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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 FROM AUTHOR]

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 FROM AUTHOR]

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 < 0.001), 24% were female (P = 0.005), and left ventricular EF was 63% (59;66; P = 0.790). MPO was increased in HFpEF compared with controls, 101 (81;132) vs. 86 (74;101 ng/mL, P = 0.015), as was uric acid 369 (314;439) vs. 289 (252;328 μmol/L, P < 0.001), calprotectin, asymmetric dimethyl arginine (ADMA), and symmetric dimethyl arginine (SDMA), while arginine was decreased. MPO correlated with uric acid (r = 0.26; P = 0.016). In patients with E/e′ > 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 < 0.001) and ADMA/SDMA (1.36 vs. 1.17; P = 0.002) were decreased in HFpEF patients, suggesting reduced NO availability and increased enzymatic clearance of ADMA, respectively. Uric acid independently predicted the endpoint [hazard ratio (HR) 3.76 (95% CI 1.19–11.85; P = 0.024)] but not MPO [HR 1.48 (95% CI 0.70–3.14; P = 0.304)] or the other biomarkers. Conclusions: In HFpEF, MPO‐dependent oxidative stress reflected by uric acid and calprotectin is increased, and SDMA is associated with diastolic dysfunction and uric acid with outcome. This suggests microvascular neutrophil involvement mirroring endothelial dysfunction, a central component of the HFpEF syndrome and a potential treatment target. [ABSTRACT FROM AUTHOR]

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 < 0.001, for descriptive models 1–4, respectively. No descriptive model independently predicted the endpoint. Conclusions: In ambulatory HFpEF patients, a quarter met FC‐HF, while most met NP and echocardiography criteria for HF. Residual FC‐HF tended to be associated with increased risk for mortality and HF hospitalization, further strengthened by NPs and echocardiographic criteria, highlighting its role in clinical risk assessment. [ABSTRACT FROM AUTHOR]

Background—Underlying mechanisms in heart failure (HF) with preserved ejection fraction remain unknown. We investigated cardiovascular plasma biomarkers in HF with preserved ejection fraction and their correlation to diastolic dysfunction, functional class, pathophysiological processes, and prognosis. Methods and Results—In 86 stable patients with HF and EF ≥45% in the Karolinska Rennes (KaRen) biomarker substudy, biomarkers were quantified by a multiplex immunoassay. Orthogonal projection to latent structures by partial least square analysis was performed on 87 biomarkers and 240 clinical variables, ranking biomarkers associated with New York Heart Association (NYHA) Functional class and the composite outcome (all-cause mortality and HF hospitalization). Biomarkers significantly correlated with outcome were analyzed by multivariable Cox regression and correlations with echocardiographic measurements performed. The orthogonal partial least square outcome-predicting biomarker pattern was run against the Ingenuity Pathway Analysis (IPA) database, containing annotated data from the public domain. The orthogonal partial least square analyses identified 32 biomarkers correlated with NYHA class and 28 predicting outcomes. Among outcome-predicting biomarkers, growth/differentiation factor-15 was the strongest and an additional 7 were also significant in Cox regression analyses when adjusted for age, sex, and N-terminal probrain natriuretic peptide: adrenomedullin (hazard ratio per log increase 2.53), agouti-related protein; (1.48), chitinase-3–like protein 1 (1.35), C–C motif chemokine 20 (1.35), fatty acid–binding protein (1.33), tumor necrosis factor receptor 1 (2.29), and TNF-related apoptosis-inducing ligand (0.34). Twenty-three of them correlated with diastolic dysfunction (E/e′) and 5 with left atrial volume index. The IPA suggested that increased inflammation, immune activation with decreased necrosis and apoptosis preceded poor outcome. Conclusions—In HF with preserved ejection fraction, novel biomarkers of inflammation predict HF severity and prognosis that may complement or even outperform traditional markers, such as N-terminal probrain natriuretic peptide. These findings lend support to a hypothesis implicating global systemic inflammation in HF with preserved ejection fraction. [ABSTRACT FROM AUTHOR]

Aims Limited data are available on long-term prognosis or causes-of-death analysis among survivors of acute myocardial infarction (MI) according to whether or not they developed ventricular fibrillation (VF) during the acute stage of MI. Methods and results Among 3670 MI patients hospitalized in France in 2005 and enrolled in this prospective follow-up cohort study, we assessed in-hospital mortality and 5-year cause of death among those who survived to hospital discharge, according to whether they developed VF (116 cases) or not, during the acute stage. 94.5% of patients had complete follow-up at 5 years. In-hospital mortality was significantly higher among VF patients (adjusted OR 7.38, 95% CI 4.27–12.75, P < 0.001). Among 3463 survivors at hospital discharge, 1024 died during a mean follow-up of 52 ± 2 months. The overall survival rate at 5 years was 74.4% (95% CI 72.8–76.0). In Cox multivariate analysis, occurrence of VF during the acute phase of MI was not associated with an increased mortality at 5 years (HR 0.78, 95% CI 0.38–1.58, P = 0.21). The distribution of causes of death at 5 years did not statistically differ according to the presence or absence of VF, especially for sudden cardiac death (13.1% in VF group vs.12.9% in non-VF group), despite a very low rate of implantation of cardioverter defibrillator in both groups (Overall rate 1.2%). Conclusion Patients developing VF in the setting of acute MI are at higher risk of in-hospital mortality. However, VF is not associated with a higher long-term all-cause or sudden cardiac death mortality. [ABSTRACT FROM PUBLISHER]

Abstract: Background: Determining a specific death cause may facilitate individualized therapy in patients with heart failure (HF). Cardiac resynchronization therapy (CRT) decreased mortality in the Cardiac Resynchronization in Heart Failure trial by reducing pump failure and sudden cardiac death (SCD). This study analyzes predictors of specific causes of death. Methods and Results: Univariate and multivariate analyses used 8 baseline and 3-month post-randomization variables to predict pump failure and SCD (categorized as “definite,” “probable,” and “possible”). Of 255 deaths, 197 were cardiovascular. There were 71 SCDs with a risk reduction by CRT of 0.47 (95% confidence interval 0.29–0.76; P = .002) with similar reductions in SCD classified as definite, probable, and possible. Univariate SCD predictors were 3-month HF status (mitral regurgitation [MR] severity, plasma brain natriuretic peptide [BNP], end-diastolic volume, and systolic blood pressure), whereas randomization to CRT decreased risk. Multivariate SCD predictors were randomization to CRT 0.56 (0.53–0.96, P = .035) and 3-month MR severity 1.82 (1.77–2.60, P = .0012). Univariate pump failure death predictors related to baseline HF state (quality of life score, interventricular mechanical delay, end-diastolic volume, plasma BNP, MR severity, and systolic pressure), whereas randomization to CRT and nonischemic cardiomyopathy decreased risk; multivariate predictors of pump failure death were baseline plasma BNP and systolic pressure and randomization to CRT. Conclusion: CRT decreased SCD in patients with systolic HF and ventricular dyssynchrony. SCD risk was increased with increased severity of MR (including the 3-month value for MR as a time-dependent covariate) and reduced by randomization to CRT. HF death was increased related to the level of systolic blood pressure, log BNP, and randomization to CRT. These results emphasize the importance and interdependence of HF severity to mortality from pump failure and SCD. [Copyright &y& Elsevier]

Background: Cardiac resynchronization reduces symptoms and improves left ventricular function in many patients with heart failure due to left ventricular systolic dysfunction and cardiac dyssynchrony. We evaluated its effects on morbidity and mortality. Methods: Patients with New York Heart Association class III or IV heart failure due to left ventricular systolic dysfunction and cardiac dyssynchrony who were receiving standard pharmacologic therapy were randomly assigned to receive medical therapy alone or with cardiac resynchronization. The primary end point was the time to death from any cause or an unplanned hospitalization for a major cardiovascular event. The principal secondary end point was death from any cause. Results: A total of 813 patients were enrolled and followed for a mean of 29.4 months. The primary end point was reached by 159 patients in the cardiac-resynchronization group, as compared with 224 patients in the medical-therapy group (39 percent vs. 55 percent; hazard ratio, 0.63; 95 percent confidence interval, 0.51 to 0.77; P<0.001). There were 82 deaths in the cardiac-resynchronization group, as compared with 120 in the medical-therapy group (20 percent vs. 30 percent; hazard ratio 0.64; 95 percent confidence interval, 0.48 to 0.85; P<0.002). As compared with medical therapy, cardiac resynchronization reduced the interventricular mechanical delay, the end-systolic volume index, and the area of the mitral regurgitant jet; increased the left ventricular ejection fraction; and improved symptoms and the quality of life (P<0.01 for all comparisons). Conclusions: In patients with heart failure and cardiac dyssynchrony, cardiac resynchronization improves symptoms and the quality of life and reduces complications and the risk of death. These benefits are in addition to those afforded by standard pharmacologic therapy. The implantation of a cardiac-resynchronization device should routinely be considered in such patients. N Engl J Med 2005;352:1539-49. [ABSTRACT FROM AUTHOR]

Abstract Aims To study prevalence and prognostic importance of diagnostic echocardiographic variables in patients with suspected heart failure with preserved ejection fraction (HFpEF) in the prospective KaRen register study. Methods and results KaRen patients were included following an acute HF-presentation, using Framingham criteria, B-type natriuretic peptide (BNP) >100 ng/L or N-terminal pro-BNP (NT-pro-BNP) >300 ng/L, and left ventricular (LV) ejection fraction ≥45%. Echocardiography was performed after 4–8 weeks and analyzed at a core laboratory. In this substudy HFpEF was diagnosed according to the ESC guidelines for heart failure 2016. A total of 539 patients were included with a follow-up after 4–8 weeks in 438 patients. Complete echocardiography and ECG were available in 356 patients. At least two abnormal echocardiographic criteria for HFpEF were found in 94% (n = 333). Echocardiographic signs of structural heart disease and diastolic dysfunction according to 4 criteria by ESC were found in 76% (n = 270). Diastolic dysfunction was graded as mild in 30% (n = 107), moderate in 27% (n = 97) or severe in 35% (n = 124). After multivariate analyses with adjustment for age, gender, EF and natriuretic peptides we found two independent predictors of worse prognosis: presence of moderate and severe diastolic dysfunction (HR 1.8, CI 1.2–2.7, p = 0.0037) and presence of a high number (≥4) of abnormal diastolic parameters (HR 2.0, CI 1.3–3.1, p = 0.0033). Conclusion The majority of KaRen patients with suspected HFpEF had diagnostic echocardiographic criteria for HFpEF according to ESC Guidelines. Our findings support using 2016 ESC HF guidelines for risk prediction in HFpEF. Highlights • A model for grading the diastolic dysfunction of the heart is proposed. • The ESC heart failure guidelines can be used for risk prediction in heart failure with preserved ejection fraction. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to investigate the impact of cardiac resynchronization therapy (CRT) on right ventricular (RV) function and the influence of RV dysfunction on the echocardiographic and clinical response to CRT among patients enrolled in the CARE-HF (Cardiac Resynchronization-Heart Failure) trial. Background: Cardiac resynchronization therapy prolongs survival in appropriately selected patients with heart failure but the benefit might be diminished in patients with RV dysfunction. Methods: Of 813 patients enrolled in the CARE-HF study, 688 had tricuspid plane systolic excursion (TAPSE) measured at baseline, and 345 of these were assigned to CRT. Their median (interquartile range) age was 66 (58 to 71) years, left ventricular (LV) ejection fraction was 24% (21% to 28%), and TAPSE was 19 (16 to 22) mm. Baseline LV function and size and QRS duration were similar among TAPSE tertiles, but those in the worst tertile (TAPSE <17.4 mm) were more likely to have ischemic heart disease. Results: Overall, CRT improved LV but not RV structure and function with little evidence of an interaction with TAPSE. During a median (interquartile range) follow-up of 748 (582 to 950) days, 213 deaths occurred. Patients with lower TAPSE had a higher mortality, regardless of assigned treatment (p < 0.001). Greater inter-ventricular mechanical delay, New York Heart Association functional class, mitral regurgitation, and N-terminal pro–B-type natriuretic peptide, lower TAPSE, and assignment to the control group were independently associated with higher mortality. Reduction in mortality with CRT was similar in each tertile of TAPSE. Conclusions: Right ventricular dysfunction is a powerful determinant of prognosis among candidates for CRT, regardless of treatment assigned, but did not diminish the prognostic benefits of CRT among patients enrolled in the CARE-HF trial. (Care-HF CArdiac Resynchronization in Heart Failure; NCT00170300) [ABSTRACT FROM AUTHOR]