Amyotrophic lateral sclerosis

Amiotrofična lateralna skleroza (ALS) je neurodegenerativna bolest koju karakterizira progresivna mišićna slabost. Očituje se znacima poremećaja gornjeg i donjeg motornog neurona. Prvi znak bolesti može biti asimetrična slabost i atrofija mišića ekstremiteta ili se najprije javljaju bulbarni simptomi. Bolest je progresivna i atrofija postepeno zahvaća sve mišiće. Bulbarni oblik bolesti brže progredira i nakon 2 do 3 godine dolazi do zatajivanja disanja, dok je kod spinalnog oblika bolesti preživljavanje nešto duže, 3 do 5 godina. Prosječna dob početka bolesti je 56 godina. Incidencija ALS-a u Europi je 2 – 3/100.000 u općoj populaciji. ALS u 90 % slučajeva nastaje sporadično (SALS), dok je 10 % familijarno (FALS). Uzrok nastanka ALS-a nije poznat. U 20 % familijarnih oblika i u 5 % sporadičnih oblika ALS-a nađena je mutacija gena koji kodira enzim Zn/Cu superoksid dizmutazu (SOD1), snažni antioksidans. Kao uzrok nastanka ALS-a danas se spominje toksično djelovanje glutamata, poremećaj imunoloških procesa, djelovanje neurotrofičnih čimbenika i čimbenika okoline (teški metali, pesticidi, trauma). Dijagnoza ALS-a temelji se na kliničkoj slici, elektrodijagnostičkom testiranju i isključenju stanja koja mogu imitirati ALS. Riluzol je jedini učinkoviti lijek koji produžuje vrijeme preživljavanja za prosječno 3 mjeseca. Optimalni tretman temelji se na liječenju simptoma i održavanju kvalitete života, osiguranih u multidisciplinarnom okruženju.Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive muscular weakness. It affects both upper and lower motor neurons. Affected individuals typically present with either asymmetric weakness of the extremities or with bulbar symptoms (dysarthria, dysphagia). Weakness is always progressive and leads to death due to respiratory failure within 2-3 years in bulbar onset cases, and 3-5 years in spinal onset ALS cases. The mean age of ALS onset is 56 years. The incidence in Europe is 2–3 cases per 100,000 individuals in the general population. ALS is sporadic in 90 % of cases (SALS), whereas only 10 % is familial (FALS). The cause of ALS is unknown although some genetic risk factors have been identified. Mutations in superoxide dismutase gene (SOD1) account for 20 % of familial and 5 % of sporadic ALS. Other possible causes include higher than normal levels of glutamate, neurotrophic factor impairment, impairment of immune system and environmental factors (toxic metals, pesticides, and trauma). The diagnosis of ALS is based on clinical features, electro-diagnostic testing, and exclusion of conditions that can mimic ALS. Riluzole remains the only effective drug, and extends the average survival by 3 months. Optimal treatment is based on symptoms management and preservation of quality of life, provided in a multidisciplinary setting

Premature stroke and cardiovascular risk in primary Sjögren's syndrome

IntroductionPrimary Sjögren's syndrome (pSS) is associated with an increased prevalence of traditional risk factors and cardiovascular diseases (CVDs). The study aimed to identify specific risk factors for CVD in pSS patients.MethodsPSS patients with and without CVD were compared. All patients fulfilled the EULAR/ACR classification criteria. Patients with CVD presented at least one of the following manifestations: myocardial infarction, transient ischemic attacks, ischemic or hemorrhagic stroke, peripheral artery disease, coronary artery disease, and carotid plaques. Data were collected by a standardized protocol and review of medical records.Results61/312 (19.6%) pSS patients presented with CVD. Traditional risk factors such as hypertension, hypercholesterinemia and diabetes (p < 0.05), pSS manifestations, in particular vasculitis (p = 0.033) and Raynaud's phenomenon (p = 0.018) were associated with CVD. Among patients with ischemic events (28/312, 9%), particularly cerebrovascular disease (n = 12/28, 42.9%), correlations with increased EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) (p = 0.039) and EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) (p = 0.048) were observed. Age at first cerebrovascular event was 55.2 [48.9–69.6] years. Multivariate analysis confirmed hypertension [odds ratio (OR) 3.7, 95% confidence interval (CI) 1.87–7.18, p < 0.001], hypercholesterinemia (OR 3.1, 95% CI 1.63–5.72, p < 0.001), male gender (OR 0.4, 95% CI 0.17–0.78, p = 0.009), Raynaud's phenomenon (OR 2.5, 95% CI 1.28–4.82, p = 0.007), and CNS involvement (OR 2.7, 95% CI 1.00–7.15, p = 0.048) as independent CVD predictors.ConclusionRaynaud's phenomen as well as vasculitis and high ESSDAI have shown a significant association to CVD. PSS patients with cerebrovascular events were younger than expected. Knowledge about risk factors may help clinicians to identify pSS patients at risk for CVD. After diagnosis of pSS, patients should be screened for risk factors such as hypertension and receive appropriate therapy to prevent or at least reduce sequelae such as infarction. However, further investigations are necessary in order to achieve a reliable risk stratification for these patients

Serum circular RNAs act as blood-based biomarkers for hypertrophic obstructive cardiomyopathy

Altres ajuts: Junge Akademie (MHH); ERC grant Longheart; Deutsche Forschungsgemeinschaft (TRR_267, KFO311).Hypertrophic cardiomyopathy (HCM) is one of the most common hereditary heart diseases and is associated with a high risk of sudden cardiac death. HCM is characterized by pronounced hypertrophy of cardiomyocytes, fiber disarray and development of fibrosis and can be divided into a non-obstructive (HNCM) and obstructive form (HOCM) therefore requiring personalized therapeutic therapies. In the present study, we investigated the expression patterns of several circulating circular RNAs (circRNAs) as potential biomarkers in patients with HCM. We included 64 patients with HCM and 53 healthy controls to the study and quantitatively measured the expression of a set of circRNAs already known to be associated with cardiac diseases (circDNAJC6) and/or being highly abundant in blood (circTMEM56 and circMBOAT2). Abundancy of circRNAs was then correlated to relevant clinical parameters. Serum expression levels of circRNAs DNAJC6, TMEM56 and MBOAT2 were downregulated in patients with HCM. The inverse association between circRNA levels and HCM remained unchanged even after adjusting for confounding factors. All circRNAs, evaluated separately or in combination, showed a robust discrimination capacity when comparing control subjects with HCM, HNCM or HOCM patients (AUC from 0.722 to 0.949). Two circRNAs, circTMEM56 and circDNAJC6, significantly negatively correlated with echocardiographic parameters for HOCM. Collectively, circulating circRNAs DNAJC6, TMEM56 and MBOAT2 can distinguish between healthy and HCM patients. In addition, circTMEM56 and circDNAJC6 could serve as indicators of disease severity in patients with HOCM. Thus, circRNAs emerge as novel biomarkers for HCM facilitating the clinical decision making in a personalized manner

Circulating cardiovascular microRNAs in critically ill COVID ‐19 patients Short title: microRNA signatures in COVID ‐19

Aims: Corona virus disease 2019 (COVID-19) is a still growing pandemic, causing many deaths and socio-economic damage. Elevated expression of the SARS-CoV-2 entry receptor ACE2 on cardiac cells of patients with heart diseases may be related to cardiovascular burden. We have thus analysed cardiovascular and inflammatory microRNAs (miRs), sensitive markers of cardiovascular damage, in critically ill, ventilated patients with COVID-19 or Influenza associated acute respiratory distress syndrome (Influenza-ARDS) admitted to intensive care unit (ICU) and healthy controls. Methods and results: Circulating miRs (miR-21, miR-126, miR-155, miR-208a and miR-499) were analyzed in a discovery cohort consisting of patients with mechanically-ventilated COVID-19 (n = 18) and healthy controls (n = 15). A validation study was performed in an independent cohort of mechanically-ventilated COVID-19 patients (n = 20), Influenza-ARDS patients (n = 13) and healthy controls (n = 32). In both cohorts RNA was isolated from serum and cardiovascular disease/inflammatory-relevant miR concentrations were measured by miR-specific TaqMan PCR analyses. In both the discovery and the validation cohort, serum concentration of miR-21, miR-155, miR-208a and miR-499 were significantly increased in COVID-19 patients compared to healthy controls. Calculating the area under the curve (AUC) using ROC-analysis miR-155, miR-208a and miR-499 showed a clear distinction between COVID-19 and Influenza-ARDS patients. Conclusion: In this exploratory study, inflammation and cardiac myocyte-specific miRs were upregulated in critically ill COVID-19 patients. Importantly, miR profiles were able to differentiate between severely ill, mechanically-ventilated Influenza-ARDS and COVID-19 patients, indicating a rather specific response and cardiac involvement of COVID-19. Keywords: ARDS; COVID-19; SARS-CoV-2; biomarker; influenza; microRNA

Therapeutic modulation of RNA-binding protein Rbm38 facilitates re-endothelialization after arterial injury.

Aims Delayed re-endothelialization after balloon angioplasty in patients with coronary or peripheral artery disease impairs vascular healing and leads to neointimal proliferation. In the present study, we examined the effect of RNA-binding motif protein 38 (Rbm38) during re-endothelialization in a murine model of experimental vascular injury. Methods and results Left common carotid arteries of C57BL/6 mice were electrically denudated and endothelial regeneration was evaluated. Profiling of RNA-binding proteins revealed dysregulated expression of Rbm38 in the denudated and regenerated areas. We next tested the importance of Rbm38 in human umbilical vein endothelial cells (HUVECS) and analysed its effects on cellular proliferation, migration and apoptosis. Rbm38 silencing in vitro demonstrated important beneficial functional effects on migratory capacity and proliferation of endothelial cells. In vivo, local silencing of Rbm38 also improved re-endothelialization of denuded carotid arteries. Luciferase reporter assay identified miR-98 and let-7f to regulate Rbm38 and the positive proliferative properties of Rbm38 silencing in vitro and in vivo were mimicked by therapeutic overexpression of these miRNAs. Conclusion The present data identified Rbm38 as an important factor of the regulation of various endothelial cell functions. Local inhibition of Rbm38 as well as overexpression of the upstream regulators miR-98 and let-7f improved endothelial regeneration in vivo and thus may be a novel therapeutic entry point to avoid endothelial damage after balloon angioplasty

Leukocyte telomere length correlates with hypertrophic cardiomyopathy severity

Telomere length is a marker of biological aging. Short leukocyte telomere length has been associated with various conditions including cardiovascular disorders. Here, we evaluated if patients with hypertrophic cardiomyopathy have altered leukocyte telomere length and whether this is associated with disease severity. A quantitative polymerase chain reaction-based method was used to measure peripheral blood leukocyte telomere length in 59 healthy control subjects and a well-characterized cohort of 88 patients diagnosed with hypertrophic cardiomyopathy: 32 patients with non-obstructive cardiomyopathy (HNCM) and 56 patients with obstructive cardiomyopathy (HOCM). We observed shorter leukocyte telomeres in both HNCM and HOCM patients compared to healthy controls. Furthermore, leukocyte telomere length was inversely associated with HCM even after adjusting for age and sex. Telomere length of HOCM patients was also inversely correlated with left ventricular outflow tract obstruction. Therefore, HOCM patients were categorized by tertiles of telomere length. Patients in the first tertile (shortest telomeres) had a significantly increased left ventricular posterior wall thickness at end-diastole and higher left ventricular outflow tract gradients, whereas the left ventricular end-diastolic diameter was lower compared with patients in the second and third tertile. In summary, telomere length is associated with the severity of the disease in the HOCM subtype.This work was supported by Deutsche Forschungsgemeinschaft (grant number BA5631/2-1 to CB), the Hannover Medical School REBIRTH Excellence cluster (to TT and JB) and the KFO311 (to TT and JB). DdG-C was recipient of a Juan de la Cierva-Incorporación grant from the Ministerio de Economía y Competitividad (IJCI-2016-29393). CIBER Cardiovascular (CB16/11/00403 to DdG-C) is a project of the Instituto de Salud Carlos III.Peer reviewe

Serum circular RNAs act as blood-based biomarkers for hypertrophic obstructive cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is one of the most common hereditary heart diseases and is associated with a high risk of sudden cardiac death. HCM is characterized by pronounced hypertrophy of cardiomyocytes, fiber disarray and development of fibrosis and can be divided into a non-obstructive (HNCM) and obstructive form (HOCM) therefore requiring personalized therapeutic therapies. In the present study, we investigated the expression patterns of several circulating circular RNAs (circRNAs) as potential biomarkers in patients with HCM. We included 64 patients with HCM and 53 healthy controls to the study and quantitatively measured the expression of a set of circRNAs already known to be associated with cardiac diseases (circDNAJC6) and/or being highly abundant in blood (circTMEM56 and circMBOAT2). Abundancy of circRNAs was then correlated to relevant clinical parameters. Serum expression levels of circRNAs DNAJC6, TMEM56 and MBOAT2 were downregulated in patients with HCM. The inverse association between circRNA levels and HCM remained unchanged even after adjusting for confounding factors. All circRNAs, evaluated separately or in combination, showed a robust discrimination capacity when comparing control subjects with HCM, HNCM or HOCM patients (AUC from 0.722 to 0.949). Two circRNAs, circTMEM56 and circDNAJC6, significantly negatively correlated with echocardiographic parameters for HOCM. Collectively, circulating circRNAs DNAJC6, TMEM56 and MBOAT2 can distinguish between healthy and HCM patients. In addition, circTMEM56 and circDNAJC6 could serve as indicators of disease severity in patients with HOCM. Thus, circRNAs emerge as novel biomarkers for HCM facilitating the clinical decision making in a personalized manner.This work was supported by Junge Akademie, MHH (to K.S.), ERC grant Longheart (to T.T.) and Deutsche Forschungsgemeinschaft, TRR_267 (to T.T.) and KFO311 (to T.T. and J.B. (D.d.G.C. was a recipient of a Juan de la Cierva-Incorporación grant from the Ministry of Science Innovation and Universities (IJCI-2016-29393). CIBER Cardiovascular (CB16/11/00403 to DdG-C) is a project from Carlos III Health Institute