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Using in vivo magnetic resonance spectroscopy, our study is the first one indicating fluid balance-dependent properties of glycerophosphocholine concentrations in human skeletal muscle. In vivo examination of GPC as organic osmolyte in human skeletal muscle marks a novel approach, which might give further insight on how water and electrolyte balance affect muscle tissue. Beside this main finding, glycerophosphocholine of both calf and thigh muscle correlated remarkably with blood laboratory parameters of lipid metabolism in our study population.

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 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.

Background: Liver damage is frequently observed in patients with cardiovascular disease but infrequently quantified. We hypothesized that in patients with cardiovascular disease undergoing cardiac magnetic resonance, liver T1-times indicate liver damage and are associated with cardiovascular outcome. Methods: We measured hepatic T1-times, displayed on standard cardiac T1-maps, in an all-comer cardiac magnetic resonance-cohort. At the time of cardiac magnetic resonance, we assessed validated general liver fibrosis scores. Kaplan-Meier estimates and Cox-regression models were used to investigate the association between hepatic T1-times and a composite endpoint of non-fatal myocardial infarction, heart failure hospitalization, and death. Results: One thousand seventy-five participants (58±18 year old, 47% female) were included (972 patients, 50 controls, 53 participants with transient elastography). Hepatic T1-times were 590±89 ms in patients and 574±45 ms in controls ( P =0.052). They were significantly correlated with cardiac size and function, presence of atrial fibrillation, NT-pro-BNP levels, and gamma-glutamyl-transferase levels ( P P Conclusions: Hepatic T1-times on standard cardiac magnetic resonance scans were significantly associated with cardiac size and function, comorbidities, natriuretic peptides, and independently predicted cardiovascular mortality and morbidity. A hepatic T1-time >610 ms seems to indicate excessive risk. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04220450.

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 P =0.01) with higher residual NT-proBNP (N-terminal pro-brain natriuretic peptide) levels ( P 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.

Background Secondary tricuspid regurgitation (STR) is frequent among patients with heart failure with reduced ejection fraction (HFrEF), however inheres considerable diagnostic challenges. The assessment of circulating biomarkers reflecting neurohumoral activation may constitute a valuable supplement to the currently imaging-based diagnostic process. This study therefore sought to investigate (i) the expression of a set of complementary biomarkers in STR, (ii) to evaluate their association with STR severity, and (iii) to analyse whether the combination of neurohormone measurement and echocardiographic grading improves the individual patient risk assessment. Methods We included 576 HFrEF patients under guideline-directed therapy recording functional, echocardiographic, invasive hemodynamic 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. Results Plasma levels of aforementioned neurohormones were significantly rising with increasing STR severity (for all P Conclusions 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 leads to a significant improvement of individual risk stratification. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): FWF - Austrian Science Fund Graphical AbstractNeurohumoral profiles of STR

Objectives This study sought to define interpapillary muscle dyssynchrony as a major contributing factor in functional mitral regurgitation (FMR) and prove the reversibility of FMR by interpapillary muscle resynchronization. Background Mechanistic features of FMR include papillary muscle displacement due to left ventricular remodeling. Intraventricular conduction delay might further augment this condition by introducing interpapillary muscle dyssynchrony. Methods We enrolled 269 chronic heart failure with reduced ejection fraction patients with conduction delay and comprehensively assessed dyssynchrony by complementary echocardiographic techniques covering the entire spectrum of dyssynchrony. Results Patients with severe FMR had markedly increased interpapillary longitudinal dyssynchrony [160 ms (interquartile range [IQR]: 120 to 200 ms])] compared with those with moderate (70 ms [IQR: 40 to 110 ms]), no, or mild FMR (60 ms [IQR: 30 to 100 ms]; p Conclusions Intraventricular dyssynchrony introduces unequal contraction by papillary muscle bearing walls, which has an adverse effect on FMR. Cardiac resynchronization therapy can effectively restore interpapillary balance and thus create a less tented leaflet configuration, resulting in a clinically meaningful reduction of FMR. The restoration of papillary muscle synchronicity in dyssynchrony-mediated FMR translates into a significantly better prognosis.

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Austrian Science Fund (FWF – identification number: KLI-818B). Background Secondary mitral regurgitation in patients with heart failure and reduced ejection fraction (sMR) results from distortion of the physiologic cardiac architecture. Underlying morphological components might account for the clinical impact of sMR but have not yet been assessed systematically or related to outcome. Objectives To investigate the morphologic features of sMR and their prognostic impact on outcome. Methods This study used morphomic network profiling in patients with stable heart failure under guideline directed medical therapy. Principal component analysis was applied and three factors extracted, of which Factor 1 and 2 were strongly related to sMR and outcome. Based on the factors, four morphologically distinct clusters were derived. Results Morphomic data from 383 patients were profiled. Factor 1 consists of high loadings of left atrial morphological information, factor 2 high loadings of left ventricular morphology. Cluster analysis revealed four morphologically distinct phenotypes. sMR was most prominent in cluster 3 and 4. The morphological difference was left ventricular size (enddiastolic volume 188ml (160-224) versus 315ml (264-408), P Conclusions These results challenge the current perception of sMR resulting exclusively from global or local LV remodeling and, supported by previous concepts, emphasize the role of the atrial component as a pathophysiologic mechanism. The association of sMR with mortality cannot be purely attributed to cardiac morphology alone. Additionally, other key aspects such as balance of closing and tethering forces contribute to mitral valve closure. The association of sMR with mortality mainly driven by the small LV cavity phenotype refines the prognostic impact of sMR in relation to the underlying anatomic variability. Abstract Figure. Survival for clusters and adj. sMR

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 &lt, 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&ndash, 1.91, p = 0.006 and adj. OR 1.45, 95%CI 1.13&ndash, 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 &lt, 0.001, continuous NRI 57%, p &lt, 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.

Background The evaluation of myocardial contractility appears to be a major determinant for the prognosis and allocation of treatment strategies in advanced systolic heart failure (HFrEF). Non-invasive measurement of myocardial work is currently emerging as a new promising method for the assessment of myocardial contractility, as it additionally accounts for hemodynamic loading conditions of the ventricle. Objectives This study sought to assess the prognostic impact of myocardial work in patients with advanced heart failure and to compare it with routinely used deformation imaging parameters. Methods We included 234 patients with HFrEF under guideline directed therapy and comprehensively assessed myocardial work, as well as global longitudinal strain (GLS) by speckle tracking echocardiography. The primary endpoint was all-cause mortality. Results Median age of the patients was 68 years (IQR 60–75) and 78% were male. Over a 5-year follow-up period, 107 patients died. Median GWI was 526 mmHg% (IQR 366–779) and median GCW was 730 mmHg% (IQR 523–988). Parameters of myocardial work displayed a strong and independent association with long-term mortality, even after careful adjustment for clinical and echocardiographic confounders (Table 1). Additionally, we observed a significantly better calibration towards long-term mortality for GCW compared to GLS as the current golden standard for myocardial deformation imaging (AUC 0.63 vs. 0.60; P=0.007). Conclusion This is the first study to comprehensively assess global myocardial work in patients with advanced heart failure. Important treatment decisions rely on the assessment of myocardial contractility and risk stratification, specifically in late stages of the disease where exact guiding of treatment success and timely allocation of more aggressive treatment strategies are warranted. By incorporating loading conditions, myocardial work seems to be able to sensitively detect changes in myocardial contractility thath predict a dismal course of the disease. Furthermore, our data suggests that global constructive work is a more sensitive parameter to predict long-term outcome compared to the currently used echocardiographic deformation imaging parameters (i.e. GLS). Funding Acknowledgement Type of funding source: None

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 (PCVmax) 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. PCVmax 1 describes high loadings of left atrial morphological information, and PCVmax 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 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.

To outline a comprehensive clinical evaluation of secondary mitral regurgitation (SMR) and to review the state-of-the-art, diagnostic advances, therapeutic challenges, and future developments. SMR is commonly observed in heart failure patients. With an increasing heart failure incidence in an aging population, the prevalence of SMR is expected to rise significantly. SMR is associated with more symptoms, increased hospitalizations for heart failure, and overall worse prognosis. Both diagnostic approach and therapeutic management are challenging, but recent studies provide solutions and significant developments in this rapidly evolving field. SMR is a complex valvular heart disease, affecting a significant proportion of heart failure patients, and is associated with a worse prognosis. Key challenges are refinement of diagnostic assessment to improve patient selection for the respective therapeutic approach. Mastering the challenge of SMR requires a multidisciplinary collaborative effort, both in clinical practice and scientific approach to optimize patient outcomes.

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

Objectives This study sought to define the relationship between functional tricuspid regurgitation (TR) and mortality in patients with heart failure with reduced ejection fraction (HFrEF); and to establish the prognostic value of quantitative measures of TR severity (i.e., effective regurgitant orifice area [EROA] and regurgitant volume). Background The significance of TR in chronic heart failure is controversial. Earlier studies have shown an independent impact of TR on mortality, whereas more recent evidence suggests myocardial impairment to be the driving force of mortality rather than TR itself. Earlier studies have used qualitative measures of TR severity, hence the prognostic value of more quantitative measures of TR severity (i.e., EROA and regurgitant volumes) remains unclear. Methods We enrolled 382 patients with HFrEF on guideline-directed medical therapy and assessed TR EROA and regurgitant volume by Doppler/2-dimensional echocardiography. All-cause mortality was defined as the primary study endpoint. Results TR severity was associated with the HFrEF phenotype with more symptoms (p = 0.004), higher neurohumoral activation (p Conclusions This large-scale outcome study demonstrates the prognostic value of quantitative Doppler-echocardiographic measures of TR severity in HFrEF. The thresholds for EROA and TR regurgitant volume associated with mortality in our study fall within current ranges defining nonsevere TR. This may potentially impact therapeutic decision making, particularly timing of intervention.

Quantitative definition of functional mitral regurgitation (FMR) remains challenging [(1)][1]. Application of the effective regurgitant orifice area (EROA) and regurgitant volume (RegVol) is potentially limited because such lesion-focused metrics inevitably lack flexibility to account for the

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.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 cmAmong 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.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.

Background Diverging guideline definitions for the quantitative assessment of severe secondary mitral regurgitation (sMR) reflect the lacking link of the sMR spectrum to mortality and has introduced a source of uncertainty and continuing debate. Objectives The current study aimed to define improved risk-thresholds specifically tailored to the complex nature of sMR that provide a unifying solution to the ongoing guideline-controversy. Methods We enrolled 423 heart failure patients under guideline directed medical therapy and assessed sMR by effective regurgitant orifice area (EROA), regurgitant volume (RegVol) and regurgitant fraction (RegFrac). Results Measures of sMR severity were consistently associated with 5-year mortality with a HR for a 1-SD increase of 1.42 (95%CI 1.25-1.63, P Conclusions Risk-based thresholds tailored to the pathophysiological concept of sMR provide a unifying solution to the ongoing guideline controversy. An algorithm based on the combined assessment of the unifying cut-offs for EROA, RegVol and RegFrac improves risk prediction compared to currently established grading. Table 1 Definition of severe sMR Cox regression analysis ROC analysis IDI analysis HR (95%CI) P-Value ROC P-Value-for-comparison IDI P-Value Unifying concept 3.76 (2.71-5.23) Abstract P1764 Figure 1 A-D

Background Application of the effective regurgitant orifice area (EROA) and regurgitant volume (RegVol) is potentially limited as such lesion-focused metrics inevitably lack flexibility to account for the heterogeneity of left ventricular size and function. A recently proposed conceptual framework seeks to rearrange EROA and RegVol cut-offs according to left ventricular end-diastolic volume (LVEDV) and left ventricular ejection fraction (LVEF), introducing the novel term "disproportionate FMR" to describe clinically meaningful FMR. Methods To test the impact of disproportionate FMR, we embedded data of 291 heart failure patients with reduced ejection fraction (HFrEF) under guideline directed therapy (GDT) into this framework. Regurgitant Volume and EROA were plotted against LVEDV using bubble plots that also account for the heterogeneity of EF (Figure 1 A and C). The black lines depict a regurgitant fraction (RegFrac) of 50% at the median EF (25%) or Vmax (4.3m/s) of the study population. Thus, above individual center lines (illustrated by different bubble sizes) FMR severity is disproportionate, within the area of measurement uncertainty it is proportionate to LV dilation and below, it is likely non-severe. The degree of uncertainty of proportionate FMR is determined by the imprecision of the measurements defined as 2SDs of regurgitant fraction (±6.6%) per Bland-Altmann analysis. Results During a median follow-up of 84 months (IQR 84-136), 166 patients died. Disproportionate FMR was associated with excess mortality (RegVol: HR 1.97, 95%CI 1.38-2.81, P Conclusions In this contemporary HFrEF cohort every fifth patient has disproportionate FMR which conveys a two-fold increased risk of mortality which provides evidence for the validity of the conceptual framework. Advancement of the proposed framework to clinical practice has several implications: 1)EROA and RegVol are metrics that do not account for the contextual variability of LVEDV and EF. 2)The RegFrac -not incorporated in ESC guidelines but integrated in AHA/ACC definitions- provides a metric proportionated to left ventricular size and function supporting its use to define relevant FMR. However, technical limits suggest its complementary use on top of more robust metrics such as EROA and RegVol. Future studies need to clarify whether disproportionate FMR reflects the subgroup of patients that benefit from mitral valve repair, and provide a robust algorithm that integrates the metrics of FMR severity in a complementary manner. Abstract P1763 Figure.

Background Secondary mitral regurgitation (sMR) drives adverse cardiac remodelling in patients with heart failure with reduced ejection fraction (HFrEF). Progression in severity over time contributes to a transition towards more advanced HF stages. Early identification of patients at risk for sMR progression remains challenging. We therefore sought to assess a broad spectrum of neurohumoral biomarkers in patients with HFrEF to explore their ability to predict progression of sMR. Methods A total of 249 HFrEF patients were enrolled. Biomarkers encompassing key neurohumoral pathways in heart failure were sampled at baseline, and sMR progression was assessed over 3 years of follow‐up. Results Of 191 patients with nonsevere sMR at baseline, 18% showed progressive sMR within three years after study enrolment. Progression of sMR was associated with higher levels of MR‐proADM (adj.OR 2.25, 95% CI 1.29‐3.93; P = .004), MR‐proANP (adj.OR 1.84, 95% CI 1.14‐3.00; P = .012), copeptin (adj.OR 1.66, 95% CI 1.04‐2.67; P = .035) and CT‐pro‐ET1 (adj.OR 1.68, 95% CI 1.06‐2.68; P = .027) but not with NT‐proBNP (P = .54). Conclusion Increased plasma levels of neurohumoral cardiac biomarkers are predictors of sMR progression in patients with HFrEF and add easily available incremental prognostic information for risk stratification. Importantly, NT‐proBNP was not useful to predict progressive sMR in the present analysis. On the contrary, MR‐proANP, primarily produced in the atria, copeptin partly triggered by intra‐cardiac and intra‐arterial pressures and MR‐proADM, a marker of forward failure and peripheral released vasoactive CT‐proET1, increase based on a progressive loading burden by sMR and may thus serve as better predictors of sMR progression.

Background Recent divergence between AHA/ACC and ESC/EACTS guidelines of the quantitative definition for severe functional mitral regurgitation (sFMR) introduced uncertainty, inconsistency and continuing debate. The relation of each threshold with long-term outcome, in patients under guideline directed therapy (GDT) remains however uncertain. Methods We enrolled 269 heart failure patients with reduced ejection fraction (HFrEF) and graded sFMR according to both guideline-recommendations [AHA/ACC: effective regurgitant orifice area (EROA) ≥40mm2 or regurgitant volume (RegVol) ≥60ml/beat and ESC/EACTS: EROA ≥20mm2 or RegVol ≥30ml/beat]. All-cause mortality was defined as the primary endpoint. Result According to AHA/ACC guidelines sFMR occurred in 17% by EROA with a median EROA of 0.5mm2 (IQR 0.4–0.6) and in 13% by RegVol with a median RegVol of 76ml/beat (IQR 69–101). According to ESC/EACTS guidelines sFMR occurred in 53% by EROA with a median EROA of 0.4mm2 (IQR 0.2–0.4)and 40% according to RegVol with a median RegVol of 51ml/beat (IQR 37–69). During 8-years follow-up, 165 patients died. We observed a significant association with outcome for sFMR according to AHA/ACC guidelines quantified by EROA (HR 1.66, 95% CI 1.13–2.43, P=0.009; Figure 1A) as well as RegVol (HR 2.02, 95% CI 1.34–3.05, P=0.001; Figure 1A). In contrast, the ESC/EACTS definition of sFMR was related with outcome exclusively if quantified by RegVol (HR 1.46, 95% CI 1.05–2.05, P=0.026; Figure 1B) but not for EROA (HR 1.30, 95% CI 0.91–1.86, P=0.15; Figure 1B). Figue 1 Conclusion In this contemporary HFrEF cohort under GDT there is significant association of the ACC/AHA proposed cut-off for severe FMR and long-term mortality. The ESC/EACTS definitions are associated with mortality exclusively for the RegVol. The lack of association between sFMR based on ESC/EACTS EROA cut-offs with mortality potentially results from incorporating patients where the regurgitant burden may still be compensated and has not yet become a driving force of disease progression. Contemporary definition of sFMR entails decision making for surgical/transcatheter repair. Cut-offs need to account for the competing risks of the procedure versus the potential benefit of reducing mortality. Lower thresholds may expose a significant proportion of patients to unnecessary risk of futile procedures and higher thresholds may withhold potentially life-extending therapies. The disagreement between the two guidelines does not only convey a source of uncertainty for treating physicians but also lead to inconsistent treatment allocation thereby hindering comprehensive and comparable research. Future studies need to approximate to the true nature of severe functional mitral valve disease in an attempt to facilitate a unifying definition of sFMR.

Introduction A recently proposed conceptual framework seeks to rearrange the effective regurgitant orifice area (EROA) and regurgitant volume (RegVol) cut-offs according to left ventricular end-diastolic volume (LVEDV) and left ventricular ejection fraction (LVEF) in functional mitral regurgitation introducing “disproportionate FMR” to describe clinically meaningful FMR. The conceptual framework, however, remains hypothetical. Purpose To test the significance of disproportionate FMR. Methods Data of 291 heart failure patients with reduced ejection fraction (HFrEF) under guideline directed therapy were embedded into this conceptual framework (Figure 1A). The black line represents the relationship when the degree of FMR is proportionate to LVEDV with a regurgitant fraction of (RegFrac) of 50%. The dashed lines represent the degree of uncertainty determined by the imprecision inherent to the measurement of RegFrac defined as 2SD for inter- and intraobserver variability by Bland-Altmann analysis (equals ±6.6%). Cox-regression and Kaplan-Meier analysis were applied to assess the association between FMR proportionality and mortality. Results Median age was 68 years (IQR 61–75), 77% were male. Median LVEF was 25% (IQR 18–33) and LVEDV was 214ml (IQR 165–267). Disproportionate FMR was present in 71 patients (24%) (red dots Figure 1A) with a median EROA of 0.26cm2 (IQR 0.18–0.34) and a median RegVol of 42ml (IQR 28–52), proportionate FMR (yellow dots Figure 1 A) in 81 patients (28%) with a median EROA of 0.12cm2 (IQR 0.09–0.17) and a median RegVol of 18ml (IQR 14–27). During 7-years follow-up, 166 patients died. Disproportionate FMR was associated with excess mortality compared to patients with non-severe FMR (HR 1.97, 95% CI 1.04–0.71, P Figure 1. Panel A and B Conclusion Every fifth patient suffers from disproportionate FMR which conveys a two-fold increased risk of mortality. Disproprtionate FMR corresponds to an EROA of roughly 0.3cm2 and a RegVol of 45ml – the unifying intersection between ESC and ACC/AHA guidelines to define severe FMR. The RegFrac provides a measure proportionated to left ventricular size and function supporting its use to define clinically relevant FMR. However, RegFrac is subject to compound error due to imputation of multiple measurements limiting its use as the leading contender for FMR grading. Regardless of the term used to describe clinically significant FMR, the conceptual framework emphasizes the unmet clinical need for recalibrated cut-offs for FMR severity condensed to an algorithm that combines the strengths of several measurements of FMR severity in an integrated manner.

Abstract Background Mechanistic features of functional mitral regurgitation (FMR) include papillary muscle displacement due to left ventricular remodeling. Intraventricular conduction delay might further augment this condition by introducing interpapillary muscle dyssynchrony. Objectives To define this mechanism as a major contributing factor in FMR and prove the reversibility of FMR by interpapillary muscle resynchronization. Methods We enrolled 269 chronic HFrEF patients with conduction delay and comprehensively assessed dyssynchrony by complementary echocardiographic techniques. Opposing wall delay, calculated by speckle tracking, was determined as the time difference between peak longitudinal strain of the mid-anterior and inferior wall from a 2-chamber view. Furthermore, opposing wall delay was assessed as the time difference between peak strain values from tissue Doppler velocity-coded data of the mid-inferior septal and mid-lateral wall segments. Results Patients with severe FMR had markedly increased interpapillary longitudinal dyssynchrony (160ms [IQR 120–200]) compared to those with moderate (70ms [IQR 40–110]), no, or mild FMR (60ms [IQR 30–100]; P Figure 1. Dyssynchrony-FMR-CRT Conclusion Intraventricular dyssynchrony introduces unequal contraction by papillary muscle bearing walls, which has an adverse effect on FMR. CRT can effectively restore interpapillary balance and thus create a less tented leaflet configuration, resulting in a clinically meaningful reduction of FMR. The restoration of papillary muscle synchronicity in dyssynchrony-mediated FMR translates into a significantly better prognosis.

Objectives To establish the prognostic value of quantitative measures of functional tricuspid regurgitation (TR) severity i.e. effective regurgitant orifice area (EROA) and regurgitant volume. Methods 382 patients with HFrEF on guideline-directed medical therapy were enrolled and TR EROA as well as regurgitant volume by Doppler/2D-echocardiography were assessed. All-cause mortality was defined as the primary study endpoint. Results Quantitative metrics of TR severity were consistently associated with mortality with a HR of 1.27 (95% CI 1.13–1.42, P Figure 1. Panels A–D Conclusions This large-scale study demonstrates the prognostic value of quantitative measures of TR severity in HFrEF. Thresholds for EROA and TR regurgitant volume associated with mortality fall within current ranges defining non-severe TR. This may potentially impact therapeutic decision making particularly timing of intervention.

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 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.

Objectives To define prevalence, long term outcome, and treatment standards of secondary mitral regurgitation (sMR) across the heart failure spectrum. Design Large scale cohort study. Setting Observational cohort study with data from the Viennese community healthcare provider network between 2010 and 2020, Austria. Participants 13 223 patients with sMR across all heart failure subtypes. Main outcome measures Association between sMR and mortality in patients assigned by guideline diagnostic criteria to one of three heart failure subtypes: reduced, mid-range, and preserved ejection fraction, was assessed. Results Severe sMR was diagnosed in 1317 patients (10%), correlated with increasing age (P Conclusion Secondary mitral regurgitation is common overall, increasing with age and associated with excess mortality. The association with adverse outcome is significant across the entire heart failure spectrum but most pronounced in those with mid-range and reduced ejection fractions. Despite these poor outcomes, surgical valve repair or replacement are rarely performed; similarly, low risk transcatheter repair, specifically in the heart failure subsets with the highest expected benefit from treatment, is seldom used. The current data suggest an increasing demand for treatment, particularly in view of an expected increase in heart failure in an ageing population.

Diverging guideline definitions for the quantitative assessment of severe secondary mitral regurgitation (sMR) reflect the lacking link of the sMR spectrum to mortality and has introduced a source of uncertainty and continuing debate.The current study aimed to define improved risk-thresholds specifically tailored to the complex nature of sMR that provide a unifying solution to the ongoing guideline-controversy.This study enrolled 423 heart failure patients under guideline-directed medical therapy and assessed sMR by effective regurgitant orifice area (EROA), regurgitant volume (RegVol), and regurgitant fraction (RegFrac).Measures of sMR severity were consistently associated with 5-year mortality with a hazard ratio of 1.42 for a 1-SD increase (95% confidence interval [CI]: 1.25 to 1.63; p 0.001) for EROA, 1.37 (95% CI: 1.20 to 1.56; p 0.001) for RegVol, and 1.50 (95% CI: 1.30 to 1.73; p 0.001) for RegFrac. Results remained statistically significant after bootstrap- or clinical confounder-based adjustment. Spline-curve analyses showed a linearly increasing risk enabling the ability to stratify into low-risk (EROA 20 mmRisk-based thresholds tailored to the pathophysiological concept of sMR provide a unifying solution to the ongoing guideline controversy. An algorithm based on the combined assessment of the unifying cutoffs for EROA, RegVol, and RegFrac improves risk prediction compared with currently established grading.

AIMS Bivalvular functional regurgitation (BVFR) defined as concomitant mitral and tricuspid insufficiency has not been described or systematically assessed before. Therefore, this study sought to define incidence, impact and natural history of BVFR in heart failure with reduced ejection fraction (HFrEF) to provide the foundation for risk assessment and directions for potential treatment strategies. METHODS AND RESULTS We enrolled 1021 consecutive patients with HFrEF under guideline-directed medical therapy and performed comprehensive echocardiographic and neurohumoral profiling. All-cause mortality during a 5 years of follow-up served as the primary endpoint. Thirty percent of patients suffered from moderate or severe BVFR. Long-term mortality increased with the presence and severity of functional regurgitation (FR) with severe BVFR representing the highest risk-subset (P

This study sought to define the relationship between functional tricuspid regurgitation (TR) and mortality in patients with heart failure with reduced ejection fraction (HFrEF); and to establish the prognostic value of quantitative measures of TR severity (i.e., effective regurgitant orifice area [EROA] and regurgitant volume).The significance of TR in chronic heart failure is controversial. Earlier studies have shown an independent impact of TR on mortality, whereas more recent evidence suggests myocardial impairment to be the driving force of mortality rather than TR itself. Earlier studies have used qualitative measures of TR severity, hence the prognostic value of more quantitative measures of TR severity (i.e., EROA and regurgitant volumes) remains unclear.We enrolled 382 patients with HFrEF on guideline-directed medical therapy and assessed TR EROA and regurgitant volume by Doppler/2-dimensional echocardiography. All-cause mortality was defined as the primary study endpoint.TR severity was associated with the HFrEF phenotype with more symptoms (p = 0.004), higher neurohumoral activation (p 0.001), progressive right-ventricular dilatation (p 0.001), and impaired function (p 0.001). Cox regression showed a strong association between quantitative measures of TR with mortality (all p 0.001). Quantitative metrics of TR severity were consistently associated with mortality with a hazard ratio of 1.009 (95% confidence interval: 1.004 to 1.013; p 0.001) per 0.01 cmThis large-scale outcome study demonstrates the prognostic value of quantitative Doppler-echocardiographic measures of TR severity in HFrEF. The thresholds for EROA and TR regurgitant volume associated with mortality in our study fall within current ranges defining nonsevere TR. This may potentially impact therapeutic decision making, particularly timing of intervention.

This study sought to define interpapillary muscle dyssynchrony as a major contributing factor in functional mitral regurgitation (FMR) and prove the reversibility of FMR by interpapillary muscle resynchronization.Mechanistic features of FMR include papillary muscle displacement due to left ventricular remodeling. Intraventricular conduction delay might further augment this condition by introducing interpapillary muscle dyssynchrony.We enrolled 269 chronic heart failure with reduced ejection fraction patients with conduction delay and comprehensively assessed dyssynchrony by complementary echocardiographic techniques covering the entire spectrum of dyssynchrony.Patients with severe FMR had markedly increased interpapillary longitudinal dyssynchrony (160 ms [interquartile range (IQR): 120 to 200 ms]) compared with those with moderate (70 ms [IQR: 40 to 110 ms]), no, or mild FMR (60 ms [IQR: 30 to 100 ms]; p 0.001). Increased interpapillary muscle dyssynchrony was correlated with regurgitant volume (r = 0.50; p 0.001) and vena contracta width (r = 0.49; p 0.001). Restoration of longitudinal papillary muscle synchronicity by cardiac resynchronization therapy was correlated with FMR regression, as reflected by the reduction in regurgitant volume (r = 0.46; p 0.001) and vena contracta width (r = 0.58; p 0.001). Conversely, the improvement of FMR was associated with improved interpapillary radial (p = 0.006) and longitudinal (p 0.001) dyssynchrony. The improvement of dyssynchrony-mediated FMR signified a better prognosis compared with no improvement in FMR during the 8-year follow-up period even after comprehensive adjustment by a bootstrap-selected confounder model (adjusted hazard ratio: 0.41; 95% confidence interval: 0.18 to 0.91; p = 0.028). The results remained virtually unchanged after adjustment for left bundle branch block.Intraventricular dyssynchrony introduces unequal contraction by papillary muscle bearing walls, which has an adverse effect on FMR. Cardiac resynchronization therapy can effectively restore interpapillary balance and thus create a less tented leaflet configuration, resulting in a clinically meaningful reduction of FMR. The restoration of papillary muscle synchronicity in dyssynchrony-mediated FMR translates into a significantly better prognosis.