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Aims: Guidelines recommend down-titration of loop diuretics (LD) once euvolaemia is achieved. In outpatients with heart failure (HF), we investigated LD dose changes in daily cardiology practice, agreement with guideline recommendations, predictors of successful LD down-titration and association between dose changes and outcomes.Methods and Results: We included 8130 HF patients from the ESC-EORP Heart Failure Long-Term Registry. Among patients who had dose decreased, successful decrease was defined as the decrease not followed by death, HF hospitalization, New York Heart Association class deterioration, or subsequent increase in LD dose. Mean age was 66 ± 13 years, 71% men, 62% HF with reduced ejection fraction, 19% HF with mid-range ejection fraction, 19% HF with preserved ejection fraction. Median [interquartile range (IQR)] LD dose was 40 (25-80) mg. LD dose was increased in 16%, decreased in 8.3% and unchanged in 76%. Median (IQR) follow-up was 372 (363-419) days. Diuretic dose increase (vs. no change) was associated with HF death [hazard ratio (HR) 1.53, 95% confidence interval (CI) 1.12-2.08; P = 0.008] and nominally with cardiovascular death (HR 1.25, 95% CI 0.96-1.63; P = 0.103). Decrease of diuretic dose (vs. no change) was associated with nominally lower HF (HR 0.59, 95% CI 0.33-1.07; P = 0.083) and cardiovascular mortality (HR 0.62, 95% CI 0.38-1.00; P = 0.052). Among patients who had LD dose decreased, systolic blood pressure [odds ratio (OR) 1.11 per 10 mmHg increase, 95% CI 1.01-1.22; P = 0.032], and absence of (i) sleep apnoea (OR 0.24, 95% CI 0.09-0.69; P = 0.008), (ii) peripheral congestion (OR 0.48, 95% CI 0.29-0.80; P = 0.005), and (iii) moderate/severe mitral regurgitation (OR 0.57, 95% CI 0.37-0.87; P = 0.008) were independently associated with successful decrease.Conclusion: Diuretic dose was unchanged in 76% and decreased in 8.3% of outpatients with chronic HF. LD dose increase was associated with worse outcomes, while the LD dose decrease group showed a trend for better outcomes compared with the no-change group. Higher systolic blood pressure, and absence of (i) sleep apnoea, (ii) peripheral congestion, and (iii) moderate/severe mitral regurgitation were independently associated with successful dose decrease. [ABSTRACT FROM AUTHOR]

Abstract Background In 2002, the European Society of Cardiology conducted the Euro Heart Survey (EHS), while in 2014concluded 1-year follow-up of the EURObservational Research Programme AF (EORP-AF) Pilot Registry. Methods We analysed differences in clinical profiles, therapeutic approaches and outcomes between these two cohorts after propensity score matching (PSM). Results After PSM, 5206 patients were analysed. In EORP-AF there were more elderly patients than EHS (p <.001). EORP-AF patients were more burdened with cardiovascular (CV) and non-CV comorbidities, with a higher proportion of patients with high thromboembolic risk. EORP-AF patients used more oral-anticoagulant (OAC) (p <.001). At 1-year follow-up EORP-AF patients had lower risk for thromboembolic and CV events, readmission for AF and other CV reasons (all p <.001), showing conversely a higher risk for CV death (p =.015). Kaplan-Meier curves showed that EORP-AF patients had higher risk for CV death (p <.0001) and all-cause death (p =.0019). Cox regression confirmed that EORP-AF patients were at higher risk for CV death (p =.021). Conclusions We found significant changes in AF epidemiology over a decade in Europe, with older patients, more burdened with comorbidities. A greater use of OAC was found. Despite a reduction in risk for thromboembolic events, a high risk of CV-related death was still evident. Highlights • Temporal changes have been found in atrial fibrillation (AF) epidemiology. • AF patients re becoming older and more burdened with comorbidities • Use of oral anticoagulant (OAC) drugs increased over the last decade in Europe. • OAC use is associated with a reduction in thromboembolic and cardiovascular events. • Despite the increased OAC use, a high risk of cardiovascular death still persists. [ABSTRACT FROM AUTHOR]

Abstract: Background: The impact of overweight and obesity on outcomes in “real world” patients with atrial fibrillation (AF) is not fully defined. Second, sex differences in AF outcomes may also exist. Methods and results: The aim was to investigate outcomes at 1 year follow‐up for AF patients enrolled in the EORP‐AF Registry, according to BMI (kg/m2), comparing patients with normal BMI (18.5 to < 25 kg/m2), overweight (25 to < 30 kg/m2) and obesity (≥ 30 kg/m2), in relation to sex differences. Among 2,540 EORP AF patients (38.9% female; median age 69) with 1 year follow‐up data available, 720 (28.3%) had a normal BMI, 1,084 (42.7%) were overweight, and 736 (29.0%) were obese. Obese patients were younger and with more prevalent diabetes mellitus and hypertension (P < 0. 001). One‐year outcomes showed that all‐cause mortality was significantly different according to BMI among female patients (9.3% normal BMI, 5.3% overweight, and 4.3 % obese, P = 0.023), but not among male patients (P = 0.748). The composite outcome of thromboembolic events and death was also significantly different, being lower in obese females (P = 0.035). Among male patients, bleeding events were significantly more frequent in obese subjects (P = 0.035). On multivariable Cox analysis, BMI was not independently associated with all‐cause mortality. Conclusions: Among AF patients, overweight and obesity are common and associated with better outcomes in females (a finding previously reported as “obesity paradox”), while no significant differences in outcomes are detected among male patients. Final multivariable model found that increasing BMI was not associated with increased risk of all‐cause death; conversely, age and comorbidities persisted as major determinants. [ABSTRACT FROM AUTHOR]

Background Despite oral anticoagulation being highly effective in reducing stroke and thromboembolism, patients with atrial fibrillation (AF) still have a significant residual excess in mortality risk. Additional management strategies are needed to reduce the mortality risk seen in AF patients. Methods Ancillary analysis from the EURObservational Research Programme Atrial Fibrillation (EORP-AF) General Pilot Registry, to evaluate 1-year outcomes in AF patients according to statin use at baseline. Results Of 2636 patients, 1286 (48.8%) patients used statins at baseline. Patients prescribed statins had more comorbidities. At 1-year follow-up, logistic regression analysis adjusted for AF type, symptomatic status and CHA 2 DS 2 -VASc score demonstrated that statin use was inversely associated with CV death (odds ratio [OR]: 0.50, 95% confidence interval [CI]: 0.30–0.82, p < 0.0001), all-cause death (OR: 0.52, 95% CI: 0.37–0.73, p < 0.0001) and the composite outcome of CV death/any thromboembolic event/bleeding (OR: 0.71, 95% CI: 0.52–0.98, p < 0.0001). Similar findings were observed for ‘high risk’ subgroups including the elderly, primary prevention and high thromboembolic risk AF patients. Survival analysis showed that statins prescribed patients had a lower risk of all-cause death at follow-up (p = 0.0433). Multivariate Cox regression analysis found that statin use remained independently associated with a lower risk for all-cause death (hazard ratio [HR]: 0.61, 95% CI: 0.42–0.88, p = 0.0077). Conclusions Statin use in AF patients was associated with improved outcomes, with an independent association with a lower risk of all-cause death at 1-year follow-up. [ABSTRACT FROM AUTHOR]

Aims The purpose of this study was too describe the associated baseline features of AF patients with heart failure ( HF) with reduced and preserved ejection fraction ( HFrEF and HFpEF). Secondly, we assessed symptomatic status and their clinical correlates. Finally, we examined independent predictors for 'heart failure' at the 1-year follow-up period. Methods and results A survey of European cardiologists from nine countries, participating in the EURObservational Research Programme Pilot survey on Atrial Fibrillation ( EORP-AF Pilot), was carried out. Of the whole cohort of 2972 patients, 1411 (47.5%) had a diagnosis of HF. Of the AF patients with HF, oral anticoagulants were prescribed to 82.1% and antiarrhythmic drugs in 36.7%. Independent predictors of HFpEF were high body mass index, high heart rate, high systolic blood pressure, low diastolic blood pressure, high CHA2DS2-VASc score, and absence of chronic kidney disease, sleep apnoea, or ischaemic cardiomyopathy. On multivariate stepwise regression analysis, independent predictors of the development of HF were mode of AF presentation, diuretic use, prior HF, COPD, and valvular disease. At 1 year, HF was associated with a greater risk of all-cause mortality (log-rank test, P < 0.001). When HFrEF was compared with HFpEF at 1 year, crude rates were significant for the composite endpoint of 'stroke/thrombo-embolism/transient ischaemic attack and death' (15.9% vs. 11.1%, P = 0.043). Conclusion We provide insights into the clinical characteristics and outcomes in AF patients with HF, who were managed by European cardiologists. Despite a high prevalence of oral anticoagulant use, 1-year mortality and morbidity remained high in AF patients with HF, whether HFrEF or HFpEF. Such patients require a holistic approach to cardiovascular risk management. [ABSTRACT FROM AUTHOR]

Aims: To evaluate the current management and survival of patients with left‐sided infective endocarditis (IE) complicated by congestive heart failure (CHF) in the ESC‐EORP European Endocarditis (EURO‐ENDO) registry. Methods and results: Among the 3116 patients enrolled in this prospective registry, 2449 (mean age: 60 years, 69% male) with left‐sided (native or prosthetic) IE were included in this study. Patients with CHF (n = 698, 28.5%) were older, with more comorbidity and more severe valvular damage (mitro‐aortic involvement, vegetations >10 mm and severe regurgitation/new prosthesis dehiscence) than those without CHF (all p ≤ 0.019). Patients with CHF experienced higher 30‐day and 1‐year mortality than those without (20.5% vs. 9.0% and 36.1% vs. 19.3%, respectively) and CHF remained strongly associated with 30‐day (odds ratio[OR] 2.37, 95% confidence interval [CI] [1.73–3.24; p < 0.001) and 1‐year mortality (hazard ratio [HR] 1.69, 95% CI 1.39–2.05; p < 0.001) after adjustment for established outcome predictors, including early surgery, or after propensity matching for age, sex, and comorbidity (n = 618 [88.5%] for each group, both p < 0.001). Early surgery, performed on 49% of these patients with IE complicated by CHF, remained associated with a substantial reduction in 30‐day mortality following multivariable analysis, after adjustment for age, sex, Charlson comorbidity index, cerebrovascular accident, Staphylococcus aureus IE, streptococcal IE, uncontrolled infection, vegetation size >10 mm, severe valvular regurgitation and/or new prosthetic dehiscence, perivalvular complication, and prosthetic IE (OR 0.22, 95% CI 0.12–0.38; p < 0.001) and in 1‐year mortality (HR 0.29, 95% CI 0.20–0.41; p < 0.001). Conclusion: Congestive heart failure is common in left‐sided IE and is associated with older age, greater comorbidity, more advanced lesions, and markedly higher 30‐day and 1‐year mortality. Early surgery is strongly associated with lower mortality but is performed on only approximately half of patients with CHF, mainly because of a surgical risk considered prohibitive. [ABSTRACT FROM AUTHOR]

The current practice of atrial fibrillation ablation (AFA) as a treatment option for atrial fibrillation (AF) in patients with heart failure (HF) across Europe, their clinical profiles and outcomes is still undefined. The European Society of Cardiology (ESC) led a prospective observational registry of consecutive patients undergoing AFA, in 27 member countries. The subgroup of patients with HF, followed-up for 1 year, was analyzed and the results are reported. Of the 3582 AF patients in the Registry, 537 (14.9%) had HF. Diabetes, hypertension, hypercholesterolemia, CHA 2 DS 2 -VASc score ≥ 2, structural heart disease and persistent AF were more common in HF than non-HF patients (all p < 0.001). However the in-hospital complications were less frequent in HF patients (5.0% vs. 8.2% p = 0.01). Both in-hospital and 1-year outcomes, including 1-year AF recurrence (15.4%) and repeat ablations (9.5%), were similar in both groups. We subdivided HF patients according to their left ventricular ejection fraction (EF) at baseline into reduced (HFrEF, <40%), mid-range (HFmEF, 40–49%), or preserved EF (HFpEF, ≥ 50%). Most patients were HFpEF (n 375, 77%), 72 (15%) were HFmEF and 8% HFrEF. The most frequent underlying conditions in HFpEF were hypertension and ischemic heart disease, while those most common in HFmEF and HFrEF were valvular and dilated cardiomyopathy. In routine care in Europe, HF patients represent a minority of patients undergoing AFA, and most belong to the HFpEF phenotype. The limited clinical research on AFA HFpEF patients is reflected by the uncertainty expressed in the current AF Guidelines and Expert statements. • A survey conducted by the ESC in 27 member countries evaluated the practice use of atrial fibrillation ablation. • 3582 ablated patients were enrolled, 537 with HF, 77% of which had preserved left ventricular ejection fraction (LVEF≥50%). • In contrast most randomized clinical research trials focused on HF with reduced LVEF (35-40%). • Such asymmetry in evidence may account for some inconsistency in current Guidelines. [ABSTRACT FROM AUTHOR]

Aims: Tricuspid regurgitation (TR) is commonly observed in patients with severe left‐sided valvular heart disease (VHD). This study sought to assess TR frequency, management and outcome in this population. Methods and results: Among 6883 patients with severe native left‐sided VHD or previous left‐sided valvular intervention enrolled in the EURObservational Research Programme prospective VHD II survey, moderate or severe TR was very frequent in patients with severe mitral VHD (30% when mitral stenosis, 36% when mitral regurgitation [MR]), especially in patients with secondary MR (46%), and rare in patients with severe aortic VHD (4% when aortic stenosis, 3% when aortic regurgitation). An increase in TR grade was associated with a more severe clinical presentation and a poorer 6‐month survival (p < 0.0001). Rates of concomitant tricuspid valve (TV) intervention at the time of left‐sided heart valve surgery were high at the time of mitral valve surgery (50% when mitral stenosis, 41% when MR). Concordance between class I indications (patients with severe TR) for concomitant TV surgery at the time of left‐sided valvular heart surgery according to guidelines and real‐practice decision‐making was very good (88% overall, 95% in patients operated on for MR). Conclusion: In this large international prospective survey among patients with severe left‐sided VHD, moderate/severe TR was frequent in patients with mitral valve disease and was associated with a poorer outcome as TR grade increased. In patients with severe TR, compliance to guidelines for class I indications for concomitant TV surgery at the time of left‐sided heart valve surgery was very good. [ABSTRACT FROM AUTHOR]

(1) Background: infective endocarditis (IE) is a significant health concern associated with important morbidity and mortality. Only limited, often monocentric, retrospective data on IE in Belgium are available. This prospective study sought to assess the clinical characteristics and outcomes of Belgian IE patients in the ESC EORP European endocarditis (EURO-ENDO) registry; (2) Methods: 132 IE patients were identified based on the ESC 2015 criteria and included in six tertiary hospitals in Belgium; (3) Results: The average Belgian IE patient was male and 62.8 ± 14.9 years old. The native valve was most affected (56.8%), but prosthetic/repaired valves (34.1%) and intracardiac device-related (5.3%) IE are increasing. The most frequently identified microorganisms were S. aureus (37.2%), enterococci (15.5%), and S. viridans (15.5%). The most frequent complications were acute renal failure (36.2%) and embolic events (23.6%). Cardiac surgery was effectively performed when indicated in 71.7% of the cases. In-hospital mortality occurred in 15.7% of patients. Predictors of mortality in the multivariate analysis were S. aureus (HR = 2.99 [1.07–8.33], p = 0.036) and unperformed cardiac surgery when indicated (HR = 19.54 [1.91–200.17], p = 0.012). (4) Conclusion: This prospective EURO-ENDO ancillary analysis provides valuable contemporary insights into the profile, treatment, and clinical outcomes of IE patients in Belgium. [ABSTRACT FROM AUTHOR]

Abstract Background Contemporary European data regarding patients with atrial fibrillation (AF) allow us to assess the use of oral anticoagulants (OACs) and long-term outcomes. Methods Patients with AF presenting to cardiologists in 9 European Society of Cardiology participating countries were enrolled and followed-up for 3-years. Results Among the 2119 patients (40.4% female; mean age 69 ± 11 years) the prevalent types of AF at baseline were first-detected (30.5%) and paroxysmal AF (27.0%). The composite of stroke/TIA/peripheral embolism/all-cause death at 3-years occurred in 18.2%, with first detected AF and permanent AF reporting the highest event rates (22.5% and 27.3%, respectively; p < 0.0001). Age, diabetes mellitus, heart failure, restrictive cardiomyopathy, chronic kidney disease and no physical activity were significant predictors of all-cause death. Paroxysmal and persistent AF patients were more likely to be hospitalised than other types of AF (34.1% and 37.9%, p < 0.0001). At follow-up, OAC drugs were used in 80.1% of patients, with non-vitamin K antagonists (NOACs) accounting for 24.3% of patients. OAC treatment at follow-up visits changed throughout time, with a shift from VKA to NOACs reported in 5.4% of the cases, while the reverse shift (from NOACs to VKA) occurred in 8.6%. Discontinuation of OAC was recorded in while in 9.5% of visits. Conclusions Patients outcomes at 3-years follow-up differ according to type of AF at baseline, with worse outcomes in patients presenting with first-detected or permanent AF. Changes in the type of OAC use with shifts from NOACs to VKA and vice-versa are not uncommon, as were interruptions of OAC. Highlights • In a 3-years follow-up outcomes differ according to atrial fibrillation (AF) type. • Patients with first-detected or permanent AF reported worse outcomes. • Risk of all-cause death was independently associated with multiple comorbidities. • Over 3-years 14% of patients shifted oral anticoagulant, while 9.5% discontinued. [ABSTRACT FROM AUTHOR]

The current study evaluates and compares the stability of anaerobic digestion of Brewery Spent Grains (BSG) with and without addition of nutrients. Based on the composition of the BSG two levels of nutrients addition were defined. Control reactor, without addition of nutrients, showed signs of instability after 3 months of operation and collapsed. On the contrary, supplemented reactors led to a COD removal rate of 60% and a methane production of 280 NL CH 4 .kg −1 VS added . According to these results, it was possible to define an additive solution adapted to BSG degradation. [ABSTRACT FROM AUTHOR]

Abstract: Background: Current guidelines strongly recommend that oral anticoagulation should be offered to patients with atrial fibrillation and ≥1 stroke risk factors. The guidelines also recommend that oral anticoagulation still should be used in the presence of stroke risk factors irrespective of rate or rhythm control. Methods: In an analysis from the dataset of the EURObservational Research Programme on Atrial Fibrillation Pilot Survey (n = 3119), we examined antithrombotic therapy prescribing, with particular focus on the risk factors determining oral anticoagulation or antiplatelet therapy use. Results: When oral anticoagulation was used among admitted patients in whom no pharmacologic cardioversion, electrical cardioversion, or catheter ablation was performed or planned, vitamin K antagonist therapy was prescribed in the majority (72.2%), whereas novel oral anticoagulants were used in the minority (7.7%). There was no significant difference in bleeding risk factors among the patients treated with the different types of antithrombotic therapies, except for those with chronic kidney disease, in whom oral anticoagulation was less commonly used (P = .0318). Antiplatelet therapy was more commonly used in patients with a high Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalized ratio, Elderly (>65 years), Drugs/alcohol concomitantly score (≥2) (P < .0001). More oral anticoagulation use was associated with female gender (P = .0245). Less novel oral anticoagulant use was associated with valvular heart disease (P < .0001), chronic heart failure (P = .0010), coronary artery disease (P < .0001), and peripheral artery disease (P = .0092). Coronary artery disease was the strongest reason for combination therapy with oral anticoagulation plus antiplatelet drug (odds ratio, 8.54; P < .0001). When the Congestive heart failure, Hypertension, Age ≥75 [Doubled], Diabetes, Stroke [Doubled]-Vascular disease, Age 65-74, and Sex category [female] score was used, 95.6% of patients with a score ≥1 received antithrombotic therapy, with 80.5% of patients with a score ≥1 receiving oral anticoagulation. Of note, 83.7% of those with a score ≥2 received antithrombotic therapy. Of the latter, 70.9% of those with a score ≥2 received oral anticoagulation, vitamin K antagonists were used in 64.1%, and novel oral anticoagulants were used in 6.9%. Conclusions: The EURObservational Research Programme on Atrial Fibrillation Pilot Survey provides contemporary data on oral anticoagulation prescribing by European cardiologists for atrial fibrillation. Although the uptake of oral anticoagulation (mostly vitamin K antagonist therapy) has improved since the Euro Heart Survey a decade ago, antiplatelet therapy is still commonly prescribed, with or without oral anticoagulation, whereas elderly patients are commonly undertreated with oral anticoagulation. [Copyright &y& Elsevier]

Aims: The aim of this study was to evaluate the in-hospital and 1-year prognostic impact of diabetes and elevated blood glucose levels at hospital admission in patients with acute heart failure (HF).Methods and Results: We studied a multinational cohort of 6926 hospitalized patients with acute HF enrolled in the European Society of Cardiology (ESC) and Heart Failure Association (HFA) Long-Term Registry, of whom 49.4% (n = 3422) had known or previously undiagnosed diabetes (defined as self-reported history, or medication use, or fasting glucose levels ≥7.0 mmol/L or haemoglobin A1c ≥6.5%). Compared with those without diabetes, patients with known or previously undiagnosed diabetes had higher cumulative rates of in-hospital mortality, 1-year mortality, and 1-year HF re-hospitalization that occurred independently of multiple clinical risk factors: in-hospital mortality [6.8 vs. 4.4%; adjusted hazard ratio (HR) 1.774; 95% confidence interval (CI) 1.282-2.456, P < 0.001], 1-year all-cause mortality (27.5 vs. 24%; adjusted HR 1.162; 95% CI 1.020-1.325, P = 0.024), and 1-year hospital re-admissions for HF (23.2 vs. 18.5%; adjusted HR 1.320; 95% CI 1.139-1.530, P < 0.001). Moreover, elevated admission blood glucose concentrations were powerfully prognostic for in-hospital mortality, but not for 1-year mortality or re-hospitalizations, in both patients with and without diabetes.Conclusions: Among patients hospitalized for acute HF, the presence of diabetes is independently associated with an increased risk of in-hospital mortality, 1-year all-cause mortality, and 1-year re-hospitalizations for HF, underscoring the need for more effective and personalized treatments of diabetes in this particularly high-risk patient population. [ABSTRACT FROM AUTHOR]

Aims The aim of this study was to evaluate the in-hospital and 1-year prognostic impact of diabetes and elevated blood glucose levels at hospital admission in patients with acute heart failure (HF). Methods and results We studied a multinational cohort of 6926 hospitalized patients with acute HF enrolled in the European Society of Cardiology (ESC) and Heart Failure Association (HFA) Long-Term Registry, of whom 49.4% (n = 3422) had known or previously undiagnosed diabetes (defined as self-reported history, or medication use, or fasting glucose levels ≥7.0 mmol/L or haemoglobin A1c ≥6.5%). Compared with those without diabetes, patients with known or previously undiagnosed diabetes had higher cumulative rates of in-hospital mortality, 1-year mortality, and 1-year HF re-hospitalization that occurred independently of multiple clinical risk factors: in-hospital mortality [6.8 vs. 4.4%; adjusted hazard ratio (HR) 1.774; 95% confidence interval (CI) 1.282-2.456, P < 0.001], 1-year all-cause mortality (27.5 vs. 24%; adjusted HR 1.162; 95% CI 1.020-1.325, P = 0.024), and 1-year hospital re-admissions for HF (23.2 vs. 18.5%; adjusted HR 1.320; 95% CI 1.139-1.530, P < 0.001). Moreover, elevated admission blood glucose concentrations were powerfully prognostic for in-hospital mortality, but not for 1-year mortality or re-hospitalizations, in both patients with and without diabetes. Conclusions Among patients hospitalized for acute HF, the presence of diabetes is independently associated with an increased risk of in-hospital mortality, 1-year all-cause mortality, and 1-year re-hospitalizations for HF, underscoring the need for more effective and personalized treatments of diabetes in this particularly high-risk patient population. [ABSTRACT FROM AUTHOR]

Simple Summary: According to our analysis of the multicenter EORP ELECTRa (European Lead Extraction ConTRolled) Registry, about one-third of the candidates to complete removal of an implantable pacemaker/defibrillator because of device infection, through standard transvenous lead extraction, presents a systemic infection. Systemic infection is associated with a higher incidence of major in-hospital complications overall and a strong trend for procedure-related complications. Moreover, systemic infection is associated with increased procedure-related and non-procedure-related in-hospital mortality. Patients with cardiac implantable devices (CIED)-related infection with systemic vs. local involvement present different characteristics suggesting that in a relevant subgroup of patients the infection can be systemic from the beginning, without progression from CIED pocket. Background: Infections of cardiac implantable devices (CIEDI) have poor outcomes despite improvement in lead extraction (TLE) procedures. Methods: To explore the influence of CIEDI on the outcomes of TLE and the differences between patients with systemic (Sy) vs. local (Lo) CIEDI, we performed a sub-analysis of the EORP ELECTRa (European Lead Extraction ConTRolled) Registry. Results: Among 3555 patients enrolled by 73 centers in 19 Countries, the indication for TLE was CIEDI in 1850: 1170 with Lo-CIEDI and 680 with Sy-CIEDI. Patients with CIEDI had a worse in-hospital prognosis in terms of major complications (3.57% vs. 1.71%; p = 0.0007) and mortality (2.27% vs. 0.49%; p < 0.0001). Sy-CIEDI was an independent predictor of in-hospital death (H.R. 2.14; 95%CI 1.06–4.33. p = 0.0345). Patients with Sy-CIEDI more frequently had an initial CIED implant and a higher prevalence of comorbidities, while subjects with Lo-CIEDI had a higher prevalence of previous CIED procedures. Time from signs of CIEDI and TLE was longer for Lo-CIEDI despite a shorter pre-TLE antibiotic treatment. Conclusions: Patients with CIEDI have a worse in-hospital prognosis after TLE, especially for patients with Sy-CIEDI. These results raise the suspicion that in a relevant group of patients CIEDI can be systemic from the beginning without progression from Lo-CIEDI. Future research is needed to characterize this subgroup of patients. [ABSTRACT FROM AUTHOR]

Aims: Hypertensive disorders occur in women with peripartum cardiomyopathy (PPCM). How often hypertensive disorders co‐exist, and to what extent they impact outcomes, is less clear. We describe differences in phenotype and outcomes in women with PPCM with and without hypertensive disorders during pregnancy. Methods and results: The European Society of Cardiology EURObservational Research Programme PPCM Registry enrolled women with PPCM from 2012–2018. Three groups were examined: (i) women without hypertension (PPCM‐noHTN); (ii) women with hypertension but without pre‐eclampsia (PPCM‐HTN); (iii) women with pre‐eclampsia (PPCM‐PE). Maternal (6‐month) and neonatal outcomes were compared. Of 735 women included, 452 (61.5%) had PPCM‐noHTN, 99 (13.5%) had PPCM‐HTN and 184 (25.0%) had PPCM‐PE. Compared to women with PPCM‐noHTN, women with PPCM‐PE had more severe symptoms (New York Heart Association class IV in 44.4% vs. 29.9%, P < 0.001), more frequent signs of heart failure (pulmonary rales in 70.7% vs. 55.4%, P = 0.002), a higher baseline left ventricular ejection fraction (LVEF) (32.7% vs. 30.7%, P = 0.005) and a smaller left ventricular end‐diastolic diameter (57.4 ± 6.7 mm vs. 59.8 ± 8.1 mm, P = 0.001). There were no differences in the frequencies of death from any cause, rehospitalization for any cause, stroke, or thromboembolic events. Compared to women with PPCM‐noHTN, women with PPCM‐PE had a greater likelihood of left ventricular recovery (LVEF ≥ 50%) (adjusted odds ratio 2.08, 95% confidence interval 1.21–3.57) and an adverse neonatal outcome (composite of termination, miscarriage, low birth weight or neonatal death) (adjusted odds ratio 2.84, 95% confidence interval 1.66–4.87). Conclusion: Differences exist in phenotype, recovery of cardiac function and neonatal outcomes according to hypertensive status in women with PPCM. [ABSTRACT FROM AUTHOR]

Background: There were gaps between guidelines and practice when surgery was the only treatment for aortic stenosis (AS).Objectives: This study analyzed the decision to intervene in patients with severe AS in the EORP VHD (EURObservational Research Programme Valvular Heart Disease) II survey.Methods: Among 2,152 patients with severe AS, 1,271 patients with high-gradient AS who were symptomatic fulfilled a Class I recommendation for intervention according to the 2012 European Society of Cardiology guidelines; the primary end point was the decision for intervention.Results: A decision not to intervene was taken in 262 patients (20.6%). In multivariate analysis, the decision not to intervene was associated with older age (odds ratio [OR]: 1.34 per 10-year increase; 95% CI: 1.11 to 1.61; P = 0.002), New York Heart Association functional classes I and II versus III (OR: 1.63; 95% CI: 1.16 to 2.30; P = 0.005), higher age-adjusted Charlson comorbidity index (OR: 1.09 per 1-point increase; 95% CI: 1.01 to 1.17; P = 0.03), and a lower transaortic mean gradient (OR: 0.81 per 10-mm Hg decrease; 95% CI: 0.71 to 0.92; P < 0.001). During the study period, 346 patients (40.2%, median age 84 years, median EuroSCORE II [European System for Cardiac Operative Risk Evaluation II] 3.1%) underwent transcatheter intervention and 515 (59.8%, median age 69 years, median EuroSCORE II 1.5%) underwent surgery. A decision not to intervene versus intervention was associated with lower 6-month survival (87.4%; 95% CI: 82.0 to 91.3 vs 94.6%; 95% CI: 92.8 to 95.9; P < 0.001).Conclusions: A decision not to intervene was taken in 1 in 5 patients with severe symptomatic AS despite a Class I recommendation for intervention and the decision was particularly associated with older age and combined comorbidities. Transcatheter intervention was extensively used in octogenarians. [ABSTRACT FROM AUTHOR]

• sUA contributes to microvascular inflammation and dysfunction in HF. • Elevated serum uric acid (sUA) levels predict poor outcome in heart failure (HF). • Role of sUA across left ventricular ejection fraction (LVEF) phenotypes is unknown. • Prognostic role of high sUA was shown in HF patients with reduced or preserved LVEF. Retrospective analyses of clinical trials indicate that elevated serum uric acid (sUA) predicts poor outcome in heart failure (HF). Uric acid can contribute to inflammation and microvascular dysfunction, which may differently affect different left ventricular ejection fraction (LVEF) phenotypes. However, role of sUA across LVEF phenotypes is unknown. We investigated sUA association with outcome in a prospective cohort of HF patients stratified according to LVEF. Through the Heart Failure Long-Term Registry of the European Society of Cardiology (ESC-EORP-HF-LT), 4,438 outpatients were identified and classified into: reduced (<40% HFrEF), mid-range (40–49% HFmrEF), and preserved (≥50% HFpEF) LVEF. Endpoints were the composite of cardiovascular death/HF hospitalization, and individual components. Median sUA was 6.72 (IQ:5.48-8.20) mg/dl in HFrEF, 6.41 (5.02-7.77) in HFmrEF, and 6.30 (5.20-7.70) in HFpEF. At a median 372-day follow-up, the composite endpoint occurred in 648 (13.1%) patients, with 176 (3.6%) deaths and 538 (10.9%) HF hospitalizations. Compared with lowest sUA quartile (Q), Q-III and Q-IV were significantly associated with the composite endpoint (adjusted HR 1.68: 95% CI 1.11–2.54; 2.46: 95% CI 1.66–3.64, respectively). By univariable analyses, HFrEF and HFmrEF patients in Q-III and Q-IV, and HFpEF patients in Q-IV, showed increased risk for the composite endpoint (P<0.05 for all); after model-adjustment, significant association of sUA with outcome persisted among HFrEF in Q-IV, and HFpEF in Q-III-IV. In a large, contemporary-treated cohort of HF outpatients, sUA is an independent prognosticator of adverse outcome, which can be appreciated in HErEF and HFpEF patients. [Display omitted] [ABSTRACT FROM AUTHOR]

Aims: We assessed the interplay between hyperkalaemia (HK) and renin-angiotensin-aldosterone system inhibitor (RAASi) use, dose and discontinuation, and their association with all-cause or cardiovascular death in patients with chronic heart failure (HF). We hypothesized that HK-associated increased death may be related to RAASi withdrawal.Methods and Results: The ESC-HFA-EORP Heart Failure Long-Term Registry was used. Among 9222 outpatients (HF with reduced ejection fraction: 60.6%, HF with mid-range ejection fraction: 22.9%, HF with preserved ejection fraction: 16.5%) from 31 countries, 16.6% had HK (≥5.0 mmol/L) at baseline. Angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) was used in 88.3%, a mineralocorticoid receptor antagonist (MRA) in 58.7%, or a combination in 53.2%; of these, at ≥50% of target dose in ACEi: 61.8%; ARB: 64.7%; and MRA: 90.3%. At a median follow-up of 12.2 months, there were 789 deaths (8.6%). Both hypokalaemia and HK were independently associated with higher mortality, and ACEi/ARB prescription at baseline with lower mortality. MRA prescription was not retained in the model. In multivariable analyses, HK at baseline was independently associated with MRA non-prescription at baseline and subsequent discontinuation. When considering subsequent discontinuation of RAASi (instead of baseline use), HK was no longer found associated with all-cause deaths. Importantly, all RAASi (ACEi, ARB, or MRA) discontinuations were strongly associated with mortality.Conclusions: In HF, hyper- and hypokalaemia were associated with mortality. However, when adjusting for RAASi discontinuation, HK was no longer associated with mortality, suggesting that HK may be a risk marker for RAASi discontinuation rather than a risk factor for worse outcomes. [ABSTRACT FROM AUTHOR]

Introduction: A strategy based on targeted gene panel sequencing identifies possibly pathogenic variants in fewer than 20% of cases in early-onset and familial form of dystonia. By using Whole Exome Sequencing (WES), we aimed to identify the missing genetic causes in dystonic patients without diagnosis despite gene panel sequencing.Material and Methods: WES was applied to DNA samples from 32 patients with early-onset or familial dystonia investigated by sequencing of a 127 movement disorders-associated gene panel. Dystonia was described according to the familial history, body distribution, evolution pattern, age of onset, associated symptoms and associated movement disorders. Rate of diagnoses was evaluated for each clinical feature.Results: We identified causative variants for 11 patients from 9 families in CTNNB1, SUCLG1, NUS1, CNTNAP1, KCNB1, RELN, GNAO1, HIBCH, ADCK3 genes, yielding an overall diagnostic rate of 34.4%. Diagnostic yield was higher in complex dystonia compared to non-complex dystonia (66.7%-5.9%; p < 0.002), especially in patients showing intellectual disability compared to the patients without intellectual disability (87.5%-16.7%; p < 0.002).Conclusion: Our approach suggests WES as an efficient tool to improve the diagnostic yield after gene panel sequencing in dystonia. Larger study are warranted to confirm a potential genetic overlap between neurodevelopmental diseases and dystonia. [ABSTRACT FROM AUTHOR]

Aims: This study aimed to assess age- and sex-related differences in management and 1-year risk for all-cause mortality and hospitalization in chronic heart failure (HF) patients.Methods and Results: Of 16 354 patients included in the European Society of Cardiology Heart Failure Long-Term Registry, 9428 chronic HF patients were analysed [median age: 66 years; 28.5% women; mean left ventricular ejection fraction (LVEF) 37%]. Rates of use of guideline-directed medical therapy (GDMT) were high (angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, beta-blockers and mineralocorticoid receptor antagonists: 85.7%, 88.7% and 58.8%, respectively). Crude GDMT utilization rates were lower in women than in men (all differences: P ≤ 0.001), and GDMT use became lower with ageing in both sexes, at baseline and at 1-year follow-up. Sex was not an independent predictor of GDMT prescription; however, age >75 years was a significant predictor of GDMT underutilization. Rates of all-cause mortality were lower in women than in men (7.1% vs. 8.7%; P = 0.015), as were rates of all-cause hospitalization (21.9% vs. 27.3%; P < 0.001) and there were no differences in causes of death. All-cause mortality and all-cause hospitalization increased with greater age in both sexes. Sex was not an independent predictor of 1-year all-cause mortality (restricted to patients with LVEF ≤45%). Mortality risk was significantly lower in patients of younger age, compared to patients aged >75 years.Conclusions: There was a decline in GDMT use with advanced age in both sexes. Sex was not an independent predictor of GDMT or adverse outcomes. However, age >75 years independently predicted lower GDMT use and higher all-cause mortality in patients with LVEF ≤45%. [ABSTRACT FROM AUTHOR]

Aims: To assess the proportion of patients with heart failure and reduced ejection fraction (HFrEF) who are eligible for sacubitril/valsartan (LCZ696) based on the European Medicines Agency/Food and Drug Administration (EMA/FDA) label, the PARADIGM-HF trial and the 2016 ESC guidelines, and the association between eligibility and outcomes.Methods and Results: Outpatients with HFrEF in the ESC-EORP-HFA Long-Term Heart Failure (HF-LT) Registry between March 2011 and November 2013 were considered. Criteria for LCZ696 based on EMA/FDA label, PARADIGM-HF and ESC guidelines were applied. Of 5443 patients, 2197 and 2373 had complete information for trial and guideline eligibility assessment, and 84%, 12% and 12% met EMA/FDA label, PARADIGM-HF and guideline criteria, respectively. Absent PARADIGM-HF criteria were low natriuretic peptides (21%), hyperkalemia (4%), hypotension (7%) and sub-optimal pharmacotherapy (74%); absent Guidelines criteria were LVEF>35% (23%), insufficient NP levels (30%) and sub-optimal pharmacotherapy (82%); absent label criteria were absence of symptoms (New York Heart Association class I). When a daily requirement of ACEi/ARB ≥ 10 mg enalapril (instead of ≥ 20 mg) was used, eligibility rose from 12% to 28% based on both PARADIGM-HF and guidelines. One-year heart failure hospitalization was higher (12% and 17% vs. 12%) and all-cause mortality lower (5.3% and 6.5% vs. 7.7%) in registry eligible patients compared to the enalapril arm of PARADIGM-HF.Conclusions: Among outpatients with HFrEF in the ESC-EORP-HFA HF-LT Registry, 84% met label criteria, while only 12% and 28% met PARADIGM-HF and guideline criteria for LCZ696 if requiring ≥ 20 mg and ≥ 10 mg enalapril, respectively. Registry patients eligible for LCZ696 had greater heart failure hospitalization but lower mortality rates than the PARADIGM-HF enalapril group. [ABSTRACT FROM AUTHOR]

Background: Valvular heart disease (VHD) is an important cause of mortality and morbidity and has been subject to important changes in management. The VHD II survey was designed by the EURObservational Research Programme of the European Society of Cardiology to analyze actual management of VHD and to compare practice with guidelines.Methods: Patients with severe native VHD or previous valvular intervention were enrolled prospectively across 28 countries over a 3-month period in 2017. Indications for intervention were considered concordant if the intervention was performed or scheduled in symptomatic patients, corresponding to Class I recommendations specified in the 2012 European Society of Cardiology and in the 2014 American Heart Association/American College of Cardiology VHD guidelines.Results: A total of 7247 patients (4483 hospitalized, 2764 outpatients) were included in 222 centers. Median age was 71 years (interquartile range, 62-80 years); 1917 patients (26.5%) were ≥80 years; and 3416 were female (47.1%). Severe native VHD was present in 5219 patients (72.0%): aortic stenosis in 2152 (41.2% of native VHD), aortic regurgitation in 279 (5.3%), mitral stenosis in 234 (4.5%), mitral regurgitation in 1114 (21.3%; primary in 746 and secondary in 368), multiple left-sided VHD in 1297 (24.9%), and right-sided VHD in 143 (2.7%). Two thousand twenty-eight patients (28.0%) had undergone previous valvular intervention. Intervention was performed in 37.0% and scheduled in 26.8% of patients with native VHD. The decision for intervention was concordant with Class I recommendations in symptomatic patients with severe single left-sided native VHD in 79.4% (95% CI, 77.1-81.6) for aortic stenosis, 77.6% (95% CI, 69.9-84.0) for aortic regurgitation, 68.5% (95% CI, 60.8-75.4) for mitral stenosis, and 71.0% (95% CI, 66.4-75.3) for primary mitral regurgitation. Valvular interventions were performed in 2150 patients during the survey; of them, 47.8% of patients with single left-sided native VHD were in New York Heart Association class III or IV. Transcatheter procedures were performed in 38.7% of patients with aortic stenosis and 16.7% of those with mitral regurgitation.Conclusions: Despite good concordance between Class I recommendations and practice in patients with aortic VHD, the suboptimal number in mitral VHD and late referral for valvular interventions suggest the need to improve further guideline implementation. [ABSTRACT FROM AUTHOR]

Background: The influence of risk factors on atrial fibrillation (AF) ablation recurrence is increasingly recognized. We present a sub‐analysis of the European Society of Cardiology‐European Heart Rhythm Association‐European Society of Cardiology AF ablation long‐term registry on the effect of traditional risk factors for AF on postablation recurrence, reablation, and complications using real‐world data. Methods: Risk factors for AF were defined as body mass index ≥27 kg/m², hypertension, chronic obstructive pulmonary disease, diabetes, alcohol ≥2 units/day, sleep apnea, smoking, no/occasional sports activity, moderate/severe mitral or aortic valve disease, any cardiomyopathy, peripheral vascular disease, chronic kidney disease, heart failure, coronary artery disease/infarction, and previous pacemaker/defibrillator implant. Patients were divided in two groups with ≥1 or without risk factors. Primary outcomes were arrhythmia recurrence after blanking period, reablation, and adverse events or death. Differences between the groups and the influence of individual risk factors were analyzed using multivariate Cox regression. Results: Three thousand sixty nine patients were included; 217 patients were without risk factors. Risk factor patients were older (58.4 vs 54.1 years), more often female (32% vs 19.8%) and had more often persistent AF (27.2% vs 23.5%). In a multivariate analysis, patients without risk factors had a hazard ratio of 0.70 (95% CI 0.49‐0.99) for recurrence compared to risk factor patients. The multivariate hazard ratios for reablation or adverse events/death were not different between the two groups. Hypertension and body mass index were univariate predictors of recurrence. Conclusions: Patients with ≥1 risk factor had a 30% higher risk for arrhythmia recurrence after ablation, but no differences in risk for repeat ablations and adverse events or death. [ABSTRACT FROM AUTHOR]

XBP1 is a stress-regulated transcription factor also involved in mammalian host defenses and innate immune response. Our investigation of XBP1 RNA splicing during rotavirus infection revealed that an additional XBP1 RNA (XBP1es) that corresponded to exon skipping in the XBP1 pre-RNA is induced depending on the rotavirus strain used. We show that the translation product of XBP1es (XBP1es) has trans-activation properties similar to those of XBP1 on ER stress response element (ERSE) containing promoters. Using monoreassortant between ES+ ("skipping") and ES- ("nonskipping") strains of rotavirus, we show that gene 7 encoding the viral translation enhancer NSP3 is involved in this phenomenon and that exon skipping parallels the nuclear relocalization of cytoplasmic PABP. We further show, using recombinant rotaviruses carrying chimeric gene 7, that the ES+ phenotype is linked to the eIF4G-binding domain of NSP3. Because the XBP1 transcription factor is involved in stress and immunological responses, our results suggest an alternative way to activate XBP1 upon viral infection or nuclear localization of PABP. [ABSTRACT FROM AUTHOR]

Summary: Objective: We aimed to characterize epilepsy of infancy with migrating focal seizures (EIMFS), a rare, severe early onset developmental epilepsy related to KCNT1 mutation, and to define specific electroencephalography (EEG) markers using EEG quantitative analysis. The ultimate goal would be to improve early diagnosis and to better understand seizure onset and propagation of EIMFS as compared to other early onset developmental epilepsy. Methods: EEG of 7 EIMFS patients with KCNT1 mutations (115 seizures) and 17 patients with other early onset epilepsies (30 seizures) was included in this study. After detection of seizure onset and termination, spatiotemporal characteristics were quantified. Seizure propagation dynamics were analyzed using chronograms and phase coherence. Results: In patients with EIMFS, seizures started and were localized predominantly in temporal and occipital areas, and evolved with a stable frequency (4‐10 Hz). Inter‐ and intrahemispheric migrations were present in 60% of EIMFS seizures with high intraindividual reproducibility of temporospatial dynamics. Interhemispheric migrating seizures spread in 71% from temporal or occipital channels to the homologous contralateral ones, whereas intrahemispheric seizures involved mainly frontotemporal, temporal, and occipital channels. Causality links were present between ictal activities detected under different channels during migrating seizures. Finally, time delay index (based on delays between the different ictal onsets) and phase correlation index (based on coherence of ictal activities) allowed discrimination of EIMFS and non‐EIMFS seizures with a specificity of 91.2% and a sensitivity of 84.4%. Significance: We showed that the migrating pattern in EIMFS is not a random process, as suggested previously, and that it is a particular propagation pattern that follows the classical propagation pathways. It is notable that this study reveals specific EEG markers (time delay and phase correlation) accessible to visual evaluation, which will improve EIMFS diagnosis. [ABSTRACT FROM AUTHOR]

Aims: To describe the characteristics and assess the 1-year outcomes of hospitalized (HHF) and chronic (CHF) heart failure patients with chronic obstructive pulmonary disease (COPD) enrolled in a large European registry between May 2011 and April 2013.Methods and Results: Overall, 1334/6920 (19.3%) HHF patients and 1322/9409 (14.1%) CHF patients were diagnosed with COPD. In both groups, patients with COPD were older, more frequently men, had a worse clinical presentation and a higher prevalence of co-morbidities. In HHF, the increase in the use of heart failure (HF) medications at hospital discharge was greater in non-COPD than in COPD for angiotensin-converting enzyme inhibitors (+13.7% vs. +7.2%), beta-blockers (+20.6% vs. +11.8%) and mineralocorticoid receptor antagonists (+20.9% vs. +17.3%), thus widening the gap in HF treatment already existing between the two groups at admission. In CHF patients, there was a similar increase in the use of these medications after enrollment visit in the two groups, leaving a significant difference of 8.2% for beta-blockers in favour of non-COPD patients (89.8% vs. 81.6%, P < 0.001). At 1-year follow-up, the hazard ratios for COPD in multivariable analysis confirmed its independent association with hospitalizations both in HHF [all-cause: 1.16 (1.04-1.29), for HF: 1.22 (1.05-1.42)] and CHF patients [all-cause: 1.26 (1.13-1.41), for HF: 1.37 (1.17-1.60)]. The association between COPD and all-cause mortality was not confirmed in both groups after adjustments.Conclusions: COPD frequently coexists in HHF and CHF, worsens the clinical course of the disease, and significantly impacts its therapeutic management and prognosis. The matter should deserve greater attention from the cardiology community. [ABSTRACT FROM AUTHOR]

Aims To describe the characteristics and assess the 1-year outcomes of hospitalized (HHF) and chronic (CHF) heart failure patients with chronic obstructive pulmonary disease (COPD) enrolled in a large European registry between May 2011 and April 2013. Methods and results Overall, 1334/6920 (19.3%) HHF patients and 1322/9409 (14.1%) CHF patients were diagnosed with COPD. In both groups, patients with COPD were older, more frequently men, had a worse clinical presentation and a higher prevalence of co-morbidities. In HHF, the increase in the use of heart failure (HF) medications at hospital discharge was greater in non-COPD than in COPD for angiotensin-converting enzyme inhibitors (+13.7% vs. +7.2%), beta-blockers (+20.6% vs. +11.8%) and mineralocorticoid receptor antagonists (+20.9% vs. +17.3%), thus widening the gap in HF treatment already existing between the two groups at admission. In CHF patients, there was a similar increase in the use of these medications after enrollment visit in the two groups, leaving a significant difference of 8.2% for beta-blockers in favour of non-COPD patients (89.8% vs. 81.6%, P <0.001). At 1-year follow-up, the hazard ratios for COPD in multivariable analysis confirmed its independent association with hospitalizations both in HHF [all-cause: 1.16 (1.04-1.29), for HF: 1.22 (1.05-1.42)] and CHF patients [all-cause: 1.26 (1.13-1.41), for HF: 1.37 (1.17-1.60)]. The association between COPD and all-cause mortality was not confirmed in both groups after adjustments. Conclusions COPD frequently coexists in HHF and CHF, worsens the clinical course of the disease, and significantly impacts its therapeutic management and prognosis. The matter should deserve greater attention from the cardiology community. [ABSTRACT FROM AUTHOR]

Lipoate serves as a cofactor for the glycine cleavage system (GCS) and four 2-oxoacid dehydrogenases functioning in energy metabolism (α-oxoglutarate dehydrogenase [α-KGDHc] and pyruvate dehydrogenase [PDHc]), or amino acid metabolism (branched-chain oxoacid dehydrogenase, 2-oxoadipate dehydrogenase). Mitochondrial lipoate synthesis involves three enzymatic steps catalyzed sequentially by lipoyl(octanoyl) transferase 2 (LIPT2), lipoic acid synthetase (LIAS), and lipoyltransferase 1 (LIPT1). Mutations in LIAS have been associated with nonketotic hyperglycinemia-like early-onset convulsions and encephalopathy combined with a defect in mitochondrial energy metabolism. LIPT1 deficiency spares GCS deficiency and has been associated with a biochemical signature of combined 2-oxoacid dehydrogenase deficiency leading to early death or Leigh-like encephalopathy. We report on the identification of biallelic LIPT2 mutations in three affected individuals from two families with severe neonatal encephalopathy. Brain MRI showed major cortical atrophy with white matter abnormalities and cysts. Plasma glycine was mildly increased. Affected individuals’ fibroblasts showed reduced oxygen consumption rates, PDHc, α-KGDHc activities, leucine catabolic flux, and decreased protein lipoylation. A normalization of lipoylation was observed after expression of wild-type LIPT2, arguing for LIPT2 requirement in intramitochondrial lipoate synthesis. Lipoic acid supplementation did not improve clinical condition nor activities of PDHc, α-KGDHc, or leucine metabolism in fibroblasts and was ineffective in yeast deleted for the orthologous LIP2 . [ABSTRACT FROM AUTHOR]

Objective: Diabetes mellitus is associated with an increased risk of cardiovascular disease (CVD) and death. Because the prevalence of diabetes is rising worldwide and chronic heart failure (CHF) is becoming increasingly common with the aging population, it is timely to examine the impact of diabetes per se on 1-year adverse outcomes in patients with CHF.Research Design and Methods: We prospectively assessed whether diabetes status independently affected the 1-year risk of all-cause and CVD mortality and first hospitalization for worsening heart failure (HF) in a multinational cohort of 9,428 outpatients with CHF enrolled in the European Society of Cardiology and Heart Failure Association Long-Term Registry.Results: Compared with those patients without diabetes, patients with diabetes (n = 3,440, 36.5%) had higher cumulative rates of 1-year all-cause death (9.4% vs. 7.2%; adjusted hazard ratio [HR] 1.28; 95% CI 1.07-1.54), CVD death (4.8% vs. 3.8%; adjusted HR 1.28; 95% CI 0.99-1.66), and HF hospitalization (13.8% vs. 9.3%; adjusted HR 1.37; 95% CI 1.17-1.60), all independent of age, sex, BMI, smoking, systolic blood pressure, estimated glomerular filtration rate, hemoglobin, HF etiology, left ventricular ejection fraction, hypertension, statin use, and prior stroke or chronic obstructive pulmonary disease. Among CHF patients with HbA1c measurements available at baseline (n = 2,567), there was a significant and independent association between increasing HbA1c levels and the risk of 1-year survival outcomes.Conclusions: The presence of diabetes markedly increases the risk of 1-year adverse clinical outcomes in outpatients with CHF independent of multiple common risk factors. More effective and personalized treatment for diabetes should be considered in this particularly high-risk patient population. [ABSTRACT FROM AUTHOR]

Rotavirus NSP3 is a translational surrogate of the PABP-poly(A) complex for rotavirus mRNAs. To further explore the effects of NSP3 and untranslated regions (UTRs) on rotavirus mRNAs translation, we used a quantitative in vivo assay with simultaneous cytoplasmic NSP3 expression (wild-type or deletion mutant) and electroporated rotavirus-like and standard synthetic mRNAs. This assay shows that the last four GACC nucleotides of viral mRNA are essential for efficient translation and that both the NSP3 eIF4G- and RNA-binding domains are required. We also show efficient translation of rotavirus-like mRNAs even with a 5’UTR as short as 5 nucleotides, while more than eleven nucleotides are required for the 3’UTR. Despite the weak requirement for a long 5’UTR, a good AUG environment remains a requirement for rotavirus mRNAs translation. [ABSTRACT FROM AUTHOR]

Objective Mutations in the syntaxin binding protein 1 gene ( STXBP1) have been associated mostly with early onset epileptic encephalopathies ( EOEEs) and Ohtahara syndrome, with a mutation detection rate of approximately 10%, depending on the criteria of selection of patients. The aim of this study was to retrospectively describe clinical and electroencephalography ( EEG) features associated with STXBP1-related epilepsies to orient molecular screening. Methods We screened STXBP1 in a cohort of 284 patients with epilepsy associated with a developmental delay/intellectual disability and brain magnetic resonance imaging ( MRI) without any obvious structural abnormality. We reported on patients with a mutation and a microdeletion involving STXBP1 found using array comparative genomic hybridization ( CGH). Results We found a mutation of STXBP1 in 22 patients and included 2 additional patients with a deletion including STXBP1. In 22 of them, epilepsy onset was before 3 months of age. EEG at onset was abnormal in all patients, suppression-burst and multifocal abnormalities being the most common patterns. The rate of patients carrying a mutation ranged from 25% in Ohtahara syndrome to <5% in patients with an epilepsy beginning after 3 months of age. Epilepsy improved over time for most patients, with an evolution to West syndrome in half. Patients had moderate to severe developmental delay with normal head growth. Cerebellar syndrome with ataxic gait and/or tremor was present in 60%. Significance Our data confirm that STXBP1 mutations are associated with neonatal-infantile epileptic encephalopathies. The initial key features highlighted in the cohort of early epileptic patients are motor seizures either focal or generalized, abnormal initial interictal EEG, and normal head growth. In addition, we constantly found an ongoing moderate to severe developmental delay with normal head growth. Patients often had ongoing ataxic gait with trembling gestures. Altogether these features should help the clinician to consider STXBP1 molecular screening. [ABSTRACT FROM AUTHOR]

Objective 17q12 microdeletion syndrome involves 15 genes, including HNF1B, and is considered to confer a high risk of neuropsychiatric disorders. Patients with HNF1B gene deletion diagnosed secondary to renal disorders are only very rarely reported to have neuropsychiatric disorders. Interestingly, however, when tested, patients with HNF1B gene deletion are found to have 17q12 deletion. This brings into question the extent to which 17q12 deletion is genuinely associated with severe neuropsychological disorders and in which patients. In this study, we sought to confirm 17q12 microdeletion in kidney patients initially diagnosed with HNF1B gene deletion and evaluate neuropsychological disorders in these patients compared with those with HNF1B point mutation. Patients and design Thirty-nine children with HNF1B disorders (26 with deletions) diagnosed secondary to renal abnormalities were included in this prospective study and tested for 17q12 microdeletion and neuropsychological disorders. Results The same 17q12 microdeletion found in patients with neuropsychological disorders was identified in all of our patients with HNF1B deletion. Neurological examinations found no severe impairments except for one patient with autism. No significant differences were found between patients with deletions and those with point mutations as concerns learning abilities and schooling. Nevertheless, patients with deletions tended to have lower developmental quotients and more difficulties at school. Conclusions Complete deletion of the HNF1B gene and 17q12 microdeletion syndrome are actually the same genetic disorder. The neuropsychological phenotype of patients appears less severe when 17q12 deletion is diagnosed secondary to kidney rather than neuropsychological abnormalities. These data may influence antenatal counselling. [ABSTRACT FROM AUTHOR]

Background There is great variability for the type of anaesthesia used during TAVI, with no clear consensus coming from comparative studies or guidelines. We sought to detect regional differences in the anaesthetic management of patients undergoing transcatheter aortic valve implantation (TAVI) in Europe and to evaluate the relationship between type of anaesthesia and in-hospital and 1 year outcome. Methods Between January 2011 and May 2012 the Sentinel European TAVI Pilot Registry enrolled 2807 patients treated via a transfemoral approach using either local (LA-group, 1095 patients, 39%) or general anaesthesia (GA-group, 1712 patients, 61%). Results A wide variation in LA use was evident amongst the 10 participating countries. The use of LA has increased over time (from a mean of 37.5% of procedures in the first year, to 57% in last 6 months, p < 0.01). MI, major stroke as well as in-hospital death rate (7.0% LA vs 5.3% GA, p = 0.053) had a similar incidence between groups, confirmed in multivariate regression analysis after adjusting for confounders. Dividing our population in tertiles according to the Log-EuroSCORE we found similar mortality under LA, whilst mortality was higher in the highest risk tertile under GA. Survival at 1 year, compared by Kaplan-Meier analysis, was similar between groups (log-rank: p = 0.1505). Conclusions Selection of anaesthesia appears to be more influenced by national practice and operator preference than patient characteristics. In the absence of an observed difference in outcomes for either approach, there is no compelling argument to suggest that operators and centres should change their anaesthetic practice. [ABSTRACT FROM AUTHOR]

Summary Purpose: STXBP1 (MUNC18-1) mutations have been associated with various types of epilepsies, mostly beginning early in life. To refine the phenotype associated with STXBP1 aberrations in early onset epileptic syndromes, we studied this gene in a cohort of patients with early onset epileptic encephalopathy. Methods: STXBP1 was screened in a multicenter cohort of 52 patients with early onset epilepsy (first seizure observed before the age of 3 months), no cortical malformation on brain magnetic resonance imaging (MRI), and negative metabolic screening. Three groups of patients could be distinguished in this cohort: (1) Ohtahara syndromes (n = 38); (2) early myoclonic encephalopathies (n = 7); and (3) early onset epileptic encephalopathies that did not match any familiar syndrome (n = 7). None of the patients displayed any cortical malformation on brain MRI and all were screened through multiple video-electroencephalography (EEG) recordings for a time period spanning from birth to their sixth postnatal month. Subsequently, patients had standard EEG or video-EEG recordings. Key Findings: We found five novel STXBP1 mutations in patients for whom video-EEG recordings could be sampled from the beginning of the disease. All patients with a mutation displayed Ohtahara syndrome, since most early seizures could be classified as epileptic spasms and since the silent EEG periods were on average shorter than bursts. However, each patient in addition displayed a particular clinical and EEG feature: In two patients, early seizures were clonic, with very early EEG studies exhibiting relatively low amplitude bursts of activity before progressing into a typical suppression-burst pattern, whereas the three other patients displayed epileptic spasms associated with typical suppression-burst patterns starting from the early recordings. Epilepsy dramatically improved after 6 months and finally disappeared before the end of the first year of life for four patients; the remaining one patient had few seizures until 18 months of age. In parallel, EEG paroxysmal abnormalities disappeared in three patients and decreased in two, giving place to continuous activity with fast rhythms. Each patient displayed frequent nonepileptic movement disorders that could easily be mistaken for epileptic seizures. These movements could be observed as early as the neonatal period and, unlike seizures, persisted during all the follow-up period. Significance: We confirm that STXBP1 is a major gene to screen in cases of Ohtahara syndrome, since it is mutated in >10% of the Ohtahara patients within our cohort. This gene should particularly be tested in the case of a surprising evolution of the patient condition if epileptic seizures and EEG paroxysmal activity disappear and are replaced by fast rhythms after the end of the first postnatal year. [ABSTRACT FROM AUTHOR]

Abstract: Very Long-Chain Acyl-CoA dehydrogenase (VLCAD) deficiency is an inborn error of mitochondrial long-chain fatty acid oxidation (FAO) most often occurring in childhood with cardiac or liver involvement, but rhabdomyolysis attacks have also been reported in adults. We report in this study the clinical, biochemical and molecular studies in 13 adult patients from 10 different families with VLCAD deficiency. The enzyme defect was demonstrated in cultured skin fibroblasts or lymphocytes. All patients exhibited exercise intolerance and recurrent rhabdomyolysis episodes, which were generally triggered by strenuous exercise, fasting, cold or fever (mean age at onset: 10years). Inaugural life-threatening general manifestations also occurred before the age of 3years in four patients. Increased levels of long-chain acylcarnitines with tetradecenoylcarnitine (C14:1) as the most prominent species were observed in all patients. Muscle biopsies showed a mild lipidosis in four patients. For all patients but two, molecular analysis showed homozygous (4 patients) or compound heterozygous genotype (7 patients). For the two remaining patients, only one mutation in a heterozygous state was detected. This study confirms that VLCAD deficiency, although being less frequent than CPT II deficiency, should be systematically considered in the differential diagnosis of exercise-induced rhabdomyolysis. Measurement of fasting blood acylcarnitines by tandem mass spectrometry allows accurate biochemical diagnosis and should therefore be performed in all patients presenting with unexplained muscle exercise intolerance or rhabdomyolysis. [Copyright &y& Elsevier]