bluuebunny/crossref_metadata_2025_split huggingface dataset:
Photobiomodulation attenuates myocardial fibrosis and diastolic dysfunction in a mouse model of heart-failure with preserved ejection fraction
Authors: Nachman D , Gavish L , Zavdi S , Aliev E , Horesh A , Shtraikh S , Gertz S D 
Published: November 2023

Abstract

Introduction
Photobiomodulation (PBM) has been shown to positively effect pathways associated with heart failure with preserved ejection fraction (HFpEF), such as reducing inflammation and increasing NO, microvascular flow, mitochondrial membrane potential, and ATP synthesis.

Purpose
This study aimed to determine whether PBM can mitigate myocardial fibrosis and diastolic dysfunction in a mouse model of HFpEF.

Methods
HFpEF was induced in 26, 3-month-old C57/black male mice by a ‘2-hit-model’ that includes high-fat diet and inhibition of NO-synthase by L-NAME (Nω-nitro-l-arginine-methyl-ester). Transcutaneous PBM was administered 3X/week[wk] for 10wks using a 904nm super-pulsed laser (90-seconds, 4.2J/cm2 per diode, n=13). 10 non-model control mice were also included. Echocardiography was performed at baseline, 7wks, and 10wks. Mice were sacrificed at ten weeks. Histological cardiac sections were stained for collagen with picrosirius red and scanned in X40 resolution. The positive pixel count algorithm of the Aperio ImageScope software (Leica Biosystems Inc.) was used to analyzed each vessel and measured the area of adventitial collagen (AC), perimeter of the external and internal elastic lamina (EEL, IEL). %Media=100*(EEL area-IEL area)/EEL Area; %Lumen=(IEL area/EEL area); and Standardized adventitial collagen = Area of AC / EEL perimeter were calculated. Significance was determined by 1-way ANOVA by group for %media, %lumen, and EEL area, and by 1-way ANCOVA by group with EEL area as a covariate for the standardized AC to take into account the variability in vessel sizes. p&lt;0.05 was considered significant.

Results
Mice that were subjected to the HFpEF 2-hit model had a significant increase in the medial area of the coronary vessels and a concomitant decrease in the lumen area compared to mice that were not subjected to the model (Mean ±SD, %Media: control 50%±11; sham: 64%±11; PBM: 63%±12, p&lt;0.001 control vs HFpEF). The model did not affect the overall vessel area defined by the EEL (p=0.547). The HFpEF model induced a significant increase in the standardized adventitial collagen compared to controls, which was attenuated by PBM: control 3.0±1.6; HFpEF sham: 3.9±1.8; PBM: 3.4±1.9, p=0.008 control vs sham, p=0.055 PBM vs control; p=0.396 control vs PBM). Moreover, diastolic flow parameters demonstrated that E’ deteriorated significantly in the sham group but not in the PBM group (E’[mm/sec], baseline-vs-10w: sham; -32.9±8.6-vs- -22.5±5.7, p=0.004; PBM; -32.1±5.9-vs- -27.9±6.4, p=0.262, p=0.037), and delayed deterioration in E/E’ (Δbaseline-7w, PBM vs sham: -3.6±7.0-vs-7.6±15.4, p=0.006).

Conclusions
PBM attenuated perivascular fibrosis and diastolic parameters deterioration in a mice model of HFpEF. Further investigations into the biomolecular and histological mechanisms are performed.Trial designResults
The use of wearable cardioverter defibrillator among patients suffering from myocarditis: data from a multicenter registry
Authors: El-Battrawy I , Koepsel K , Kovacs B , Blockhaus C , Gotzmann M , Klein N , Shin D I , Abumayyaleh M , Saguner A M , Erath J W , Duru F , Muegge A , Aweimer A , Akin I , Beiert T 
Published: November 2023

Abstract

Background
Data on the use of the wearable cardioverter defibrillator (WCD) among patients suffering from myocarditis in a large cohort remains sparse. Subsequently several guidelines give a different recommendation regarding WCD indication in this cohort.

Methods
1596 patients were included in a multicenter registry from ten European centers. Among this cohort 132 (8%) patients received a WCD due to myocarditis. The mean follow-up time of the whole cohort was 620.2±607.8 days. The presence of ventricular tachyarrhythmias and/or WCD shocks during WCD use were evaluated.

Results
The mean age of patients was 52.5±16.3 years (75% males). 20% of patients suffered from atrial fibrillation, 17% diabetes mellitus, 40% were smoker and 38.9% suffered from arterial hypertension. The body-mass-index (BMI) of the cohort was 27.8±5.7 kg/m². The initial left ventricular ejection fraction (LVEF) was 33.4±14.6% and increased to 45.9±13.2% (p&lt;0.05) over long-term follow-up. Patient were discharged on ACE-inhibitors (62.5%), ARNI (21.2%), aldosterone-antagonist (50%), beta-blockers (89.5%) and amiodarone (13.6%). An improvement of LVEF (LVEF&gt;35%) was documented in 81.2% of patients. The BNP level was at baseline 7401±30584 pg/ml and decreased to 530±803 pg/ml (p&lt;0.05) over long-term follow-up. The wear duration was 78.5±51.5 days and 34% of patients wore the WCD for longer than 90 days. The wear-hours per day were 21.1±4.8 hours. In 3.1% sustained ventricular tachycardia, 0.8% ventricular fibrillation and 9.1% non-sustained ventricular tachycardia were documented. Subsequently 3% of patients suffered from an appropriate WCD shock. The rate of inappropriate WCD shock was 0.8%. Patients suffering from WCD shock were at age 31, 31, 61, 24 and 51 years and suffered a former non-sustained ventricular tachycardia before receiving a WCD. Among these patients suffering from appropriate WCD shock only two patients showed an LVEF&lt;35%. Among the myocarditis patients 48% suffered from a former ventricular tachycardia and/or ventricular fibrillation and therefore received a WCD.

Conclusions
Myocarditis patients can be effectively protected by WCD and may benefit from its’ use. WCD shock occurred also in patients with an LVEF &gt;35%.
Impact of isorhamnetin for suppression of action potential aberrations associated with atrial fibrillation
Authors: Aonuma K , Xu D , Murakoshi N , Tajiri K , Yuan Z , Murakata Y , Tominaga K , Nogami A , Aonuma K , Isoda H 
Published: November 2023

Abstract

Background
Isorhamnetin, a natural flavonoid, has potent antioxidant, antifibrotic and L-type Cav1.2 channel modulation effects, but its antiarrhythmic effect has not been reported.

Purpose
The purpose of this study is to investigate the effect of isorhamnetin on angiotensin II (Ang II)-induced atrial fibrillation (AF) in mice.

Methods
Wild-type male mice (C57BL/6J, 8 weeks old) were randomly divided into the following three groups: 1) control group, 2) Ang II treated group, 3) Ang II+isorhamnetin treated group. Ang II (1000 ng/kg/min) was administered by an implantable osmotic pump for two consecutive weeks, and isorhamnetin (5 mg/kg) was administered intraperitoneally for three weeks, one week before the initiation of Ang II administration. HL-1 cells were also assigned three groups. Ang II (1 μM) was treated for one day, and isorhamnetin (10 μM) was pretreated one hour before the beginning of Ang II treatment. To evaluate the effect of isorhamnetin on AF, electrophysiologic study including AF induction and action potential duration (APD) measurement with atrial tissue and HL-1 cells was performed. The expression of ion channel genes and proteins, including Cav1.2, were also evaluated.

Results
AF induction rate was markedly increased by Ang II and significantly decreased by isorhamnetin. AF duration was remarkably prolonged by Ang II and significantly shortened by isorhamnetin. Atrial effective refractory period (AERP) shortened by Ang II and reversed by isorhamnetin. Ang II administration significantly prolonged APD; that was alleviated by isorhamnetin. In addition, Ang II increased the frequency of delayed afterdepolarization (DAD), whereas isorhamnetin reduced its frequency. Cav1.2 channel expression was enhanced by Ang II and normalized by isorhamnetin. On the other hand, Ang II and isorhamnetin had no effect on potassium channels.

Conclusion
The findings in this study suggest that isorhamnetin prevents APD prolongation via the modulation of Cav1.2 channel and reduced the frequency of DAD, which is one of the mechanisms to prevent AF vulnerability.Effect of isorhamnetin on APD
Roles of aldosterone on ventricular arrhythmias, and associated gap junction and ion channel remodeling in hypertrophic heart
Authors: Kobara M , Toba H , Nakata T 
Published: November 2023

Abstract

Background
Ventricular arrhythmias are critical causes of death in patients with chronic heart failure (CHF). Aldosterone (Ald) is an exacerbating factor of CHF and mineral corticoid receptor antagonist (MRA) is usual drug for the management of CHF. MRA also suppressed sudden cardiac death, however, mechanisms of these effects remain unknown. We investigated the effects of MRA on ventricular arrhythmias and arrhythmogenic factors using Dahl Salt sensitive (DS) rats.

Methods
(in vivo) DS rats were divided into three groups; low salt group (LS), high salt group (HS), and eplerenone-, an MRA, treated high salt group (HS+EPL). Low salt (0.3% NaCl) or high salt (8% NaCl) were administrated for 8 weeks and EPL was administrated in the last 4 weeks. Cardiac geometry and function were assessed by echocardiography. Susceptibility of ventricular arrhythmias were assessed using programmed stimulation. Myocyte hypertrophy and cardiac fibrosis were examined by Masson’s trichrome staining. Expression and distribution of connexin43 (Cx43) were examined by immunostaining and western blotting. mRNA expression of Ca transient-related factors, such as phospholamban, SERCA2a, and ryanosin 2, and potassium ion channel-related factors, such as KCNE1 and KCNQ1, was examined by RT-PCR. (in vitro) Ald (1-100 nM) was administrated to cultured rat neonatal cardiomyocytes. Expression of Cx43, Ca transient-related, and potassium ion channel-related factors are also examined as mentioned above. Effects of Src tyrosin kinase inhibitor, PP2, and ERK inhibitor, PD98059, on Ald-induced Cx43 reduction were examined by RT-PCR and immunostaining.

Results
Systolic blood pressure and Ald concentrations in cardiac tissue were higher in HS group than LS group, and EPL did not affect them. In HS group left ventricular hypertrophy, dilatation and systolic dysfunction were observed in association with myocyte hypertrophy and interstitial fibrosis. EPL significantly recovered cardiac function and histological impairments. In addition, elongation of QTc in ECG and susceptibility of ventricular tachycardia were remarkable in HS group rather than LS and EPL attenuated them. Distribution of Cx43 was scattered in HS group, and EPL attenuated these changes. Decrease in SERCA2a and increase in KCNE1/KCNQ1 mRNA expression were found in HS group, and these changes were attenuated by EPL. In cultured myocytes, Ald decreased Cx43 mRNA and protein expression in a dose dependent fashion. Ald-induced Cx43 reduction was inhibited by PP2 and PD98059. In addition, Ald (100 nM) also decreased SERCA2a and increased KCNE1/KCNQ1 mRNA expression.

Conclusion
These results indicate that Ald reduced and dispersed the Cx43 expression reduction and dispersion through Src tyrosin kinase and ERK signaling pathways, and also mediated SRECA2A and KCNE1/KCNQ1 expression, which induced QTc prolongation and susceptibility of lethal ventricular arrhythmias in hypertensive cardiac hypertrophy.
A Maltese landscape of cardiac genetics
Authors: Abela M , Schembri J , Scerri J , Debattista J , Felice T , Caruana M , Sammut M A , Said E , Scerri C 
Published: November 2023

Abstract

Introduction
Advances in human genetics have improved our understanding of various inherited cardiovascular conditions (ICC). Genetic testing is now an important pillar in the management of patients suffering from cardiomyopathies, channelopathies and aortic and other vascular disorders. Existing population databases may not cater for the local gene pool. The local genetic yield of ICCs has never been explored.

Objective
The aim of this study was to evaluate the population referred for genetic testing and to assess the genetic yield according to the referring phenotype.

Methodology
Probands referred for genetic testing between 2018-2022 were included. Data was retrospectively reviewed in close liaison with the molecular genetics lab at a university. Variants classified as pathogenic or likely pathogenic by ACMG criteria were labelled as ‘gene positive’ for the purpose of this study.

Results
328 patients were referred for genetic testing (63.7% Male, 51.3±18.7 years). The majority were referred because of a cardiomyopathy phenotype (64.02%) followed by arrhythmic disorders (20.7%), aortic/vascular disorders (12.5%), familial hyperlipidaemia (1.5%) and complex congenital heart disease (0.6%). Two (0.6%) did not have a reason specified.
94 (28.7%) probands were gene positive, 5 patients (1.5%) had two mutations, 41.4% of all mutations were novel. The highest genetic yield was seen in cardiomyopathy patients (34.8%), followed by aortic/vascular disorders (24.4%) and arrhythmic disorders (14.7%).
A separate analysis was also performed for each individual phenotype (Table 1). The dominant genes for each condition: MYH7 (24.4%) and MYBPC3 (22.0%) for hypertrophic cardiomyopathy; TTN (52.9%) and FLNC (23.5%) for dilated cardiomyopathy; DSG2 (45.5%) and FLNC (18.2%) for arrhythmogenic cardiomyopathy; TTN (40.0%) and MYH7 (40.0%) for left ventricular non-compaction cardiomyopathy; TTR (100%) for cardiac amyloid; SCN5A (37.5%) for non-specific cardiomyopathy; KCNH2 (50.0%) and KCNQ1 (50.0%) for long QT syndrome; SCN5A (37.5%) for Brugada Syndrome; FBN1 (40.0%) for skeletal phenotype; FBN1 (33.3%) for aortic phenotype; and LDL-R (100.0%) for familial hyperlipidaemia

Conclusion
The overall ICC genetic yield in Malta is 28.7%. A substantial proportion were novel mutations. The highest genetic yield is in the cardiomyopathy group. The yield for most phenotypes is comparable to other labs. The proportion of gene positive LQTS patients is surprisingly very small, a phenotype with an established high genetic yield in various studies (up to 80%). Clinicians caring for patients with ICCs now have local diagnostic yield data to better counsel patients when referred for genetic testing.
Prognostic value of modified ADMIIRE-HF risk score in patients with implantable cardioverter defibrillator: a prospective comparative study with 6-minute walk distance
Authors: Kawasaki M , Yamada T , Watanabe T , Morita T A K A S H , Kikuchi A , Kondo T , Kawai T , Nishimoto Y , Nakamura J , Fujita T , Chang Y , Taniichi M , Oshita T , Fukunami M 
Published: November 2023

Abstract

Background
ADIMIRE-HF risk score is a novel risk score that combines clinical characteristics and MIBG imaging variables to predict serious arrhythmic risk in patients with chronic heart failure (CHF) and recent studies showed that highest occurrence of severe arrhythmic events (SAE) was seen in patients with an intermediate decrease in MIBG uptake rather than the lowest values. Six-minute walk distance (6MWD) has also been shown to detect high risk patients with CHF. However, there is no information available on the long-term prognostic value of these indices for the prediction of ventricular tachyarrhythmias in patients with implantable cardioverter defibrillator (ICD).

Methods and Results
We prospectively enrolled 231 consecutive outpatients with ICD (age: 65±14 years, male: 81%, NYHA class: 1.7±0.7, LVEF: 47±17%). At entry, cardiac MIBG imaging, echocardiography and 6-minute walk test were performed. Modified ADMIRE-HF risk score was derived from the sum of the point values of the following parameters: LVEF (&lt;25%:5 points), MIBG heart-to-mediastinum ratio on delayed planar image (HMR 1.4-1.9: 12 points) and systolic blood pressure (&lt;120: 3 points, 120-139: 0 point, &gt;140: -3 points). During a follow-up period of 4.4±2.8 years, 72 patients had appropriate ICD therapy (ATx). At multivariate Cox analysis, modified ADMIRE-HF risk score and 6MWD were significantly and independently associated with ATx after adjustment of age, sex, non-sustained ventricular tachycardia and NYHA functional class. ATx was significantly more frequently observed in patients with both higher modified ADMIRE HF risk score (&gt;9: median value) and shorter 6MWD (&lt;300m) and with either, than with none of them (54% vs 34% vs 18%, respectively p&lt;0.0001).

Conclusion
Combination of modified ADMIRE-HF risk score and 6MWD would be strongly associated with an increased risk for ventricular tachyarrhythmias in ICD patients.
Large scale genome-wide association analyses identify novel genetic loci and mechanisms in hypertrophic cardiomyopathy
Authors: Tadros R , Zheng S L , Grace C , Jorda P , Francis C , Jurgens S J , Thomson K L , Harper A R , Wilde A A , Olivotto I , Adler A , Goel A , Ware J S , Bezzina C R , Watkins H 
Published: November 2023

Abstract

Background
Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality with both monogenic and polygenic components. Prior genome-wide association studies (GWAS) identified few genomic loci and disease genes due to limited sample size.

Purpose
To discover novel genetic loci, genes and mechanisms implicated in HCM using a large scale GWAS and multi-trait analysis of GWAS (MTAG).

Methods and results
We performed the largest HCM GWAS meta-analysis and MTAG to date including 5,900 HCM cases, 68,359 controls, and 36,083 UK Biobank (UKB) participants with cardiac magnetic resonance (CMR) imaging. We estimated the heritability of HCM attributable to common genetic variation (h2SNP) to be 0.25±0.02 using genome-based restricted maximum likelihood (GREML), with higher h2SNP in non-sarcomeric (0.29±0.02) compared to sarcomeric HCM (0.16±0.04). We identified a total of 70 loci (50 novel) associated with HCM (Figure 1), and 62 loci (32 novel) associated with relevant left ventricular (LV) structural or functional traits. Amongst the common variant HCM loci, we identify a novel HCM disease gene, SVIL, which encodes the actin-binding protein supervillin. We performed rare variant burden analysis including 1,845 clinically-diagnosed unrelated HCM cases and 37,481 controls and demonstrated a 10.5-fold (95% CI: 4.1-26.8; P=0.0000002) excess burden of SVIL loss of function (LoF) variants in HCM cases. Two-sample mendelian randomization analyses using LV contractility as exposure and obstructive (oHCM) and non-obstructive HCM (nHCM) as outcomes support a causal role of increased LV contractility in both oHCM and nHCM (Figure 2), suggesting common disease mechanisms and anticipating shared response to therapy.

Conclusion
We identify 50 novel genomic loci associated with HCM. Our data suggest that LoF variants in SVIL are a cause of HCM, and that increased contractility mediate both nHCM and oHCM. Taken together, the findings significantly increase our understanding of the genetic basis and molecular mechanisms of HCM, with potential implications for disease management.Figure 1Figure 2
Porphyromonas gingivalis systemic infection is associated with calcific aortic valve stenosis through IL-1-dependent signaling pathways
Authors: Zhang E , Meng Z , Wang C , Xu C S , Wang M , Natarajan R , Wu Y 
Published: November 2023

Abstract

Background
Calcific aortic valve stenosis (CAVS) is characterized by inflammation mediated valvular calcification. Porphyromonas gingivalis, a keystone pathogen for periodontitis, has been associated with various chronic inflammatory diseases. We assessed the impact of intravenous inoculation with P. gingivalis on the progression of CAVS.

Methods
Wide-type (WT) C57BL/6, ApoE deficient (ApoE-/-), and IL1B deficient (IL-1β-/-) mice were fed with normal chow or high-fat diet (HFD). A series of metagenomic, morphometric, and molecular signaling experiments, including 16S rRNA gene sequencing, RNA sequencing (RNA-Seq), quantitative real-time polymerase chain reaction (qPCR), immunostaining, and western blotting, were conducted. Valvular calcification and aortic stenosis were evaluated by Alizarin red staining, and mice echocardiography, respectively.

Results
By using 16S rRNA gene sequencing and qPCR, we found that P. gingivalis was the 3rd most significantly enriched bacterial species in aortic valves from CAVS patients compared with controls. Morphometric assays showed predominant P. gingivalis infiltration inside of human aortic valves. Intravenous inoculation of P. gingivalis in either WT or ApoE-/- mice resulted in increased bacterial infiltration in aortic valves, irrespective of chow- or HFD. Alizarin red staining and echocardiographic evaluation further revealed that P. gingivalis bacteremia markedly enhanced valvular calcification, leading to hemodynamically significant aortic stenosis in the murine models, which were ameliorated by intraperitoneal metronidazole prophylaxis. RNA-Seq and qPCR validation showed that the gene expression of IL1B, RUNX2, and BMP2 was upregulated in P. gingivalis-stimulated valvular interstitial cells (VIC). Similar changes on IL1B were observed in aortic valves form P. gingivalis-challenged WT and ApoE-/- mice, and in valvular specimens from CAVS patients. qPCR and Alizarin red staining showed that IL1B knockdown decreased P. gingivalis-induced RUNX2 and BMP2 expression, and attenuated calcification in VICs. Consistently, P. gingivalis-induced changes on bacterial infiltration, valvular calcification, and hemodynamically significant aortic stenosis were markedly blunted in IL-1β-/- mice. Furthermore, the level of serum IL-1β and SAA were increased in response to P. gingivalis challenge in ApoE-/- mice, but not in WT or IL-1β-/- mice.

Conclusions
This study demonstrated, for the first time, that P. gingivalis infiltration in aortic valves promoted IL-1β-mediated local inflammation and valvular calcification, thus resulting in the progression of CAVS.Central Illustration: Pg promotes CAVS
A novel mouse model for mineral homeostasis disrupting induced calcific aortic valve stenosis
Authors: Qian N J , Liu X B , Wang J A 
Published: November 2023

Abstract

Background
Calcific aortic valve disease (CAVD) is the most common valve disease that has been occurring with rapidly increasing morbidity. Chronic kidney disease (CKD) which disrupts mineral homeostasis due the impaired renal function, is one of the known factors, largely contributing to risk of CAVD, independent of atherosclerosis. To the best of our knowledge, there are few calcific aortic valve stenosis mouse models simulating conditions under CKD that develop hemodynamically significant stenosis as well as calcification,

Purpose
The purpose was to assess the feasibility to develop a mouse model of CAVD considering risks under CKD.

Methods
For this model, C57/BL6 mice were firstly underwent aortic valve wire injury by spring guidewires inserting into left ventricle via right common carotid artery. Vitamin D was subcutaneous injected on 3 consecutive days from the second day of aortic valve wire injury. Echocardiography was performed to evaluate aortic valve function at 7, 14 and 28 days. Then the mice were sacrificed and aortic valves were collected to make histological analysis.

Results
An obvious increase in aortic velocity was already observed at 7 days after injury by continuous echocardiographic assessment and remained stable from 14 days compared with sham mice. Alizarin red staining showed calcium nodules formation in valve leaflets 14 days after injury and became more conspicuous at 28 days. Aortic valve thickening, increased macrophage infiltration, fibrosis and remarkable osteogenic markers were found in aortic valves at 28 days after injury.

Conclusions
We develop a novel mouse model of CAVD, especially simulating risks under CKD and mineral homeostasis disrupting. This model may be a convenient and valuable tool to investigate the mechanism of CAVD and further explore potential therapeutic strategies.Fig1.Alizarin red staining aortic valvesFig2.Immunostaining of aortic valves