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Objectives: This study aimed to assess the guideline recommended diagnostic tools NT-proBNP and NYHA classification, with a focus on sex-specific differences., Background: Patients with Type 2 Diabetes (T2D) face a heart failure (HF) risk up to four times higher than those without T2D, particularly affecting women more than twice as much as men. Despite distinct pathophysiological differences between men and women, there are currently no sex-specific recommendations for the diagnostic algorithm of HF in diabetic patients., Methods: A total of 2083 patients with T2D were enrolled, and the primary endpoint was heart failure during hospitalization within a 5-year timeframe. The secondary endpoint was all-cause death., Results: In female patients, frequency of HF diagnosis prior to or during hospitalization and mortality did not differ significantly between NYHA II and III, in contrast to male patients. Additionally, there was no notable difference in mean NT-proBNP levels between NYHA stage II and III only in female patients. The multivariable regression analysis highlighted NYHA classification not to be a predictor of NT-proBNP levels in female but solely in male patients. On multivariable Cox regression NYHA score was also no significant risk factor for occurence of HF in female patients. Furthermore, there was no significant disparity in mortality between men with NT-proBNP levels between 125 and 400 pg/ml and those below 125 pg/ml, whereas in women mortality was significantly higher in the group with NT-proBNP levels between 125 and 400 pg/ml than below 125 pg/ml., Conclusion: These findings suggest that NYHA classification may not be the most suitable tool for assessing the diagnosis of HF in female patients with T2D. Moreover, the need for consideration of a more symptom-independent screening for HF in female patients with T2D and re-evaluation of current guidelines especially regarding sex-specific aspects is highlighted., (© 2024. The Author(s).)

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: Depending on volume status, secondary tricuspid regurgitation (sTR) has a strong dynamic component. In contrast, associated structural dilatation of the tricuspid annulus and the right heart chambers may be less volume dependent. This study aimed to assess the prognostic value of right heart remodelling in isolated severe sTR (isoTR)., Methods and Results: A total of 36 000 patients from the longitudinal echocardiographic database of our tertiary centre were screened for severe isoTR [vena contracta (VC) ≥ 7 mm] in the absence of atrial fibrillation (AF), other valve disease, and/or reduced systolic left ventricular function. Echocardiographic examinations were re-read, focusing on right ventricular (RV) parameters and on quantitative and qualitative parameters of isoTR. All-cause mortality was defined as the primary endpoint. Two hundred and sixteen patients fulfilled the inclusion criteria. Severe TR was predominant; only few were classified in the new grades massive [n = 23 (10%)] and torrential TR [n = 4 (2%)]. During a median follow-up of 35 months (20-53), all-cause mortality was 31% (n = 67). Multivariate Cox regression analysis revealed no association of VC, effective regurgitant orifice area, or regurgitant volume with all-cause mortality. However, indexed RV end-diastolic diameter (P < 0.001), indexed right atrial dimensions (P = 0.019), and particularly tricuspid valve (TV) annulus diameter diastole index (P = 0.002) and TV annulus diameter systole index (P = 0.001) were significantly associated with outcome., Conclusion: Severe isolated TR in the absence of AF is a rare finding with a grim prognosis. Tricuspid annular diameter dimensions rather than quantitative measures of TR proved to be of significant prognostic value indicating a continuous remodelling leading to a 'point of no return' with a dismal outcome., Competing Interests: Conflict of interest: None declared., (© 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.)

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: 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: 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.

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: 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.

Neprilysin (NEP) inhibition is a successful novel therapeutic approach in heart failure with reduced ejection fraction. Assessing individual NEP status might be important for gathering insights into mechanisms of disease and optimising individualised patient care. NEP is a zinc-dependent multisubstrate-metabolising oligoendopeptidase localised in the plasma membrane with the catalytic site facing the extracellular space. Although NEP activity in vivo is predominantly tissue-based, NEP can be released into the circulation via ectodomain shedding and exosomes. Attempts to determine circulating NEP concentrations and activity have not yet resulted in convincingly coherent results relating NEP biomarkers to heart failure disease severity or outcomes. NEP is naturally expressed on neutrophils, opening up the possibility of measuring a membrane-associated form with integrity. Small studies have linked NEP expression on neutrophils with inflammatory state and initial data might indicate its role in heart failure with reduced ejection fraction. Future studies need to assess the regulation of systemic NEP activity, which is assumed to be tissue-based, and the relationship of NEP activation with disease state. The relationship between tissue NEP activity and easily accessible circulating NEP biomarkers and the impact of the latter remains to be established., Competing Interests: Disclosure: The authors have no conflicts of interest to declare., (Copyright © 2020, Radcliffe Cardiology.)

Aims: Cancer patients suffer from impaired cardiovascular function. Elevated resting heart rate (RHR) has been identified as a marker for increased long-term mortality in cancer patients prior to the receipt of anticancer treatment. We aimed to establish whether RHR is associated with survival in treatment-naïve cancer patients., Methods and Results: This prospective study enrolled 548 unselected treatment-naïve cancer patients between 2011 and 2013. The median age of the cohort was 62 years; 40.9% were male and 32.7% had metastatic disease. Median RHR was 72 b.p.m. Most patients were in sinus rhythm (n = 507, 92.5%). Clinical heart failure was noted in 37 (6.8%) patients. RHR was not related to cancer stage (P = 0.504). Patients in the highest RHR tertile had higher levels of high-sensitivity troponin (P = 0.003) and N-terminal pro-B-type natriuretic peptide (P = 0.039). During a median follow-up of 25 months (interquartile range: 16-32 months; range: 0-40 months), 185 (33.8%) patients died from any cause [1-year-mortality: 17%, 95% confidence interval (CI) 13-20%]. In univariate survival analysis, RHR predicted all-cause mortality [crude hazard ratio (HR) for a 5 b.p.m. increase in RHR: 1.09, 95% CI 1.04-1.15; P < 0.001], and remained significantly associated with outcome after adjustment for age, gender, tumour entity, tumour stage, cardiac status and haemoglobin (adjusted HR for a 5 b.p.m. increase in RHR: 1.10, 95% CI 1.04-1.16; P < 0.001). There was no significant impact of metastatic/non-metastatic disease state on the predictive value of RHR (P = 0.433 for interaction). In subgroup analyses, the strongest associations for RHR with mortality were observed in lung (crude HR 1.14; P = 0.007) and gastrointestinal (crude HR 1.31; P < 0.001) cancer., Conclusions: Treatment-naïve cancer patients with higher RHRs display higher levels of cardiovascular biomarkers. RHR was independently associated with all-cause mortality, especially in lung and gastrointestinal cancers. Elevated RHR and cardiovascular biomarkers may represent early signs of incipient cardiac dysfunction., (© 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

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.)