AIMS:Long-term arrhythmic risk after myocarditis remains uncertain, and optimal management is debated. We aimed to assess the incidence and predictors of major arrhythmic events (MAEs) after myocarditis. METHODS AND RESULTS:We conducted a systematic literature review and meta-analysis including 19 observational studies on myocarditis and MAEs during follow-up. Major arrhythmic events were defined as a composite of sudden cardiac death (SCD), ventricular fibrillation (VF), aborted cardiac arrest (ACA), sustained ventricular tachycardia (sVT), and appropriate implantable cardioverter defibrillator (ICD) or wearable-cardioverter defibrillator (WCD) intervention. The primary outcome was the incidence of MAEs after discharge; secondary outcomes included occurrence of each component of MAEs and the composite of all-cause mortality or heart transplantation (HTx). Three thousand nine hundred and fifty-four patients (71% male, 67% acute, 88% complicated myocarditis) were included. At presentation, 15% had high-grade atrioventricular block (AVB), 31% heart failure, 38% MAEs. At a median follow-up of 24 months (interquartile range 19-57), 28% suffered MAEs, with a median time of presentation of 12 months. The incidence of sVT, ACA/VF, appropriate ICD/WCD intervention, and SCD were 22%, 6%, 20%, and 1%, respectively. The combined rate of all-cause mortality/HTx was 11%. At meta-regression analysis, high-grade AVB, MAEs at presentation, and fulminant myocarditis were associated with higher risk of MAEs during follow-up, while male gender resulted as a protective factor. CONCLUSION:The incidence of MAEs after a complicated acute myocarditis can be high over time. Further prospective studies are needed to better stratify high-risk patients, identify those with an underlying arrhythmogenic cardiomyopathy, and guide antiarrhythmic strategies.

Background: Circulatory support escalation is often required during cardiogenic shock (CS) treatment. Currently, no large-scale data is available to inform how escalation strategies integrate in contemporary CS management and affect outcomes. Methods: We assessed the frequency, outcomes, and prognostic implications of escalation from a retrospective international registry of CS patients from 4 cardiac intensive care units. Escalation was defined as any incremental change in the circulatory support strategy after an initial bundle of care was established for at least 4 hours. Results: Among 602 consecutive CS patients, escalation was required in 30%. Patients were escalated to inotropes/vasopressors (36%), IABP (39%), Impella (14%) or V-A ECMO (11%). Escalation was associated with a higher hospital mortality rate (43% vs 21%; p<0.001; ORadj 3.42; 95% CI 2.21-3.35) and a greater transition to heart replacement therapies (23% vs 5%; p<0.001; ORadj 6.01; 95% CI 3.31-11.27), when adjusted for age, sex, chronic kidney disease, markers of CS severity on admission, CS etiology, and admission source. Escalation was associated with a higher risk of complications including acute kidney injury, major bleeding, and stroke. These outcomes occurred more frequently with high-profile mechanical circulatory support (Impella, V-A ECMO). Complications mediated 24% (95%CI 9-40%) of the association between escalation and hospital death. Escalated patients were successfully discharged alive in 42%. Age, SCAI B to C stage at escalation, TAPSE at escalation, and mean urinary output ≥1 mL/kg/hour in the 6 hours preceding escalation were independently associated with successful escalation when adjusted for sex, chronic kidney disease, and markers of CS severity on admission and at time of escalation. Conclusions: Circulatory support escalation is prevalent in patients treated for CS. Escalation is associated with a higher risk of hospital death, complications and transition to HRT, consistently with the intrinsically higher risk profile and expected trajectory of escalated patients. However, outcomes may differ according to the specific escalation strategy. Resorting to escalation in younger patients, in less severe CS stages, when the right ventricular function and urinary output are still preserved is associated with a higher chance of subsequent survival.

BACKGROUND:Temporary mechanical circulatory support (tMCS) is increasingly used in managing cardiogenic shock, yet women remain underrepresented in studies evaluating its role. This analysis aims to clarify sex-specific in-hospital outcomes among cardiogenic shock patients treated with and without tMCS. METHODS:We analyzed consecutive cardiogenic shock patients enrolled from January 2020 to November 2023 in the multicenter Altshock-2 Registry. The primary outcome was in-hospital mortality. RESULTS:Among 692 patients [162 (23%) women, 530 (77%) men, mean age 65 (SD 14) years], cardiogenic shock was due to myocardial infarction in 50.1% and heart failure in 29.1%. Other causes were more common in females vs. males (30.5 vs. 17.8%, P value 0.03). At presentation, women had higher lactate levels [3.4 (1.7-7.3) vs. 2.6 (1.6-5.3) mmol/l, P value 0.03] and more frequent severe right ventricular dysfunction (61.8 vs. 49.6%, P value 0.02). tMCS was used in 445 (64.7%) patients without significant sex differences (P value 0.5). Intra-aortic balloon pump was the most used device (73% women vs. 82% men, P value 0.06), followed by extra corporeal membrane oxygenation (33.7 vs. 29.7%, P value 0.4) and Impella (18.8 vs. 23.5%, P value 0.3). A not-significant higher in-hospital mortality in women emerged in the overall (41.4 vs. 33.2%, P value 0.06) and in the tMCS (41.6 vs. 32%, P value 0.07) groups. At multivariate Cox regression analysis, female sex was associated with higher in-hospital mortality only in the tMCS group (adjusted hazard ratio 1.59; 95% confidence interval 1.05-2.39; P value 0.03). No differences emerged in terms of MCS-related complications (28 vs. 25%, P value 0.6). CONCLUSION:Female sex is associated with a worse in-hospital survival among cardiogenic shock patients treated with tMCS. Future research should ensure adequate female representation to clarify underlying mechanisms.

BACKGROUND:The organ perfusion pressure (OPP) is a surrogate for end-organ hypoperfusion and was shown to predict outcomes in a multicenter cohort of cardiogenic shock (CS) patients. This investigation was conducted to externally validate the independent prognostic efficacy of admission OPP in predicting in-hospital mortality in CS. METHODS:This was a retrospective analysis of a Multicenter International Registry that enrolled consecutive patients admitted for CS from July 2023 to October 2024. Only patients with CS related to heart failure (HF) or acute myocardial infarction (AMI) were included. Admission OPP was calculated as the difference between mean arterial pressure and central venous pressure. The primary outcome was in-hospital all-cause death. RESULTS:About 621 patients were considered (mean age 62 ± 13 years; 138 [22.2%] female): 518 (83.4%) patients presented with SCAI stage ≥ C severity. In-hospital all-cause death occurred in 247 (39.8%) individuals. As compared to survivors, nonsurvivors had significantly lower OPP (59 mmHg [IQR 49-69 mmHg] vs 70 mmHg [60-80 mmHg], P-value < .001). In univariable analysis, low OPP (<57 mmHg) was associated with significantly higher in-hospital all-cause mortality (OR 3.20 [95% CI 2.25-4.56], P-value < .001); this result was consistent across both AMI-CS and HF-CS cohorts. In a multivariable logistic regression analysis including age, diabetes, SCAI stage, Sequential Organ Failure Assessment Score, creatinine, lactates, Vasoactive Inotropic Score, OPP, central venous pressure and cardiac arrest, lower OPP significantly predicted the primary outcome (OR per mmHg decrease: 1.03 [95% CI 1.01-1.06], P-value = .020). The C-index for OPP as a predictor of in-hospital mortality was 0.691 (slope = 1.01; intercept = 0.01). CONCLUSIONS:In this multicenter CS cohort, admission OPP was an independent prognostic marker of in-hospital mortality, irrespective of underlying CS etiology. Its inherent simplicity and demonstrated clinical robustness may support its integration into risk stratification and CS protocols.

Cardiogenic shock (CS) is a critical state of primary cardiac dysfunction characterized by tissue hypoperfusion and cellular hypoxia, with in-hospital mortality rates persistently between 30% and 50%. This review synthesizes contemporary evidence to redefine risk stratification through a dynamic, multi-modal lens, moving beyond static snapshots to prioritize longitudinal assessment aimed at anticipating clinical instability, therapeutic response, or physiological recovery. The evolution of CS staging is evaluated, specifically the Society for Cardiovascular Angiography and Interventions (SCAI) five-stage continuum, which tracks patient progression from "At risk" (Stage A) to "Extremis" (Stage E) and identifies critical windows for preemptive stabilization in Stage B. Essential hemodynamic "signposts" are examined, including cardiac index, right atrial pressure over pulmonary capillary wedge pressure ratio and pulmonary artery pulsatility index, which help identify high-risk phenotypes like the right-dominant CS. We highlight the role of echocardiography, lung ultrasonography and Venous Excess Ultrasound (VExUS) score as real-time biomarkers for monitoring forward flow and central and systemic congestion. Ultimately, accurate prognostication requires a multi-modal risk portrait integrating shock severity, biological phenotype, and patient-specific modifiers to identify non-responders early and allow for the timely treatment escalation, or proper de-escalation of intensive therapies as clinical improvement occurs. In this context, predictive approaches are primarily intended to anticipate imminent clinical deterioration or recovery, whereas prognostic models aim to estimate outcome probabilities, particularly mortality risk, once cardiogenic shock is established.

Background Loop diuretics are used to solve congestion in acute heart failure. However, a clear indication about the best infusion modality, dose, and duration of the treatment has not yet been established. In this analysis of the DIUR-AHF (Different Loop Diuretic Dosing and Administration in Acute Heart Failure) study, we aimed to investigate the effects of different diuretic administration modalities (ie, intermittent versus continuous furosemide infusion) and dose (high dose [HD] versus low dose) on congestion, renal function, and outcome. Methods Patients received intermittent or continuous intravenous loop diuretics infusion combined as a 1:1 ratio for a period of 72 to 120 hours. HD was defined as a high loop diuretic dose >120 mg/d. Clinical outcome was evaluated in terms of death or heart failure rehospitalization over a 6-month follow-up period. Results A total of 370 patients with AHF were included in this analysis, 189 treated with continuous intravenous loop diuretics infusion and 181 with intermittent intravenous loop diuretics infusion. At baseline, the continuous intravenous loop diuretic infusion group showed increased median values of blood urea (P=0.010) and creatinine (P=0.017). Dividing our sample according to loop diuretic dosage, the HD group revealed similar congestion and weight loss compared with the low-dose group; however, the HD group showed a reduced diuretic efficiency (-0.13 [-0.22 to -0.07] versus -0.32 [-0.59 to -0.20] kg/d; P<0.001) and an increased rate of adverse event occurrence (55% versus 20%; P<0.001). Multivariable analysis showed the association between HD treatment and poor postdischarge outcome (hazard ratio, 1.95 [95% CI, 1.23-3.10]; P=0.005). Conclusions An HD of loop diuretics infusion revealed an increased risk for adverse events together with reduced diuretic response. Our results extend previous findings revealing the association between HD diuretics and prognosis in patients with chronic HF. Additional studies may confer loop diuretic response in relation to the other decongestive treatments.

Vericiguat reduces cardiovascular death and heart failure (HF) hospitalization in high-risk patients with HF and reduced ejection fraction (HFrEF), but its non-invasive haemodynamic and remodelling effects in real-world practice remain incompletely characterized. We aimed to evaluate changes in non-invasive hemodynamic surrogates and cardiac remodeling parameters 6 months after vericiguat initiation in patients with HFrEF. We conducted a prospective, single-center study of consecutive patients with chronic HFrEF initiating vericiguat while receiving stable, optimized guideline-directed medical therapy (GDMT). Co-primary endpoints were paired 6-month changes in LVEF and LV outflow tract (LVOT) velocity-time integral (VTI). Echocardiograms were analyzed blinded to subsequent clinical outcomes. An exploratory "responder" phenotype was defined by improvement in ≥1 of: LVEF (increase > 2%), LVOT VTI (increase > 1.0 cm), or E/e' (reduction > 1.0), without deterioration in the remaining indices. Clinical events were assessed using a 6-month landmark analysis. Among 113 patients (age 64±11; median NT-proBNP 1433 pg/mL; baseline LVEF 28.0±7.5%, average use of 4 pillars of GDMT 94%), LVEF increased from 28.0±7.5% to 29.8±8.0% (p=0.002); LVOT VTI from 16.0±3.4 to 16.8±4.1 cm (p=0.009) at 6 months. E/e' decreased from 13.3±5.3 to 11.9±5.1 (exploratory; p=0.036), and NT-proBNP levels declined (p<0.001). Responder patients experienced fewer clinical events after the 6-month landmark (p=0.013). In conclusion, among real-world optimally treated patients with HFrEF, vericiguat initiation was associated with modest but statistically significant improvements in LVEF and LVOT VTI at 6 months. Favorable echocardiographic hemodynamic response appeared associated with improved subsequent clinical outcomes, supporting the role of non-invasive hemodynamic phenotyping to characterize response to soluble guanylate cyclase stimulation.

Vasodilator challenge during right heart catheterization (RHC), by improving right ventricular (RV) loading conditions, could provide an assessment of RV functional reserve. We hypothesized that a dynamic evaluation of RV function with sodium nitroprusside (NTP) infusion could enhance conventional risk stratification for post-left ventricular assist device (LVAD) early RV failure (RVF). We performed an observational retrospective multicenter study including consecutive LVAD recipients undergoing vasodilator challenge within 3 months from surgery. We evaluated the association of clinical, echocardiographic, and hemodynamic data at baseline and after NTP infusion with post-LVAD early RVF. Of 160 patients, RVF occurred in 58 (36.3%) and was associated with higher in-hospital mortality (32.8% vs . 3.9%, p < 0.001). Among baseline hemodynamics, pulmonary artery pulsatility index (PAPi) <2 was the single variable associated with RVF ( p = 0.038). In a multivariable model adjusted for in-study outcome predictors, a blunted PAPi response to vasodilator challenge (PAPi increase <2.2) emerged as the strongest independent RVF predictor (odds ratio [OR] = 4.56, 95% confidence interval [CI] = 1.88-11.07, p = 0.001). Patients with a blunted PAPi response had an increased RVF risk both in the baseline PAPi <2 (61.9% vs . 12.5%, p = 0.022) and in the baseline PAPi ≥2 (40.2% vs . 17.5%, p = 0.004) groups. Vasodilator challenge, by unveiling RV functional reserve, could improve patient selection and optimization before LVAD implant.

Bedside pressure-flow variables in cardiogenic shock (CS) incompletely characterize ventricular energetics and coupling. We prospectively derived bedside pressure-volume (PV) loop surrogates from paired pulmonary artery catheter and echocardiographic data in 68 patients (263 paired assessments) with acute myocardial infarction-related CS (AMI-CS) or heart failure-related CS (HF-CS) during microaxial support, intra-aortic balloon pump (IABP) support, or medical therapy. In AMI-CS with microaxial support, arterial elastance decreased (-1.22 mm Hg/ml) with improved coupling (ventriculoarterial coupling [VAC] -1.42), stroke work increased (+140 mm Hg·ml), and pressure-volume area declined (PVA -103 mm Hg·ml), yielding an efficiency rise from ~32% to ~40%, suggesting unloading. In HF-CS, microaxial support reduced elastance modestly (-0.35) with probable efficiency gain (+5%) but heterogeneous PVA changes. In AMI-CS treated with IABP, coupling improved (VAC -0.42) with modest energetic augmentation, whereas HF-CS showed pressure and energy amplification (end-systolic pressure +23.9 mm Hg; PVA +220.6 mm Hg ·ml). Without mechanical support, AMI-CS demonstrated reduced elastance and pressure, while HF-CS exhibited ventricular dilation (end-diastolic volume [EDV]/end-systolic volume ESV increase) with higher energetic demand. Pressure-volume-derived metrics identify device-specific energetic signatures not fully captured by conventional hemodynamic assessment and may provide mechanistic insight into ventricular unloading strategies; validation against conductance catheter-derived PV measurements remains warranted.

AIMS:The diagnosis of cardiogenic shock (CS) relies upon signs and/or symptoms of end-organ hypoperfusion. The combination of hypoperfusion and systemic congestion identifies patients at particularly high risk. This study evaluated organ perfusion pressure (OPP), calculated as mean arterial pressure minus invasive central venous pressure, as a predictor of outcomes in CS. METHODS AND RESULTS:All consecutive patients with acute myocardial infarction-related CS (AMI-CS) or acutely decompensated heart failure-related CS (ADHF-CS) enrolled in the multicentre Altshock-2 registry between January 2020 and November 2023 were included. The primary outcome was in-hospital all-cause mortality. Overall, 316 patients were included (mean age: 64 ± 13 years, 62 [20%] female, median left ventricular ejection fraction: 22% [interquartile range, IQR 15-30%], 261 [85.9%] SCAI stage C or worse, median OPP at presentation: 57.0 mmHg [IQR 47.0-69.8 mmHg]). A total of 117 (37%) patients died during the hospitalization. Low OPP (i.e. <57.0 mmHg) was associated with significantly higher in-hospital all-cause mortality (hazard ratio [HR] 1.757, 95% confidence interval [CI] 1.208-2.556, p = 0.003), whereas low mean arterial pressure alone was not (HR 1.323, 95% CI 0.901-1.941, p = 0.153). After multivariable adjustment for significant clinical data available at first bedside assessment (age and Sequential Organ Failure Assessment score), low OPP still predicted significantly higher in-hospital all-cause mortality (HR per mmHg decrease: 1.016, 95% CI 1.004-1.029, p = 0.010). Low OPP appeared particularly powerful in predicting higher in-hospital all-cause mortality among ADHF-CS patients (HR 3.172, p = 0.002). CONCLUSION:In this multicentre, observational, prospective study on patients hospitalized for CS, lower OPP on admission was associated with significantly higher in-hospital all-cause mortality.

Introduction The treatment of patients with cardiogenic shock (CS) has been focused historically on single interventions (medical treatments, percutaneous and surgical interventions and, more recently, various temporary mechanical circulatory supports). However, none of these interventions has significantly changed the short-term prognosis of CS. Moreover, considerable interest in interventions applied in the acute setting has not been matched with comprehensive assessment of patients’ long-term follow-up, not only for survival and rehospitalisation but also for quality of life and functional status, recovery from critical illness and its destructive sequelae, and a global evaluation of the overall sustainability of pathways of care. To fill this knowledge gap, the ENIGMA study will be conducted.Methods and analysis This is a prospective and retrospective multicentre registry conducted under the scientific coordination of the IRCCS Fondazione Don Gnocchi and funded by the Italian Ministry of Health (PNRR-MCNT2-2023-12377767). Data referring to 2000 patients included in the Altshock registry, the largest multicentre CS registry in Italy, will be analysed. A standardised protocol of high-intensity cardiac rehabilitation has been defined and will be followed by the involved institutions after the inclusion of the first 1000 patients. Where feasible, this new pathway will be implemented in every institution. All the patients enrolled will be evaluated according to the Long-Term Conditions Questionnaire, the Kansas City Cardiomyopathy Questionnaire and a questionnaire on the patient experience at 6-month follow-up, to evaluate real-life comparative effects on patient outcomes and experiences. In conclusion, a health technology assessment (HTA) analysis, grounded in the EUnetHTA Core Model, will be conducted to define the potential multidimensional benefits and effects with regard to the overall economic, organisational and social sustainability of the innovative dedicated pathway. Various data sources will be used to conduct the HTA: (1) literature evidence, to define the evidence-based comparative indicators considering both surgical approaches; (2) real-world anonymised data from the hospitals included in the study, to enable costing of the rehabilitative pathways; and (3) healthcare professionals’ perceptions, defining the perceived added value of the innovative pathway versus the historical one, based on an evaluation scale ranging from −3 to +3.Ethics and dissemination The study was approved by the ethical committee (EC) of Lombardy Region (CET 44/24), on 28 May 2024, and is under evaluation by the EC of three other centres. The study protocol will be evaluated for ethics by 10 more centres in January 2025. Study results will be published in peer-reviewed publications and disseminated through conference presentations. The Associazione Nazionale Scompensati Cardiaci (AISC; ‘National Association of Patients with Heart Failure’), the Progetto Vita initiative and the non-profit organisation ‘Heart Helps Heart’ have endorsed the project and will be involved in disseminating information about the project and its outcomes to the general public.Clinical trial registration number The ENIGMA-shock study has been registered at ClincialTrials.gov: NCT06572826.

AIMS:We aimed to assess the impact of pre-admission beta-blocker (BB) therapy on the clinical characteristics, in-hospital treatment and outcomes of patients with cardiogenic shock (CS). METHODS:All patients enrolled in the multicentre prospective Altshock-2 registry since March 2020 with available data on pre-admission BB therapy were included. Clinical characteristics, in-hospital management, haemodynamic parameters and clinical outcomes were compared in patients with versus without BB therapy. The primary endpoint was in-hospital mortality. RESULTS:A total of 668 patients were included [median age 66 (56-74) years, male sex 76.5%]: 299 patients (44.8%) with and 369 patients (55.2%) without previous BB therapy. Patients receiving pre-admission BB therapy had more frequently heart failure-related CS (43.8% vs. 17.9%) and less frequently cardiac arrest at presentation (20.1% vs. 27.8%, P = 0.027). Levosimendan was used less frequently and dobutamine was used more frequently in patients with baseline BB therapy (P = 0.033 and P = 0.043, respectively). Differences in the early haemodynamic response to vasoactive drugs were observed between patients with and without previous BB therapy, with a significant impact of baseline BB on mean arterial pressure (MAP) response during norepinephrine infusion (P = 0.012) and with dobutamine having a reduced response in MAP and heart rate in patients receiving BBs before admission (P = 0.023 and P = 0.001, respectively). In-hospital mortality was not significantly different between the BB and no-BB groups (40% vs. 33.7%; adjusted odds ratio 1.32, 95% confidence interval 0.84-2.07, P = 0.224). Similarly, baseline BB therapy was not independently associated with 48 h mortality (12.7% vs. 14.6%; adjusted odds ratio 1.09, 95% confidence interval 0.64-1.87, P = 0.749). The lack of association between baseline BB therapy and mortality was also confirmed at inverse probability of treatment weighting-adjusted analysis. CONCLUSIONS:In a real-world, contemporary cohort of patients with CS, previous BB therapy influenced the haemodynamic response to vasoactive drugs, but it was not associated with in-hospital mortality.

BACKGROUND:Transcatheter edge-to-edge repair (TEER) for severe functional mitral regurgitation (FMR) in patients with reduced left ventricular ejection fraction (LVEF) may lead to an acute increase in left ventricular afterload, termed afterload mismatch (AM). This study aimed to redefine AM clinically, analyse its determinants, and assess its prognostic impact post-TEER in FMR patients. METHODS:A multicenter case-control study was conducted, involving FMR patients with LVEF ≤35% undergoing TEER. AM post-TEER was defined as the acute (within 24 h) need for escalation of inotropic or mechanical circulatory support. Sixty-eight AM cases were compared with 68 propensity-matched patients. Primary endpoints included in-hospital mortality post-TEER and 2-year all-cause mortality. RESULTS:Median age was 68 years, 76% male. Procedural success was achieved in 92% of patients. Proportionate MR was associated with a higher risk of AM (adj-HR 1.6, 95% CI 1.01-2.6, p = .04). Conversely, pretreatment with levosimendan (adj-HR .29, 95% CI .12-.70, p < .01) and higher furosemide dose (adj-HR per furosemide 10 mg increase .86, 95% CI .76-.98, p = .03) were protective. In-hospital mortality was higher in the AM cohort (10% vs. 2%, p = .03), while 2-year mortality rates were similar (34% vs. 20%, p = .09). Multivariable analysis revealed higher AM grades and post-procedural MR as predictors of in-hospital mortality and lack of procedural success for 2-year mortality. CONCLUSIONS:Among patients with LVEF ≤35% and severe FMR undergoing TEER, AM was associated with in-hospital mortality but did not impact long-term outcomes. Proportionate MR increased the risk of AM, while pretreatment with levosimendan and higher furosemide doses was protective.

Aims Severe functional mitral regurgitation (FMR) may benefit from mitral transcatheter edge-to-edge repair (TEER), but selection of patients remains to be optimized. Objectives The aim of this study was to use machine-learning (ML) approaches to uncover concealed connections between clinical, echocardiographic, and haemodynamic data associated with patients’ outcomes. Methods and results Consecutive patients undergoing TEER from 2009 to 2020 were included in the MITRA-AI registry. The primary endpoint was a composite of cardiovascular death or heart failure (HF) hospitalization at 1 year. External validation was performed on the Mitrascore cohort. 822 patients were included. The composite primary endpoint occurred in 250 (30%) patients. Four clusters with decreasing risk of the primary endpoint were identified (42, 37, 25, and 20% from Cluster 1 to Cluster 4, respectively). Clusters were combined into a high-risk (Clusters 1 and 2) and a low-risk phenotype (Clusters 3 and 4). High-risk phenotype patients had larger left ventriculars (LVs) (>107 mL/m2), lower left ventricular ejection fraction (<35%), and more prevalent ischaemic aetiology compared with low-risk phenotype patients. Within low-risk groups, permanent atrial fibrillation amplified that of HF hospitalizations. In the Mitrascore cohort, the incidence of the primary endpoint was 48, 52, 35, and 42% across clusters. Conclusion A ML analysis identified meaningful clinical phenotypic presentations in FMR undergoing TEER, with significant differences in terms of cardiovascular death and HF hospitalizations, confirmed in an external validation cohort.