Major Cardiac Events in Patients and Relatives With Hereditary Hypertrophic Cardiomyopathy

BackgroundLittle evidence is available on the disease expression in relatives of index patients with hypertrophic cardiomyopathy (HCM). This information has important implications for family screening programs, genetic counseling, and management of affected families.ObjectivesThe purpose of this study was to investigate the disease expression and penetrance in relatives of index patients carrying pathogenic/likely pathogenic (P/LP) variants in recognized HCM genes.MethodsA total of 453 consecutive and unrelated HCM index patients underwent clinical and genetic investigations. A total of 903 relatives of genotype-positive index patients were invited for clinical investigations and genetic testing. Penetrance, disease expression, and incidence rates of major adverse cardiac events (MACEs) were investigated in individuals carrying P/LP variants.ResultsForty percent (183/453) of index patients carried a P/LP variant. Eighty-four percent (757/903) of all relatives of index patients with P/LP variants were available for the investigation, of whom 54% (407/757) carried a P/LP variant. The penetrance of HCM among relatives was 39% (160/407). Relatives with HCM and index patients were diagnosed at a similar age (43 ± 18 years vs 46 ± 15 years; P = 0.11). There were no differences in clinical characteristics or incidence rates of MACE during 8 years of follow-up.ConclusionsThe disease expression of HCM among index patients and affected relatives carrying P/LP variants in recognized disease genes was similar, with an equal risk of experiencing MACE. These findings provide evidence to support family screening and follow-up of genotype-positive HCM families to improve management and diminish the number of adverse disease complications among relatives

Loss-of-activity-mutation in the cardiac chloride-bicarbonate exchanger AE3 causes short QT syndrome

Mutations in potassium and calcium channel genes have been associated with cardiac arrhythmias. Here, Jensen et al. show that an anion transporter chloride-bicarbonate exchanger AE3 is also responsible for the genetically-induced mechanism of cardiac arrhythmia, suggesting new therapeutic targets for this diseas

An automated in vitro model for the evaluation of ultrasound modalities measuring myocardial deformation

<p>Abstract</p> <p>Background</p> <p>Echocardiography is the method of choice when one wishes to examine myocardial function. Qualitative assessment of the 2D grey scale images obtained is subjective, and objective methods are required. Speckle Tracking Ultrasound is an emerging technology, offering an objective mean of quantifying left ventricular wall motion. However, before a new ultrasound technology can be adopted in the clinic, accuracy and reproducibility needs to be investigated.</p> <p>Aim</p> <p>It was hypothesized that the collection of ultrasound sample data from an in vitro model could be automated. The aim was to optimize an in vitro model to allow for efficient collection of sample data.</p> <p>Material & Methods</p> <p>A tissue-mimicking phantom was made from water, gelatin powder, psyllium fibers and a preservative. Sonomicrometry crystals were molded into the phantom. The solid phantom was mounted in a stable stand and cyclically compressed. Peak strain was then measured by Speckle Tracking Ultrasound and sonomicrometry.</p> <p>Results</p> <p>We succeeded in automating the acquisition and analysis of sample data. Sample data was collected at a rate of 200 measurement pairs in 30 minutes. We found good agreement between Speckle Tracking Ultrasound and sonomicrometry in the in vitro model. Best agreement was 0.83 ± 0.70%. Worst agreement was -1.13 ± 6.46%.</p> <p>Conclusions</p> <p>It has been shown possible to automate a model that can be used for evaluating the in vitro accuracy and precision of ultrasound modalities measuring deformation. Sonomicrometry and Speckle Tracking Ultrasound had acceptable agreement.</p

Use of the prognostic biomarker suPAR in the emergency department improves risk stratification but has no effect on mortality:a cluster-randomized clinical trial (TRIAGE III)

Abstract Background Risk stratification of patients in the emergency department can be strengthened using prognostic biomarkers, but the impact on patient prognosis is unknown. The aim of the TRIAGE III trial was to investigate whether the introduction of the prognostic and nonspecific biomarker: soluble urokinase plasminogen activator receptor (suPAR) for risk stratification in the emergency department reduces mortality in acutely admitted patients. Methods The TRIAGE III trial was a cluster-randomized interventional trial conducted at emergency departments in the Capitol Region of Denmark. Eligible hospitals were required to have an emergency department with an intake of acute medical and surgical patients and no previous access to suPAR measurement. Three emergency departments were randomized; one withdrew shortly after the trial began. The inclusion period was from January through June of 2016 consisting of twelve cluster-periods of 3-weeks alternating between intervention and control and a subsequent follow-up of ten months. Patients were allocated to the intervention if they arrived in interventional periods, where suPAR measurement was routinely analysed at arrival. In the control periods suPAR measurement was not performed. The main outcome was all-cause mortality 10 months after arrival of the last patient in the inclusion period. Secondary outcomes included 30-day mortality. Results The trial enrolled a consecutive cohort of 16,801 acutely admitted patients; all were included in the analyses. The intervention group consisted of 6 cluster periods with 8900 patients and the control group consisted of 6 cluster periods with 7901 patients. After a median follow-up of 362 days, death occurred in 1241 patients (13.9%) in the intervention group and in 1126 patients (14.3%) in the control group. The weighted Cox model found a hazard ratio of 0.97 (95% confidence interval, 0.89 to 1.07; p = 0.57). Analysis of all subgroups and of 30-day all-cause mortality showed similar results. Conclusions The TRIAGE III trial found no effect of introducing the nonspecific and prognostic biomarker suPAR in emergency departments on short- or long-term all-cause mortality among acutely admitted patients. Further research is required to evaluate how prognostic biomarkers can be implemented in routine clinical practice. Trial registration clinicaltrials.gov, NCT02643459. Registered 31 December 2015

Biomarkers of neutrophil activity and extracellular matrix turnover predict long-term response to vedolizumab in patients with Crohn's disease

Background Crohn‘s disease (CD) is a form of inflammatory bowel disease characterized by high infiltration of immune cells into the intestinal tissue, resulting in increased proteolytic mediated extracellular matrix (ECM) remodeling. Disease management has improved with the use of biologics such as vedolizumab (VEDO). However, considering the high rate of primary non-response to VEDO, there is an unmet need for predictive serum biomarkers capable of determining response to treatment prior to its initiation. This study investigated whether biomarkers of neutrophil activity, mucosal damage, and ECM remodeling could serve as non-invasive tools for predicting long-term response to VEDO in patients with CD. Methods Serum biomarkers of human neutrophil elastase (HNE)-derived fragment of calprotectin (CPa9-HNE [serum calprotectin]) and matrix metalloproteinase (MMP)-derived fragments of type I (C1M), III (C3M), IV (C4M), type III collagen formation (PRO-C3), basement membrane turnover (PRO-C4) and T-cell activity (C4G), were measured using protein fingerprint assays in patients with CD (n=32) before VEDO therapy initiation. The ratio C4M/C4G (myeloid/lymphoid mediated degradation) was computed. Long-term response was defined as the continuation of treatment beyond one year after the start of therapy. Baseline biomarker levels were compared between responders and non-responders using Mann-Whitney U-tests, and area under the curve (AUC) values were generated using receiver operating characteristics (ROC) statistics. Biomarker levels were divided into tertiles and chi-square tests were used to investigate the relationship between tertiles and response proportions. Results Biomarkers CPa9-HNE, C1M, C3M, C4M, PRO-C3, C3M/PRO-C3, and C4M/C4G were significantly increased at baseline in non-responders compared with responders (all P<0.05). All markers were able to predict response to VEDO at baseline (AUC [95% CI]: CPa9-HNE 0.81 [0.66–0.96]; C1M 0.85 [0.75–0.98]; C3M 0.79 [0.62–0.95]; C4M 0.77 [0.6–0.93]; C3M/PRO-C3 0.78 [0.6–0.95]; C4M/C4G 0.74 [0.56–0.92] all P<0.05). Proportions of long-term VEDO users were highest in the first tertiles for all the markers (73–91%) and decreased in a concentration-dependent manner across the second and third tertiles, indicating that patients with the lowest concentrations of these markers less frequently discontinued treatment at one year after initiation (Figure 1). Conclusion Baseline levels of serum biomarkers for neutrophil activity (CPa9-HNE [serum calprotectin]) and mucosal damage (C1M, C3M, C4M, C4G, PRO-C4, and PRO-C3) could predict long-term response to VEDO in patients with CD. Therefore, these biomarkers could aid in early decision making concerning treatment with vedolizumab in patients with CD

Type I collagen degradation fragments (C1M) and human neutrophil elastase-derived fragments of calprotectin (CPa9-HNE) reflect biochemical and endoscopic disease activity in patients with Inflammatory Bowel Disease

Background Crohn’s disease (CD) and ulcerative colitis (UC) are characterized by intestinal inflammation and increased extracellular matrix (ECM) remodeling, which are key pathophysiological mechanisms in patients with IBD and highly related to mucosal damage. Alterations in intestinal ECM turnover as well as macrophage and neutrophil activity may be reflected by secreted products that are released into the systemic circulation. In this study, we aimed to investigate associations between serum biomarkers of neutrophil activity (serum calprotectin) and collagen degradation (mucosal damage), and disease activity in patients with IBD. Methods Serological biomarkers of collagen formation (PRO-C3, PRO-C4, PRO-C6), matrix metalloproteinase (MMP)-mediated collagen degradation (C1M, C3M, C4M, C4G, C6Ma3) and intestinal inflammation (VICM [macrophage activity], human neutrophil elastase-derived fragment of calprotectin (CPa9-HNE [serum calprotectin, neutrophil activity]) were measured using Protein FingerPrint assay (PFA) technology in 100 patients with IBD (CD: n=44; UC: n=56). Biochemical disease activity was assessed using C-reactive protein (CRP) levels and available faecal calprotectin (FCal) levels. Endoscopic disease activity was determined using the Simple Endoscopic Score for CD (SES-CD) and Mayo endoscopic subscore for UC. Results C1M strongly associated with elevated CRP levels (defined as >5mg/L, P<0.001) in patients with IBD and significantly associated with faecal calprotectin levels in patients with UC (Spearman’s ρ=0.75, P<0.001). In patients with CD, C1M reasonably discriminated between patients with mild and moderate-to-severe endoscopic disease activity (AUC=0.73, P=0.01), whereas this discrimination was more subtle in patients with UC (AUC=0.68, P=0.08). CPa9-HNE levels were significantly increased in patients with elevated CRP levels (P=0.002 for both CD and UC) and associated best with faecal calprotectin levels in patients with CD compared with UC (CD: ρ=0.43, P=0.06; UC: ρ=0.20, P=0.45). Finally, CPa9-HNE levels were able to discriminate between mild and moderate-to-severe endoscopic disease activity in patients with CD (AUC=0.75, P<0.01). Conclusion C1M and CPa9-HNE levels associate with biochemical (CRP, FCal) and endoscopic disease activity in patients IBD, where C1M demonstrated higher accuracy in UC and CPa9-HNE appeared to be more useful in CD in this cohort. Therefore, C1M and CPa9-HNE could serve as surrogate biomarkers for the assessment of disease activity in patients with UC and CD, respectively. Our results should be validated in additional prospective, larger patient cohorts to corroborate these findings