Importance:In transthyretin amyloid cardiomyopathy (ATTR-CM), tricuspid regurgitation (TR) severity may be underestimated by conventional (semi-)quantitative echocardiographic criteria derived from nonamyloid populations, given the restrictive, low-flow hemodynamics characteristic of the disease. Objectives:To derive and validate disease-specific prognostic, quantitative TR risk thresholds in ATTR-CM and to compare their prognostic performance with current guideline definitions and the Tricuspid Valve Academic Research Consortium (TVARC) 5-grade extension. Design, Setting, and Participants:This international, multicenter cohort study was conducted from January 2016 to February 2026 at 8 high-volume tertiary referral centers across Austria, Italy, Germany, and the Netherlands, with data analysis February to May 2026. Patients with newly diagnosed ATTR-CM were enrolled and underwent standardized transthoracic echocardiography with blinded core laboratory quantitative analysis of echocardiography TR severity parameters (vena contracta width [VCW], effective regurgitant orifice area [EROA], and regurgitant volume [RegVol]). Exposures:TR severity defined by VCW, EROA, and RegVol from blinded core laboratory quantitative analysis and TR severity according to 2025 European Society of Cardiology/European Association for Cardio-Thoracic Surgery, 2020 American Heart Association/American College of Cardiology, 2017 American Society of Echocardiography, and 2023 TVARC grading schemes. Main Outcomes and Measures:Outcomes were all-cause mortality (primary end point) and time to first heart failure hospitalization (HFH; secondary end point). Results:A total of 1124 patients with newly diagnosed ATTR-CM were enrolled (derivation cohort: n = 745; validation cohort: n = 379). Median (IQR) patient age was 80 (75-84) years, and 260 patients (23.1%) were female. Over a median (IQR) follow-up of 25.2 (12.2-43.2) months, 324 patients (28.8%) died and 251 (22.3%) experienced HFH. All TR metrics independently predicted both end points. Spline-derived thresholds delineated intermediate (VCW ≥3 mm; EROA ≥0.15 cm2; RegVol ≥10 mL), high (≥5 mm; ≥0.25 cm2; ≥20 mL), and extreme risk (≥8 mm; ≥0.50 cm2; ≥40 mL), with stepwise Kaplan-Meier separation in both cohorts. Whereas the guideline-based and TVARC schemes each classified 130 patients (11.6%) as having severe TR, the proposed framework classified 334 patients (29.7%) as having at least high or extreme risk (P < .001 for comparison to all other definitions). The framework was independently associated with both end points, with the highest point estimate among the schemes (mortality: hazard ratio [HR], 1.41; 95% CI, 1.23-1.62; HFH: HR, 1.31; 95% CI, 1.12-1.54), and showed superior discrimination over guideline definitions, particularly at later time points. Conclusions and Relevance:In this multicenter cohort study among patients with ATTR-CM, a validated, risk-based conceptual framework of echocardiographic parameters to quantify TR improved prediction of mortality and HFH over standard classification of TR severity, better reflecting restrictive low-flow pathophysiology and supporting disease-specific TR grading in ATTR-CM.

BACKGROUND:Atrial functional mitral regurgitation (AfMR) is a distinct entity of functional mitral regurgitation (fMR) with substantial clinical implications. Variation among published definitions introduces uncertainty regarding prevalence, morphology, and mortality, precluding consistent clinical decision making. A JACC Expert Consensus proposed a definition that was recently challenged by the European Society of Cardiology (ESC) valve guidelines. A unified, broadly applicable definition requires systematic evaluation of existing criteria. OBJECTIVES:The authors undertook sensitivity analyses of previously published AfMR definitions regarding classification, valve features, population characteristics, and prognosis, with a particular focus on the JACC Expert Consensus and the ESC guidelines definitions. METHODS:PubMed, Embase, and Web of Science were systematically searched for publications on AfMR. All identified definitions were applied to an independent single-center database of severe fMR patients (n = 581). Moderate fMR (n = 6,755) served as comparator group. Sensitivity analyses evaluated the robustness of results across definition specifications. RESULTS:Seventy-two unique AfMR definitions were identified. There was considerable variability in prevalence (2%-62%), valve features (annular diameter: 31.5-37.1 mm; tenting area: 146-229 mm2; Carpentier classification IIIb: 0%-49%), and outcome (HR: 1.17-2.42). Clustering by ejection fraction, left atrial dilation, and atrial fibrillation demonstrated that conceptually similar definitions frequently classified distinct populations. The JACC and ESC definitions showed similar overall prevalence but defined heterogeneous populations with differences in left atrial thresholds (40 mL/m2 in JACC vs 34 mL/m2 in ESC) and inclusion of 25% Carpentier IIIb cases with JACC (ESC: Carpentier type I only). Both were associated with higher mortality vs moderate fMR (JACC HR: 2.08 [95% CI: 1.42-3.04; P < 0.001]; ESC HR: 1.88 [95% CI: 1.26-2.82; P = 0.002]). After multivariate adjustment and correction for multiple testing, the JACC Expert Consensus definition remained significant, whereas the ESC guidelines definition did not. CONCLUSIONS:AfMR definitions show considerable variability in prevalence, valve features, and prognostic performance. Although the ESC guidelines and JACC Expert Consensus definitions yield similar prevalence, the JACC definition demonstrated robust prognostic validity and adaptability to a wider morphologic spectrum, including restrictive posterior leaflet (Carpentier IIIb) configurations. The robustness and flexibility indicate that the JACC definition provides a solid foundation for a unified, clinically applicable AfMR definition.

BACKGROUND:Aortic stenosis (AS) frequently coexists with heart failure (HF), but its prevalence, prognostic impact and management across the full HF spectrum remain incompletely characterised. METHODS:In this retrospective cohort study, we analysed 22 906 patients with HF undergoing echocardiography between 2010 and 2020. AS was classified as mild, moderate, low-gradient (LG) or severe according to guideline criteria. Outcomes were assessed using Cox regression, stratified by HF subtype and adjusted for clinical confounders. The primary endpoint was event-free survival, defined as all-cause mortality or aortic valve replacement (AVR). RESULTS:Moderate AS was present in 5.5%, LG AS in 2.5% and severe AS in 6.5% of HF patients, with HF with preserved ejection fraction (HFpEF) being the most common HF subtype across all AS grades. Increasing AS severity was associated with a stepwise increase in adverse outcomes compared with HF patients without AS (adjusted HR 2.20 (95% CI 2.00 to 2.41) for moderate AS; 3.32 (95% CI 2.97 to 3.72) for LG AS and 6.20 (95% CI 5.74 to 6.69) for severe AS). These associations were consistent across HFpEF, HF with mildly reduced EF and HF with reduced EF. Despite established guideline indications, only 59.5% (95% CI 57% to 62%) of HF patients with severe AS underwent AVR within 2 years. CONCLUSIONS:AS is common in HF and is associated with substantially worse long-term outcomes across all HF subtypes, even at non-severe stages. The high mortality risk and frequent lack of intervention highlight major treatment gaps and underscore the need for prospective trials evaluating earlier intervention strategies.

BACKGROUND:Mitral annular disjunction (MAD) is increasingly recognised on cardiac magnetic resonance (CMR) imaging, yet its clinical significance remains under discussion. We aimed to determine the prevalence, prognostic impact, and association with native T1 relaxation time of MAD assessed in both end-systole and end-diastole in an all-comer CMR cohort. METHODS:We analysed data from 1969 patients enrolled in a prospective CMR registry at the Vienna General Hospital. MAD was defined as ≥ 1 mm separation between the left atrial wall at the mitral valve hinge point and the adjacent left ventricular myocardium. Native T1 relaxation times were measured at septal and lateral positions of the mitral annulus in the 4-chamber view. All-cause mortality was analysed by Cox proportional hazards regression. RESULTS:End-systolic MAD was present in 509 patients (25.9%), end-diastolic in 366 (18.6%). MAD patients were younger (59.6 ± 18.5 vs. 65.2 ± 17.9 years, p < 0.001), had fewer comorbidities, and had higher left ventricular ejection fractions (58.8% ± 10.4% vs. 56.8% ± 14.4%, p = 0.009). MAD distance correlated with native annular T1 relaxation time (r = 0.24, p < 0.001), and patients with MAD ≥ 5 mm showed higher T1 relaxation time than those < 5 mm (1041 ± 148 vs. 1010 ± 72 ms, p = 0.028), while mid-septal T1 relaxation time showed no difference (r = 0.06, p = 0.252). During 63.7 months median follow-up, 485 deaths occurred. After multivariable adjustment, end-diastolic MAD was not associated with mortality (HR 0.95, 95%-CI 0.74-1.23, p = 0.712). CONCLUSIONS:MAD is common and prognostically neutral after adjustment. However, larger disjunction distances are associated with higher native T1 relaxation time values at the annulus, suggesting local subclinical myocardial remodelling.

In patients presenting with acute coronary syndrome (ACS) and multivessel disease, it is unclear whether non-culprit lesions should be revascularized immediately or in a staged procedure. We performed a meta-analysis of randomized controlled trials that compared immediate versus staged revascularization strategies. Two authors independently screened records from the online databases PubMed, Embase, Web of Science, and the Cochrane Library to identify eligible trials up to November 2025. The primary outcome was all-cause mortality at 1 year. Secondary outcomes included cardiovascular events at 1 year. Meta-regressions were performed to explore the influence of study-level characteristics. This study was registered in PROSPERO (CRD42023446181). Ten trials with a total of 5651 patients were included in the final analysis. All-cause death at 1 year occurred in 109 (3.9

BACKGROUND:Concerns about worsening renal function often limit the use of guideline-directed medical therapy (GDMT) in heart failure (HF) with reduced ejection fraction (HFrEF). Although changes in estimated glomerular filtration rate (eGFR) are commonly monitored during GDMT up-titration, the added value of urine albumin-to-creatinine ratio (UACR) and Kidney Disease: Improving Global Outcomes (KDIGO) risk categories remains less studied. OBJECTIVES:The objectives of the study were to assess changes in eGFR, UACR, and KDIGO risk categories following GDMT optimization in HFrEF and to evaluate their association with renal and HF outcomes. METHODS:Consecutive HFrEF (n = 234) outpatients with baseline and 12-month follow-up data were analyzed from the VIENNA-HF registry. KDIGO risk trajectories and their association with renal and HF outcomes were assessed. RESULTS:At follow-up, GDMT dosages significantly increased. eGFR declined (60 vs 56 mL/min/1.73 m2; P = 0.007), whereas UACR improved (31 vs 24 mg/g; P = 0.003). 56%, 24%, and 20% of patients exhibited stable, worsening, or improved KDIGO trajectories. UACR contributed to over half of all reclassifications and was the sole determinant in 35% of cases. Event rates increased stepwise across baseline KDIGO risk classes (renal events: 4% vs 12% vs 15% vs 27%; P < 0.001; HF events: 19% vs 29% vs 37% vs 56%; P < 0.001, 2-years estimate). Similarly and worsening KDIGO trajectories were associated with higher event rates (renal events: 6% vs 15% vs 21%; P = 0.034; HF events: 11% vs 43% vs 46%; P = 0.007, 2-year estimate). CONCLUSIONS:KDIGO risk trajectories vary substantially during GDMT optimization in HFrEF. UACR provides complementary information beyond eGFR and may improve risk stratification for renal and HF outcomes.

Background The characteristics and prognostic implications of bivalvular functional regurgitation (FR) in heart failure (HF) patients are largely unknown. Aims To define prevalence, clinical features, and long-term outcome of bivalvular FR across the HF spectrum. Methods This large-scale observational cohort study included 13,000 consecutive HF patients (2010–2020) from the Viennese-community healthcare provider network who were assigned according to HF subtypes: preserved ejection fraction (HFpEF), mildly reduced ejection fraction (HFmrEF), and reduced ejection fraction (HFrEF). Association of bivalvular functional regurgitation (FR) (mitral regurgitation [FMR] and tricuspid regurgitation [FTR]) with mortality across the HF spectrum was assessed. Results Distribution of bivalvular FR was no/mild/single moderate FR in 68%, moderate FMR + ≥ moderate FTR in 22%, severe FMR ± FTR in 9%, and isolated severe FTR in 1%. Moderate FMR + ≥ moderate FTR occurred across the entire HF spectrum and displayed an intermediate risk phenotype in terms of echocardiographic and biomarker features between no/mild/single moderate FR and severe FMR ± FTR.After a median of 5 years, moderate FMR + ≥ moderate FTR was associated with increased mortality compared to no/mild/single moderate FR (heart rate [HR] 1.29; 95% confidence interval [CI] 1.25–1.33). The association between moderate FMR + ≥ moderate FTR and mortality was consistent after multivariate adjustment and across all HF subgroups. Whereas in HFpEF/HFmrEF survival was worse in severe FMR compared to moderate FMR + ≥ moderate FTR, mortality was similarly increased among HFrEF patients (adjusted hazard ratio [aHR] 0.97; 95% confidence interval [CI] 0.81–1.15). Conclusion Moderate FMR+≥moderate FTR is frequent across the HF spectrum and associated with excess mortality. In HFrEF, survival of moderate FMR ≥moderate FTR is equally impaired to severe FMR. Despite these poor outcomes, no treatment recommendations beyond conventional HF management currently exist.

Background Cardiogenic shock due to simultaneous degeneration of multiple prosthetic valves is rare and is associated with prohibitive surgical risk. Case Summary A 73-year-old woman with 3 prior sternotomies presented with acute decompensated heart failure, which rapidly progressed to cardiogenic shock after atrial fibrillation. Multimodality imaging demonstrated severe dysfunction of both aortic and mitral bioprostheses, with biventricular dysfunction. Refractory shock necessitated venoarterial extracorporeal membrane oxygenation (ECMO). Given extreme surgical risk, a transcatheter strategy was pursued. Sequential transfemoral aortic and transseptal mitral valve-in-valve implantations were successfully performed under ECMO support. Hemodynamics improved immediately, allowing ECMO explantation. At the 3-year follow-up, both valves demonstrated durable function with sustained clinical recovery. Discussion The increasing integration of mechanical circulatory support with rapidly evolving transcatheter valve technologies is enabling a new paradigm of complex and high-risk structural heart interventions. Take-Home Message Dual transcatheter valve-in-valve implantation is feasible and effective in selected patients on mechanical circulatory support.

Background Patients with severe aortic stenosis (AS) and volume overload (VO) remain at an increased risk for heart failure and death after transcatheter aortic valve replacement (TAVR). The EASE-TAVR (Bioimpedance guided management of patients scheduled for transcatheter aortic valve replacement) trial demonstrated that decongestive treatment by bioimpedance spectroscopy (BIS) improves 1-year outcomes post-TAVR, whereas long-term effects are unknown. Objectives This study aimed to investigate outcomes of BIS-guided decongestion in AS patients at 36 months after TAVR. Methods EASE-TAVR randomized patients with severe AS and VO defined by BIS (≥1.0 L and/or ≥7%) 1:1 into: 1) BIS-guided decongestion (n = 55); or 2) decongestion by clinical judgment alone (n = 56) post-TAVR. Patients without VO (n = 121) served as the euvolemic control group. BIS-guided decongestion was performed for 12 months. The primary endpoint was a composite of heart failure hospitalization (HFH) and all-cause death at 36 months. The secondary endpoints included separate analyses of primary endpoint components and frequency of HFH. Results Patients in the BIS-guided group had higher diuretic doses compared to the non–BIS-guided group throughout the entire study. At 36 months, the primary endpoint occurred in 21.8% in the BIS-guided and 46.4% in the non–BIS-guided group yielding a hazard reduction of 60% (HR: 0.40; 95% CI: 0.20-0.79). BIS-guided decongestion led to a reduced cumulative incidence of first HFH (3.6%; 95% CI: 0.7-11.2 vs 25.0%; 95% CI: 14.5-37.0), a reduced HFH frequency (28 vs 173 per 1,000 patient years; P < 0.001), and showed a nonsignificant reduced mortality hazard (HR: 0.54; 95% CI: 0.26-1.14) compared to decongestion as per clinical judgment alone. Conclusions In patients with severe AS and VO, outcome benefits of BIS-targeted decongestive treatment persist up to 3 years after TAVR.

BACKGROUND:Cardiac magnetic resonance (CMR) derived hepatic T1-time is associated with outcome. However, the interplay between tricuspid regurgitation (TR), which can cause congestive hepatopathy and liver T1-time is unclear. METHODS:We measured hepatic T1-time in CMR all-comers, who underwent echocardiography within 3 weeks of CMR. Kaplan-Meier estimates and Cox regression models were used to investigate the association between hepatic T1-time, TR severity and a composite endpoint of heart failure hospitalisation and all-cause death. RESULTS:1029 participants (67 ± 17 y/o, 44% female) had a mean hepatic T1-time of 605 ± 79 ms. Overall, 41% (417) presented with non/trace, 38% (391) with mild, 13% (135) with moderate and 8% (85) with severe/massive/torrential TR. Liver T1-time was significantly associated with TR severity (no/trace: 586 ± 72 ms; mild: 601 ± 74 ms; moderate: 634 ± 84 ms; severe/massive/torrential: 665 ± 83 ms; β = 25.4 ms, [95% CI:19.7-31.2, p < .001]). After adjustment for serum NT-proBNP and right ventricular function in a linear regression model, TR severity remained significantly associated with hepatic T1-time (p < .001). During follow-up (mean 53 ± 36 months) 326 (32%) events occurred. Hepatic T1-time (adj.HR 1.69 [95% CI: 1.49-1.92] per 100 ms increase, p < .001) and TR (adj.HR 1.66 [95% CI: 1.49-1.84], p < .001) were both associated with outcome. Even after adjustment for serum NT-proBNP, cardiac structure and function, age, sex and TR severity, hepatic T1-time remained significantly associated with event-free survival (adj.HR 1.42 [95% CI: 1.20-1.68] per 100 ms increase, p < .001). CONCLUSION:TR exerts a notable influence on hepatic T1-time. Nevertheless, after adjustment for serum NTproBNP, cardiac function and TR severity, hepatic T1-time still independently predicts outcomes. This underscores the importance of hepatic T1-time both as a marker of TR and prognosis.

BACKGROUND:Severe secondary tricuspid regurgitation (STR) in heart failure patients is associated with excess mortality. Quantification associated risk assessment, remains challenging, specifically with contextual anatomic variability. Recent observations identified different morphological STR substrates based on predominance of ventricular or atrial remodeling, the extent of which can be expressed as right atrial/right ventricular area (RA/RV) ratio. OBJECTIVES:This study aims to investigate prognostic implications of RA/RV ratio in patients with STR. METHODS:This observational study included 13,174 STR patients, 1,219 had severe STR. Patients were allocated to predominant atrial remodeling (RA/RV ratio ≥1.17) vs predominant ventricular remodeling (RA/RV ratio <1.17). The primary endpoint was all-cause mortality. RESULTS:Both groups showed similar STR severity (effective regurgitant orifice area: 0.45 vs 0.46; P > 0.904, vena contracta: 13.7 vs 13.5; P = 0.322) and neurohumoral activation (N-terminal pro-brain natriuretic peptide 3,452 vs 3,567 P = 0.6). Long-term mortality was higher for predominant atrial remodeling than predominant ventricular remodeling (47% vs 39%, respectively). Spline analysis revealed increasing hazard with larger RA/RV ratio, and incline of hazard subsequently flattens in predominant atrial remodeling. Both STR remodeling types had impaired survival compared to patients at risk for severe STR (predominant atrial remodeling: HR: 2.1; 95% CI: 1.9-2.4; P < 0.001; predominant ventricular remodeling: HR: 1.6; 95% CI: 1.4-1.8; P < 0.001). This effect remained after multivariable adjustment. CONCLUSIONS:RA/RV ratio, an easily obtainable metric, associates with morphological features of valve apparatus distortion secondary to differential remodeling. Despite comparable quantified STR and neurohumoral activation, association between RA/RV ratio and mortality is robust. Whether RA/RV ratio might help identify patients benefiting from STR-tailored treatment, needs to be demonstrated by future research.

AIMS:The impact of treatment for tricuspid regurgitation (TR) across different levels of left ventricular ejection fraction (LVEF) remains uncertain. This study aimed to compare the outcomes of surgical and transcatheter tricuspid valve interventions (TTVI) to conservative (medical) management across LVEF categories. METHODS AND RESULTS:Patients with severe isolated TR from the TRIGISTRY, a multicentre international registry, were categorized based on LVEF (preserved ejection fraction [pEF]: ≥50%, mildly reduced ejection fraction [mrEF]: 41-49%, and reduced ejection fraction [rEF]: ≤40%). We assessed the impact of treatment modality and procedural success (mild-to-moderate or lower residual TR) on 2-year survival within each LVEF category. Among 2384 patients, 1383 had pEF, 400 had mrEF, and 601 had rEF. Compared to conservative management, surgery (p < 0.0005) and TTVI (p < 0.0001) were associated with a survival benefit in patients with pEF. No significant survival advantage was observed in patients with mrEF (p = 0.28 for both), nor in those with rEF (p = 0.76 and p = 0.22, respectively). Similar results were obtained when surgical and transcatheter interventions were grouped (p < 0.0001, p = 0.17 and p = 0.29 in patients with pEF, mrEF and rEF, respectively). Patients with residual TR after TTVI exhibited a trend toward worse survival compared to those managed conservatively across all LVEF categories (p = 0.47, p = 0.33 and p = 0.008 in pEF, mrEF and rEF, respectively). CONCLUSIONS:Transcatheter tricuspid valve intervention, whether surgical or transcatheter-based, was associated with improved survival in patients with pEF but not in those with mrEF or rEF. Residual TR remained a significant prognostic factor across the entire LVEF spectrum. These findings highlight the need for careful patient selection when considering TTVI in individuals with rEF.

BACKGROUND:Severe functional mitral regurgitation (fMR) is a heterogenous disease that exhibits different underlying pathophysiological mechanisms and represents independent entities. The aim of this study was to characterize remodeling patterns defined by the left atrial (LA) to left ventricular (LV) volume ratio in patients with severe fMR and heart failure, and to examine its prognostic implications. METHODS:A total of 13 052 patients with fMR were included. Based on the LA/LV volume ratio, patients with severe fMR were divided into 2 distinct groups: predominant LV remodeling (PLVR [ratio ≤0.56, n=581]) and predominant LA remodeling (PLAR [ratio >0.56, n=582]). RESULTS:Patients with PLAR were more often female, with the peak age a decade later. PLAR was associated with lower leaflet tethering indices, as indicated by the leaflet tenting area (PLVR versus PLAR: 227 mm2 versus 181 mm2, P<0.001) and angles (PLVR versus PLAR: posterior leaflet: 42° versus 36°, P<0.001; anterior leaflet: 28° versus 23°, P<0.001). PLAR was the predominant subtype in heart failure with preserved (76%) and heart failure with mildly reduced ejection fraction (61%), but a significant proportion could be observed in heart failure with reduced ejection fraction (32%). The median follow-up time for severe fMR was 66 months (interquartile range, 60-85). After 4 years, 42.1% with PLAR and 34.1% with PLVR had died. At 8 years, 57.3% of patients with PLAR, and 49.6% of patients with PLVR had died. Compared with PLVR, PLAR showed excess mortality, with a hazard ratio of 1.37 ([95% CI, 1.13-1.65]; P=0.001) in the univariate analysis. This effect remained after multivariable adjustment. CONCLUSIONS:The LA/LV volume ratio indicates the prevailing remodeling pattern in severe fMR. It is associated with morphological features of valve apparatus distortion resulting from differential remodeling. A strong correlation is observed between the LA/LV volume ratio and mortality.

Background: Extracellular volume (ECV) by cardiovascular magnetic resonance (CMR) imaging is associated with disease burden and clinical outcomes. Recent studies in patients with valvular heart disease (VHD) have suggested that the indexed total ECV (iECV) = ECVx(LVmass/1.05)/body surface area may supersede ECV in terms of prognostication. In this study, we aimed to compare the prognostic capability of conventional ECV and iECV in an all-comer CMR cohort. Methods: From January 2012 to 2023, ECV and iECV were measured in consecutive CMR patients. Adverse outcomes were defined as a composite of hospitalization for heart failure (HF) and/or death. All patients underwent transthoracic echocardiography within 3 weeks of CMR. Results: Overall, 1525 patients (44% female, mean age 65 ± 18 years) were included. The mean ECV was 29 ± 9% and the mean iECV was 21 ± 13 mL/m2. During 52 ± 36 months of follow-up, 414 (27%) events occurred. Both ECV (HR = 1.04, 95% CI = 1.04-1.05, p < 0.001) and iECV (HR = 1.03, 95% CI = 1.02-1.03, p < 0.001) were significantly associated with outcomes. Having been stratified for ECV and iECV tertiles, Kaplan-Meier analyses showed a significant association with event-free survival for both parameters (log-rank, p < 0.001 for both; central illustration). Regarding multivariate analysis, adjusted for age, sex, left ventricular function, and NT-proBNP, both ECV and iECV remained independently associated with the composite endpoint (ECV: HR = 1.31, 95% CI = 1.20-1.44, p < 0.001; iECV: HR = 1.17, 95% CI = 1.06-1.29, p = 0.002). In addition, ECV was significantly associated with aortic valve velocity (p < 0.001) pertaining to echocardiography, whereas iECV did not show an association (p = 0.41). Conclusions: Both conventional ECV and iECV provided profound prognostic information regarding the risk of HF hospitalizations and death. However, iECV, which is more complex to determine, did not add value.

BackgroundImplementation of GDMT in HFrEF remains incomplete. Prescription manners may vary based on the development of adverse effects. An HFA position paper proposed patient profiling and individualized prescription manners. This study aims to assess the eligibility for GDMT up-titration and its success in the context of clinical profiles in chronic severe HFrEF outpatients.MethodsClinical characteristics of 900 HFrEF patients at first presentation were assessed, and GDMT up-titration limiting factors were identified by applying thresholds of mutual consent. GDMT prescription was analyzed at 6 months and 1 year.Results75% of patients had no GDMT up-titration limiting factor at baseline. Significant up-titration could be achieved in all four HF drug classes, especially within the first 6 months, irrespective of GDMT up-titration limiting factors (p ≤ 0.035 for administration and dosage, all drug classes). During up-titration, there was a balanced transition between up-titration limiting factors. 35% of patients received triple therapy on target dosages with a 2.6% one-year mortality rate. Regarding the HFA profiles, 62% of patients could not be classified into a specific HFA phenotype, including most severe patients. 98% of classifiable patients belonged to only four phenotypes, while GDMT up-titration could be achieved in all of these HFA profiles (p ≤ 0.007).ConclusionIn this real-world study, 75% of patients with chronic severe HFrEF are eligible for GDMT up-titration towards target dosages. The clinical profile concept of the HFA might be adapted, as most classifiable patients can be up-titrated, and most severe patients are missed by the classification.

Background. Real-world evidence shows alarmingly suboptimal utilization of GDMT in HFrEF. One of the barriers of GDMT implementation appears to be concerns about the potential development of drug-related adverse events (AEs), particularly in high-risk patients. This study aimed to evaluate whether advanced HFrEF patients can be up-titrated safely and whether advanced HFrEF predisposes to the occurrence of putatively drug-related AEs. Methods. A total of 373 HFrEF patients with documented baseline, 2 months and 12 months visits were analyzed for utilization and target dosages (TDs) of HF-drugs. Successful up-titration and AEs were evaluated for different stages of HF reflected by NT-proBNP (<1000pg/ml, 1000-2000pg/ml, >2000pg/ml). Results. A stepwise increase in HF medications could be observed for all drug classes during follow-up. At 12 months 73%, 75%, 62%, 86% and 45% of patients received ≥90% of TDs of beta-blockers (BB), renin-angiotensin system inhibitors (RASi), mineralocorticoid receptor antagonists (MRA), sodium-glucose cotransporter-2 inhibitors (SGLT2i), and triple-therapy, respectively. Predictors of successful up-titration in logistic regression were baseline HF-drug TDs, eGFR, and potassium, but not NT-proBNP or age. The development of AEs was rare, with hyperkalemia as the most common event (34% at 12 months). AEs were comparable in all stages of HF. However, development of hyperkalemia was more frequent in patients with higher NT-proBNP and also accounted for most cases for incomplete up-titration. Conclusions. This study suggests that with dedicated protocols and frequent visits GDMT can be successfully implemented across all stages of HFrEF, including patients with highest NT-proBNP levels who probably profit the most. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement No external funding was received ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All investigations were conducted in strict adherence to the principles outlined in the Declaration of Helsinki and received institutional ethics committee approval (Ethikkommission der Medizinischen Universität Wien, EK1612/2015). Every patient gave informed consent I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data will not be shared or will be available upon request.

Background/Objectives: Real-world evidence shows alarmingly suboptimal utilization of guideline directed medical therapy (GDMT) in heart failure with reduced ejection fraction (HFrEF). One of the barriers of GDMT implementation appears to be concerns about the potential development of drug-related adverse events (AEs), particularly in high-risk patients. This study aimed to evaluate whether advanced HFrEF (AHF) patients can be up-titrated safely and whether AHF predisposes individuals to the occurrence of putatively drug-related AEs. Methods: A total of 373 HFrEF patients with documented baseline, 2 months, and 12 months visits were analyzed for utilization and target dosages (TDs) of HF drugs. Successful up-titration and AEs were evaluated for different stages of HF reflected by N-terminal pro-B type natriuretic peptide (NT-proBNP) (<1000 pg/mL, 1000–2000 pg/mL, >2000 pg/mL). Results: A stepwise increase in HF medications was observed for all drug classes during follow-up. At 12 months, 73%, 75%, 62%, 86%, and 45% of patients received ≥90% of TDs of beta-blockers (BBs), renin–angiotensin system inhibitors (RASis), mineralocorticoid receptor antagonists (MRAs), sodium–glucose cotransporter-2 inhibitors (SGLT2 i), and triple-therapy, respectively. Predictors of successful up-titration in logistic regression were baseline HF drug TDs, estimated glomerular filtration rate (eGFR), and potassium, but not NT-proBNP or age. The development of AEs was rare, with hyperkalemia as the most common event (34% at 12 months). AEs were comparable in all stages of HF. However, the development of hyperkalemia was more frequent in patients with higher NT-proBNP and also accounted for most cases of incomplete up-titration. Conclusions: This study suggests that with dedicated protocols and frequent visits, GDMT can be successfully implemented across all stages of HFrEF, including patients with AHF.

Background Degenerative severe aortic stenosis (AS) is treated by valve replacement to improve outcome. Despite diagnostic advancements, many AS patients are still diagnosed late with advanced heart failure. Objectives The aim of the study was to assess multiorgan dysfunction in severe AS using blood biomarkers and their association with quantitative fluid levels and clinical outcomes after transcatheter aortic valve implantation (TAVI). Methods Consecutive AS patients undergoing TAVI received comprehensive preinterventional assessment with serum biomarker profiles reflecting organ dysfunction and quantitative fluid overload (FO) using bioelectrical impedance spectroscopy. FO by bioelectrical impedance spectroscopy was defined according to a previously established cut-off (≥1.0 L). Time to first heart failure hospitalization or death served as composite primary endpoint. Results Among 880 patients (age 81 ± 7 years, 47% female), 41% had FO and 89% had biomarker abnormalities of at least one domain. Ascending fluid levels were independently associated with distorted biomarkers across domains of myocyte stress, hepatic dysfunction, renal dysfunction, inflammation, and anemia. After 2.4 ± 1.0 years of follow-up, 27% had reached the primary endpoint (29 heart failure hospitalization, 194 deaths, 13 both). Biomarkers across all domains were individually and independently associated with outcomes. In a multidomain approach, every affected extra-cardiac domain was associated with a 71% increase in event hazard (adjusted HR: 1.71; 95% CI: 1.39-2.11). Also, for each domain, the combination of distorted biomarkers and FO had the highest event risk. Conclusions Biomarker abnormalities are highly prevalent in severe AS, influenced by congestion, and associated with impaired prognosis post-TAVI. Multiorgan dysfunction faces a particularly dismal outcome.

BACKGROUND:Severe tricuspid regurgitation (TR) is associated with high morbidity and mortality. Isolated TR, defined as TR without overt heart disease, is typical and offers limited cardiac treatment options other than interventional repair or replacement. Survival history of cancer or active cancer treatment may lead to an unnecessary delay of TR treatment. METHODS:We included all patients diagnosed with severe TR at the Medical University of Vienna between 2003 and 2016 who had normal left ventricular function and no other valvular lesions. Outcome analysis was performed on cancer type, status and the number of organs affected by cancer. RESULTS:A total of 973 patients were included. 182 (19%) patients had cancer, 52 were active and 130 had a history of cancer at the time of TR diagnosis. Oncologic patients were divided into subgroups of gastrointestinal, skin, glands, gynaecological, breast, urogenital, lung and other cancers. Ten-year mortality of patients with cancer was higher than those without cancer (p < 0.001). Multivariate analysis adjusting for age did not reveal significantly higher mortality in patients with a history of cancer compared to patients without cancer (p = 0.59). Patients with lung, active, or multi-organ cancer showed the highest mortality. CONCLUSIONS:Mortality in patients with severe isolated TR is high and increased by active or multi-organ cancer but not by a history of cancer. These patients should be discussed in interdisciplinary cardio-oncology teams to avoid delaying life-saving treatment of TR and cancer.

AbstractAimsRegulation 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 resultsThree 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.ConclusionsWhile 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.