Aims
To determine the prognostic value of multilevel assessment of fibrosis in dilated cardiomyopathy (DCM) patients.
Methods and results
We quantified fibrosis in 209 DCM patients at three levels: ...(i) non‐invasive late gadolinium enhancement (LGE) at cardiac magnetic resonance (CMR); (ii) blood biomarkers amino‐terminal propeptide of procollagen type III (PIIINP) and carboxy‐terminal propeptide of procollagen type I (PICP), (iii) invasive endomyocardial biopsy (EMB) (collagen volume fraction, CVF). Both LGE and elevated blood PICP levels, but neither PIIINP nor CVF predicted a worse outcome defined as death, heart transplantation, heart failure hospitalization, or life‐threatening arrhythmias, after adjusting for known clinical predictors adjusted hazard ratios: LGE 3.54, 95% confidence interval (CI) 1.90–6.60; P < 0.001 and PICP 1.02, 95% CI 1.01–1.03; P = 0.001. The combination of LGE and PICP provided the highest prognostic benefit in prediction (likelihood ratio test P = 0.007) and reclassification (net reclassification index: 0.28, P = 0.02; and integrated discrimination improvement index: 0.139, P = 0.01) when added to the clinical prediction model. Moreover, patients with a combination of LGE and elevated PICP (LGE+/PICP+) had the worst prognosis (log‐rank P < 0.001). RNA‐sequencing and gene enrichment analysis of EMB showed an increased expression of pro‐fibrotic and pro‐inflammatory pathways in patients with high levels of fibrosis (LGE+/PICP+) compared to patients with low levels of fibrosis (LGE‐/PICP‐). This would suggest the validity of myocardial fibrosis detection by LGE and PICP, as the subsequent generated fibrotic risk profiles are associated with distinct cardiac transcriptomic profiles.
Conclusion
The combination of myocardial fibrosis at CMR and circulating PICP levels provides additive prognostic value accompanied by a pro‐fibrotic and pro‐inflammatory transcriptomic profile in DCM patients with LGE and elevated PICP.
Multilevel assessment of myocardial fibrosis demonstrates significant correlations between histology, non‐invasive imaging, and blood markers. A combined multi‐parametric approach with carboxy‐terminal propeptide of procollagen type I (PICP) and late gadolinium enhancement (LGE) allows the best risk stratification of idiopathic dilated cardiomyopathy (DCM) patients, accompanied with a profile of high expression of combined pro‐inflammatory and pro‐fibrotic genes, indicating a potential marker for disease activity.
Background: Walker-Warburg syndrome (WWS) is an autosomal recessive condition characterised by congenital muscular dystrophy, structural brain defects, and eye malformations. Typical brain ...abnormalities are hydrocephalus, lissencephaly, agenesis of the corpus callosum, fusion of the hemispheres, cerebellar hypoplasia, and neuronal overmigration, which causes a cobblestone cortex. Ocular abnormalities include cataract, microphthalmia, buphthalmos, and Peters anomaly. WWS patients show defective O-glycosylation of α-dystroglycan (α-DG), which plays a key role in bridging the cytoskeleton of muscle and CNS cells with extracellular matrix proteins, important for muscle integrity and neuronal migration. In 20% of the WWS patients, hypoglycosylation results from mutations in either the protein O-mannosyltransferase 1 (POMT1), fukutin, or fukutin related protein (FKRP) genes. The other genes for this highly heterogeneous disorder remain to be identified. Objective: To look for mutations in POMT2 as a cause of WWS, as both POMT1 and POMT2 are required to achieve protein O-mannosyltransferase activity. Methods: A candidate gene approach combined with homozygosity mapping. Results: Homozygosity was found for the POMT2 locus at 14q24.3 in four of 11 consanguineous WWS families. Homozygous POMT2 mutations were present in two of these families as well as in one patient from another cohort of six WWS families. Immunohistochemistry in muscle showed severely reduced levels of glycosylated α-DG, which is consistent with the postulated role for POMT2 in the O-mannosylation pathway. Conclusions: A fourth causative gene for WWS was uncovered. These genes account for approximately one third of the WWS cases. Several more genes are anticipated, which are likely to play a role in glycosylation of α-DG.
Patients with non–ST-segment elevation myocardial infarction and elevated high-sensitivity cardiac troponin levels often routinely undergo invasive coronary angiography (ICA), but many do not have ...obstructive coronary artery disease.
This study investigated whether cardiovascular magnetic resonance imaging (CMR) or computed tomographic angiography (CTA) may serve as a safe gatekeeper for ICA.
This randomized controlled trial (NCT01559467) in 207 patients (age 64 years; 62% male patients) with acute chest pain, elevated high-sensitivity cardiac troponin T levels (>14 ng/l), and inconclusive electrocardiogram compared a CMR- or CTA-first strategy with a control strategy of routine clinical care. Follow-up ICA was recommended when initial CMR or CTA suggested myocardial ischemia, infarction, or obstructive coronary artery disease (≥70% stenosis). Primary efficacy and secondary safety endpoints were referral to ICA during hospitalization and 1-year outcomes (major adverse cardiac events and complications), respectively.
The CMR- and CTA-first strategies reduced ICA compared with routine clinical care (87% p = 0.001, 66% p < 0.001, and 100%, respectively), with similar outcome (hazard ratio: CMR vs. routine, 0.78 95% confidence interval: 0.37 to 1.61; CTA vs. routine, 0.66 95% confidence interval: 0.31 to 1.42; and CMR vs. CTA, 1.19 95% confidence interval: 0.53 to 2.66). Obstructive coronary artery disease after ICA was found in 61% of patients in the routine clinical care arm, in 69% in the CMR-first arm (p = 0.308 vs. routine), and in 85% in the CTA-first arm (p = 0.006 vs. routine). In the non-CMR and non-CTA arms, follow-up CMR and CTA were performed in 67% and 13% of patients and led to a new diagnosis in 33% and 3%, respectively (p < 0.001).
A novel strategy of implementing CMR or CTA first in the diagnostic process in non–ST-segment elevation myocardial infarction is a safe gatekeeper for ICA.
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Abstract The initial Phase-I single centre, single dose, randomized, double-blind, cross-over study was planned to assess the pharmacokinetic and pharmacodynamic bioequivalence of the trastuzumab ...biosimilar (MYL-1401O) compared to the reference Herceptin ® . Their respective immunomodulation profile presented in this paper involved healthy males receiving a single infusion of both monoclonals, separated by a washout period. Sixty parameters were assessed in total, including serum cytokines, peripheral mononuclear cell (PBMC) subsets, cell activation and response to recall antigens and mitogen, pre- and post- infusion, as well as a cytokine release assay (CRA) at baseline. Trastuzumab infusion induced a transient and weak peak of serum IL-6 at 6 h, and a modulation of mononuclear cell subset profile and activation level, notably CD16 + cells. Except for CD8 + T cells, there were no significant differences between Herceptin ® and MYL-1401O . In CRA, PBMC stimulated with MYL-1401O or Herceptin ® similarly secreted IL-6, TNF-α, IL-1β, GM-CSF, IFN-γ, and IL-10, but no or low level of IL-2. Interestingly, some observed adverse events correlated with IL-2 and IFN-γ in CRA. MYL-1401O exhibited a very similar immunomodulation profile to Herceptin ® , strongly supporting its bioequivalence. This approach may thus be included in a proof-of-concept study. CRA may be used as a predictive assay for the evaluation of clinical monoclonals.
Synaptic dysfunction is associated with many brain disorders, but robust human cell models to study synaptic transmission and plasticity are lacking. Instead, current in vitro studies on human ...neurons typically rely on spontaneous synaptic events as a proxy for synapse function. Here, we describe a standardized in vitro approach using human neurons cultured individually on glia microdot arrays that allow single-cell analysis of synapse formation and function. We show that single glutamatergic or GABAergic forebrain neurons differentiated from human induced pluripotent stem cells form mature synapses that exhibit robust evoked synaptic transmission. These neurons show plasticity features such as synaptic facilitation, depression, and recovery. Finally, we show that spontaneous events are a poor predictor of synaptic maturity and do not correlate with the robustness of evoked responses. This methodology can be deployed directly to evaluate disease models for synaptic dysfunction and can be leveraged for drug development and precision medicine.
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•We establish a single-cell model to study synapses in iPSC-derived neurons•This platform allows quantitative analysis of synaptic transmission and plasticity•The platform is validated for GABA- or glutamatergic iPSC-derived human neurons•The platform is scalable and suitable for compound screening and disease modeling
This multisite study by Meijer et al. establishes a standardized in vitro approach to study synapse formation and function in single iPSC-derived human neurons. They validate this approach for GABA and glutamatergic human neurons. The methodology is scalable and suitable for compound screening and disease modeling.
The geodesic acoustic mode (GAM) is a coherently oscillating zonal flow that may regulate turbulence in toroidal plasmas. Uniquely, the complete poloidal and toroidal structure of the magnetic ...component of the turbulence-driven GAM has been mapped in the TCV tokamak. Radially localized measurements of the fluctuating density, ECE radiative temperature and poloidal flow show that the GAM is a fully coherent, radially propagating wave. These observations are consistent with electrostatic, gyrokinetic simulations.
Studies using induced pluripotent stem cells (iPSCs) are gaining momentum in brain disorder modelling, but optimal study designs are poorly defined. Here, we compare commonly used designs and ...statistical analysis for different research aims. Furthermore, we generated immunocytochemical, electrophysiological, and proteomic data from iPSC-derived neurons of five healthy subjects, analysed data variation and conducted power simulations. These analyses show that published case-control iPSC studies are generally underpowered. Designs using isogenic iPSC lines typically have higher power than case-control designs, but generalization of conclusions is limited. We show that, for the realistic settings used in this study, a multiple isogenic pair design increases absolute power up to 60% or requires up to 5-fold fewer lines. A free web tool is presented to explore the power of different study designs, using any (pilot) data.
Introduction
Nonfocal transient neurological attacks (TNAs) are associated with an increased risk of future dementia, but it is unclear whether TNAs are also associated with concurrent cognitive ...impairment. We hypothesized that recent TNAs are related to worse cognitive functioning. We tested our hypothesis in patients with heart failure, as these patients are at risk of cerebral hypoperfusion, which might play a role in the etiology of TNAs.
Methods
We performed neuropsychological testing in all patients with heart failure enrolled in the Heart Brain Connection study. We assessed global cognition, attention-psychomotor speed, executive functioning, memory and language. All patients were interviewed with a standardized questionnaire on the occurrence of TNAs in the preceding 6 months. We studied associations between TNAs and cognitive functioning with linear and logistic regression analyses, adjusted for age, sex and education. We performed additional analyses in patients without previous stroke or TIA and in patients without brain infarction on MRI.
Results
Thirty-seven (23%) of 158 patients (mean age 70 years, 67% men) experienced one or more TNAs. Patients with a recent TNA were more likely to be impaired on ≥ 1 cognitive domains than patients without TNAs 41% vs. 18%, adjusted odds ratio 4.6, 95% confidence interval (CI) 1.8–11.8. Patients with TNAs performed worse than patients without TNAs on global cognition (mean difference in
z
scores − 0.36, 95% CI − 0.54 to − 0.18), and on the cognitive domains attention-psychomotor speed (mean difference − 0.40, 95% CI − 0.66 to − 0.14), memory (mean difference − 0.57, 95% CI − 0.98 to − 0.15) and language (mean difference − 0.47, 95% CI − 0.79 to − 0.16). These associations were independent of cardiac output and volume of white matter hyperintensities. Subgroup analyses in patients without previous stroke or TIA or brain infarction on MRI (
n
= 78) yielded comparable results, with the exception of the cognitive domain language, which was no longer different between patients with and without TNAs.
Conclusion
Among patients with heart failure, TNAs are associated with cognitive impairment, which warrants the need for more clinical awareness of this problem.
Needs assessment tools can facilitate healthcare professionals in timely recognition of palliative care needs. Despite the increased attention for implementation of such tools, most studies provide ...little or no attention to the context of implementation. The aim of this study was to explore factors that contribute positively and negatively to timely screening of palliative care needs in advanced chronic heart failure.
Qualitative study using individual interviews and focus groups with healthcare professionals. The data were analysed using a deductive approach. The Consolidated Framework for Implementation Research was used to conceptualise the contextual factors.
Twenty nine healthcare professionals with different backgrounds and working in heart failure care in the Southern and Eastern parts of the Netherlands participated. Several factors were perceived to play a role, such as perception and knowledge about palliative care, awareness of palliative care needs in advanced chronic heart failure, perceived difficulty when and how to start palliative care, limited acceptance to treatment boundaries in cardiology, limited communication and collaboration between healthcare professionals, and need for education and increased attention for palliative care in advanced chronic heart failure guidelines.
This study clarified critical factors targeting patients, healthcare professionals, organisations to implement a needs assessment tool for timely recognition of palliative care needs in the context of advanced chronic heart failure. A multifaceted implementation strategy is needed which has attention for education, patient empowerment, interdisciplinary collaboration, identification of local champions, chronic heart failure specific guidelines and culture.
A subset of patients with atrial fibrillation (AF) presents without established AF risk factors and normal left ventricular (LV) systolic function, called idiopathic AF (IAF). Traditionally, ...echocardiography derived LV dimensions and ejection fraction (EF) are used to exclude LV dysfunction in IAF, but their sensitivity is limited. Our objective is to evaluate the presence of subtle alterations in LV function despite normal LVEF in patients with IAF compared to healthy controls, using speckle-tracking echocardiography (STE) based global longitudinal strain (GLS).
Standard transthoracic echocardiography was performed in 80 patients with IAF and 129 healthy controls. Patients with overt cardiac disease as well as known established AF risk factors were excluded. STE analysis was performed to assess GLS of the LV, and left atrial strain (LAS).
LVEF was normal and comparable between patients with IAF and healthy controls (63 ± 4% for both groups; p = 0.801). Mean GLS was within normal limits for both groups but statistically significantly more negative in patients with IAF (−20.6 ± 2.5% vs. -19.7 ± 2.5%; p = 0.016), however not when indexed for ventricular cycle length (p = 0.784). No differences in LA volume or non-indexed LAS were seen in patients with IAF compared to healthy controls.
In this selected group of IAF patients, STE did not detect any overt LV or LA dysfunction compared to healthy controls. Thus, IAF occurred in these patients not only in the absence of established AF risk factors but also without evidence of ventricular or atrial dysfunction.
•Idiopathic atrial fibrillation occurred in the absence of established AF risk factors.•Global longitudinal strain was normal in patients with idiopathic atrial fibrillation.•Speckle-tracking imaging did not detect any overt LV dysfunction compared to healthy controls.
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