BACKGROUND AND AIMS:Patients with LMNA gene variants are at high risk for dilated cardiomyopathy and heart failure (HF), but no prediction model for severe HF events exists. This study aimed to describe the incidence of severe HF events and develop a prediction model in a large cohort of patients with adult-onset laminopathies. METHODS:From a population of 660 patients enrolled in the French LMNA nationwide registry, 470 adults were included in the derivation cohort. An independent international validation cohort included 245 additional patients. Baseline characteristics at genetic testing were assessed and the cumulative incidence of the primary endpoint HF-major adverse cardiac events (HF-MACE) was calculated, defined as HF hospitalization, HF-related death, mechanical circulatory support, or heart transplantation. Predictors of HF-MACE were studied after excluding patients with left ventricular ejection fraction (LVEF) <30% at baseline using a Fine-Gray competing risk model, adjusted hazard ratio (aHR) with 95% confidence interval (CI), and Harrell's concordance (C-) index. A secondary composite endpoint, without hospitalization, was also studied. RESULTS:Among 470 patients of the derivation cohort, HF-MACE occurred in 65 over a median follow-up of 7.1 years (interquartile range: 3.4-12.1). Four independent predictors of HF-MACE were identified: male sex (aHR 1.86; 95% CI 1.060-3.290), LVEF <50% (aHR 2.18; 95% CI 1.080-4.400), missense variants in head and rod domains (aHR 2.91; 95% CI 1.110-7.630), and complete left bundle branch block (aHR 2.99; 95% CI 1.400-6.400). The C-index of the model was 0.750 (95% CI 0.720-0.780) in the derivation cohort and 0.758 (95% CI 0.720-0.800) in the validation cohort. The 5-year cumulative incidence of HF-MACE was 1.5% (95% CI 0.6-3.6), 5.0% (95% CI 1.8-8.2), and 22.0% (95% CI 15.6-28.4) among patients with 0, 1, and ≥2 risk factors, respectively. In patients with LVEF <30% at baseline, the 1-year incidence of HF-MACE was 50%, and those patients were excluded from the risk score. CONCLUSIONS:The first prediction model for severe HF events in adult laminopathies was developed, which may facilitate early and optimal preventive management. CLINICAL TRIAL REGISTRATION:URL: https://www.clinicaltrials.gov Unique identifier: NCT03058185.

Background:Mavacamten has been shown to be efficient in the treatment of obstructive hypertrophic cardiomyopathy (HOCM). However, its use may be associated with toxicity and subsequent adverse events. CYP2C19 genotyping is therefore recommended to optimize dosing and minimize risks in daily practice. Case summary:We report the case of a 39-year-old woman with a history of sleeve gastrectomy and HOCM. She was initiated on mavacamten 5 mg once daily (CYP2C19 genotyping showed no mutation) because of persistent significant obstruction and dyspnoea (NYHA class II) under nebivolol. Although initial tolerance was good with a reassuring transthoracic echocardiography at 4 months, she experienced a severe cardiogenic shock related to mavacamten overdose in the context of esomeprazole initiation (proton pump inhibitor that strongly interacts with the cytochrome CYP2C19 and CYP3A4) for an oesophageal pyrosis by her general practitioner 8 months later. Notably, the toxicity could be completely overcome by rifampicin initiation (600 mg twice daily for 3 days), which allowed the normalization of the plasma level of mavacamten within a few days and patient recovery. Discussion:The present case highlights that drug interactions in patients with HOCM receiving mavacamten are critical and may lead to a high level of toxicity and severe heart failure events, including cardiogenic shocks. Patient and caregiver information about these potential interactions is highly important. This case also emphasizes that the dosage of mavacamten is now available (and should be used in specific situations) and that mavacamten toxicity can rapidly be overcome by early rifampicin administration, a strong hepatic enzyme inducer.

The 6-minute walk distance (6MWD) is commonly used to assess functional capacity in patients with systemic sclerosis (SSc), but its ability to reflect changes in cardiopulmonary status during follow-up remains uncertain. This study aimed to investigate whether variations in the 6MWD accurately mirror changes in organ involvement over time in SSc patients. We conducted a longitudinal study on a global cohort of 227 consecutive SSc patients, including a subgroup of 88 patients with ILD or PH, over a two-year follow-up period. Statistical analyses were performed to assess associations between variations (Δ) of 6MWD (Δ6MWD) and evolution of organ involvement. The 6MWD varied only mildly during follow-up (mean Δ6MWD − 11.6 ± 67.5 m), including in patients with ILD or PH (mean Δ6MWD − 16 ± 74 m). Significant associations were noted between Δ6MWD and variations of several SSc parameters, mostly with modifications in functional status (changes in ΔBorg (ΔΔBorg) score, p = 0.002; ΔNYHA, p < 10− 3), PH parameters (Δright atrial area, p = 0.045; persistently elevated Nt-pro-BNP levels, p < 10− 3), chronotropic function (ΔΔheart rate, p = 0.015; Δinitial heart rate, p = 0.024), musculoskeletal involvement (occurrence of joint symptoms, p = 0.006) and perceived quality of life (ΔHAQ-DI score, p = 0.023). In most cases, the strength of these associations was mild to moderate (R2 = 0.53, adjusted R2 = 0.36 in multivariate analysis), suggesting the influence of additional factors to explain the majority of Δ6MWD. While it remains valuable as a marker of disability and functioning, the variation in the 6MWD does not seem to be a robust surrogate for modifications in organ involvements of SSc patients.

Aims:The aim of this study was to analyse the feasibility, safety, and clinical benefit of the CardioMEMS HF System in different healthcare systems outside the United States of America. Methods and results:Prospective, open-label registry of NYHA class III patients with at least one heart failure hospitalization (HFH) within 12 months before enrolment, regardless of left ventricular ejection fraction. The primary safety endpoints assess the freedom from device/system-related complications (DSRC) and freedom from pressure sensor failure (PSF) at 2 years post-implant. The primary efficacy endpoint was the rate of HFH one year before and one year after implantation.Three hundred and four patients from 37 centres in 6 countries underwent a CardioMEMS implant procedure, which was successful in 98.3% of the cases. At 2 years, there were no DSRCs and only 1 PSF. There were 517 HFH in the year before implant compared with 144 HFH in the year post-implant (risk reduction: 69% (RR: 0.31 95% CI [0.25-0.37]; P < 0.0001). Pulmonary artery (PA) pressures were significantly lowered (mean PA pressure reduction: -3.07 ± 5.91 mmHg, P < 0.0001) with a significant improvement in functional class and quality of life (mean EQ-5D-5L visual analogue score increase 8.1 ± 22.7, P < 0.0001). Conclusion:The results of the COAST study demonstrate that the CardioMEMS HF System is a reliable device, with no device-related complications and very few pressure sensor failures. Its use is associated with a substantial HFH risk reduction, with a significant reduction in PA pressures, an improvement in NYHA classification, and an improvement in quality of life. Clinical registration number:ClinicalTrials.gov Identifier: NCT02954341.

Pediatric cardiomyopathies (CM) are rare and heterogeneous heart disorders, including hypertrophic, dilated, restrictive, arrhythmogenic, and non-dilated CM. While their genetic basis is well characterized in adults, it remains less clearly defined in children particularly in early-onset apparently isolated and syndromic forms. We conducted a retrospective study (2018-2024) of 59 pediatric patients who underwent Whole-Exome Sequencing (WES) for CM at Amiens and Lille University Hospitals, aiming to characterize the genetic architecture of pediatric CM. WES identified at least one Variant Of Interest (VOI) in 62.7% of patients (37/59), including 45.8% (27/59) of P/LP variants, and 16.9% (10/59) of VUS. VOI identification yields for HCM and DCM were respectively 67.7% and 57.1%. Yield was higher in patients diagnosed before 1 year of age compared with those diagnosed later (72.7% vs. 56.7%). Variants were identified in classical CM genes, including sarcomeric genes, but also in less typical and syndromic genes. Among patients diagnosed before 6 months, 55% carried a variant in genes associated with syndromic cardiomyopathy, including cases with initially isolated cardiac phenotypes. These findings support the use of WES as a first-line approach in pediatric CM and highlight the contribution of complex and syndromic genetic architectures to early-onset and severe diseases.

BACKGROUND:Real-life data is very useful for gaining a better understanding of care in practice and identifying areas for improvement. This study aimed to assess changes in the clinical characteristics, care and outcomes of patients hospitalised with acute heart failure (HF). METHODS:Two multicentre snapshot surveys were conducted in 2009 and 2021 following the same methodology and enrolled 1658 and 1513 patients, respectively. Clinical characteristics, hospitalisation pathways, in-hospital management and short-term outcomes during a 6-month follow-up were collected. RESULTS:While the age of patients and the proportion in each left ventricular ejection fraction (LVEF) category remained largely unchanged (76 years and 53% with reduced LVEF in the two surveys), there was a rise in the prevalence of most comorbidities. Emergency department was the predominant and increasing route for hospitalisation (64-71%), and admission to critical care units remained frequent and stable (40%). In patients with reduced LVEF, the prescription rate of ACE inhibitors, angiotensin receptor blockers or angiotensin receptor-neprilysin inhibitors (ARNis) decreased from 77.8% to 70.6%, while the use of beta-blockers and mineralocorticoid receptor antagonists increased (67.7-74.2% and 26.6-35.5%, respectively) at discharge. Mortality at 1 and 6 months declined from 8.9% to 7.6% and from 24.7% to 21.3%, respectively. This difference was also significant after matching the two cohorts (HR 0.78 (0.66-0.94)). This improvement in mortality was observed in most patients except in the most elderly and those with preserved LVEF. CONCLUSIONS:A comparison of two cross-sectional surveys of acute HF, conducted 12 years apart, reveals an increasing burden of comorbidities, as well as a lack of dedicated admission pathways and a significant shortcoming in the prescription of evidence-based HF drugs on discharge. However, there has been a significant decrease in short-term mortality. TRIAL REGISTRATION NUMBER:NCT01080937 and NCT05232058.

Aims Acute heart failure (AHF) represents a major cause of morbi-mortality. In the last decade, the management of HF has changed, but up-to-date real-life data are scarce. The aim of our study was to describe contemporary data about AHF patients' medical pathway, management and to identify predictors of in-hospital outcomes.Methods and results OFICA2 is a French prospective multicenter cohort led from March to April 2021 in 80 participating centres. In-hospital outcomes were defined as a composite of all-cause death, cardiogenic shock or transfer to intensive care unit. A total of 1513 consecutive patients (mean age 76 years, 61% male) hospitalized for AHF were included. One in five patients was not admitted in cardiology wards. A triggering factor was identified in 70% of cases, mostly supraventricular arrhythmia (21%). Median hospital stay was 11 days, and in-hospital mortality was 4.6%. Predictive factors of worse outcomes were a younger age, an initial acute coronary syndrome, a ventricular arrhythmia, a left ventricular ejection fraction (LVEF) <= 40%, a lower systolic blood pressure, a worse kidney function, and a higher C-reactive protein level on admission. At discharge, 61% of patients had an appointment scheduled with a cardiologist, 1 out of 4 patients with LVEF <= 40% had a combination of beta-blocker, renin-angiotensin system blocker and mineralocorticoid receptor antagonist, while 12% had no HF medication.Conclusion This comprehensive survey about patients hospitalized with AHF emphasizes HF care pathway, medical therapies and follow-up as weak spots. Filling these gaps might improve patients' management and prognosis. This paper reports the entire out- and in-hospital journey of patients with Acute Heart Failure (AHF), in a large prospective multicenter database. The OFICA2 cohort included 1513 patients hospitalized for AHF in 80 participating centres during a 3-week period in 2021. A unique aspect of this cohort is the inclusion of all AHF patients, including those not hospitalized in cardiology wards, with an interdisciplinary care pathway. The OFICA2 survey provides robust contemporary data on AHF management, including the medical pathway, in-hospital resource use, and prognosis. These results will enhance knowledge on AHF epidemiology and management.

AIMS:Post-capillary pulmonary hypertension (pcPH) is a frequent complication of heart failure (HF), associated with poor outcomes. While right heart catheterization (RHC) is the diagnostic gold standard, echocardiographic indices such as left atrial volume index (LAVI) and the TAPSE/PASP ratio may offer non-invasive prognostic value. OBJECTIVES:To assess the prognostic utility of LAVI and TAPSE/PASP compared with invasive haemodynamic parameters in patients with HF and pcPH undergoing RHC. METHODS AND RESULTS:The PH-HF study is a prospective multicentre cohort of adults with chronic HF and confirmed pcPH (mPAP > 20 mmHg and pulmonary arterial wedge pressure > 15 mmHg) enrolled across 13 French centres (2012-2018). Patients with precapillary PH or severe pulmonary/renal comorbidities were excluded. The primary outcome was a 3-year composite of all-cause mortality, urgent heart transplantation or LVAD, or unplanned HF hospitalization. Cox regression was used for survival analyses. Overall, 55% of patients met the composite echocardiographic risk criterion (LAVI > 35 mL/m² or TAPSE/PASP < 0.40), which was associated with increased risk of adverse events (HR 1.97, 95% CI 1.41-2.75; P < 0.0001). Results were consistent across HFrEF and HFpEF phenotypes. In a multivariable model including the MAGGIC score, both the echocardiographic criterion and the clinical score remained independently associated with outcomes, supporting their complementary value in risk stratification. CONCLUSION:LAVI and TAPSE/PASP are strong, non-invasive predictors of adverse outcomes in HF with pcPH and may enhance prognostic assessment beyond invasive haemodynamics and clinical scores.

A genome-wide association study (GWAS) identified neuron navigator 3 (NAV3) as a potential genetic determinant of myocardial recovery in dilated cardiomyopathy (DCM). This study aimed to understand its functional role in cardiac pathophysiology by leveraging omics approaches. Single-cell RNA-seq transcriptomic data from previously published adult human hearts indicate that NAV3 expression is highest in cardiac fibroblasts, suggesting its functional role in these cells. In vitro, stimulation of primary human ventricular cardiac fibroblasts with transforming growth factor β1 (TGF-β1) induced NAV3 expression in a dose and time-dependent manner. Small-interfering-RNA-mediated knockdown of NAV3 significantly attenuated TGF-β1-induced fibroblast activation, reducing the expression of α-smooth muscle actin (α-SMA), collagens, and fibronectin. RNA sequencing of NAV3-silenced fibroblasts, confirmed by Western blot, revealed upregulation of cell cycle regulators and downregulation of profibrotic markers, suggesting that NAV3 facilitates TGF-β1-induced cell cycle arrest and fibroblast-to-myofibroblast transition. Notably, NAV3 silencing did not alter canonical SMAD2/3 phosphorylation, implying a role for NAV3 in modulating fibrotic signaling through other pathways. Our findings provide functional and mechanistic insights into NAV3's novel role in cardiac fibrosis, showing that reduced NAV3 expression attenuates TGF-β1-mediated fibroblast activation by regulating cell cycle signaling. These results support further investigation of NAV3 as a potential modulator of cardiac fibrosis and myocardial recovery in DCM.NEW & NOTEWORTHY This study uncovers a previously unrecognized role for NAV3 in TGF-β1-driven cardiac fibroblast activation. We show that NAV3 facilitates profibrotic remodeling through noncanonical signaling and cell cycle arrest, independently of SMAD2/3. These findings position NAV3 as a novel regulator of fibroblast phenotype and a potential modulator of cardiac fibrosis.

Diagnostic work-up of patients with hypertrophic cardiomyopathy is crucial for appropriate management. However, the optimal genetic strategy remains debatable. We compared two strategies: targeted testing based on careful examination of clinical red flags versus large multigene panel analysis without gene prioritization. We applied the strategy to the diagnosis of Fabry disease or Hereditary Transthyretin Amyloidosis (GLA or TTR genes respectively). We studied 341 hypertrophic cardiomyopathy index patients. Patients of subgroup 1 (n = 42) had careful clinical analysis and high suspicion of Hereditary Transthyretin Amyloidosis or Fabry disease. They underwent targeted Sanger sequencing. Patients in subgroup 2 (n = 299) did not have clinical selection, and underwent next-generation sequencing analysis of 107 cardiac genes. The yield of genetic testing for pathogenic/likely pathogenic variants in GLA and/or TTR was 28.6

PURPOSE:The purpose of this study was to evaluate the diagnostic performance of myocardial extracellular volume (ECV) quantification using dual-source photon-counting detector computed tomography (PCCT) compared to cardiac magnetic resonance imaging (MRI) for assessing the severity of myocardial fibrosis in patients with hypertrophic cardiomyopathy (HCM). MATERIALS AND METHODS:Patients with HCM due to sarcomere mutations underwent cardiac computed tomography angiography (CCTA) using a first-generation PCCT scanner, followed by comprehensive cardiac MRI. The CCTA protocol included a late iodine enhancement acquisition in spectral mode, 5 min after contrast media injection. ECV was calculated from the iodine ratio of the myocardium and blood pool on late iodine enhancement PCCT images. Cardiac MRI biomarkers included T1 mapping, ECV, and late gadolinium enhancement percentage (LGE). Diagnostic capabilities of PCCT were estimated using sensitivity, specificity, accuracy, interobserver agreement for myocardial fibrosis, area under the receiver operating characteristic curve (AUC) analyses for optimal thresholds, and correlations between tissue characteristics, functional capacity, and biomarkers. RESULTS:Thirty patients were retrospectively included. There were 22 men and eight women with a mean age of 59 ± 13.8 (standard deviation [SD]). The mean dose length product of late enhancement PCCT scanning was 105 ± 45 (SD) mGy.cm. No significant differences were found between global PCCT-derived ECV (30.0 ± 4.8 [SD] %) and MRI-derived ECV (30.62 ± 4.2 [SD] %) (P = 0.59). Linear regression revealed a strong segmental correlation between PCCT and MRI (basal, r = 0.89; mid-ventricular, r = 0.85; apical, r = 0.85; P < 0.001). An optimal PCCT-derived ECV threshold of 33.4 % allowed the diagnosis of LGE ≥ 15 % with 80 % sensitivity, 76 % specificity, and an AUC of 0.77, not significantly different from MRI-derived ECV (threshold 33.9 %; sensitivity, 80 %; specificity, 76 %, AUC, 0.80; P = 0.176). PCCT-derived ECV correlated with peak VO₂ (r = -0.76) and NT-proBNP levels (r = 0.59). CONCLUSION:PCCT-derived ECV shows promise for quantifying myocardial fibrosis in HCM, offering a valuable non-invasive alternative to cardiac MRI, especially for patients with contraindications or those requiring combined CCTA and myocardial assessment.

Aims: To assess the prognostic impact of both the frequency and timing of prior heart failure (HF) hospitalisations on outcomes in patients with reduced left ventricular ejection fraction (LVEF). Methods and results: This nationwide retrospective cohort study used the French national health insurance database to identify 730,052 adults with HF in 2017. A validated algorithm classified 226,747 as HF with reduced LVEF (<45 %), of whom 54,504 (24 %) had at least one HF-related hospitalisation >24 h within the preceding 24 months (worsening HF group). Patients were stratified by (1) time since the last HF hospitalisation (0–6, 6–24 months) and (2) number of hospitalisations (1, 2, ≥3). Mean age was 76 ± 15 years. Prior HF hospitalisation was the strongest predictor of mortality among all variables. After multivariable adjustment, prior hospitalisation was associated with increased risk of all-cause death (HR 1.61, 95 % CI 1.56–1.65), all-cause hospitalisation (HR 1.34, 95 % CI 1.32–1.37), and recurrent HF hospitalisation (HR 2.51, 95 % CI 2.43–2.59). Risks were greatest when the most recent hospitalisation occurred within 6 months and rose progressively with the number of prior events. Conclusion: In patients with reduced LVEF, both recent and recurrent HF hospitalisations are strong predictors of mortality and rehospitalisation. These two simple markers identify highly vulnerable patients and should trigger intensified follow-up, optimisation of guideline-directed therapies, and implementation of transitional care and remote monitoring programs.

AIMS:In the Tri.FR trial, tricuspid transcatheter edge-to-edge repair (T-TEER) reduced severity of tricuspid regurgitation (TR) and improved the composite clinical score, driven by patient-reported outcomes. The purpose of this study was to describe the longitudinal impact of T-TEER on different dimensions and items of quality of life compared with guideline-directed medical treatment (OMT) alone. METHODS AND RESULTS:Patients were randomized to T-TEER +OMT (n = 152) or OMT alone (n = 148). Health status was assessed at baseline, 6 weeks, 6 months, and 1 year using the Kansas City Cardiomyopathy Questionnaire (KCCQ) and the Minnesota Living with Heart Failure (MLHF) Questionnaire. Mixed effects linear regression analysed changes over time. Patients receiving T-TEER + OMT experienced a significant increase in KCCQ overall summary score (KCCQ-OS) at all time points: +17.0 points (95% confidence interval [CI] 13.1-21.5) at 6 weeks, +15.9 points (95% CI 11.2-20.6) at 6 months, and +18.7 points (95% CI 13.8-23.6) at 1 year. The mean between-group difference in KCCQ-OS was +10.3 points (95% CI 5.6-15.0) in favour of T-TEER + OMT, evident at 6 weeks and sustained for 1 year. Similarly, MLHF total scores improved significantly in the T-TEER group (mean between-group difference -8.61 points, 95% CI -12.6 to -4.6), including physical (-3.9, 95% CI -5.9 to -1.9) and emotional (-2.2, 95% CI -3.4 to -1.0) subscales. CONCLUSIONS:Compared with OMT alone, T-TEER resulted in substantial, multidimensional, and sustained improvements in patient-reported quality of life. These findings reinforce the value of T-TEER in managing severe symptomatic TR.

Éducation thérapeutique, réseaux de soins et télésurveillance font partie de l’arsenal thérapeutique de l’insuffisance cardiaque (IC). L’éducation thérapeutique a débuté dans les années 1990, rapidement intégrée aux réseaux de soins, qui se sont modernisés ces dernières années avec le développement des outils connectés de surveillance. En France, la télésurveillance est remboursée depuis 2023 par l’Assurance maladie. Cette prise en charge non médicamenteuse repose sur un paradoxe. La majorité des équipes spécialisées dans l’IC est persuadée que cette prise en charge est efficace malgré une démonstration scientifique insuffisante. Les résultats contradictoires des études peuvent s’expliquer par la grande difficulté à les concevoir (étude ouverte, prise en charge variable des patients par les centres, technologies de surveillance différentes, sévérité des patients…). Dans le futur, l’évolution de la technologie permettra sans doute d’améliorer l’interprétation des informations recueillies par les outils de télésurveillance.

Titin truncating variants (TTNtv) are the main genetic cause of dilated cardiomyopathies (DCMs). The phenotype and prognosis of probands have been evaluated in several large cohorts. However, few data are available on intrafamilial expressivity. To evaluate the phenotypical variability, we selected probands and family members carrying a unique TTN variant and recorded cardiac and genetic information. The cohort included 332 probands (314 TTNtv probands and 18 probands with in silico predicted in-frame exon skipping probands) and 191 relatives of TTNtv probands including 98 affected family members. Within TTNtv families, 96% of the affected relatives presented the same cardiomyopathy subtype as the proband, and 60% shared severity criteria (heart transplantation, implantable cardioverter-defibrillator, personal sudden death). Furthermore, we reported 18 probands that carry predicted in-frame exon skipping variants; they presented DCM (84%) as TTNtv patients but lower rate of rhythm disorders (0% vs. 29% respectively). In this work, we extend the genetic spectrum of TTNtv associated with DCM and show that within a family, and the cardiomyopathy phenotype is homogenous but the expressivity could vary. Such results are helpful for appropriate genetic counseling to better predict and manage the phenotype of mutation carriers.

Background European guidelines recommend initial monotherapy in PAH patients with cardiovascular (CV) comorbidities based on the limited of evidence for combination therapy in this growing population. Methods A retrospective analysis was conducted on incident PAH patients enrolled in the French Pulmonary Hypertension Registry between 2009 and 2020. Propensity score matching was used to investigate initial dual oral combination therapy versus oral monotherapy in patients with at least one CV comorbidity ( i.e. , hypertension, obesity, diabetes and coronary artery disease). Results Of the 1784 patients identified, 1088 had ≥1 CV comorbidity, including 20% with ≥3 comorbidities. In the propensity score matched population (N=708), the majority of patients were female, with idiopathic/heritable/drug-induced PAH, at intermediate 1-year mortality risk. At first follow-up, initial dual therapy led to larger improvements in symptoms, exercise capacity, hemodynamics, and risk status than initial monotherapy, with no differences in long-term survival. Treatment discontinuations were observed in 23% of patients initiated on dual therapy and 24% of those initiated on monotherapy. Conclusions Initial dual oral combination therapy may be beneficial and well tolerated in most PAH patients with CV comorbidities.