Truncating variants in the
gene (TTNtv) are the commonest cause of heritable dilated cardiomyopathy. This study aimed to study the phenotypes and outcomes of TTNtv carriers.
Five hundred thirty-seven ...individuals (61% men; 317 probands) with TTNtv were recruited in 14 centers (372 69% with baseline left ventricular systolic dysfunction LVSD). Baseline and longitudinal clinical data were obtained. The primary end point was a composite of malignant ventricular arrhythmia and end-stage heart failure. The secondary end point was left ventricular reverse remodeling (left ventricular ejection fraction increase by ≥10% or normalization to ≥50%).
Median follow-up was 49 (18-105) months. Men developed LVSD more frequently and earlier than women (45±14 versus 49±16 years, respectively;
=0.04). By final evaluation, 31%, 45%, and 56% had atrial fibrillation, frequent ventricular ectopy, and nonsustained ventricular tachycardia, respectively. Seventy-six (14.2%) individuals reached the primary end point (52 68% end-stage heart failure events, 24 32% malignant ventricular arrhythmia events). Malignant ventricular arrhythmia end points most commonly occurred in patients with severe LVSD. Male sex (hazard ratio, 1.89 95% CI, 1.04-3.44;
=0.04) and left ventricular ejection fraction (per 10% decrement from left ventricular ejection fraction, 50%; hazard ratio, 1.63 95% CI, 1.30-2.04;
<0.001) were independent predictors of the primary end point. Two hundred seven of 300 (69%) patients with LVSD had evidence of left ventricular reverse remodeling. In a subgroup of 29 of 74 (39%) patients with initial left ventricular reverse remodeling, there was a subsequent left ventricular ejection fraction decrement. TTNtv location was not associated with statistically significant differences in baseline clinical characteristics, left ventricular reverse remodeling, or outcomes on multivariable analysis (
=0.07).
TTNtv is characterized by frequent arrhythmia, but malignant ventricular arrhythmias are most commonly associated with severe LVSD. Male sex and LVSD are independent predictors of outcomes. Mutation location does not impact clinical phenotype or outcomes.
Background
Patients with atrial fibrillation (AF) and heart failure (HF) have a high risk of thromboembolism and other outcomes and anticoagulation is recommended.
Hypothesis
This study was aimed to ...explore the risk factors associated with HF worsening in patients with AF and HF taking rivaroxaban in Spain.
Methods
Multicenter, prospective, observational study that included adults with AF and chronic HF, receiving rivaroxaban ≥4 months before entering. HF worsening was defined as first hospitalization or emergency visit because of HF exacerbation.
Results
A total of 672 patients from 71 Spanish centers were recruited, of whom 658 (97.9%) were included in the safety analysis and 552 (82.1%) in the per protocol analysis. At baseline, mean age was 73.7 ± 10.9 years, 64.9% were male, CHA2DS2‐VASc was 4.1 ± 1.5, HAS‐BLED was 1.6 ± 0.9% and 51.3% had HF with preserved ejection fraction. After 24 months of follow‐up, 24.9% of patients developed HF worsening, 11.6% died, 2.9% had a thromboembolic event, 3.1% a major bleeding, 0.5% an intracranial bleeding and no patient had a fatal hemorrhage. Older age, the history of chronic obstructive pulmonary disease, the previous use of vitamin K antagonists, and restrictive or infiltrative cardiomyopathies, were independently associated with HF worsening. Only 6.9% of patients permanently discontinued rivaroxaban treatment.
Conclusions
Approximately one out of four patients with HF and AF treated with rivaroxaban developed a HF worsening episode after 2 years of follow‐up. The identification of those factors that increase the risk of HF worsening could be helpful in the comprehensive management of this population.
Multicenter, prospective, observational study that included 672 adults from 71 Spanish centers with AF and chronic HF, receiving rivaroxaban. At baseline, mean age was 73.7 ± 10.9 years, 64.9% were male, CHA2DS2‐VASc was 4.1 ± 1.5, HAS‐BLED was 1.6 ± 0.9% and 51.3% had HF with preserved ejection fraction. After 24 months of follow‐up, 24.9% of patients developed HF worsening, 11.6% died, 2.9% had a thromboembolic event, 3.1% a major bleeding, 0.5% an intracranial bleeding and no patient had a fatal hemorrhage. Older age, the history of chronic obstructive pulmonary disease, the previous use of vitamin K antagonists, and restrictive or infiltrative cardiomyopathies, were independently associated with HF worsening. Only 6.9% of patients permanently discontinued rivaroxaban treatment.
The clinical relevance of genetic variants in nonischemic dilated cardiomyopathy (DCM) is unsettled.
The study sought to assess the prognostic impact of disease-causing genetic variants in DCM.
...Baseline and longitudinal clinical data from 1,005 genotyped DCM probands were retrospectively collected at 20 centers. A total of 372 (37%) patients had pathogenic or likely pathogenic variants (genotype positive) and 633 (63%) were genotype negative. The primary endpoint was a composite of major adverse cardiovascular events. Secondary endpoints were end-stage heart failure (ESHF), malignant ventricular arrhythmia (MVA), and left ventricular reverse remodeling (LVRR).
After a median follow-up of 4.04 years (interquartile range: 1.70-7.50 years), the primary endpoint had occurred in 118 (31.7%) patients in the genotype-positive group and in 125 (19.8%) patients in the genotype-negative group (hazard ratio HR: 1.51; 95% confidence interval CI: 1.17-1.94; P = 0.001). ESHF occurred in 60 (16.1%) genotype-positive patients and in 55 (8.7%) genotype-negative patients (HR: 1.67; 95% CI: 1.16-2.41; P = 0.006). MVA occurred in 73 (19.6%) genotype-positive patients and in 77 (12.2%) genotype-negative patients (HR: 1.50; 95% CI: 1.09-2.07; P = 0.013). LVRR occurred in 39.6% in the genotype-positive group and in 46.2% in the genotype-negative group (P = 0.047). Among individuals with baseline left ventricular ejection fraction ≤35%, genotype-positive patients exhibited more major adverse cardiovascular events, ESHF, and MVA than their genotype-negative peers (all P < 0.02). LVRR and clinical outcomes varied depending on the underlying affected gene.
In this study, DCM patients with pathogenic or likely pathogenic variants had worse prognosis than genotype-negative individuals. Clinical course differed depending on the underlying affected gene.
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In May 2011, the city of Lorca, in Spain, suffered an earthquake of magnitude Mw=5.1. Even though the intensity was not particularly high, as the epicentre was only a few kilometres away from the ...city severe damage was caused to many buildings. The movements generated by the earthquake, together with the special characteristics of the reinforced concrete (RC) building structures in the region, gave rise to different types of structural damage, which are analysed and classified in this paper. After carrying out inspections on buildings in the town itself, a number of deficiencies responsible for the damage caused were detected in RC elements, as well as behavioural alterations caused by non-load-bearing walls. Variations in the local or general stiffness due to staircases, which are usually considered to be secondary elements, were another factor that played a role in the buildings' response. From the study we learned a number of lessons about what happened in Lorca and these should be borne in mind in the future when designing RC building structures in areas prone to earthquakes.
•In 2011, one of the severest earthquakes suffered by Spain took place in Lorca.•Most of the buildings in the city had reinforced concrete (RC) structures.•This paper shows the lessons learnt from the Lorca earthquake.•Almost all the damage sustained by RC structures took place in the columns.
In the present study, we evaluated the effects of a medicinal plant leaf extract (MPLE; 10%, ursolic acid, 3% other triterpenic compounds; 2% verbascoside and < 1% polyphenols) obtained from Lippia ...citriodora and Salvia officinalis on somatic growth and immune responses in juvenile gilthead seabream (Sparus aurata). Fish (initial body weight = 26.0 ± 0.1 g) were fed two isoproteic (48% crude protein, 7% fishmeal), isolipidic (17% crude fat) and isoenergetic diets (21.7 MJ/kg), one of them containing 0.1% MPLE. Both diets were tested using four replicate tanks during 92 days. At the end of the trial, a significant increase in growth was observed in fish fed the diet containing the additive in comparison to fish fed the control diet (189.6 ± 2.5 g vs. 173.8 ± 4.1 g, respectively; P < 0.05). Specific growth rates (SGR) in fish fed the feed supplemented with 0.1% MPLE were significantly higher than in fish fed the control diet (SGR0–92 days (0.1% MPLE diet) = 2.26 ± 0.01% day−1, SGR0–92 days (control diet) = 2.16 ± 0.02% day−1; P < 0.05). Feed conversion ratio (FCR) values in fish fed the control diet were higher than those in fish fed the MPLE diet (FCRcontrol diet = 1.23 ± 0.02 vs. FCR 0.1% MPLE diet = 1.10 ± 0.02; P < 0.05). When evaluating non-specific immune plasmatic parameters, no significant variations were registered at the level of bacteriolytic and complement activities, nor protein IgM levels (P > 0.05). In order to evaluate the cellular immune competence of fish, an ex vivo assay with splenocytes primary cell culture (SPCC) from both dietary groups was conducted. SPCC were incubated with lipopolysaccharide (LPS) for 24 h and the expression of genes associated to several immune processes was evaluated (humoral immune response, pro- and anti-inflammatory cytokines, cell surface markers, and antioxidant enzymes). Particularly at 4 h post-exposure, dietary supplementation with 0.1% MPLE enhanced SPCC immune response to LPS by the up-regulation of genes involved in humoral immunity (lys, IgM), pro- (tnf-α, il-1β) and anti-inflammatory (tgf-β1, il10) cytokines, the leucocyte cell surface marker cd4, and antioxidative stress enzymes (mn-sod, cat). Therefore, a medicinal plant leaf extract (MPLE) obtained from L. citriodora and S. officinalis may be considered as efficient additive to be used in aquafeed since it does not induce a significant immune reaction under basal conditions, but it provides immune protection after LPS treatment, together with increasing overall fish growth and improvement of feed efficiency values.
•Leaf extracts from Salvia officinalis and Lippia citriodora are suitable feed additives.•Triterpenic compounds and verbascoside promote growth and reduce feed conversion values.•These phytochemicals mediated a tight control of the immune response (immune homeostasis).•The evaluated additive enhanced the systemic immune response as the ex vivo trial indicated.
Fragile X syndrome (FXS), the most common inherited intellectual disability, is caused by the loss of expression of the Fragile X Messenger Ribonucleoprotein (FMRP). FMRP is an RNA-binding protein ...that negatively regulates the expression of many postsynaptic as well as presynaptic proteins involved in action potential properties, calcium homeostasis and neurotransmitter release. FXS patients and mice lacking FMRP suffer from multiple behavioral alterations, including deficits in motor learning for which there is currently no specific treatment.
We performed electron microscopy, whole-cell patch-clamp electrophysiology and behavioral experiments to characterise the synaptic mechanisms underlying the motor learning deficits observed in Fmr1KO mice and the therapeutic potential of positive allosteric modulator of mGluR4.
We found that enhanced synaptic vesicle docking of cerebellar parallel fiber to Purkinje cell Fmr1KO synapses was associated with enhanced asynchronous release, which not only prevents further potentiation, but it also compromises presynaptic parallel fiber long-term potentiation (PF-LTP) mediated by β adrenergic receptors. A reduction in extracellular Ca
concentration restored the readily releasable pool (RRP) size, basal synaptic transmission, β adrenergic receptor-mediated potentiation, and PF-LTP. Interestingly, VU 0155041, a selective positive allosteric modulator of mGluR4, also restored both the RRP size and PF-LTP in mice of either sex. Moreover, when injected into Fmr1KO male mice, VU 0155041 improved motor learning in skilled reaching, classical eyeblink conditioning and vestibuloocular reflex (VOR) tests, as well as the social behavior alterations of these mice.
We cannot rule out that the activation of mGluR4s via systemic administration of VU0155041 can also affect other brain regions. Further studies are needed to stablish the effect of a specific activation of mGluR4 in cerebellar granule cells.
Our study shows that an increase in synaptic vesicles, SV, docking may cause the loss of PF-LTP and motor learning and social deficits of Fmr1KO mice and that the reversal of these changes by pharmacological activation of mGluR4 may offer therapeutic relief for motor learning and social deficits in FXS.
The transcriptomic response of the head kidney, the main lymphohematopoietic tissue of the body, was evaluated in Atlantic salmon (
Salmo salar
) smolts fed a functional feed containing a phytogenic ...rich in verbascoside and triterpenic compounds like ursolic acid. Fish (initial body weight = 55.0 ± 0.1 g) were fed two experimental diets (40% crude protein, 22% crude fat; 21.6 MJ/kg gross energy) that only differed in the phytogenic content (0.1% inclusion). Each diet has six replicates and was tested over a period of 133 days. The tested zootechnical feed additive a medicinal plant leaf extract (MPLE) obtained from sage (
Salvia officinalis
) and lemon verbena (
Lippia citriodora
). At the end of the trial, smolts fed the MPLE diet were heavier than their congeners from the control group (271.5 ± 7.9 g vs. 240.2 ± 19.3 g, respectively;
P
< 0.05). Feed conversion ratio (FCR) values in fish fed the control diet were higher than those in fish fed the MPLE diet (FCR
control diet
= 1.27 ± 0.08 vs. FCR
0
.
1% MPLE diet
= 1.08 ± 0.05;
P
< 0.05). The immunomodulatory properties of the functional diet were evaluated by means of an
in vivo
challenge with
Aeromonas salmonicida
subsp.
salmonicida
(1 × 10
7
CFU mL
–1
). The microarray analysis of head kidney samples from both dietary groups revealed 1,178 differentially expressed genes (802 upregulated and 376 downregulated). Among them, several biological processes related to immunity were identified in fish fed the MPLE diet (
i.e
., interferon-gamma-mediated signaling pathway, antigen processing and presentation of peptide antigen
via
MHC class II, autophagy, regulation of i-kappaB kinase/NF-kappaB signaling, and leukocyte activation). Results from the bacterial challenge showed that survival rates were higher in smolts from the MPLE group (90.6 ± 6.4%) in comparison to the control group (60.7 ± 13.5%), confirming the functional benefits of the phytogenic in terms of host’s immunity and disease resistance. Biological processes such as cytoskeleton organization and regulation of cellular protein metabolic process detected in fish fed the MPLE diet supported the metabolic changes related to increased somatic growth promoted. The present findings showed that the inclusion at 0.1% of the tested MPLE obtained from sage and lemon verbena in diets for Atlantic salmon smolts promoted somatic growth, and enhanced their systemic immune response and reduced mortality when fish were challenged with
A
.
salmonicida
cumulative, the causative agent of furunculosis in salmonids.
•Seven full-scale RC beam-column joints strengthened externally by steel caging.•Specimens reinforcement designed with non-ductile details.•Experimental test with gravity and horizontal cyclic ...loads.•The strengthening improve the bond between reinforcement and concrete inside the joint.•Angles contributed notably to the bending moment capacity of the specimen.
Beam-column joints suffer intense damage from seismic events and are the cause of many buildings collapsing. These zones present complex behaviour under cyclic loads, including tensile-compression cycles, which make reinforcement adherence worse and cause severe cracking in concrete. Although columns can be strengthened by various methods (e.g. concrete jacketing, fibre-reinforced polymers and steel jacketing-caging), beam column joints require complex systems being applied, but are not always effective. In Europe, fitting steel caging around columns is one of the most frequently used techniques, although its effectiveness against seismic events requires further study. The aim of this work is to analyse the behaviour of beam-column joints strengthened by steel caging subjected to cyclic loading, for which an ambitious experimental campaign was carried out on seven full-scale steel-caged specimens with a variety of strengthening solutions at joints. The results provide insight into the complex behaviour of joints with columns strengthened in this way, used as the basis for practical recommendations for engineers and architects who have to routinely retrofit structures against seismic events.
Abstract
Background and Aims
Emery–Dreifuss muscular dystrophy (EDMD) is caused by variants in EMD (EDMD1) and LMNA (EDMD2). Cardiac conduction defects and atrial arrhythmia are common to both, but ...LMNA variants also cause end-stage heart failure (ESHF) and malignant ventricular arrhythmia (MVA). This study aimed to better characterize the cardiac complications of EMD variants.
Methods
Consecutively referred EMD variant-carriers were retrospectively recruited from 12 international cardiomyopathy units. MVA and ESHF incidences in male and female variant-carriers were determined. Male EMD variant-carriers with a cardiac phenotype at baseline (EMDCARDIAC) were compared with consecutively recruited male LMNA variant-carriers with a cardiac phenotype at baseline (LMNACARDIAC).
Results
Longitudinal follow-up data were available for 38 male and 21 female EMD variant-carriers mean (SD) ages 33.4 (13.3) and 43.3 (16.8) years, respectively. Nine (23.7%) males developed MVA and five (13.2%) developed ESHF during a median (inter-quartile range) follow-up of 65.0 (24.3–109.5) months. No female EMD variant-carrier had MVA or ESHF, but nine (42.8%) developed a cardiac phenotype at a median (inter-quartile range) age of 58.6 (53.2–60.4) years. Incidence rates for MVA were similar for EMDCARDIAC and LMNACARDIAC (4.8 and 6.6 per 100 person-years, respectively; log-rank P = .49). Incidence rates for ESHF were 2.4 and 5.9 per 100 person-years for EMDCARDIAC and LMNACARDIAC, respectively (log-rank P = .09).
Conclusions
Male EMD variant-carriers have a risk of progressive heart failure and ventricular arrhythmias similar to that of male LMNA variant-carriers. Early implantable cardioverter defibrillator implantation and heart failure drug therapy should be considered in male EMD variant-carriers with cardiac disease.
Structured Graphical Abstract
Structured Graphical Abstract
Graphic depiction of new cardiac disease features demonstrated by this study (top left) with arrows to relevant analyses. Kaplan Meier survival analysis for the primary malignant ventricular arrhythmia endpoint during follow-up for male EMD and male LMNA variant-carriers with a baseline cardiac phenotype (top right). Cardiac disease features at last evaluation for male LMNA, male EMD and female EMD variant-carriers (bottom left). Violin plots comparing age at cardiac diagnosis for male EMD, female EMD and male LMNA variant-carriers (bottom right). Abbreviations: AF, atrial fibrillation; EDMD1, Emery–Dreifuss muscular dystrophy Type 1; ESHF, end-stage heart failure; LVSD, left ventricular systolic dysfunction; MVA, malignant ventricular arrhythmia; NSVT, non-sustained ventricular tachycardia.
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