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Fabry disease (FD) constitutes a rare, X-linked lysosomal storage disorder affecting multiple organ systems, most notably heart, kidneys, and the central nervous system. Neurofilament light chains (NfL) have emerged as a prime candidate for a body fluid biomarker reflecting neuro-axonal injury. We aimed to evaluate its addition to the diagnostic and monitoring armamentarium in FD. Serum NfL concentrations (sNfL) were measured in 50 people with FD (PwFD) and 30 healthy control subjects (HC) using the Simoa© technology, followed by calculation of Z-scores adjusted for age and body mass index. In addition, clinical disease severity in PwFD was measured using the FOS-MSSI (Fabry outcome study – Mainz severity score index), which comprises clinical and paraclinical parameters. PwFD show elevated sNfL Z-scores compared to HC (PwFD: 1.12 [SD 1.5], HC: 0.01 [SD 1.2], p  < 0.001). In PwFD, males showed higher sNfL Z-scores than females (1.75 [SD 1.5] vs. 0.73 [SD 1.4]). Importantly, sNfL Z-scores were increased in PwFD with ischemic white matter lesions of the CNS (1.5, SD 2.2 vs. 0.5, SD 2.9, p  = 0.03). In our small cohort, sNfL Z-scores correlated fairly with FOS-MSSI (Kendall’s-Tau [τ] = 0.25, p  = 0.01), and, interestingly with serum creatinine (τ = 0.28, p  = 0.005) and estimated glomerular filtration rate (eGFR, τ =-0.28, p  = 0.005). Based on these exploratory results, sNfL might provide value as a biomarker of neuroaxonal damage in FD, possibly reflecting cerebrovascular injury. Additionally, the correlation of sNfL with renal function warrants further investigation.

Background Pregnancy and delivery outcomes in women with Fabry disease are not well described. Methods Retrospective cohort-study of women with Fabry disease in Austria using a specific questionnaire and the Austrian Mother–Child Health Passport. Results Out of a total of 44 enrolled women (median age at study entry 44 years, p25: 30, p75: 51), 86.4% showed signs and symptoms of Fabry disease with an increase in pain burden during pregnancy, primarily in women with moderate pain before pregnancy. Thirty-two of 44 women with Fabry disease reported a total of 70 pregnancies (median age at first pregnancy 24 years, p25: 21, p75: 31), 61 (87.1%) of which resulted in 64 live births including 3 sets of twins, six miscarriages (8.6%) in five women, and three induced abortions (4.3%) in two women. Risk factors for poor maternal and foetal outcomes during pregnancy, overrepresented in our cohort as compared to the general population, were hypertension ( n  = 10, 16.4%), proteinuria ( n  = 17, 27.9%) and smoking ( n  = 24, 39.3%). Preeclampsia was reported in 7 pregnancies (11.5%). Fifty-one (79.7%) children were born at term and 13 (20.3%) were preterm (including one neonatal death), with a median gestational age of 39 weeks (p25: 38, p75: 40) and delivery by C-section in 15 pregnancies (24.6%). Thirteen (20.3%) children presented with low birth weight and 18 (28.1%) were small for their gestational age. In comparison to global and national data-sets, preeclampsia, prematurity, low birth weight, being small for their gestational age as well as inpatient stay were significantly more common in patients with Fabry disease. Conclusions Our cohort-study in women with Fabry disease shows an increase of pain burden during pregnancies and clearly points to an increased risk for preeclampsia, prematurity, and neonates small for gestational age. With a substantial number of high-risk pregnancies, neonatal outcomes are somewhat worse in Fabry disease than in the general public. Thus, we provide valuable data enabling informed decision-making in pregnancy counselling for Fabry disease.

Data on cardiac remodeling in veteran athletes are conflicting but of clinical importance. Sixty-nine clinically stable and healthy individuals >50 years were identified (median 55 (IQR 52-64), 26% female). Echocardiographic features were identified in individuals, who have performed endurance sports at 70% of their maximum heart rate for at least 1 hour 3 times/ week over the previous 5 years. Median training time in all participants was 6 hours per week. Therefore, based on these 6 hours of weekly training, participants were grouped into 45 ambitious endurance-trained amateur athletes (EAA) and 24 recreationally active endurance-trained athletes (RAP) training ≥6 hours (6-10) and <6 hours (3.5-5), respectively. Left ventricular (LV) diameters were slightly larger in EAA than in RAP (27 mm/m2 (25-28) vs. 25 mm/m2 (24-27), p = 0.023) and EAA showed preserved diastolic function (p = 0.028) with lower E/E' ratio (7 (6-9) vs. 9 (7-10), p = 0.039). Interventricular septal thickness and relative wall thickness ratio were similar. Global right ventricular and LV strain were similar, but left atrial (LA) reservoir strain was higher in EAA than in RAP (27% (22-34) vs. 20% (15-29), p = 0.002). Endurance training in healthy athletes >50 years is not associated with chamber dilatation or LV hypertrophy. A weekly training duration of ≥6 hours seems beneficial to preserve diastolic function associated with an increased LA reservoir function.

Background Temporary epicardial pacing wires, implemented in patients during heart transplantation, are routinely removed before discharge. However, in some cases, these wires may remain in situ and are often considered as a contraindication for cardiovascular magnetic resonance (CMR) imaging in the future. Therefore, we aimed to provide data about safety and image quality of CMR in these patients. Methods This is a report on a subpopulation out of 88 patients after heart transplantation that were included in a prospective cohort study and underwent multiple CMR in their post-transplant course. During CMR, patients were monitored by electrocardiogram and all examinations were observed by a physician to document potential adverse events. Additionally, image quality was assessed by an imaging specialist. Results Nineteen of 88 patients included had temporary pacing wires in situ. These patients underwent a total of 51 CMR studies. No major adverse event and only one single, mild sensory event could be documented. All CMR studies showed preserved diagnostic image quality. Temporary pacing wires were visible in 100% of HASTE and cine sequences. In less than 50% of the examinations, temporary pacing wires were also visible in T1 and T2 mapping, short tau inversion recovery (STIR), and late gadolinium enhancement (LGE) sequences, without any impairment of image quality. Conclusions With a low event rate of only one mild adverse event during 51 CMR examinations (2%), CMR appears to be safe in patients with retained temporary epicardial pacing wires after heart transplantation. Moreover, image quality was not impaired by the presence of pacing wires.

Background: Fabry cardiomyopathy is characterized by left ventricular hypertrophy, myocardial fibrosis, arrhythmia, and premature death. Treatment with migalastat, an oral pharmacological chaperone, was associated with a stabilization of cardiac biomarkers and a reduction in left ventricular mass index, as measured by echocardiography. A recent study, using cardiac magnetic resonance (CMR) as the gold standard, found a stable course of myocardial involvement after 18 months of treatment with migalastat. Our study aimed to provide long-term CMR data for the treatment with migalastat. Methods: A total of 11 females and four males with pathogenic amenable GLA mutations were treated with migalastat and underwent 1.5T CMR imaging for routine treatment effect monitoring. The main outcome was a long-term myocardial structural change, reflected by CMR. Results: After migalastat treatment initiation, left ventricular mass index, end diastolic volume, interventricular septal thickness, posterior wall thickness, estimated glomerular filtration rate, and plasma lyso-Gb3 remained stable during the median follow-up time of 34 months (min.: 25; max.: 47). The T1 relaxation times, reflecting glycosphingolipid accumulation and subsequent processes up to fibrosis, fluctuated over the time without a clear trend. No new onset of late gadolinium enhancement (LGE) areas, reflecting local fibrosis or scar formation of the myocardium, could be detected. However, patients with initially present LGE showed an increase in LGE as a percentage of left ventricular mass. The median α-galactosidase A enzymatic activity increased from 37.3% (IQR 5.88–89.3) to 105% (IQR 37.2–177) of the lower limit of the respective reference level (p = 0.005). Conclusion: Our study confirms an overall stable course of LVMi in patients with FD, treated with migalastat. However, individual patients may experience disease progression, especially those who present with fibrosis of the myocardium already at the time of therapy initiation. Thus, a regular treatment re-evaluation including CMR is needed to provide the optimal management for each patient.

Background: Police first responder systems also including automated external defibrillation (AED) has in the past shown considerable impact on favourable outcomes after out-of-hospital cardiac arrest (OHCA). While short hands-off times in chest compressions are known to be beneficial, various AED models use different algorithms, inducing longer or shorter durations of crucial timeframes along basic life support (BLS). Yet, data on details of these differences, and also of their potential impact on clinical outcomes are scarce. Methods: For this retrospective observational study, patients with OHCA of presumed cardiac origin and initially shockable rhythm treated by police first responders in Vienna, Austria, between 01/2013 and 12/2021 were included. Data from the Viennese Cardiac Arrest Registry and AED files were extracted, and exact timeframes were analyzed. Results: There were no significant differences in the 350 eligible cases in demographics, return of spontaneous circulation, 30-day survival, or favourable neurological outcome between the used AED types. However, the Philips HS1 and -FrX AEDs showed immediate rhythm analysis after electrode placement (0 [0–1] s) and almost no shock loading time (0 [0–1] s), as opposed to the LP CR Plus (3 [0–4] and 6 [6–6] s, respectively) and LP 1000 (3 [2–10] and 6 [5–7] s, respectively). On the other hand, the HS1 and -FrX had longer analysis times of 12 [12–16] and 12 [11–18] s than the LP CR Plus (5 [5–6] s) and LP 1000 (6 [5–8] s). The duration from when the AED was turned on until the first defibrillation were 45 [28–61] s (Philips FrX), 59 [28–81] s (LP 1000), 59 [50–97] s (HS1), and 69 [55–85] s (LP CR Plus). Conclusion: In a retrospective analysis of OHCA-cases treated by police first responders, we could not find significant differences in clinical patient outcomes concerning the respective used AED model. However, various differences in time durations (e.g., electrode placement to rhythm analysis, analysis duration, or AED turned on until first defibrillation) along the BLS algorithm were seen. This opens up the question of AED-adaptations and tailored training methods for professional first responders.

Background: The diagnosis and follow-up of cardiac involvement in Fabry disease constitutes an important challenge for clinicians caring for affected patients. Combining cardiac imaging with laboratory biomarkers appears most appropriate for longitudinal monitoring. Therefore, we examined the use of NT-proBNP and its association with imaging findings in patients with Fabry disease. Methods: We analysed cardiac MRI and echocardiography data, as well as laboratory results, from a single-centre prospective registry. Results: Repetitive follow-ups of 38 patients with Fabry disease, of whom 18 presented with left ventricular hypertrophy (LVH), revealed a correlation of NT-proBNP with left ventricular (LV) interventricular septal thickness, LV maximum wall thickness, LV and right ventricular (RV) mass index and trabecular mass in patients with LVH. Patients without LVH did not exhibit any tangible association between NT-proBNP and the mentioned parameters. Conversely, we could not detect an association of NT-proBNP with impairment of LV or RV ejection fraction or diastolic volume. Conclusions: NT-proBNP plays a pivotal role as a biomarker for cardiac involvement in patients with Fabry disease. Interestingly, in this specific population with mostly preserved ejection fraction, it seems to reflect ventricular hypertrophy rather than ventricular dysfunction or dilatation. While strong associations were found in hypertrophic patients, NT-proBNP’s prognostic value appears limited in non- or pre-hypertrophic stages.

Regular physical exercise was found to be associated with an improved immune response in previous studies. RANTES and CD40L play a pivotal role in host defense, and individuals lacking adequate expression are prone to virus and opportunistic infections. A total of 98 participants were enrolled in this study. The probands were asked to perform moderate physical activity, and bicycle stress tests were performed at the baseline and after 8 months of training to evaluate individual performance. RANTES and CD40L were found to be increased by long-term physical exercise. In particular, probands with a performance gain of ≥3% displayed a pronounced elevation of both markers, paired with a decrease in circulating IL6 levels and an improved lipid profile. In summary, we were able to highlight rising levels of serum RANTES and CD40L under the conditions of physical exercise. Taking their role in host defense into account, a conjunction of physical activity and the adaptive immune system could therefore be assumed. Furthermore, low inflammatory profiles in probands with a significant performance gain suggest a modulation through exercise rather than a generalized pro-inflammatory status.

Background: Critically ill patients often display systemic immune dysregulation and increased inflammatory activity. Hemophagocytic lymphohistiocytosis (HLH) represents a rare syndrome defined by the inappropriate survival of cytotoxic T cells and the occurrence of cytokine storms. Although HLH is characterized by relatively high mortality rates, little is known about the predictive value of its diagnostic criteria. Accordingly, our objective was to evaluate these properties within an unselected cohort of critically ill patients admitted to a tertiary intensive care unit (ICU). Methods: This single-center prospective observational study included 176 consecutive patients. Available HLH criteria at admission were assessed, including sCD25 measurements performed using ELISA. Results: Overall, 30-day mortality rates were significantly higher in patients exhibiting two or more criteria of HLH (21.9% vs. 43.3%, p = 0.033). Moreover, sCD25 emerged as an independent risk predictor of 30-day mortality independent of age, sex, the use of vasopressors, and mechanical ventilation (HR 2.72 for the highest tertile vs. lowest tertile, p = 0.012). Additionally, fibrinogen was significantly decreased in non-survivors (p = 0.019), and its addition to the SAPS II score significantly increased its prognostic capability (p = 0.045). In contrast, ferritin and triglyceride levels were not different in survivors versus non-survivors. Conclusions: Critically ill patients displaying two or more HLH criteria exhibit a dramatic increase in 30-day mortality, even in the absence of an established HLH diagnosis. Furthermore, elevated levels of sCD25 and decreased levels of fibrinogen were found to be significant predictors of mortality.

Background: Fabry disease is a hereditary genetic defect resulting in reduced activity of the enzyme α-galactosidase-A and the accumulation of globotriaosylceramide (Gb3) in body fluids and cells. Gb3 accumulation was especially reported for the vascular endothelium in several organs. Methods: Three Fabry disease patients were screened using a micro-RNA screen. An in vitro approach in human endothelial cells was used to determine miRNA regulation by Gb3. Results: In a micro-RNA screen of three Fabry patients undergoing enzyme replacement therapy, we found that miRNAs let-7a and let-7d were significantly increased after therapy. We demonstrate in vitro in endothelial cells that Gb3 induced activation of NF-κB and activated downstream targets. In addition, NF-κB activity directly reduced let-7a and let-7d miRNA expression as inhibiting NF-kB nuclear entry abolished the Gb3 effects. Conclusion: We suggest that let-7a and let-7d are potential markers for enzyme activity and inflammation in Fabry disease patients.