stimulate further research, characterizing subpopulations of neutrophils and searching for key molecules involved in the downward spiral of inflammation and heart failure.

Transcatheter aortic valve replacement (TAVR) has established itself as a safe and efficient treatment option in patients with severe aortic valve stenosis, regardless of the underlying surgical risk. Widespread adoption of transfemoral procedures led to more patients than ever being eligible for TAVR. This increase in procedural volumes has also stimulated the use of vascular closure devices (VCDs) for improved access site management. In a single-center examination, we investigated 871 patients that underwent transfemoral TAVR from 2010 to 2020 and assessed vascular complications according to the Valve Academic Research Consortium (VARC) III recommendations. Patients were grouped by the VCD and both, vascular closure success and need for intervention were analyzed. In case of a vascular complication, the type of intervention was investigated for all VCDs. The Proglide VCD was the most frequently used device ( n = 670), followed by the Prostar device ( n = 112). Patients were old (median age 83 years) and patients suffered from high comorbidity burden (60% coronary artery disease, 30% type II diabetes, 40% atrial fibrillation). The overall rate of major complications amounted to 4.6%, it was highest in the Prostar group (9.6%) and lowest in the Manta VCD group (1.1% p = 0.019). The most frequent vascular complications were bleeding and hematoma ( n = 110, 13%). In case a complication occurred, 72% of patients did not need any further intervention other than manual compression or pressure bandages. The rate of surgical intervention after complication was highest in the Prostar group ( n = 15, 29%, p = 0.001). Temporal trends in VCD usage highlight the rapid adoption of the Proglide system after introduction at our institution. In recent years VCD alternatives, utilizing other closure techniques, such as the Manta device emerged and increased vascular access site management options. This 10-year single-center experience demonstrates high success rates for all VCDs. Despite successful closure, a significant number of patients does experience minor vascular complications, in particular bleeding and hematoma. However, most complications do not require surgical or endovascular intervention. Temporal trends display a marked increase in TAVR procedures and highlight the need for more refined vascular access management strategies., Competing Interests: MA has received institutional research funding (Edwards, Abbott, Medtronic, LSI) and has served as a proctor/speaker/consultant (Edwards, Abbott, Medtronic). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Heitzinger, Brunner, Koschatko, Dannenberg, Mascherbauer, Halavina, Doná, Koschutnik, Spinka, Nitsche, Mach, Andreas, Wolf, Loewe, Neumayer, Gschwandtner, Willfort-Ehringer, Winter, Lang, Bartko, Hengstenberg and Goliasch.)

Objectives: The aim of this work was to identify the key morphological and functional features in secondary mitral regurgitation (sMR) and their prognostic impact on outcome., Background: Secondary sMR in patients with heart failure and reduced ejection fraction typically results from distortion of the underlying cardiac architecture. The morphological components which may account for the clinical impact of sMR have not been systematically assessed or correlated with clinical outcomes., Methods: Morphomic and functional network profiling were performed on a cohort of patients with stable heart failure optimized on guideline-based medical therapy. Principal component (PC) analysis and subsequent cluster analysis were used to condense the morphomic and functional data first into PCs with varimax rotation (PC Vmax ) and second into homogeneous clusters. Clusters and PCs were tested for their correlations with clinical outcomes., Results: Morphomic and functional data from 383 patients were profiled and subsequently condensed into PCs. PC Vmax 1 describes high loadings of left atrial morphological information, and PC Vmax 2 describes high loadings of left ventricular (LV) topology. Based on these components, 4 homogeneous clusters were derived. sMR was most prominent in clusters 3 and 4, with the morphological difference being left ventricular size (median end-diastolic volume 188 mL [interquartile range: 160 mL-224 mL] vs 315 mL [264 mL-408 mL]; P < 0.001). Clusters were associated with mortality (P < 0.001), but sMR remained independently associated with mortality after adjusting for the clusters (adjusted HR: 1.42; 95% CI: 1.14-1.77; P < 0.01). The detrimental association of sMR with mortality was mainly driven by cluster 3 (HR: 2.18; 95% CI: 1.32-3.60; P = 0.002), the "small LV cavity" phenotype., Conclusions: These results challenge the current perceptions that sMR in heart failure with reduced ejection fraction results exclusively from global or local LV remodeling and are suggestive of a potential role of the left atrial component. The association of sMR with mortality cannot be purely attributed to cardiac morphology alone, supporting other complementary key aspects of mitral valve closure consistent with the force balance theory. Unsupervised clustering supports the association of sMR with mortality predominantly driven by the small LV cavity phenotype, as previously suggested by a conceptional framework and termed disproportionate sMR., Competing Interests: Funding Support and Author Disclosures This work was supported by a grant of the Austrian Science Fund (KLI-818B). Dr Mascherbauer has received speaker fees from Edwards Lifesciences, Boston Scientific, Medtronic, and Abbott. Dr Hengstenberg has received proctor fees, Speakers Bureau, and an institutional grant from Edwards Lifesciences and Boston Scientific. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Significant expression of neprilysin (NEP) is found on neutrophils, which present the transmembrane integer form of the enzyme. This study aimed to investigate the relationship of neutrophil transmembrane neprilysin (mNEP) with disease severity, adverse remodeling, and outcome in HFrEF. In total, 228 HFrEF, 30 HFpEF patients, and 43 controls were enrolled. Neutrophil mNEP was measured by flow-cytometry. NEP activity in plasma and blood cells was determined for a subset of HFrEF patients using mass-spectrometry. Heart failure (HF) was characterized by reduced neutrophil mNEP compared to controls ( p < 0.01). NEP activity on peripheral blood cells was almost 4-fold higher compared to plasma NEP activity ( p = 0.031) and correlated with neutrophil mNEP ( p = 0.006). Lower neutrophil mNEP was associated with increasing disease severity and markers of adverse remodeling. Higher neutrophil mNEP was associated with reduced risk for mortality, total cardiovascular hospitalizations, and the composite endpoint of both ( p < 0.01 for all). This is the first report describing a significant role of neutrophil mNEP in HFrEF. The biological relevance of neutrophil mNEP and exact effects of angiotensin-converting-enzyme inhibitors (ARNi) at the neutrophil site have to be determined. However, the results may suggest early initiation of ARNi already in less severe HF disease, where effects of NEP inhibition may be more pronounced.

Background: Inflammation-based scores are widely tested in cancer and have been evaluated in cardiovascular diseases including heart failure. Objectives: We investigated the impact of established inflammation-based scores on disease severity and survival in patients with stable heart failure with reduced ejection fraction (HFrEF) paralleling results to an intra-institutional cohort of treatment naïve cancer patients. Methods: HFrEF and cancer patients were prospectively enrolled. The neutrophil-to-lymphocyte-ratio (NLR), the monocyte-to-lymphocyte-ratio (MLR), the platelet-to-lymphocyte-ratio (PLR), and the prognostic nutritional index (PNI) at index day were calculated. Association of scores with disease severity and impact on overall survival was determined. Interaction analysis was performed for the different populations. Results: Between 2011 and 2017, a total of 818 patients (443 HFrEF and 375 cancer patients) were enrolled. In HFrEF, there was a strong association between all scores and disease severity reflected by NT-proBNP and NYHA class ( p ≤ 0.001 for all). In oncologic patients, association with tumor stage was significant for the PNI only ( p = 0.035). In both disease entities, all scores were associated with all-cause mortality ( p ≤ 0.014 for all scores). Kaplan-Meier analysis confirmed the discriminatory power of all scores in the HFrEF and the oncologic study population, respectively (log-rank p ≤ 0.026 for all scores). A significant interaction with disease (HFrEF vs. cancer) was observed for PNI ( p interaction = 0.013) or PLR ( p interaction = 0.005), respectively, with higher increase in risk per inflammatory score increment for HFrEF. Conclusion: In crude models, the inflammatory scores NLR, MLR, PLR, and PNI are associated with severity of disease in HFrEF and with survival in HFrEF similarly to cancer patients. For PNI and PLR, the association with increase in risk per increment was even stronger in HFrEF than in malignant disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Arfsten, Cho, Prausmüller, Spinka, Novak, Goliasch, Bartko, Raderer, Gisslinger, Kornek, Köstler, Strunk, Preusser, Hengstenberg, Hülsmann and Pavo.)

Aims: Concomitant secondary atrioventricular regurgitation is frequent in patients with severe aortic stenosis scheduled for transcatheter aortic valve replacement (TAVR). The future implications of leaving associated valve lesions untreated after TAVR remain unknown. Aim of the present study was to characterize the evolution of concomitant secondary atrioventricular regurgitations and to evaluate their impact on long-term prognosis., Methods and Results: We prospectively enrolled 429 consecutive TAVR patients. All patients underwent comprehensive clinical, laboratory, and echocardiographic assessments prior to TAVR, at discharge, and yearly thereafter. All-cause mortality was chosen as primary study endpoint. At baseline, severe concomitant secondary mitral regurgitation (sMR) was present in 54 (13%) and severe concomitant secondary tricuspid regurgitation (sTR) in 75 patients (17%). After TAVR 59% of patients with severe sMR at baseline experienced sMR regression, whereas analogously sTR regressed in 43% of patients with severe sTR. Persistence of sTR and sMR were associated with excess mortality after adjustment for our bootstrap-selected confounder model with an adjusted HR of 2.44 (95% CI 1.15-5.20, P = 0.021) for sMR and of 2.09 (95% CI 1.20-3.66, P = 0.01) for sTR. Patients showing regression of atrioventricular regurgitation exhibited survival rates indistinguishable to those seen in patients without concomitant atrioventricular regurgitation (sMR: P = 0.83; sTR: P = 0.74)., Conclusion: Concomitant secondary atrioventricular regurgitation in patients with severe AS is a highly dynamic process with up to half of all patients showing regression of associated valvular regurgitation after TAVR and subsequent favourable post-interventional outcome. Persistent atrioventricular regurgitation is a major determinant of unfavourable outcome after TAVR and proposes a window of early sequel intervention., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

The clinical relevance of as well as the optimal treatment strategy for coronary artery disease (CAD) in patients undergoing transcatheter aortic valve replacement (TAVR) for severe aortic stenosis (AS) are unclear. Current data are conflicting, and mainly derived from high-risk patients. We aimed to investigate the feasibility and safety of complete revascularization prior to TAVR for severe AS in low- and intermediate-risk patients. We enrolled 449 patients at low (STS score < 4%) and intermediate risk (STS score 4-8%) undergoing TAVR for severe AS and investigated the influence of recent (<3 months) and prior (>3 months) complete revascularization on clinical outcome. Primary study endpoint was all-cause mortality. Overall, 58% of patients had no or non-significant CAD; 18% had a history of complete revascularization prior to TAVR and 24% had complete revascularization shortly before TAVR. Two-year all-cause mortality was not different between patients with recent revascularization prior to TAVR and patients with no or non-significant CAD (13.7% vs. 14.2%, p = 0.905). Cox regression did not reveal an effect on all-cause mortality for recent revascularization. The present analysis reassures that percutaneous complete revascularization prior to TAVR procedures is neutral in terms of all-cause mortality in patients at low and intermediate surgical risk.

Aims: As NEP degrades many substrates, the specific therapeutic mechanism of NEP inhibition with angiotensin receptor neprilysin inhibitor (ARNi) in heart failure with reduced ejection fraction (HFrEF) is not entirely evident. The aim of this study was to investigate the response of two substrates of NEP-the tachykinin and enkephalin systems-to the initiation of ARNi therapy in HFrEF., Methods and Results: Between 2016 and 2018, 141 consecutive patients with stable HFrEF [74 with initiation of ARNi and 67 controls on continuous angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) therapy] were prospectively enrolled. Plasma proenkephalin-A 119-159 (PENK) and pro-substance P (pro-SP) were serially determined. Proenkephalin-A 119-159 and pro-SP correlated strongly with each other (r s  = 0.67, P < 0.001) and kidney function (r s  = -0.66, P < 0.001 and r s  = -0.54, P < 0.001) and modestly with NT-proBNP (r s  = 0.32, P < 0.001 and r s  = 0.24, P = 0.006, respectively). Concentrations of circulating PENK were slightly elevated after 1 and 2 year follow-up compared with baseline (BL) [BL median: 67.4 pmol/L (IQR: 57.3-89.8), 1 year: 83.5 pmol/L (IQR: 62.4-111.6), 2 years: 92.3 pmol/L (IQR: 63.1-101.9); BL vs. 1 year: P = 0.017 and BL vs. 2 years: P = 0.019] in the overall analysis, but lost significance at 2 year follow-up when assessed in paired subanalysis (P = 0.116). Plasma pro-SP levels remained comparable during the entire follow-up [BL median: 78.3 pmol/L (IQR: 67.9-90.6), 1 year: 75.9 pmol/L (IQR: 58.6-96.3), 2 years: 79.7 pmol/L (IQR: 59.9-105.3); P = ns for both timepoints]. Biomarker patterns of ARNi patients were independent from baseline therapy, that is, ACEi or ARB (P > 0.05 between groups)., Conclusions: Although enkephalins and SP are known substrates of NEP, NEP inhibition by ARNi does not clearly affect the circulating precursors PENK and pro-SP in HFrEF., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: The myocardium exhibits an adaptive tissue-specific renin-angiotensin system (RAS), and local dysbalance may circumvent the desired effects of pharmacologic RAS inhibition, a mainstay of heart failure with reduced ejection fraction (HFrEF) therapy., Objectives: This study sought to investigate human myocardial tissue RAS regulation of the failing heart in the light of current therapy., Methods: Fifty-two end-stage HFrEF patients undergoing heart transplantation (no RAS inhibitor: n = 9; angiotensin-converting enzyme [ACE] inhibitor: n = 28; angiotensin receptor blocker [ARB]: n = 8; angiotensin receptor neprilysin-inhibitor [ARNi]: n = 7) were enrolled. Myocardial angiotensin metabolites and enzymatic activities involved in the metabolism of the key angiotensin peptides angiotensin 1-8 (AngII) and Ang1-7 were determined in left ventricular samples by mass spectrometry. Circulating angiotensin concentrations were assessed for a subgroup of patients., Results: AngII and Ang2-8 (AngIII) were the dominant peptides in the failing heart, while other metabolites, especially Ang1-7, were below the detection limit. Patients receiving an ARB component (i.e., ARB or ARNi) had significantly higher levels of cardiac AngII and AngIII (AngII: 242 [interquartile range (IQR): 145.7 to 409.9] fmol/g vs 63.0 [IQR: 19.9 to 124.1] fmol/g; p < 0.001; and AngIII: 87.4 [IQR: 46.5 to 165.3] fmol/g vs 23.0 [IQR: <5.0 to 59.3] fmol/g; p = 0.002). Myocardial AngII concentrations were strongly related to circulating AngII levels. Myocardial RAS enzyme regulation was independent from the class of RAS inhibitor used, particularly, a comparable myocardial neprilysin activity was observed for patients with or without ARNi. Tissue chymase, but not ACE, is the main enzyme for cardiac AngII generation, whereas AngII is metabolized to Ang1-7 by prolyl carboxypeptidase but not to ACE2. There was no trace of cardiac ACE2 activity., Conclusions: The failing heart contains considerable levels of classical RAS metabolites, whereas AngIII might be an unrecognized mediator of detrimental effects on cardiovascular structure. The results underline the importance of pharmacologic interventions reducing circulating AngII actions, yet offer room for cardiac tissue-specific RAS drugs aiming to limit myocardial AngII/AngIII peptide accumulation and actions., Competing Interests: Funding Support and Author Disclosures This project has been funded by the Anniversary Fund of the Österreichische Nationalbank (OeNB). Drs. Poglitsch and Domenig are employed by Attoquant Diagnostics, a company that received payments for RAS Fingerprint and enzyme activity measurements. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: The clinically investigated rationale for neprilysin (NEP)-inhibition by angiotensinreceptor-NEPinhibitor (ARNi) therapy is to induce elevations in endogenous natriuretic peptides. NEP, however, cleaves a broad spectrum of substrates, which partially hold significant implications in heart failure with reduced ejection fraction (HFrEF). The effect of NEP inhibition on these peptides has not been investigated thoroughly. This study explored the response of adrenomedullin (ADM) regulation to the initiation of ARNi., Methods: Seventy-four patients with stable HFrEF and initiation of ARNi were prospectively enrolled, 67 patients on continuous angiotensin-converting-enzyme inhibitor(ACEi)/angiotensin-receptor blocker (ARB) therapy served as control. Plasma bioactive-ADM (bio-ADM), mid-regional-pro-ADM (MR-proADM), B-typenatriuretic peptide (BNP) and N-terminal-pro-BNP (NT-proBNP) were determined at baseline, short-term, 1-year and 2-year follow up., Results: Following ARNi initiation both bio-ADM and MR-proADM concentrations were significantly increased at early and long-term follow up (bio-ADM [pg/mL]: 26.0 [interquartile range {IQR}: 17.7-37.5] vs. 50.8 [IQR: 36.5-78.1] vs. 54.6 [IQR: 42.0-97.1] vs. 57.4 [IQR: 48.5-161.6]; MR-proADM [nmol/L]: 0.87 [IQR: 0.64-1.12] vs. 1.25 [IQR: 0.93-1.79] vs. 1.42 [IQR: 0.95-1.90] vs. 1.60 [IQR: 1.12-2.46], P < .0001 for all). The ratios bio-ADM/MR-proADM and BNP/NT-proBNP increased during ARNi-therapy proving improved availability of bioactive peptides. The proportional increase of bio-ADM markedly exceeded BNP increase. Patients converted to ARNi showed similar biomarker patterns irrespective of baseline renin-angiotensin system blocker therapy, i.e. ACEi or ARB (P > .05 for all), indicating that activation of the ADM-axis arises particularly from NEPinhibition., Conclusion: The significant increase of MR-proADM and bio-ADM together with an elevated bioADM/MR-proADM ratio suggest both enhanced formation and reduced breakdown of bioactive ADM following the initiation of ARNi. Activation of the ADM-axis represents a so far unrecognized effect of ARNi., (© 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: Recently, the European Society of Cardiology (ESC) and European Association for the Society of Diabetes (EASD) introduced a new cardiovascular disease (CVD) risk stratification model to aid further treatment decisions in individuals with diabetes. Our study aimed to investigate the prognostic performance of the ESC/EASD risk model in comparison to the Systematic COronary Risk Evaluation (SCORE) risk model and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in an unselected cohort of type 2 diabetes mellitus (T2DM)., Methods and Results: A total of 1690 T2DM patients with a 10-year follow up for fatal CVD and all-cause death and a 5-year follow up for CVD and all-cause hospitalizations were analyzed. According to ESC/EASD risk criteria 25 (1.5%) patients were classified as moderate, 252 (14.9%) high, 1125 (66.6%) very high risk and 288 (17.0%) were not classifiable. Both NT-proBNP and SCORE risk model were associated with 10-year CVD and all-cause death and 5-year CVD and all-cause hospitalizations while the ESC/EASD model was only associated with 10-year all-cause death and 5-year all-cause hospitalizations. NT-proBNP and SCORE showed significantly higher C-indices than the ESC/EASD risk model for CVD death [0.80 vs. 0.53, p < 0.001; 0.64 vs. 0.53, p = 0.001] and all-cause death [0.73, 0.66 vs. 0.52, p < 0.001 for both]. The performance of SCORE improved in a subgroup without CVD aged 40-64 years compared to the unselected cohort, while NT-proBNP performance was robust across all groups., Conclusion: The new introduced ESC/EASD risk stratification model performed limited compared to SCORE and single NT-proBNP assessment for predicting 10-year CVD and all-cause fatal events in individuals with T2DM.

Background: While secondary mitral regurgitation (sMR) is associated with adverse outcome in heart failure with reduced ejection fraction (HFrEF), key pathophysiologic mechanisms remain poorly understood and might be elucidated by microRNAs (miRNA/miR), that were recently related to cardiac remodelling. This study sought to assess (i) the differences of miRNA profiles in patients with severe sMR compared to matched disease controls, (ii) the correlation between circulating miRNAs and surrogates of sMR severity as well as (iii) the prognostic implications of miRNA levels in severe sMR., Materials and Methods: Sixty-six HFrEF patients were included, of these 44 patients with severe sMR 2:1 matched to HFrEF controls with no/mild sMR. A comprehensive set of miRNAs (miR-21, miR-29a, miR-122, miR-132, miR-133a, miR-let7i) were measured and correlated to echocardiographic sMR severity., Results: miRNA patterns differed distinctly between patients with severe sMR and HFrEF controls (P < .05). Among the panel of assessed miRNAs, miR-133a correlated most strongly with surrogates of sMR severity (r = -0.41, P = .001 with sMR vena contracta width). Interestingly, elevated levels of miR-133 were associated with an increased risk for cardiovascular death and/or HF hospitalizations with and adjusted HR of 1.85 (95% CI 1.24-2.76, P = .003)., Conclusions: This study unveils distinct pathophysiologic maladaptions at a cellular level in patients with severe sMR compared to no/mild sMR by showing significant differences in miRNA profiles and correlations with sMR severity, supporting the concept that sMR drives cardiac remodelling in heart failure. Moreover, the increased risk for adverse outcome in HFrEF patients with severe sMR conveyed by miR-133a might indicate irreversible myocardial damage., (© The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

Background: Secondary tricuspid regurgitation (sTR) is frequent in patients with heart failure with reduced ejection fraction and is associated with adverse outcomes despite guideline-directed therapy. However, little is known about the natural course of nonsevere sTR and its relation to cardiac remodeling and outcomes. The aims of this study were therefore to investigate the natural course of sTR progression using quantitative measurements, to assess the prognostic impact on long-term mortality, and to identify risk factors associated with progressive sTR., Methods: A total of 216 patients with heart failure with reduced ejection fraction receiving guideline-directed therapy were included in this long-term observational study. Progression of sTR was quantitatively defined as an increase of 0.2 cm 2 in effective regurgitant orifice area or 15 mL in regurgitant volume, with transition to at least moderate sTR. Kaplan-Meier and Cox regression analyses were applied to assess survival during a 5-year follow-up period., Results: Among patients with nonsevere sTR at baseline, 62 (29%) experienced sTR progression. Progressive sTR was accompanied by larger left and right atrial volumes (P = .02 and P < .02, respectively) and a higher prevalence of atrial fibrillation (P < .04). During a median follow-up period of 60 months (interquartile range, 37-60 months), 82 patients died. Progression of sTR conveyed a higher risk for long-term mortality (hazard ratio, 1.77; 95% CI, 1.1-2.83; P < .02), even after multivariate adjustment for bootstrap-selected (adjusted hazard ratio, 1.70; 95% CI, 1.06-2.74; P < .03) and clinical confounder (adjusted hazard ratio, 1.80; 95% CI, 1.07-3.05; P < .03) models., Conclusions: The incidence of progressive sTR despite guideline-directed therapy is associated with adverse cardiac and valvular remodeling as well as a significantly higher long-term mortality. Biatrial enlargement as well as atrial fibrillation are associated with the development of subsequent progressive sTR and may help identify patients at risk for sTR progression, potentially creating a window of opportunity for closer follow-up and newly arising minimally invasive transcatheter repair therapies., (Copyright © 2020 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Secondary tricuspid regurgitation (sTR) is frequent among patients with heart failure with reduced ejection fraction (HFrEF), however it confers considerable diagnostic challenges. The assessment of neurohumoral activation may constitute a valuable supplement to the current imaging-based diagnostic process. This study sought to investigate the expression of complementary biomarkers in sTR and to evaluate the effectiveness of integrating their assessment into the diagnostic process. We enrolled 576 HFrEF patients recording echocardiographic and biochemical measurements, i.e., N-terminal pro-B-type natriuretic peptide, mid-regional pro-atrial natriuretic peptide (MR-proANP), mid-regional pro-adrenomedullin, C-terminal pro-endothelin-1 (CT-pro-ET1), and copeptin. Plasma levels of the aforementioned neurohormones were significantly elevated with increasing sTR severity ( p < 0.001 for all). CT-pro-ET1 and MR-proANP were the closest related to severe sTR (adj. OR 1.46; 95%CI 1.11-1.91, p = 0.006 and adj. OR 1.45, 95%CI 1.13-1.87, p = 0.004, respectively). In patients with moderate-to-severe sTR, adding selected biomarkers (i.e., CT-pro-ET1 and MR-proANP) resulted in a substantial improvement in the discriminatory power regarding long-term mortality (C-statistic: 0.54 vs. 0.65, p < 0.001; continuous NRI 57%, p < 0.001). Circulating biomarkers closely relate to sTR severity and correlate with hemodynamic and morphologic mechanisms of sTR. Specifically, MR-proANP and CT-pro-ET1 are closely linked to the presence of severe sTR, and a combined assessment with the guideline recommended echocardiographic grading significantly improves individual risk stratification.

Atherosclerotic lesions in the great arteries are frequent findings in the elderly. Numerous studies have shown their strong predictive value for cardiovascular disease, embolic events, and mortality. We sought to determine the risk of all-cause mortality depending on the localization of plaques in the thoracic aorta evaluated by transesophageal echocardiography (TEE). A total of 2,054 patients (median age 65 years, interquartile range 52-73; 58% men) who underwent a TEE examination between 01/2007 and 03/2015 were retrospectively analyzed. For each patient, the presence of atherosclerotic lesions in the ascending aorta, the aortic arch, and in the descending aorta, as well as cardiovascular risk factors and survival were documented. Median follow-up period was 48 months (interquartile range 38-58). Multivariate Cox regression analysis indicated plaque in the ascending aorta (HR of 1.36, 95% CI 1.01-1.83, P = 0.046), the aortic arch (HR of 1.78, 95% CI 1.29-2.45, P < 0.001), the descending aorta (HR of 2.01, 95% CI 1.54-2.77, P < 0.001), and plaque in any part of the thoracic aorta (HR of 1.84, 95% CI 1.42-2.4, P < 0.001), as independent predictors for all-cause mortality after adjusting for age, sex, arterial hypertension, hyperlipidemia, smoking, and diabetes. In this study, we could demonstrate that more than mild plaque at any site of the thoracic aorta predicts all-cause mortality. Assessment of atherosclerotic lesions in all segments of the thoracic aorta should be part of every routine TEE examination.

Background Neprilysin is a transmembrane endopeptidase involved in the breakdown of a variety of vasoactive peptides and serves as a therapeutic target in heart failure with reduced ejection fraction (HFrEF). This study aimed to investigate the relationship of circulating neprilysin with neurohumoral activation and the impact of plasma neprilysin activity on prognosis in HFrEF. Methods and Results A total of 369 chronic HFrEF patients were enrolled prospectively. Plasma neprilysin concentration and activity were determined by a specific ELISA and a fluorometric method. The association between plasma neprilysin and heart failure (HF) severity, neurohumoral activation, ie norepinephrine and absolute renin concentration, as well as all-cause mortality was assessed. Median plasma neprilysin concentrations and activity levels were 413 pg/mL (interquartile range 0-4111) and 2.36 nmol/mL per minute (interquartile range 1.16-4.59). No correlation could be shown between plasma neprilysin concentrations and activity ( r s =0.09, P =0.088). Plasma neprilysin activity correlated with HF severity reflected by New York Heart Association stage ( P =0.003) and tertiles of N-terminal pro-B-type natriuretic peptide ( P <0.001), whereas neprilysin concentrations did not ( P =0.220; P =0.849). There was no relevant relationship between plasma neprilysin concentrations and activity, with neurohumoral activation reflected by absolute renin concentration ( r s =-0.02, P =0.648; r s =0.03, P =0.574) or norepinephrine levels ( r s =-0.06, P =0.248; r s =0.20, P <0.001). Neither circulating neprilysin concentrations nor activity were associated with outcome. Conclusions Plasma neprilysin concentrations and activity are not directly related to neurohumoral activation, indicating that neprilysin regulation is either more complex or not correctly mirrored by circulating neprilysin as a biomarker. Circulating neprilysin concentrations and activity were not associated with overall survival, implicating limited prognostic value of plasma neprilysin measurements in HFrEF patients.

Aims: Recent progress in the diagnosis of functional valve regurgitation forms a coherent perception of severity thresholds by quantitative assessment. However, thresholds focused on either valve in isolation-not accounting for the global haemodynamic burden arising from concomitant functional regurgitation of the mitral and tricuspid valves. We sought to determine whether the global regurgitant volume is associated with adverse cardiac remodelling and mortality., Methods and Results: This long-term observational study included 414 patients on guideline-directed medical therapy. Baseline global regurgitant load defined as the sum of mitral and tricuspid regurgitant volume was assessed by the proximal flow convergence method. All-cause mortality during 5 years follow-up served as the primary endpoint. The median global regurgitant load was 30 mL (interquartile range 15-49) with 67% accounting for mitral and 33% accounting for tricuspid regurgitant volume. The global regurgitant load had significant impact on outcome with a crude hazard ratio of 1.46 (1.28-1.66; P < 0.001) for a 1-SD increase in global regurgitant volume, results that remained virtually unchanged after bootstrap or clinical confounder-based adjustment (P < 0.001 for adjusted models). Spline curve analysis showed a linearly increasing risk with a threshold of 50 mL and sustained increasing risk thereafter., Conclusions: The present study demonstrates the detrimental effect of the global regurgitant load in patients with heart failure with reduced ejection fraction. The threshold where heart failure is driven by the valve lesions is a global regurgitant volume of 50 mL with continuously increasing risk beyond that threshold. Future studies need to address whether an attempt to reduce the global regurgitant volume can improve outcome., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Background: Various biomarkers have been associated with coronary artery disease (CAD) and ischemic heart failure. The aim of this study was to investigate the correlation of serum levels of soluble urokinase-type plasminogen activator receptor (suPAR), growth differentiation factor 15 (GDF-15), heart-type fatty acid-binding protein (H-FABP), and soluble suppression of tumorigenicity 2 (sST2) with left ventricular ejection fraction (EF) in CAD patients and controls., Methods and Results: CAD patients were divided into three groups according to their EF as measured by the biplane Simpson method (53-84%, 31-52%, ≤30%). Overall, 361 subjects were analyzed. In total, 155 CAD patients had an EF of 53-84%, 71 patients had an EF of 31-52%, and 23 patients had an EF of ≤30% as compared to 112 healthy controls (age 51.3 ± 9.0 years, 44.6% female). Mean ages according to EF were 62.1 ± 10.9, 65.2 ± 10.1, and 66.6 ± 8.2 years, respectively, with females representing 29.0, 29.6, and 13.0%. suPAR, GDF-15, H-FABP, and sST2 values were significantly higher in CAD patients and showed an exponential increase with decreasing EF. In a multiple logistic regression model, GDF-15 ( p = 0.009), and NT-brain natriuretic peptide ( p = 0.003) were independently associated with EF., Conclusion: Biomarkers such as suPAR, GDF-15, H-FABP, and sST2 are increased in CAD patients, especially in highly impaired EF. Besides NT-proBNP as a well-known marker for risk prediction, GDF-15 may be an additional tool for diagnosis and clinical follow-up.

Objective: MRI parameters of iron concentration (R2*, transverse relaxation rate), microstructural integrity (mean diffusivity and fractional anisotropy), as well as gray and white matter volumes were analyzed in patients with subarachnoid hemorrhage (SAH) and uncomplicated clinical course to detect the evolution of brain tissue changes 3 weeks and 12 months after ictus., Methods: MRI scans of 14 SAH patients (aneurysm of the anterior communicating artery, n = 5; no aneurysm n = 9) were compared with 14 age-matched healthy control subjects. Statistical parametric mapping (SPM) was applied to objectively identify focal changes of MRI parameters throughout the entire brain and to correlate image parameters with neuropsychological measures., Results: SPM localized significant bilateral increases in R2* signal within the white matter compartment of the temporal and parietal lobe and the cingulate gyrus ( P < 0.001) which did not change significantly at 12 months. Significant gray matter volume reduction of the left insula and superior temporal gyrus ( P < 0.001), as well as decreases in fractional anisotropy of the cingulate gyrus ( P < 0.01) were also evident at 12 months. Significant correlations were found between fractional anisotropy signal alterations adjacent to the left middle and superior frontal gyrus and cognitive parameters of executive dysfunction ( P < 0.001)., Interpretation: The study indicates that iron is trapped predominantly throughout large portions of the white matter compartment in SAH patients at 12 months postbleeding. Increased disintegration of fiber tracts colocalizing with iron overload and correlating with lower executive function performance suggests that the white matter compartment is primarily susceptible toward long-term damage in patients with good clinical grade SAH.