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Background Survival rates in refractory out-of-hospital cardiac arrest (OHCA) remain low with conventional advanced cardiac life support (ACLS). Extracorporeal life support (ECLS) implantation during ongoing resuscitation, a method called extracorporeal cardiopulmonary resuscitation (ECPR), may increase survival. This study examined whether ECPR is associated with improved outcomes. Methods Prague OHCA trial enrolled adults with a witnessed refractory OHCA of presumed cardiac origin. In this secondary analysis, the effect of ECPR on 180-day survival using Kaplan–Meier estimates and Cox proportional hazard model was examined. Results Among 256 patients (median age 58 years, 83% male) with median duration of resuscitation 52.5 min (36.5–68), 83 (32%) patients achieved prehospital ROSC during ongoing conventional ACLS prehospitally, 81 (32%) patients did not achieve prehospital ROSC with prolonged conventional ACLS, and 92 (36%) patients did not achieve prehospital ROSC and received ECPR. The overall 180-day survival was 51/83 (61.5%) in patients with prehospital ROSC, 1/81 (1.2%) in patients without prehospital ROSC treated with conventional ACLS and 22/92 (23.9%) in patients without prehospital ROSC treated with ECPR (log-rank p  < 0.001). After adjustment for covariates (age, sex, initial rhythm, prehospital ROSC status, time of emergency medical service arrival, resuscitation time, place of cardiac arrest, percutaneous coronary intervention status), ECPR was associated with a lower risk of 180-day death (HR 0.21, 95% CI 0.14–0.31; P  < 0.001). Conclusions In this secondary analysis of the randomized refractory OHCA trial, ECPR was associated with improved 180-day survival in patients without prehospital ROSC. Trial registration : ClinicalTrials.gov Identifier: NCT01511666, Registered 19 January 2012.

Background Pegunigalsidase alfa is a novel, PEGylated α-galactosidase-A enzyme-replacement therapy approved in the EU and US to treat patients with Fabry disease (FD). Objective/methods BRIDGE is a phase 3 open-label, switch-over study designed to assess safety and efficacy of 12 months of pegunigalsidase alfa (1 mg/kg every 2 weeks) treatment in adults with FD who had been previously treated with agalsidase alfa (0.2 mg/kg every 2 weeks) for ≥ 2 years. Results Twenty-seven patients were screened; 22 met eligibility criteria; and 20 (13 men, 7 women) completed the study. Pegunigalsidase alfa was well-tolerated, with 97% of treatment-emergent adverse events (TEAEs) being of mild or moderate severity. The incidence of treatment-related TEAEs was low, with 2 (9%) discontinuations due to TEAEs. Five patients (23%) reported infusion-related reactions. Overall mean (SD; n = 22) baseline estimated glomerular filtration rate (eGFR) was 82.5 (23.4) mL/min/1.73 m 2 and plasma lyso-Gb 3 level was 38.3 (41.2) nmol/L (men: 49.7 [45.8] nmol/L; women: 13.8 [6.1] nmol/L). Before switching to pegunigalsidase alfa, mean (standard error [SE]) annualized eGFR slope was − 5.90 (1.34) mL/min/1.73 m 2 /year; 12 months post-switch, the mean eGFR slope was − 1.19 (1.77) mL/min/1.73 m 2 /year; and mean plasma lyso-Gb 3 reduced by 31%. Seven (35%) out of 20 patients were positive for pegunigalsidase alfa antidrug antibodies (ADAs) at ≥ 1 study timepoint, two of whom had pre-existing ADAs at baseline. Mean (SE) changes in eGFR slope for ADA-positive and ADA-negative patients were + 5.47 (3.03) and + 4.29 (3.15) mL/min/1.73 m 2 /year, respectively, suggesting no negative impact of anti-pegunigalsidase alfa ADAs on eGFR slope. Conclusion Pegunigalsidase alfa may offer a safe and effective treatment option for patients with FD, including those previously treated with agalsidase alfa. TRN : NCT03018730. Date of registration: January 2017.

Fabry disease is an X-linked lysosomal storage disorder that causes accumulation of glycosphingolipids in body tissues and fluids, leading to progressive organ damage and life-threatening complications. It can affect both males and females and can be classified into classic or later-onset phenotypes. The disease severity in females ranges from asymptomatic to the more severe, classic phenotype. Most females are hemizygous and the X-linked inheritance is associated with variable X-activation pattern and residual enzymatic activity. The heterogeneity of clinical presentation in females requires different approaches to diagnosis and management than males. A European group of 7 physicians, experienced in the management of Fabry disease, convened to discuss patient perspectives and published guidelines. The experts discussed the need to focus on psychological treatment in relation to individual coping styles when monitoring targets, and the lack of data supporting the use of plasma globotriaosylsphingosine over enzyme activity in the diagnosis of these patients. It was suggested that the high phenotypic variability in female patients may be related to the dynamic nature of the X-chromosome inactivation process and further understanding of this process could help predict the progression of Fabry disease in females and facilitate timely intervention. Due to the range of disease severity they exhibit, female patients with Fabry disease may require a more individualized treatment approach than males. Despite current recommendations, the experts agreed that early disease-specific treatment initiation in high-risk females could improve clinical outcome.

Table 1 Lysosomal storage disease causing cardiac disease Disease group and subtypes General manifestations Cardiac manifestations Glycogen storage diseases (lysosomal) Autosomal recessive Massive LVH and RVH, cardiac failure (only in the infantile form) Myopathy, hypotonia, hepatomegaly, macroglossia cardiopulmonary failure, Short PR, broad QRS; endomyocardial fibrosis Type IIb (Danon disease, LAMP-2 deficiency) X-linked Hypertrophic cardiomyopathy, isolated cardiac variants, short PR, progressive conduction system disease Myopathy, mental retardation Mucopolysaccharidoses IH (Hurler) Autosomal recessive Valvular involvement (thickening, regurgitation, stenosis); endomyocardial infiltration; interstitial infiltration-fibrosis; hypertrophy; systolic dysfunction-dilated cardiomyopathy (less frequent); coronary artery infiltration-stenosis; aortic stenosis (abdominal); arterial hypertension IS (Scheie) X-linked - MPS II (Hunter) II (Hunter) Dysmorphic features, organomegaly, decreased joint mobility, bone deformities, loss of motor skills, mental retardation, corneal clouding, recurrent otitis or pneumonia, hearing loss III (Sanfilippo) IV (Morquio) VI (Maroteaux-Lamy) VII (Sly) IX (Natowicz) Sphingolipidoses Gaucher disease (β-glucocerebrodiase) Autosomal recessive Pulmonary hypertension, cor pulmonale; pericardial effusion (rare); valvular involvement (rare) Chronic non-neuronopathic (type I) Gaucher cells-lipid laden macrophages Acute (type II) Hepatosplenomegaly, anaemia, thrombocytopenia, bone involvement Chronic neuronopathic (type III) Neurodegeneration (neuronopathic forms) Niemann Pick disease (acid sphingomyelinase) Autosomal recessive Endomyocardial fibrosis (very rare) Type A Early onset, neurological involvement, hypotonia, psychomotor retardation (type A), hepatosplenomegaly, pancytopenia, pulmonary involvement Type B Anderson-Fabry disease (α-galactosidase A) X-linked Cardiac hypertrophy; short PR, progressive conduction system dysfunction, arrhythmias; valvular involvement; coronary involvement (decreased coronary reserve) Multiorgan involvement LVH, left ventricular hypertrophy; RVH, right ventricular hypertrophy. [...]many studies have shown that affected women experience symptoms similar to hemizygous males, albeit in a milder form with a delayed onset and slower progression compared to men; similarly, the frequency of end-stage renal disease is much lower and the median cumulative survival greater (70 years vs 50 years) in women. 1 Disease expression in female patients is attributed to random X chromosome inactivation and the incapacity of cells expressing the wild-type allele to cross-correct the metabolic defect. 5 Pathogenesis of cardiac disease in AFD Cross-sectional data in patients of different ages suggest that disease evolution in the heart is characterised initially by myocardial hypertrophy; as the disease progresses interstitial abnormalities and replacement myocardial fibrosis become important.

Compared with Western Europe, the decline in cardiovascular (CV) mortality has been delayed in former communist countries in Europe, including the Czech Republic. We have assessed longitudinal trends in major CV risk factors in the Czech Republic from 1985 to 2016/17, covering the transition from the totalitarian regime to democracy. There were 7 independent cross-sectional surveys for major CV risk factors conducted in the Czech Republic in the same 6 country districts within the WHO MONICA Project (1985, 1988, 1992) and the Czech post-MONICA study (1997/98, 2000/01, 2007/08 and 2016/2017), including a total of 7,606 males and 8,050 females. The population samples were randomly selected (1%, aged 25-64 years). Over the period of 31/32 years, there was a significant decrease in the prevalence of smoking in males (from 45.0% to 23.9%; p < 0.001) and no change in females. BMI increased only in males. Systolic and diastolic blood pressure decreased significantly in both genders, while the prevalence of hypertension declined only in females. Awareness of hypertension, the proportion of individuals treated by antihypertensive drugs and consequently hypertension control improved in both genders. A substantial decrease in total cholesterol was seen in both sexes (males: from 6.21 ± 1.29 to 5.30 ± 1.05 mmol/L; p < 0.001; females: from 6.18 ± 1.26 to 5.31 ± 1.00 mmol/L; p < 0.001). The significant improvement in most CV risk factors between 1985 and 2016/17 substantially contributed to the remarkable decrease in CV mortality in the Czech Republic.

Patients with pulmonary hypertension (PH) frequently suffer from supraventricular tachycardias (SVT). The main purpose of our study was to identify the cumulative incidence of SVT in patients with different etiologies of PH. The secondary objective was to analyse the clinical impact of SVT. We retrospectively studied the prevalence of SVT and the clinical outcome in 755 patients (41% males; 60 ± 15 years; mean follow-up 3.8 ± 2.8 years) with PH of different etiologies. The prevalence of SVT was analysed separately in isolated pre-capillary PH (Ipc-PH) and in patients with combined post- and pre-capillary PH (Cpc-PH). The prevalence of SVT in the Ipc-PH group (n = 641) was 25% (n = 162). The most prevalent arrhythmias were atrial fibrillation followed by a typical atrial flutter (17% and 4.4% of all Icp-PH patients). An excessive prevalence of SVT was found in patients with pulmonary arterial hypertension associated with congenital heart disease (35%, p = 0.01). Out of the overall study population, Cpc-PH was present in 114 (15%) patients. Patients with Cpc-PH manifested a higher prevalence of SVT than subjects with Ipc-PH (58; 51% vs. 162; 25%; p <0.0001) and were more likely to have persistent or permanent atrial fibrillation (38; 29% vs. 61; 10%; p <0.0001). Parameters significantly associated with mortality in a multivariate analysis included age, male gender, functional exercise capacity and right atrial diameter (p < 0.05). Neither diagnosis of SVT nor type of arrhythmia predicted mortality. The study detected a significant prevalence of SVT in the population of PH of different origins. Different spectrum and prevalence of arrhythmia might be expected in different etiologies of PH. Patients with an elevated post-capillary pressure showed a higher arrhythmia prevalence, predominantly due to an excessive number of atrial fibrillations. The diagnosis of SVT was not associated with mortality.

Aims Fabry disease (FD) is often associated with heart failure (HF). However, data on HF prevalence, prognosis, and applicability of echocardiographic criteria for HF diagnosis in FD remain uncertain. Methods and results We evaluated patients with genetically proven FD for symptoms and natriuretic peptides indicating HF. We then analysed the diagnostic utility of the currently recommended European Society of Cardiology (ESC) echocardiographic criteria for HF diagnosis and their relationship to natriuretic peptides. Finally, we examined the association between HF and echocardiographic criteria with mortality and cardiovascular events during follow‐up. Of 116 patients with FD, 48 (41%) had symptomatic HF (mean age 58 ± 11 years, 62% male). HF with preserved ejection fraction (HF‐pEF) was diagnosed in 43 (91%) patients, representing the dominant phenotype. Left ventricular mass index (LVMi) had the highest diagnostic utility (sensitivity 71% and specificity 83%) for HF diagnosis in FD, followed by E/e′ > 9 (sensitivity 76% and specificity 78%) and global longitudinal strain (GLS) <16% (sensitivity 54% and specificity 88%). Log N‐terminal pro‐brain natriuretic peptide correlated significantly with LVMi (r = 0.60), E/e′ (r = 0.54), and GLS (r = 0.52) (all Ps < 0.001) but not with left ventricular ejection fraction (r = −0.034, P = 0.72). During follow‐up (mean 1208 ± 444 days), patients diagnosed with HF had a higher rate of all‐cause mortality and worsening HF (33% vs. 1.5%, P < 0.001). Abnormal LVMi, E/e′ > 9, and GLS < 16% were all associated with higher all‐cause mortality and worsening HF. Conclusions This study found a high prevalence of symptomatic HF in FD patients. HF‐pEF was the dominant phenotype. LVMi, E/e′, and GLS yielded the highest diagnostic utility for HF diagnosis and were significantly correlated with natriuretic peptides levels. Echocardiographic criteria proposed by current ESC HF guidelines apply to Fabry patients and predict cardiovascular events. At follow‐up, Fabry patients with HF diagnosis had high event rates and significantly worse prognosis than patients without HF.

Short-term mechanical circulatory supports (MCS) are used to stabilize patients with severe cardiogenic shock (CS). Catheter ablation may be an option to suppress recurrent arrhythmias preventing MCS weaning. We retrospectively analysed a dedicated registry to identify CS patients who underwent a catheter ablation between January 2020 and August 2024 for treatment resistant and hemodynamically significant arrhythmias while being on the MCS. Patients with supraventricular and ventricular tachycardias (SVT/VT) were analysed separately. Nine patients (8 males, 69 [IQR 60;74] years) were ablated for a refractory VT. Impella CP was used in 6 patients, VA ECMO in 2 patients, and 1 patient was on ECPELLA. Seven patients (78%) were successfully weaned off the MCS after the catheter ablation. 3 patients (33%) died within 30 days. The arrhythmia recurred in 5 patients (56%). Significant complications of MCS were reported in 6 patients (66%). The catheter ablation was complicated in one patient. SVT ablation was performed in 4 patients (3 males, 73 [IQR 67; 78] years, 1x VA ECMO, 2x Impella CP, 1x Impella 5.5). Three patients with atrial fibrillation were treated by a non-selective AV node ablation (pace and ablate strategy). One patient underwent an ablation of focal atrial tachycardia. The MCS was successfully explanted in all patients and no patient died in 30 days. The MCS use was complicated in one patient. Catheter ablation of refractory arrhythmias in CS patients treated by MCS is a safe and feasible approach to facilitate the MCS weaning process.

BackgroundPegunigalsidase alfa is a PEGylated α-galactosidase A enzyme replacement therapy. BALANCE (NCT02795676) assessed non-inferiority of pegunigalsidase alfa versus agalsidase beta in adults with Fabry disease with an annualised estimated glomerular filtration rate (eGFR) slope more negative than −2 mL/min/1.73 m2/year who had received agalsidase beta for ≥1 year.MethodsPatients were randomly assigned 2:1 to receive 1 mg/kg pegunigalsidase alfa or agalsidase beta every 2 weeks for 2 years. The primary efficacy analysis assessed non-inferiority based on median annualised eGFR slope differences between treatment arms.ResultsSeventy-seven patients received either pegunigalsidase alfa (n=52) or agalsidase beta (n=25). At baseline, mean (range) age was 44 (18–60) years, 47 (61%) patients were male, median eGFR was 74.5 mL/min/1.73 m2 and median (range) eGFR slope was −7.3 (−30.5, 6.3) mL/min/1.73 m2/year. At 2 years, the difference between median eGFR slopes was −0.36 mL/min/1.73 m2/year, meeting the prespecified non-inferiority margin. Minimal changes were observed in lyso-Gb3 concentrations in both treatment arms at 2 years. Proportions of patients experiencing treatment-related adverse events and mild or moderate infusion-related reactions were similar in both groups, yet exposure-adjusted rates were 3.6-fold and 7.8-fold higher, respectively, with agalsidase beta than pegunigalsidase alfa. At the end of the study, neutralising antibodies were detected in 7 out of 47 (15%) pegunigalsidase alfa-treated patients and 6 out of 23 (26%) agalsidase beta-treated patients. There were no deaths.ConclusionsBased on rate of eGFR decline over 2 years, pegunigalsidase alfa was non-inferior to agalsidase beta. Pegunigalsidase alfa had lower rates of treatment-emergent adverse events and mild or moderate infusion-related reactions.Trial registration number NCT02795676.

BackgroundAgalsidase β is a form of enzyme replacement therapy for Fabry disease, a genetic disorder characterised by low α-galactosidase A activity, accumulation of glycosphingolipids and life-threatening cardiovascular, renal and cerebrovascular events. In clinical trials, agalsidase β cleared glycolipid deposits from endothelial cells within 6 months; clearance from other cell types required sustained treatment. We hypothesised that there might be a ‘lag time’ to clinical benefit after initiating agalsidase β treatment, and analysed the incidence of severe clinical events over time in patients receiving agalsidase β.MethodsThe incidence of severe clinical events (renal failure, cardiac events, stroke, death) was studied in 1044 adult patients (641 men, 403 women) enrolled in the Fabry Registry who received agalsidase β (average dose 1 mg/kg every 2 weeks) for up to 5 years.ResultsThe incidence of all severe clinical events was 111 per 1000 person-years (95% CI 84 to 145) during the first 6 months. After 6 months, the incidence decreased and remained stable within the range of 40–58 events per 1000 patient-years. The largest decrease in incidence rates was among male patients and those aged ≥40 years when agalsidase β was initiated.ConclusionsContrary to the expected increased incidence of severe clinical events with time, adult patients with Fabry disease had decreased incidence of severe clinical events after 6 months treatment with agalsidase β 1 mg/kg every 2 weeks.Trial registration numberNCT00196742.