Rationale and design of the French Observatory of Acute Heart Failure (OFICA2).

BACKGROUND: Acute heart failure (AHF) is a leading cause of hospitalization and mortality - especially in patients aged≥65 years in high-income countries - and represents a high healthcare burden. In the past decade, the epidemiology and management of heart failure (HF) has changed, with the emergence of new medical and interventional therapeutics, but up-to-date real-life data are scarce. AIMS: The main objectives are to describe baseline characteristics (with an emphasis on lifestyle, cognitive status, HF knowledge and treatment adherence), management, and in-hospital and mid-term outcomes of AHF patients in France. Secondary objectives are to investigate determinants of prognosis, modalities of treatment and follow-up, and identify gaps between guidelines and real-life management. METHODS: OFICA2 is a prospective multicentre observational survey that enrolled 1513 patients hospitalized for AHF in 80 participating centres in France during March and April 2021. The diagnosis of AHF was made according to the European Society of Cardiology guidelines definition. Inclusion criteria were age≥18years, health coverage and consent to participate. Detailed information was collected prospectively starting at admission. Thanks to direct linking with the French National Health Database, the anteriority up to 2years before inclusion, as well as a 3-year follow-up is specified for each patient and includes individual information on death, hospital admissions, major clinical events, drug delivery and use of reimbursed health resources. CONCLUSION: This cohort provides a representative snapshot on contemporary AHF, with a particular focus on self-care determinants, and will improve knowledge about AHF presentation, management and outcomes.

Post-capillary pulmonary hypertension in heart failure: impact of current definition in the PH-HF multicentre study.

BACKGROUND AND AIMS: Based on retrospective studies, the 2022 European guidelines changed the definition of post-capillary pulmonary hypertension (pcPH) in heart failure (HF) by lowering the level of mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR). However, the impact of this definition and its prognostic value has never been evaluated prospectively. METHODS: Stable left HF patients with the need for right heart catheterization were enrolled from 2010 to 2018 and prospectively followed up in this multicentre study. The impact of the successive pcPH definitions on pcPH prevalence and subgroup [i.e. isolated (IpcPH) vs. combined pcPH (CpcPH)] was evaluated. Multivariable Cox regression analysis was used to assess the prognostic value of mPAP and PVR on all-cause death or hospitalization for HF (primary outcome). RESULTS: Included were 662 HF patients were (median age 63 years, 60% male). Lowering mPAP from 25 to 20 mmHg resulted in +10% increase in pcPH prevalence, whereas lowering PVR from 3 to 2 resulted in +60% increase in CpcPH prevalence (with significant net reclassification improvement for the primary outcome). In multivariable analysis, both mPAP and PVR remained associated with the primary outcome [hazard ratio (HR) 1.02, 95% confidence interval (CI) 1.00-1.03, P = .01; HR 1.07, 95% CI 1.00-1.14, P = .03]. The best PVR threshold associated with the primary outcome was around 2.2 WU. Using the 2022 definition, pcPH patients had worse survival compared with HF patients without pcPH (log-rank, P = .02) as well as CpcPH compared with IpcPH (log-rank, P = .003). CONCLUSIONS: This study is the first emphasizing the impact of the new pcPH definition on CpcPH prevalence and validating the prognostic value of mPAP > 20 mmHg and PVR > 2 WU among HF patients.

Right Ventriculoarterial Coupling Surrogates and Long-Term Survival in LVAD Recipients: Results of the ASSIST-ICD Multicentric Registry.

BACKGROUND: Prediction of outcomes remains an unmet need in candidates for LVADs. The development of right-heart failure portends an excess in mortality rates, but imaging parameters of right ventricular systolic function have failed to demonstrate a prognostic role. By integrating pulmonary pressure, right ventriculoarterial coupling could fill this gap. METHODS: The ASSIST-ICD registry was used to test right ventriculoarterial coupling as a surrogate parameter at implantation for the prediction of all-cause mortality. RESULTS: The ratio of the tricuspid annular-plane systolic excursion over the estimated systolic pulmonary pressure (TAPSE/sPAP) was not associated with long-term survival in univariate analysis (P = 0.89), nor was the pulmonary artery pulsatility index (PAPi) (P = 0.13). Conversely, the ratio of the right atrial pressure over the pulmonary capillary wedge pressure (RAP/PCWP) was associated with all-cause mortality (P < 0.01). After taking tricuspid regurgitation severity, LVAD indication, LVAD model, age, blood urea nitrogen levels, and pulmonary vascular resistance into account, RAP/PCWP remained associated with survival (HR 1.35 [1.10 - 1.65]; P < 0.01). CONCLUSION: Among pre-implant RVAC surrogates, only RAP/PCWP was associated with long-term all-cause mortality in LVAD recipients. This association was independent of established risk factors.

Sacubitril/valsartan has an underestimated impact on the right ventricle in patients with sleep-disordered breathing, especially central sleep apnoea syndrome.

BACKGROUND: Sacubitril/valsartan has been demonstrated to significantly improve left ventricular performance and remodelling in patients with heart failure. However, its effects on the right ventricle in patients with chronic heart failure and sleep-disordered breathing (SDB) have not been studied. AIM: To investigate the impact of sacubitril/valsartan treatment on right ventricular function in patients with SDB. METHODS: This was a subanalysis of an observational prospective multicentre study involving 101 patients. At inclusion, patients were evaluated by echocardiography and nocturnal ventilatory polygraphy, which allowed patients to be divided into three groups: "central-SDB"; "obstructive-SDB"; and "no-SDB". RESULTS: After 3 months of sacubitril/valsartan therapy, a positive impact on right ventricular function was observed. In the general population, tricuspid annular plane systolic excursion increased by +1.32±4.74mm (P=0.024) and systolic pulmonary artery pressure decreased by -3.1±10.91mmHg (P=0.048). The central-SDB group experienced the greatest echocardiographic improvement, with a significant increase in tricuspid annular plane systolic excursion of +2.1±4.9mm (P=0.045) and a significant reduction in systolic pulmonary artery pressure of -8.4±9.7mmHg (P=0.001). CONCLUSIONS: Sacubitril/valsartan improved right ventricular function in patients with heart failure and SDB after only 3 months of treatment. The greatest improvement in right ventricular function was observed in the central-SDB group.

Risk stratification refinements with inclusion of haemodynamic variables at follow-up in patients with pulmonary arterial hypertension.

BACKGROUND: Haemodynamic variables are prognostic factors in pulmonary arterial hypertension (PAH). However, right heart catheterisation (RHC) is not systematically recommended to assess the risk status during follow-up. This study aimed to assess the added value of haemodynamic variables in prevalent patients to predict the risk of death or lung transplantation according to their risk status assessed by the non-invasive four-strata model as recommended by the European guidelines. METHODS: We evaluated incident patients with PAH enrolled in the French pulmonary hypertension registry between 2009 and 2020 who had a first follow-up RHC. Cox regression identified, in each follow-up risk status, haemodynamic variables significantly associated with transplant-free survival. Optimal thresholds were determined by time-dependent receiver operating characteristics. Several multivariable Cox regression models were performed to identify the haemodynamic variables improving the non-invasive risk stratification model. RESULTS: We analysed 1240 incident patients reassessed within 1 year by RHC. None of the haemodynamic variables were significantly associated with transplant-free survival among low-risk (n=386) or high-risk (n=71) patients. Among patients at intermediate (intermediate-low, n=483 and intermediate-high, n=300) risk at first follow-up, multivariable models including either stroke volume index (SVI) or mixed venous oxygen saturation (S vO2 ) were the best. The prognostic performance of a refined six-strata risk stratification model including the non-invasive four-strata model and SVI >37 mL·m-2 and/or S vO2 >65% for patients at intermediate risk (area under the curve (AUC) 0.81; c-index 0.74) was better than that of the four-strata model (AUC 0.79, p=0.009; c-index 0.72). CONCLUSION: Cardiopulmonary haemodynamics may improve risk stratification at follow-up in patients at intermediate risk.

Impact of sacubitril/valsartan on cardiac and systemic hypoxia in chronic heart failure.

In heart failure patients with reduced ejection fraction, Sacubitril/valsartan (S/V) increased proBNP T71 glycosylation, which is regulated negatively by hypoxia via miR-30a in vitro. Using a cohort of 73 HFrEF patients who were transitioned from standard HF medication to S/V, we found that the increase in proBNP T71 glycosylation after S/V was associated with a decrease in cardiac hypoxia. We further found that plasma levels of K709-acteylated HIF1α, HIF-regulated and HIF-independent biomarkers also evolved consistently with a decrease in hypoxia. We further confirmed that biomarker changes were related to hypoxia, in a rat model subjected to isobaric hypoxia. We measured them in rats subjected to isobaric hypoxia. Overall, these data strongly suggest that optimally treated HFrEF patients exhibited subclinical hypoxia that is improved by S/V. The data also posit proBNP T71 glycosylation as a biomarker of cardiac hypoxia.

NEXN Gene in Cardiomyopathies and Sudden Cardiac Deaths: Prevalence, Phenotypic Expression, and Prognosis.

BACKGROUND: Few clinical data are available on NEXN mutation carriers, and the gene's involvement in cardiomyopathies or sudden death has not been fully established. Our objectives were to assess the prevalence of putative pathogenic variants in NEXN and to describe the phenotype and prognosis of patients carrying the variants. METHODS: DNA samples from consecutive patients with cardiomyopathy or sudden cardiac death/sudden infant death syndrome/idiopathic ventricular fibrillation were sequenced with a custom panel of genes. Index cases carrying at least one putative pathogenic variant in the NEXN gene were selected. RESULTS: Of the 9516 index patients sequenced, 31 were carriers of a putative pathogenic variant in NEXN only, including 2 with double variants and 29 with a single variant. Of the 29 unrelated probands with a single variant (16 males; median age at diagnosis, 32.0 [26.0-49.0] years), 21 presented with dilated cardiomyopathy (prevalence, 0.33%), and 3 presented with hypertrophic cardiomyopathy (prevalence, 0.14%). Three patients had idiopathic ventricular fibrillation, and there were 2 cases of sudden infant death syndrome (prevalence, 0.46%). For patients with dilated cardiomyopathy, the median left ventricle ejection fraction was 37.5% (26.25-50.0) at diagnosis and improved with treatment in 13 (61.9%). Over a median follow-up period of 6.0 years, we recorded 3 severe arrhythmic events and 2 severe hemodynamic events. CONCLUSIONS: Putative pathogenic NEXN variants were mainly associated with dilated cardiomyopathy; in these individuals, the prognosis appeared to be relatively good. However, severe and early onset phenotypes were also observed-especially in patients with double NEXN variants. We also detected NEXN variants in patients with hypertrophic cardiomyopathy and sudden infant death syndrome/idiopathic ventricular fibrillation, although a causal link could not be established.

Remote management of worsening heart failure to avoid hospitalization in a real-world setting.

AIMS: From a patient and health system perspective, managing worsening heart failure (WHF) as an outpatient has become a priority. Remote management allows early detection of WHF, enabling timely intervention with the aim of preventing hospitalization. The objective of the study was to evaluate the feasibility and safety of remotely managing WHF events using a multiparametric platform. METHODS AND RESULTS: All patients enrolled in the heart failure remote management programme of the Bordeaux University Hospital Telemedicine Center between 1 January and 31 December 2021 were included in the study. Follow-up data were collected until 1 March 2022. Inclusion criteria were chronic heart failure (HF) with New York Heart Association ≥II symptoms and an elevated B-type natriuretic peptide (BNP > 100 pg/mL or N-terminal-pro-BNP > 1000 pg/mL). Patient assessments were performed remotely and included measurements of body weight, blood pressure, heart rate, symptoms, biochemical parameters, and data from cardiac implantable electronic devices when available. In total, 161 patients (71 ± 11 years old, 79% male) were followed for a mean of 291 ± 66 days with a mean adherence to the remote monitoring system of 80 ± 20%. Over this period, 52 (32.3%) patients had 105 WHF events, of which 66 (63%) were successfully managed remotely, the remaining requiring hospitalization. Freedom from WHF events and hospitalization at 300 days were 66% and 85%, respectively (P < 0.001 for the difference). Increased level of BNP was associated with an increased risk of WHF event [hazard ratio (HR) per unit increase in BNP: 1.001; 95% confidence interval (CI) 1-1.002; P = 0.001] and hospitalization (HR 1.002; 95% CI 1.002-1.003; P = 0.002). A decrease in the level of glomerular filtration rate was associated with an increased risk of hospitalization (HR per unit decrease in estimated glomerular filtration rate: 0.946; 95% CI 0.906-0.989; P = 0.014). WHF event recurrence and (re)hospitalization rates at 1-month were similar among patients managed remotely (18% and 12%, respectively) and those requiring hospitalization (21% and 10%, respectively). Iatrogenic complications occurred more often during hospitalization than remote management (26% vs. 3%, P < 0.001). CONCLUSIONS: Our study suggests that remote management of WHF events based on a multiparametric approach led by a telemedical centre is feasible and safe. Adopting such a strategy for patients with chronic HF could reduce HF-related hospitalizations with expected benefits for patients, care providers, and health care systems.

Prognostic impact of precipitated cardiac decompensation in symptomatic heart failure with reduced ejection fraction and severe secondary mitral regurgitation.

BACKGROUND: Our aim was to assess the distribution of primary (with no trigger) and secondary (with a decompensation trigger) heart failure events in a severe heart failure population and their association with 2-year all-cause mortality in the Mitra.Fr study. METHODS: We included 304 patients with symptomatic heart failure, and severe mitral regurgitation and guideline directed medical therapy randomized to medical therapy alone or medical therapy with percutaneous mitral valve repair. According to the follow-up, we defined 3 categories of events: follow-up without any heart failure event, at least 1 decompensation starting with a primary heart failure decompensation or starting with a precipitated secondary heart failure event. The primary outcome was 2-years all-cause mortality. RESULTS: A total of 179 patients (59 %) had at least 1 heart failure decompensation within 24-months of follow-up. 129 heart failure decompensations (72%) were a first primary heart failure and 50 (28%) were a first secondary decompensation. Finally, 30 patients had both types of decompensations but these were not taken into account for the comparison of primary and secondary decompensations. Primary decompensations were 3-times more frequent than secondary decompensations, but the mean number of heart failure decompensations was similar in the "Primary heart failure group" compared to the "Secondary heart failure group": (1.94 ± 1.39 vs 1.80 ± 1.07 respectively; P = .480). Compared to patients without heart failure decompensation, patients with "Only primary decompensation" or with "Only secondary decompensation" had a significantly increased risk of death (HR = 4.87, 95% CI [2.86, 8.32] and 2.68 95%CI [1.64, 4.37] respectively). All-cause mortality, was not significantly different between these 2 type of decompensations (HR = 1.82, 95% CI [0.93, 3.58]; P = .082), but each additional heart failure recurrence was associated with a significant increase in mortality risk (HR = 1.27, 95% CI [1.08; 1.50]; P = .005). CONCLUSIONS: In heart failure with reduced ejection fraction and severe secondary mitral regurgitation patients, primary heart failure decompensations were 3-times more frequent compared to precipitated decompensations with a nonsignificant trend in increased risk of all-cause mortality. Our results fail to support the differentiation between primary and secondary decompensations as they seem to portend the same outcome impact.

Perceptions and satisfaction of patients with chronic heart failure when using a remote monitoring web application named Satelia® Cardio.

INTRODUCTION: The use of telehealth, such as remote patient monitoring (RPM), for chronic heart failure (CHF) impacts patient pathways. Patient-centricity in chronic disease management is valuable. Even though RPM is recommended in practice, the evaluation of patient satisfaction has been limited to date. The objective of this study was to assess the perceptions and satisfaction of patients with CHF when using RPM. METHODS: A voluntary declarative survey was conducted with users of Satelia® Cardio, an RPM web application which was included in an experimental model program in France funded by the ETAPES program initiative sponsored by the French Ministry of Health. Monitoring was based on patient-reported outcomes (seven questions on symptoms, one question on weight) which were answered online (digitally literate patients) or by phone with a nurse (patients with poor digital literacy). The survey included questions on perceived usefulness, ease of use and impact on quality of life (QoL). RESULTS: Overall, 87% of the 825 patients were satisfied with having their CHF digitally monitored. Patients found that the application was easy to use (94%), problem free (95%), provided well-timed notifications (98%), easily accessible (96.5%), understandable (89%), and did not require an unreasonable amount of time to answer questions (99%). Most patients felt that RPM helped physicians provide better care during their follow-ups (70%, mean score: 7.98/10) and 45% of the digitally literate patients indicated an improved QoL. CONCLUSION: Poor digitally literate patients may need human-based or assisted RPM. Patients monitored daily for CHF through RPM expressed strong satisfaction and acceptance.

Deconvolution of BNP and NT-proBNP Immunoreactivities by Mass Spectrometry in Heart Failure and Sacubitril/Valsartan Treatment.

BACKGROUND: Elevated BNP and the N-terminal fragment of the proBNP (NT-proBNP) are hallmarks of heart failure (HF). Generally, both biomarkers parallel each other. In patients receiving sacubitril/valsartan, BNP remained stable while NT-proBNP decreased. As BNP and NT-proBNP assays have limited specificity due to cross-reactivity, we quantified by mass spectrometry (MS) the contributing molecular species. METHODS: We included 356 healthy volunteers, 100 patients with acute dyspnoea (49 acute decompensated HF; 51 dyspnoea of non-cardiac origin), and 73 patients with chronic HF and reduced ejection fraction treated with sacubitril/valsartan. BNP and NT-proBNP immunoreactivities (BNPir and NT-proBNPir) were measured by immunoassays (Abbott ARCHITECT and Roche Diagnostics proBNPII) and proBNP-derived peptides and glycosylation at serine 44 by MS on plasma samples. RESULTS: BNPir corresponded to the sum of proBNP1-108, BNP1-32, BNP3-32, and BNP5-32 (R2 = 0.9995), while NT-proBNPir corresponded to proBNP1-108 and NT-proBNP1-76 not glycosylated at serine 44 (R2 = 0.992). NT-proBNPir was better correlated (R2 = 0.9597) than BNPir (R2 = 0.7643) with proBNP signal peptide (a surrogate of proBNP production). In patients receiving sacubitril/valsartan, non-glycosylated NT-proBNP1-76 remained constant (P = 0.84) despite an increase in NT-proBNP1-76 and its glycosylation (P < 0.0001). ProBNP1-108 remained constant (P = 0.12) while its glycosylation increased (P < 0.0001), resulting in a decrease in non-glycosylated proBNP1-108 (P < 0.0001), and in NT-proBNPir. CONCLUSIONS: Glycosylation interfered with NT-proBNPir measurement, explaining the discrepant evolution of these 2 biomarkers in patients receiving sacubitril/valsartan. Both BNPir and NT-proBNPir are surrogates of proBNP1-108 production, NT-proBNPir being more robust in the clinical contexts studied.

Feasibility and accuracy of linking a heart failure registry to the national claims database using indirect identifiers.

BACKGROUND: Heart failure (HF) registries include rich data on patient inclusion characteristics, but follow-up information is often incomplete. Medicoadministrative databases may provide less clinical information than registries, e.g. on left ventricular ejection fraction (LVEF), but long-term data are exhaustive and reliable. The combination of the two types of database is therefore appealing, but the feasibility and accuracy of such linking are largely unexplored. AIMS: To assess the feasibility and accuracy of linking an HF registry (FRESH; FREnch Survey on Heart Failure) with the French National Healthcare System database (SNDS). METHODS: A probabilistic algorithm was developed to link and match patient data included in the FRESH HF registry with anonymized records from the SNDS, which include: hospitalizations and diagnostic codes; all care-related reimbursements by national health system; and deaths. Consistency was assessed between deaths recorded in the registry and in the SNDS. A comparison between the two databases was carried out on several identifiable clinical characteristics (history of HF hospitalization, diabetes, atrial fibrillation, chronic bronchopneumopathy, severe renal failure and stroke) and on events during 1-year follow-up after inclusion. RESULTS: Of 2719 patients included in the FRESH registry (1049 during decompensation; 1670 during outpatient follow-up), 1885 could be matched with a high accuracy of 94.3% for deaths. Mortality curves were superimposable, including curves according to type of HF and LVEF. The rates of missing data in the FRESH registry were 2.3-8.4% for clinical characteristics and 17.5% for hospitalizations during follow-up. The discrepancy rate for clinical characteristics was 3-13%. Hospitalization rates were significantly higher in the SNDS than in the registry cohort. CONCLUSIONS: The anonymous matching of an HF research cohort with a national health database is feasible, with a significant proportion of patients being accurately matched, and facilitates combination of clinical data and a reduced rate of losses to follow-up.

proANP Metabolism Provides New Insights Into Sacubitril/Valsartan Mode of Action.

BACKGROUND: Sacubitril/valsartan (S/V) treatment is beneficial in patients with heart failure with reduced ejection fraction (HFrEF), but its mode of action remains elusive, although it involves the increase in ANP (atrial natriuretic peptide). METHODS: Combining mass spectrometry and enzymatic assay in the plasma of 73 HFrEF patients treated with S/V and controls, we deciphered proANP processing that converts proANP into 4 vasoactive peptides. RESULTS: We found that proANP processing is sequential and involved meprin B, ECE (endothelin-converting enzyme) 1, and ANPEP (aminopeptidase N). This processing is limited in HFrEF patients via the downregulation of proANP production, corin, and meprin B activities by miR-425 and miR1-3p. S/V restored or compensated proANP processing by downregulating miR-425 and miR1-3p, hence increasing levels of proANP-derived bioactive peptides. In contrast, S/V directly and indirectly partially inhibited ECE1 and ANPEP. ECE1 partial inhibition resulted in a lower-than-expected increase in ET1 (endothelin 1), tilting the vasoactive balance toward vasodilation, and possibly hypotension. Furthermore, proANP glycosylation interferes with the midregional proANP assay -a clinical surrogate for proANP production, preventing any pathophysiological interpretation of the results. The analysis of S/V dose escalation with respect to baseline treatments suggests S/V-specific effects. CONCLUSIONS: These findings offer mechanistic evidence to the natriuretic peptide -defective state in HFrEF, which is improved by S/V. These data also strongly suggests that S/V increases plasma ANP by multiple mechanisms that involve 2 microRNAs, besides its protection from NEP (neprilysin) cleavage. Altogether, these data provide new insights on HFrEF pathophysiology and the mode of action of S/V.

Glycaemic Variability and Hyperglycaemia as Prognostic Markers of Major Cardiovascular Events in Diabetic Patients Hospitalised in Cardiology Intensive Care Unit for Acute Heart Failure.

(1) Background: Hyperglycaemia and hypoglycaemia are both emerging risk factors for cardiovascular disease. Nevertheless, the potential effect of glycaemic variability (GV) on mid-term major cardiovascular events (MACE) in diabetic patients presenting with acute heart failure (AHF) remains unclear. This study investigates the prognostic value of GV in diabetic patients presenting with acute heart failure (AHF). (2) Methods: this was an observational study including consecutive patients with diabetes and AHF between January 2015 and November 2016. GV was calculated using standard deviation of glycaemia values during initial hospitalisation in the intensive cardiac care unit. MACE, including recurrent AHF, new-onset myocardial infarction, ischaemic stroke and cardiac death, were recorded. The predictive effects of GV on patient outcomes were analysed with respect to baseline characteristics and cardiac status. (3) Results: In total, 392 patients with diabetes and AHF were enrolled. During follow-up (median (interquartile range) 29 (6−51) months), MACE occurred in 227 patients (57.9%). In total, 92 patients died of cardiac causes (23.5%), 107 were hospitalised for heart failure (27.3%), 19 had new-onset myocardial infarction (4.8%) and 9 (2.3%) had an ischaemic stroke. Multivariable logistic regression analysis showed that GV > 50 mg/dL (2.70 mmol/L), age > 75 years, reduced left ventricular ejection fraction (LVEF < 30%) and female gender were independent predictors of MACE: hazard ratios (HR) of 3.16 (2.25−4.43; p < 0.001), 1.54 (1.14−2.08; p = 0.005), 1.47 (1.06−2.07; p = 0.02) and 1.43 (1.05−1.94; p = 0.03), respectively. (4) Conclusions: among other well-known factors of HF, a GV cut-off value of >50 mg/dL was the strongest independent predictive factor for mid-term MACE in patients with diabetes and AHF.

Iron deficiency in heart failure patients: the French CARENFER prospective study.

AIMS: Iron deficiency (ID) is reported as one of the main co-morbidities in patients with chronic heart failure (CHF), which then influences quality of life and prognosis. The CARENFER study aimed to assess the prevalence of ID in a large panel of heart failure (HF) patients at different stages of the disease. METHODS AND RESULTS: This prospective cross-sectional nationwide study was conducted in 48 medical units in France in 2019. Serum ferritin concentration and transferrin saturation (TSAT) index were determined in all eligible patients with a diagnosis of HF. ID diagnosis was based on the European Society of Cardiology (ESC) 2016 guidelines. Patients were classified as having either a decompensated HF or a CHF. Left ventricular ejection fraction (LVEF) was categorized as preserved (≥50%), mildly reduced (40-49%), or reduced (<40%). ID diagnosis was determined in 1661 patients, of whom 1475 could be classified as having a decompensated HF or a CHF. Patients' median age was 78 years. Decompensated HF represented 60.1% of cases. The overall prevalence of ID was 49.6% (47.1-52.1). In CHF and decompensated HF patients, respectively, ID prevalence was 39.0% (35.1-43.1) and 58.1% (54.7-61.4), P < 0.001; TSAT < 20% was respectively reported in 34.7% and 70.0% of patients (P < 0.001). Patients with preserved LVEF were more likely to have an ID (57.5%) compared with patients with mildly reduced (47.4%) or reduced LVEF (44.3%) (P < 0.001). CONCLUSIONS: Iron deficiency was highly prevalent in patients with decompensated HF or CHF with preserved LVEF. ID prevalence defined by TSAT was higher than by the ESC criteria in decompensated HF patients, questioning the importance of ID definition to assess its prevalence.

External validation of a refined four-stratum risk assessment score from the French pulmonary hypertension registry.

INTRODUCTION: Contemporary risk assessment tools categorise patients with pulmonary arterial hypertension (PAH) as low, intermediate or high risk. A minority of patients achieve low risk status with most remaining intermediate risk. Our aim was to validate a four-stratum risk assessment approach categorising patients as low, intermediate-low, intermediate-high or high risk, as proposed by the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) investigators. METHODS: We evaluated incident patients from the French PAH Registry and applied a four-stratum risk method at baseline and at first reassessment. We applied refined cut-points for three variables: World Health Organization functional class, 6-min walk distance and N-terminal pro-brain natriuretic peptide. We used Kaplan-Meier survival analyses and Cox proportional hazards regression to assess survival according to three-stratum and four-stratum risk approaches. RESULTS: At baseline (n=2879), the four-stratum approach identified four distinct risk groups and performed slightly better than a three-stratum method for predicting mortality. Four-stratum model discrimination was significantly higher than the three-stratum method when applied during follow-up and refined risk categories among subgroups with idiopathic PAH, connective tissue disease-associated PAH, congenital heart disease and portopulmonary hypertension. Using the four-stratum approach, 53% of patients changed risk category from baseline compared to 39% of patients when applying the three-stratum approach. Those who achieved or maintained a low risk status had the best survival, whereas there were more nuanced differences in survival for patients who were intermediate-low and intermediate-high risk. CONCLUSIONS: The four-stratum risk assessment method refined risk prediction, especially within the intermediate risk category of patients, performed better at predicting survival and was more sensitive to change than the three-stratum approach.

Sacubitril-valsartan initiation in chronic heart failure patients impacts sleep apnea: the ENTRESTO-SAS study.

AIMS: Optimizing medical cardiac treatment for sleep apnoea (SA) in patients with chronic heart failure and reduced ejection fraction (HFrEF) is an expert Grade C recommendation based on six studies encompassing a total of 67 patients only. Whether sacubitril-valsartan (SV), a cornerstone of HFrEF medical treatment, impacts SA is unknown and requires evaluation. METHODS AND RESULTS: The ENTRESTO-SAS trial is a six-centre, prospective, open-label real-life cohort study (NCT02916160). Ambulatory patients eligible for SV (i.e. HFrEF adults who remain symptomatic despite optimal treatment) were evaluated before and after 3 months of SV (including nocturnal ventilatory polygraphy); 118 patients were final analysed [median age was 66 (IQ25-75 : 56-73) years, 81.4% male, 36.5% New York Heart Association III-IV, N-terminal pro-B-type natriuretic peptide level of 1564 (701-3376) ng/L, left ventricular ejection fraction of 30 (25-34)%, 60.7% ischaemic HFrEF, 97.5% initially treated with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, 83.9% with beta-blockers, 64.4% with mineralocorticoid receptor antagonists, and 74.6% with diuretics]. Three groups were defined according to initial central/obstructive apnoea-hypopnoea indices (AHIs): G1 (n = 49, AHIcentral  ≥ 5/h and AHIobstructive  < 15/h); G2 (n = 27, AHIobstructive  ≥ 15/h); and G3 (n = 42, AHIcentral  < 5/h and AHIobstructive  < 15/h). At 3 months, the AHI (main predefined outcome) decreased significantly by -7.10/h (IQ25-75 : -16.10 to 0.40; P < 0.001) in G1 + G2 without positive airway pressure treatment (45 patients, median initial AHI of 24.20 (IQ25-75 : 16.40-43.50)/h). Of these, 24.4% presented an AHI decrease ≥50% and 37.78% had a final AHI < 15/h (tendency for improvement from an initial value of 20%: P = 0.0574). For G1 patients (n = 37), AHI significantly decreased from a median of 22.90 (16.00-43.50)/h to 19.20 (12.70-31.10)/h (P = 0.002). For G2 patients (n = 8), AHI decreased from a median of 30.10 (26.40-47.60)/h to 22.75 (14.60-36.90)/h (statistically non-significant, P = 0.059). CONCLUSIONS: In this real-life population, SV treatment for 3 months in SA patients is associated with a significant decrease in AHI. These results support the current guidelines that recommend first an optimization of the HFrEF treatment in patients with HFrEF and central SA. A potential positive airway pressure sparing effect merits further investigation.

Association between Initial Treatment Strategy and Long-Term Survival in Pulmonary Arterial Hypertension.

Rationale: The relationship between the initial treatment strategy and survival in pulmonary arterial hypertension (PAH) remains uncertain. Objectives: To evaluate the long-term survival of patients with PAH categorized according to the initial treatment strategy. Methods: A retrospective analysis of incident patients with idiopathic, heritable, or anorexigen-induced PAH enrolled in the French Pulmonary Hypertension Registry (January 2006 to December 2018) was conducted. Survival was assessed according to the initial strategy: monotherapy, dual therapy, or triple-combination therapy (two oral medications and a parenteral prostacyclin). Measurements and Main Results: Among 1,611 enrolled patients, 984 were initiated on monotherapy, 551 were initiated on dual therapy, and 76 were initiated on triple therapy. The triple-combination group was younger and had fewer comorbidities but had a higher mortality risk. The survival rate was higher with the use of triple therapy (91% at 5 yr) as compared with dual therapy or monotherapy (both 61% at 5 yr) (P < 0.001). Propensity score matching of age, sex, and pulmonary vascular resistance also showed significant differences between triple therapy and dual therapy (10-yr survival, 85% vs. 65%). In high-risk patients (n = 243), the survival rate was higher with triple therapy than with monotherapy or dual therapy, whereas there was no difference between monotherapy and double therapy. In intermediate-risk patients (n = 1,134), survival improved with an increasing number of therapies. In multivariable Cox regression, triple therapy was independently associated with a lower risk of death (hazard ratio, 0.29; 95% confidence interval, 0.11-0.80; P = 0.017). Among the 148 patients initiated on a parenteral prostacyclin, those on triple therapy had a higher survival rate than those on monotherapy or dual therapy. Conclusions: Initial triple-combination therapy that includes parenteral prostacyclin seems to be associated with a higher survival rate in PAH, particularly in the youngest high-risk patients.

Outcomes of patients with decreased arterial oxyhaemoglobin saturation on pulmonary arterial hypertension drugs.

BACKGROUND: Drugs approved for the treatment of pulmonary arterial hypertension (PAH) improve long-term outcomes. These drugs have pulmonary vasodilator properties which may potentially cause a decrease in arterial oxyhaemoglobin saturation (S aO2 ) in some patients. The present retrospective study of the French Pulmonary Hypertension Registry aimed to describe the clinical characteristics and outcomes of patients showing a ≥3% decrease in S aO2 while treated with PAH drugs. METHODS: We reviewed 719 PAH patients. The exclusion criteria were PAH associated with congenital heart disease and PAH with overt features of venous/capillaries involvement. RESULTS: 173 (24%) patients had a ≥3% decrease in S aO2 . At diagnosis, they were older with a lower diffusing capacity of the lung for carbon monoxide and a shorter 6-min walk distance compared with those who did not display a ≥3% decrease in S aO2 . The percentage of patients meeting the European Society of Cardiology/European Respiratory Society (ESC/ERS) low-risk criteria at re-evaluation was significantly lower in those with a ≥3% decrease in S aO2 and more patients started long-term oxygen therapy in this group (16% versus 5%; p<0.001). A ≥3% decrease in S aO2 was associated with a poorer survival (hazard ratio 1.81, 95% CI 1.43-2.34; p<0.0001). In a multivariate Cox analysis, a ≥3% decrease in S aO2 was a prognostic factor independent of age at diagnosis and ESC/ERS risk stratification at follow-up. CONCLUSIONS: When treated with PAH drugs, a large subset of patients experience a ≥3% decrease in S aO2 , which is associated with worse long-term outcomes and reduced survival.

Clinical profile and midterm prognosis of left ventricular thrombus in heart failure.

AIMS: We documented the midterm prognosis of left ventricular thrombus (LVT) in heart failure (HF) patients with dilated cardiomyopathy (DCM) and ischaemic cardiomyopathy (ICM). We aimed to characterize patients with LVT in the context of HF with reduced (≤40%) left ventricular ejection fraction and evaluate their risk for death and/or embolic events, overall, and specifically in patients with ischaemic or non-ischaemic aetiology. We also intended to identify risk factors for LVT in patients with DCM. METHODS AND RESULTS: We included all HF patients (N = 105, age 56 ± 13) admitted from 2005 to 2018 in our institution for LVT without significant valve disease/prosthesis, heart transplant/left ventricular assist device, congenital heart disease, or acute myocardial infarction. Our primary endpoint was the 1 year risk of the composite of all-cause mortality (ACM) and symptomatic embolic events. Mean left ventricular ejection fraction was 23 ± 9%, and median BNP was 1795 pg/mL. Most (97%) patients were treated with vitamin K anticoagulants, and 64% had ICM. Symptomatic embolic events and/or ACM occurred in 20% of the population [embolic events (all within 30 days of LVT diagnosis) 15% and ACM 6%] and was similarly frequent in DCM or ICM (P > 0.05). Suspected/transient embolic events were more frequent in DCM (overall 13%; 29% in DCM vs. 5% in ICM, P < 0.01). Major bleeding occurred in 5% of patients. Left ventricular reverse remodelling occurred in 65% of patients, more frequently in DCM (86% in DCM vs. 65% in ICM, P = 0.02). In a case-control analysis matching DCM patients, BNP level was the only factor significantly associated with LVT (2447 pg/mL in LVT vs. 347 pg/mL, P < 0.001). CONCLUSIONS: Patients with LVT have markedly high natriuretic peptides and experience a 20% 1 year risk for embolic events and/or death following diagnosis despite anticoagulant treatment. Most patients have favourable remodelling/recovery. As all symptomatic embolic events occurred within 30 days of LVT diagnosis, a very careful initial management is warranted.