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Abstract Aims Heart failure (HF) with preserved ejection fraction (HFpEF) is associated with cardiovascular (CV) and non‐CV events, but long‐term risk is poorly studied. We assessed incidence and predictors of the long‐term CV and non‐CV events. Methods and results Patients presenting with acute HF, EF ≥ 45%, and N‐terminal pro‐brain natriuretic peptide > 300 ng/L were enrolled in the Karolinska‐Rennes study in 2007–11 and were reassessed after 4–8 weeks in a stable state. Long‐term follow‐up was conducted in 2018. The Fine–Gray sub‐distribution hazard regression was used to detect predictors of CV and non‐CV deaths, investigated separately from baseline acute presentation (demographic data only) and from the 4–8 week outpatient visit (including echocardiographic data). Of 539 patients enrolled [median age 78 (interquartile range: 72–84) years; 52% female], 397 patients were available for the long‐term follow‐up. Over a median follow‐up time from acute presentation of 5.4 (2.1–7.9) years, 269 (68%) patients died, 128 (47%) from CV and 120 (45%) from non‐CV causes. Incidence rates per 1000 patient‐years were 62 [95% confidence interval (CI) 52–74] for CV and 58 (95% CI 48–69) for non‐CV death. Higher age and coronary artery disease (CAD) were independent predictors of CV death, and anaemia, stroke, kidney disease, and lower body mass index (BMI) and sodium concentrations of non‐CV death. From the stable 4–8 week visit, anaemia, CAD, and tricuspid regurgitation (>3.1 m/s) were independent predictors of CV death, and higher age of non‐CV death. Conclusions In patients with acute decompensated HFpEF, over 5 years of follow‐up, nearly two‐thirds of patients died, half from CV and the other half from non‐CV causes. CAD and tricuspid regurgitation were associated with CV death. Stroke, kidney disease, lower BMI, and lower sodium were associated with non‐CV death. Anaemia and higher age were associated with both outcomes. [Correction added on 24 March 2023, after first online publication: In the first sentence of the Conclusions, ‘two‐thirds’ has been inserted before ‘of patients died...’ in this version.]

Abstract Aims Functional tricuspid regurgitation (TR) is a turning point in cardiac diseases. Symptoms typically appear late. The optimal timing for proposing a valve repair remains a challenge. We sought to analyse the characteristics of right heart remodelling in patients with significant functional TR to identify the parameters that could be used in a simple prognostic model predicting clinical events. Methods and results We designed a prospective observational French multicentre study including 160 patients with significant functional TR (effective regurgitant orifice area > 30 mm2) and left ventricular ejection fraction > 40%. Clinical, echocardiographic, and electrocardiogram data were collected at baseline and at the 1 and 2 year follow‐up. The primary outcome was all‐cause death or hospitalization for heart failure. At 2 years, 56 patients (35%) achieved the primary outcome. The subset with events showed more advanced right heart remodelling at baseline, but similar TR severity. Right atrial volume index (RAVI) and the tricuspid annular plane systolic excursion to systolic pulmonary arterial pressure (TAPSE/sPAP) ratio, reflecting right ventricular–pulmonary arterial coupling, were 73 mL/m2 and 0.40 vs. 64.7 mL/m2 and 0.50 in the event vs. event‐free groups, respectively (both P 0.4 (odds ratio = 0.41, 95% confidence limit 0.2 to 0.82) and RAVI > 60 mL/m2 (odds ratio = 2.13, 95% confidence limit 0.96 to 4.75), providing a clinically valid prognostic evaluation. Conclusions RAVI and TAPSE/sPAP are relevant for predicting the risk for event at 2 year follow‐up in patients with an isolated functional TR.

Abstract Aims In the heart failure (HF) with preserved ejection fraction (HFpEF) PARAGON‐HF trial, sacubitril/valsartan vs. valsartan improved mortality/morbidity in patients with left ventricular ejection fraction (LVEF) below median (57%). We assessed eligibility for sacubitril/valsartan based on four scenarios. Methods and results Eligibility was assessed in the Karolinska‐Rennes study (acute HFpEF, LVEF ≥ 45%, and N‐terminal pro‐B‐type natriuretic peptide ≥300 pg/mL subsequently assessed as outpatients including echocardiography) in (i) a trial scenario (all trial criteria); (ii) a pragmatic scenario (selected trial criteria); (iii) LVEF below lower limit of normal range (

Abstract Aims Heart failure (HF) with preserved ejection fraction (HFpEF) has poor long‐term prognosis. We assessed rates and predictors of outcome 10 years after an acute episode of HF. Methods and results The Karolinska‐Rennes (KaRen) study enrolled HFpEF patients with acute HF, ejection fraction ≥ 45%, and N‐terminal pro‐brain natriuretic peptide > 300 ng/L in 2007–11. Clinical data were collected at enrolment and after 4–8 weeks including detailed echocardiography. Follow‐up data were collected 10 years after study initiation, starting from 6 months after enrolment until 2018 assessed by telephone. Independent predictors of primary (all‐cause mortality or HF hospitalization) and secondary (all‐cause mortality) outcomes were assessed by multivariable Cox regression. Of 539 patients, long‐term follow‐up data were available for 397 patients [52% female; median (interquartile range) age 79 (73, 84) years]. Over a follow‐up of 5.44 (2.06–7.89) years, 1, 3, 5, and 10 year mortality rates were 15%, 31%, 47%, and 74%, respectively, with an incidence rate of 130/1000 patient‐years. The primary outcome was met in 84% of the population, with an incidence rate of 227/1000 patient‐years. The independent predictors of the primary outcome were tricuspid regurgitation peak velocity (m/s) [hazard ratio 1.87 (1.34–2.62)], diabetes mellitus [1.75 (1.11–2.74)], and cancer [1.75 (1.01–3.03)] while female sex was associated with reduced risk [0.64 (0.41–0.98)]. Conclusions In HFpEF, 1, 3, 5, and 10 year mortality was 15%, 31%, 47%, and 74% and mortality or first HF hospitalization was 35%, 54%, 67%, and 84%, respectively. Independent predictors of mortality or HF hospitalization were tricuspid regurgitation peak velocity, diabetes mellitus, cancer, and male sex. In clinical management of HFpEF, attention should be paid to both cardiac and non‐cardiac conditions.

Abstract Aims Studies have demonstrated the reliability of B‐lines evaluated by lung ultrasonography to identify pulmonary congestion, but information is lacking about its utility as a prognostic marker of heart failure (HF). We sought to assess the prognostic midterm value of B‐lines in ambulatory patients presenting with dyspnoea, as an additive tool for patient management and to avoid acute HF exacerbations. Methods and results A total of 93 patients presenting with dyspnoea (New York Heart Association ≥2) were prospectively recruited in an outpatient clinic, and underwent clinical and echocardiographic evaluation, as well as B‐line evaluation with lung ultrasonography in eight zones. Primary endpoint was HF hospitalization at 1 year. A total of 88 patients were included, age 72.3 ± 9.6, with left ventricular ejection 47.7 ± 28.6%; E/e' 16.9 ± 10.9, left atrial volume 51.9 ± 22.5 mL/m2; peak tricuspid regurgitation velocity 2.6 ± 0.5 m/s, average B‐line count 7.7 ± 10. 8 (9%) patients were hospitalized for HF, seven of which had ≥6 B‐lines. B‐line cut‐off ≥6 (specificity = 66.2%; sensitivity = 87.5%) was predictive for HF hospitalization, with an odds ratio at 13.7 for HF hospitalization at 1 year [IC95% (1.6–117.4), P = 0.017]. Conclusions Ambulatory patients with ≥6 B‐lines have a higher risk of HF hospitalization at 1 year. This study highlights the prognostic value of B‐lines in evaluating HF risk in dyspnoeic patients.

Abstract Aims Echocardiographic predictors of outcomes in heart failure with preserved ejection fraction (HFpEF) have not been systematically or independently validated. We aimed at identifying echocardiographic predictors of cardiovascular events in a large cohort of patients with HFpEF and to validate these in an independent large cohort. Methods and results We assessed the association between echocardiographic parameters and cardiovascular outcomes in 515 patients with heart failure with preserved left ventricular (LV) ejection fraction (>50%) in the MEtabolic Road to DIAstolic Heart Failure (MEDIA) multicentre study. We validated out findings in 286 patients from the Karolinska‐Rennes Prospective Study of HFpEF (KaRen). After multiple adjustments including N‐terminal pro‐brain natriuretic peptide (NT‐proBNP), the significant predictors of death or cardiovascular hospitalization were pulmonary arterial systolic pressure > 40 mmHg, respiratory variation in inferior vena cava diameter > 0.5, E/e' > 9, and lateral mitral annular s' 35% 1 year risk. Adding these four echocardiographic variables on top of clinical variables and NT‐proBNP yielded significant net reclassification improvement (33.8%, P

Abstract Aims In heart failure (HF) with preserved ejection fraction (HFpEF), microvascular inflammation is proposed as an underlying mechanism. Myeloperoxidase (MPO) is associated with vascular dysfunction and prognosis in congestive HF. Methods and results MPO, MPO‐related biomarkers, and echocardiography were assessed in 86 patients, 4–8 weeks after presentation with acute HF (EF ≥ 45%), and in 46 healthy controls. Patients were followed up for median 579 days (Q1;Q3 276;1178) regarding the composite endpoint all‐cause mortality or HF hospitalization. Patients were 73 years old, 51% were female, EF was 64% (Q1;Q3 58;68), E/e′ was ratio 10.8 (8.3;14.0), and left atrial volume index (LAVI) was 43 mL/m2 (38;52). Controls were 60 (57;62) years old (vs. patients; P 14, uric acid and SDMA were elevated (421 vs. 344 μM, P = 0.012; 0.54 vs. 0.47 μM, P = 0.039, respectively), and MPO was 121 vs. 98 ng/mL (P = 0.090). The ratios of arginine/ADMA (112 vs. 162; P

Abstract Aims Neuregulin1‐β (NRG1‐β) is released from microvascular endothelial cells in response to inflammation with compensatory cardioprotective effects. Circulating NRG1‐β is elevated in heart failure (HF) with reduced ejection fraction (HFrEF) but not studied in HF with preserved EF (HFpEF). Methods and results Circulating NRG1‐β was quantified in 86 stable patients with HFpEF (EF ≥45% and N‐terminal pro‐brain natriuretic peptide >300 ng/L), in 86 patients with HFrEF prior to and after left ventricular assist device (LVAD) and/or heart transplantation (HTx) and in 21 healthy controls. Association between NRG1‐β and the composite outcome of all‐cause mortality/HF hospitalization in HFpEF and all‐cause mortality/HTx/LVAD implantation in HFrEF with and without ischaemia assessed as macrovascular coronary artery disease was assessed. In HFpEF, median (25th–75th percentile) NRG1‐β was 6.5 (2.1–11.3) ng/mL; in HFrEF, 3.6 (2.1–7.6) ng/mL (P = 0.035); after LVAD, 1.7 (0.9–3.6) ng/mL; after HTx 2.1 (1.4–3.6) ng/mL (overall P < 0.001); and in controls, 29.0 (23.1–34.3) ng/mL (P = 0.001). In HFrEF, higher NRG1‐β was associated with worse outcomes (hazard ratio per log increase 1.45, 95% confidence interval 1.04–2.03, P = 0.029), regardless of ischaemia. In HFpEF, the association of NRG1‐β with outcomes was modified by ischaemia (log‐rank P = 0.020; Pinteraction = 0.553) such that only in ischaemic patients, higher NRG1‐β was related to worse outcomes. In contrast, in patients without ischaemia, higher NRG1‐β trended towards better outcomes (hazard ratio 0.71, 95% confidence interval 0.48–1.05, P = 0.085). Conclusions Neuregulin1‐β was reduced in HFpEF and further reduced in HFrEF. The opposing relationships of NRG1‐β with outcomes in non‐ischaemic HFpEF compared with HFrEF and ischaemic HFpEF may indicate compensatory increases of cardioprotective NRG1‐β from microvascular endothelial dysfunction in the former (non‐ischaemic HFpEF), but this compensatory mechanism is overwhelmed by the presence of ischaemia in the latter (HFrEF and ischaemic HFpEF).

Abstract Aims This study aims to assess prognostic impact of Framingham criteria for heart failure (FC‐HF) in patients with stable heart failure (HF) with preserved ejection fraction (HFpEF). Methods and results In the prospective Karolinska‐Rennes (KaRen) study, we assessed stable HFpEF patients after an acute HF episode. We evaluated associations between the four descriptive models of HFpEF and the composite endpoint of all‐cause mortality and HF hospitalization. The descriptive models were FC‐HF alone, FC‐HF + natriuretic peptides (NPs) according to the PARAGON trial, FC‐HF + NPs + echocardiographic HFpEF criteria according to European Society of Cardiology HF guidelines, and FC‐HF + NPs + echocardiographic criteria according to the PARAGON trial. Out of the 539 patients enrolled in KaRen, 438 returned for the stable state revisit after 4–8 weeks, 13 (2.4%) patients died before the planned follow‐up, and 88 patients (16%) declined or were unable to return. Three hundred ninety‐nine patients have FC registered at follow‐up, and among these, the four descriptive models were met in 107 (27%), 82 (22%), 61 (21%), and 69 (22%) patients, and not met in 292 (73%). The 107 patients that had FC‐HF at stable state (descriptive model 1) could also be part of the other models because all patients in models 1–4 had to fulfil the FC‐HF. The patients in model 0 did not fulfil the criteria for FC‐HF but could have single FC. Of single FC, only pleural effusion predicted the endpoint [hazard ratio (HR) 3.38, 95% confidence interval (CI) 1.47–7.76, P = 0.004]. Patients without FC‐HF had better prognosis than patients meeting FC‐HF. The unadjusted associations between the four HFpEF descriptive models and the endpoint were HR 1.54, 95% CI 1.14–2.09, P = 0.005; HR 1.71, 95% CI 1.24–2.36, P = 0.002; HR 1.95, 95% CI 1.36–2.81, P = 0.001; and HR 2.05, 95% CI 1.45–2.91, P