bluuebunny/crossref_metadata_2025_split huggingface dataset:
Monocyte priming during acute myocardial infarction
Authors: Moggio A , Mauersberger C , Khangholi D , Dutsch A , Schunkert H , Kessler T , Sager H 
Published: November 2023

Abstract

Introduction Purpose
Myocardial infarction (MI) inflicts a sterile wound on the heart which recruits hundreds of thousands of monocytes from the blood. The bone marrow (BM) responds to cardiac ischemia with an increase in monocyte production, hence meeting the high demand of these cells. Apart from this quantitative response, little is known whether the BM supplies qualitatively different monocytes during the course of MI.

Methods & Results
We isolated BM Ly6Chigh monocytes from non-infarcted mice and from mice which were infarcted 72h prior (surgically induced by permanent coronary ligation) and contrasted monocytic transcriptomes using RNA sequencing. We found 672 differentially expressed genes (DEG) of which 289 were up- and 383 down-regulated (log2FoldChange³±1.0, adjusted p&lt;0.05). Since most DEG were enriched in "cell adhesion and recruitment" pathways, we tested the functional relevance of our findings in the context of monocyte recruitment to the heart using competitive adoptive transfer experiments. Our data revealed that the BM provides monocytes that are primed for better recruitment (relative recruitment: 56.1% 12h after MI vs. 43.9% steady state, p&lt;0.01) at the early inflammatory phase following coronary ligation (12h after MI). In contrast, monocytes displayed worse recruitment capacities (relative recruitment: 30.4% 72h after MI vs. 65.8% steady state, p&lt;0.01) at the end of the inflammatory phase (72h after MI). We next sought to identify key players in this BM-controlled cardiac recruitment process. Our RNA sequencing data revealed that – in monocytes with poor recruitment capacities – the cell adhesion molecule CD209 was among the most significantly downregulated genes at 72h after MI over steady state. To investigate the molecular role of CD209 in the process of leukocyte recruitment to the myocardium during MI, we cloned human CD209 from a cDNA library into an overexpression plasmid system. After ectopic overexpression of CD209, THP-1 cells (a cell line derived from immortalized human blood monocytes) showed enhanced adhesion to endothelial cells (HUVECs) compared to THP-1 cells under control conditions. Finally, we infarcted wild type (CD209+/+) and CD209 knockout (CD209-/-) mice and found decreased numbers of Ly6Chigh monocytes in infarcted hearts of CD209-/- mice in comparison to CD209+/+ mice (491+52 vs. 915+180 Ly6Chigh monocytes/mg infarct tissue, mean+SEM, p&lt;0.05) while numbers of blood Ly6Chigh monocytes were unchanged.

Conclusions
The BM responds to MI and provides an altered monocyte repertoire in terms of numbers and function and hence remotely controls monocyte/macrophage accumulation in the ischemic heart. Consequently, the heart–bone marrow axis may represent a novel therapeutic target to beneficially modify post-MI cardiac remodeling, a major contributor of MI-related morbidity and mortality.
Empagliflozin treatment prevented oxidative stress, macrophage infiltration, pro-inflammatory and pro-fibrotic responses in the left ventricle of isoprenaline-induced Takotsubo-like syndrome in rats
Authors: Tatarcheh T , Amissi S , Matsushita K , Mroueh A , Trimaille A , Gong D S , Fakih W , Muzammel H , Faucher L , Granier A , Pieper M P , Schini-Kerth V , Morel O 
Published: November 2023

Abstract

Introduction
Takotsubo Syndrome (TTS) is an acute heart failure (HF) syndrome induced by both emotional and physical stressors involving a surge of catecholamines and apical ballooning. Currently, there is no specific treatment for TTS. Sodium-glucose cotransporter2 inhibitors (SGLT2i) showed major cardiovascular protective effects in patients with HF independent of glycemic control. SGLT2i have also been shown to have anti-inflammatory and anti-oxidant effects, and to improve the endothelial function in experimental models of cardiac disease. However, a possible protective role of SGLT2i in TTS is unclear. Thus, this study evaluated the effect of SGLT2i on isoprenaline-induced TTS-like syndrome in rats, and determined the underlying mechanism.

Methods
32 female Sprague-Dawley rats (10 weeks old) were divided into 4 groups: control, empagliflozin (30 mg/kg/day provided in the diet for 2 weeks), isoprenaline (Iso, 100 mg/kg, i.p.) to induce a TTS-like syndrome, and Iso plus empagliflozin (IE group). After 6 h of Iso injection, echocardiography was performed to determine left ventricular (LV) ejection fraction (EF) by area and heart rate (HR). At day 3, rats were sacrificed, main mesenteric artery and microvessels were collected for vascular reactivity studies, and LV was divided into base and apex to study mRNA expression levels using RT-qPCR, macrophage infiltration by in situ CD68 immunofluorescence staining, and oxidative stress using dihydroethidium.

Results
The injection of Iso to rats caused at 6 h an increased LVEF and HR in the Iso and the IE groups as compared to their corresponding controls. The HR response was significantly smaller in the IE group compared to Iso group whereas LVEF was similar. In addition, in mesenteric microvessels but not the main mesenteric artery, Iso group showed significant decreased relaxations to acetylcholine and increased contractile responses to phenylephrine in intact rings both of which were not observed in the IE group. Hearts showed significantly increased mRNA levels of IL-1β, TNF-α, NOX2, VCAM-1, MMP-9, TGF-β1 and collagen-1, oxidative stress levels and CD68 staining in the apex compared to the base in the ISO group, all of which were significantly reduced in IE group.

Conclusions
The present findings indicate that ISO injection caused in the LV elevated levels of oxidative stress, macrophage infiltration, pro-inflammatory, pro-remodeling and pro-fibrosis responses that were more pronounced in the apex compared to the base, and also endothelial dysfunction in the systemic microcirculation, all of which were significantly prevented by the empagliflozin treatment. They further suggest that SGLT2 appears as an interesting target in TTS.
Eight-year follow-up of cardiosphere-derived cell transplantation in patients with single ventricle congenital heart disease
Authors: Hirai K , Baba K , Kasahara S , Oh H 
Published: November 2023

Abstract

Background
Although transcoronary infusion of cardiosphere-derived cells (CDCs) in patients with single ventricles provides short-term improvement in cardiac function, the long-term efficacy is still unknown.
Purpose: We tested the hypothesis that CDC infusion is associated with improved long-term clinical outcome in patients with single ventricles and heart failure.
Methods: Patients were enrolled in the TICAP phase 1 (Transcoronary Infusion of Cardiac Progenitor Cells in Patients With Single Ventricle Physiology) and PERSEUS phase 2 (Cardiac Progenitor Cell Infusion to Treat Univentricular Heart Disease) trials between January 5, 2011, and January 30, 2015. The inclusion criteria were that patients were aged &lt;6 years who were diagnosed with single ventricle lesions undergoing stage 2 (bidirectional Glenn: BDG) or stage 3 (total cavopulmonary connection: TCPC) palliation. Ventricular ejection fraction should be &lt;60% during the initial screening through the final enrollment. Medical records of patients with single ventricles were obtained and analyzed as a control group who were eligible but were treated by staged palliation alone. We evaluated the effectiveness of CDCs using an integrated cohort study in 93 patients with single ventricles, including 41 patients who received CDC infusion and 52 controls.
Results: At the time of this study, 36 patients with CDC infusion and 42 controls were alive without cardiac transplantation, with mean follow-up of 9.7±1.2 years. Survival rate did not differ between the 2 groups (log-rank P = 0.351), whereas overall patients treated by CDCs had lower incidents of late failure defined as late death, protein-losing enteropathy, plastic bronchitis, BDG or TCPC take down, disqualified TCPC candidate, Ross classification 3 or 4, or rehospitalization for heart failure (P = 0.048) compared with controls. Adverse events defined as unplanned cardiac operation, arrhythmia, thromboembolic events, cerebral hemorrhage, or tumor formation (P = 0.057) and unplanned catheter intervention (P = 0.094) did not differ between 2 groups.
Conclusions: Intracoronary delivery of CDCs in patients with single ventricles did not improve all-cause mortality rate but significantly reduced the incidence of late failure at 8 years of follow-up.
AAV6-mediated gene transfer of HCN1-ddd generates slightly faster baseline beating rates as compared to Hcn2 yet with a potential risk for pro-arrhythmia
Authors: Cervera Barea A , Wang J , Jonker T , Klerk M , Boender A , Jansen M , Visser J , Van Nieuwburg-Fennema M , Kirzner O , Vos M , Tan H , Barnett P , Christoffels V , Neef K , Boink G 
Published: November 2023

Abstract
Electronic pacing is the current treatment of choice for complete heart block (CHB) that revolutionised last century’s standard of care. Despite its success, some critical issues remain such as providing suboptimal cardiac output and a lack of direct autonomic responsiveness. To develop a more physiological and hardware-free pacemaker, we focused on developing gene therapy-based biological pacemakers by means of ion channel over-expression. Previous studies with adenoviral gene transfer indicated possible superior outcomes for the engineered mutant HCN1-ΔΔΔ as compared to wild-type Hcn2, yet a head-to-head comparison was never made.
To assess the long-term biological pacemaker efficacy for AAV6-mediated gene transfer of HCN1-ΔΔΔ and Hcn2.
Functional biological pacemaker studies were conducted in a porcine model of radiofrequency ablation-induced CHB. Four weeks after the ablation, animals were studied in two different groups: AAV6-cTnT-HCN1-ΔΔΔ and AAV6-cTnT-Hcn2, both immunosuppressed with prednisolone and Cyclosporine A. All animals were then followed for another four weeks to evaluate in vivo biological pacemaker performance and then organs were harvested to assess transduction efficiency.
Biological pacing effectiveness was evaluated in view of maximal (max) and basal (mean) beating rates (HR), and pacemaker dependency that animals had shown throughout the study. Four weeks after the induction of CHB, on the day of the injection, all animals (n = 6) presented an average mean HR of 53,67 ± 7,64 bpm (Figure 1B) and a pacemaker dependency above 65% (Figure 1C). One week after gene transfer, these beating rates rapidly increased and pacemaker dependency declined. Hcn2 and HCN1-ΔΔΔ groups displayed a notable increase in max HR (Figure 1A), where HCN1-ΔΔΔ offered the most potent and sustained response (Hcn2 153,33 ± 47,26 bpm vs. HCN1-ΔΔΔ 220 ± 43,59 bpm; Figure 1A). In terms of mean HR, they similarly trended up in both groups (Hcn2 57,81 ± 5,49 bpm vs. HCN1-ΔΔΔ 59,22 ± 2,28 bpm; Figures 1B and E). Lastly, these faster beating rates in HCN1-ΔΔΔ resulted in modestly lower dependency in electronic back-up pacing (52 ± 7,94 % vs. 48,3 ± 22,37 % for HCN1-ΔΔΔ vs. HCN2; Figures C and F).
AAV6-mediated HCN1-ΔΔΔ gene transfer produced slightly faster mean heart rates as compared to Hcn2, yet HCN1-ΔΔΔ generated persistently increased maximal heart rates (in two out of three animals) that exceeded the physiological desirable range. These findings possibly relate to the much faster channel gating kinetics of HCN1-ΔΔΔ that were previously found to be profoundly pro-arrhythmic with the chimera channel HCN212.Figure 1Abstract ESC 2023
The role of latrophilin-2 in maintaining cardiac cell-to-cell junctions and its implications for dilated cardiomyopathy and sudden death
Authors: Cho H J , Kang M J , Son H J , Seo H J , Kim H S 
Published: November 2023

Abstract

Background
Identifying genes that are important for maintaining heart function and characterizing their roles and pathways are essential for developing therapeutic approaches. Latrophilin-2 (LPHN2), a relatively unknown GPCR, critically contributes to differentiation from pluripotent stem cells (PSC) to the cardiac lineage, but it is not known whether LPHN2 is active in the adult heart.

Purpose
In this study, we explored the functions of LPHN2 in adult hearts.

Methods and Results
To determine whether there is an association between variation in LPHN2 and cardiac phenotypes in humans, we used gnomAD and UK Biobank data. The data suggested that LPHN2 variants could be fatal. Accordingly, we developed a mouse model for further analysis of Lphn2. Deletion of Lphn2 causes embryonic lethality, so we generated a cardiac-specific, tamoxifen-inducible Lphn2 conditional knockout mouse (Lphn2icKO mouse) by cross-breeding Lphn2flox/flox mice with the TMX-inducible Cre recombinase (MerCreMer) under control of the α-Myh6 (α-myosin heavy chain) promoter mice. After administering tamoxifen, we found that the left ventricle became dilated and the systolic function was decreased, and gaps were created between cardiomyocytes. We also observed ventricular tachycardia and atrioventricular block associated with the dilated cardiomyopathy and subsequent sudden cardiac death. Cell-to-cell junctions (adherence, gap, and desmosomes,) were found to be dysregulated in the Lphn2icKO adult mouse heart and the heart at embryonic day 13.5 of Lphn2−/− (homozygous Lphn2 deficiency). To investigate Lphn2 function in a disease model, we generated a myocardial infarction (MI) in Lphn2icKO mice. MI with tamoxifen group showed wide QRS tachycardia and various types of block, and a survival reduction of 40% compared with that of the MI group. Regarding underlying mechanisms, we found that PGC-1α, a factor downstream of p38-MAPK that contributes to arrhythmia and maturation of PSC-derived cardiomyocytes, was downregulated (Figure).

Conclusions
LPHN2 is a key molecule that maintain adult heart integrity via its effects on cell-to-cell junctions, and the deficiency of Lphn2 exacerbates heart failure. Our findings provide evidence in support of LPHN2 being a pivotal regulator of heart function through the p38-MAPK-PGC-1α pathway.Schematic illustration
Wearable cardioverter defibrillator after ICD-system explantation: data from a multicenter registry
Authors: El-Battrawy I , Beiert T , Koepsel K , Kovacs B , Blockhaus C , Klein N , Kuntz T , Shin D I , Abumayyaleh M , Saguner A M , Erath J W , Duru F , Muegge A , Akin I , Aweimer A 
Published: November 2023

Abstract

Background
Data on the use of wearable cardioverter defibrillator (WCD) among patients after cardiac implantable electronic device explantation of 1- to 3-chamber Implantable Cardioverter-defibrillator system (ICD) are sparse. Subsequently several guidelines give a different recommendation regarding WCD indication in this cohort.

Objectives
We aimed to study the baseline characteristics and outcome of patients treated with WCD after ICD explantation. The primary outcome is appropriate WCD shock.

Methods
1104 patients were included in a multicenter registry from seven European centers. Among this cohort 109 patients received a WCD to bridge the time after ICD-system explantation until reimplantation due to a persistent ICD-indication. The mean follow-up time of the whole cohort was 824±773 days. Cardiovascular history and non-cardiovascular morbidities were evaluated. In addition, the presence of ventricular tachyarrhythmias and/or WCD shocks was evaluated in the explantation group. Furthermore, after ICD-reimplantation the rate of rehospitalization for ventricular tachyarrhythmias, atrial fibrillation, stroke and congestive heart failure was followed.

Results
In the explantation group patients were older (65±14 versus 59±15; p&lt;0.001) and were hospitalized longer (21±15 days versus 14±12 days; p&lt;0.001). The index LVEF differed significantly (35.7±14.1% versus 29.3±11.5%; p&lt;0.001). The LVEF value did not differ significantly over short-term follow-up (35.7±14.2% versus 37.9±11.9%; p=0.204). Wear days among patients after ICD-system explantation were 61±46 days. An appropriate WCD shock was documented in 7.3% after ICD-system explantation during WCD use. Up to 80.6% of patients after ICD-system explantation received a reimplantation. The rate of rehospitalization due to ventricular tachyarrhythmias was 7.3%, due to heart failure 6.8% and due to atrial fibrillation 4.1%. After ICD-implantation the rate of appropriate shocks was 12/89 (13.4%). In the multivariable regression analysis myocarditis and ICD-system explantation were positive predictors for the risk of ventricular tachyarrhythmias, but nevertheless an improved left ventricular ejection fraction (LVEF) and use of aldosterone antagonists were negative predictors for the risk of ventricular tachyarrhythmias.

Conclusions
Cccurrence of malignant arrythmia after ICD-system explantation is high and the use of WCD among these patients could be beneficial in preventing sudden cardiac death.
Hepatokine selenoprotein P has an important role in cardiac remodeling
Authors: Usui S , Takashima S , Goten C , Inoue O , Takeda Y , Yamaguchi K , Hashimuko D , Takamura M 
Published: November 2023

Abstract

Background
In heart failure, the failure of the pump function results in reduced blood flow and dysfunction of energy metabolism in tissues and organs throughout the body. The liver is the largest organ in the human body and plays a central role in lipid and glucose metabolism. Hepatokine selenoprotein P (SeP) contributes to insulin resistance and hyperglycemia in patients with type 2 diabetes. Inhibition of SeP protects the heart from ischemia reperfusion injury and serum levels of SeP are elevated in patients with heart failure with reduced ejection fraction.

Objective
We investigated the role of SeP in the regulation of cardiac remodeling in response to pressure overload.

Methods and Results
To examine the role of SeP in cardiac remodeling, transverse aortic constriction (TAC) was subjected to SeP knockout (KO) and wild-type (WT) mice for 2 weeks. LV weight/tibial length (TL) was significantly smaller in SeP KO mice than in WT mice. Lung weight/TL was significantly smaller in SeP KO than in WT mice. TAC-induced cardiac upregulation of the fetal type genes, including atrial and brain natriuretic factors, was significantly attenuated in SeP KO compared to WT. Furthermore, azan staining revealed that there was significantly less interstitial fibrosis in hearts after TAC in SeP KO than in WT mice.
Expression of SeP in the liver of WT mice was significantly increased by TAC, while expression in the heart was unchanged. Hepatocyte-specific SeP KO mice were generated using the albumin-Cre-LoxP system. LV weight/TL was significantly smaller in hepatocyte-specific SeP KO than in WT mice. To determine whether hepatic overexpression of SeP affects TAC-induced cardiac hypertrophy, a hydrodynamic injection method was used to generate mice that overexpress SeP mRNA in the liver. Hepatic overexpression of SeP in SeP KO mice lead to a significant increase in LV weight/TL after TAC compared to that in other SeP KO mice.

Conclusions
These results suggest that cardiac pressure overload induced hepatic expression of SeP and the absence of endogenous SeP attenuated cardiac hypertrophy, dysfunction and fibrosis in response to pressure overload in mice. SeP possibly plays a maladaptive role against progression of heart failure through the cardiohepatic interaction.
Heart failure stimulates colorectal tumour growth through gut microbial alterations of specific populations
Authors: De Wit S , Geerlings L , Aboumsallem J P , Shi C , Schouten E M , Blancke G , Andries V , Yntema T , Koonen D , Vereecke L , Sillje H H W , De Boer R A 
Published: November 2023

Abstract

Background/purpose
The field of reverse cardio-oncology has received growing attention in the last years, since epidemiological studies showed that patients with HF are at increased risk of developing cancer. In addition, HF can stimulate tumour growth directly in distant organs, including colon cancer. The exact mechanisms underlying this phenomenon, however, remain largely unknown. The connection between the microbiome and colorectal cancer (CRC) has been studied extensively and microbial dysbiosis in CRC is linked to cancer progression. Recent studies have also shown that HF patients display microbial dysbiosis. We hypothesized that microbial dysbiosis might contribute to HF-induced CRC tumour growth.

Methods
C57BL/6J mice were subjected to myocardial infarction (MI), with sham surgery as control. After six weeks faeces were collected, processed for 16s rRNA sequencing, and pooled for faecal microbial transplantation. CRC tumour growth was provoked in germ-free mice by treating them with Azoxymethane (AOM)/Dextran sodium sulphate (DSS). The CRC mice were transplanted with faeces from MI or sham mice. Disease progression was monitored using the disease severity score and endoscopy. After ten weeks mice were sacrificed, and tumour number and proliferation were quantified. All experimental procedures were performed in accordance with the European Union guidelines (CCD_8141, the Netherlands, LA_1400637, Belgium).

Results
MI-induced HF resulted in a decrease in microbial diversity (Shannon diversity p=0.018), characterized by a decrease in short chain fatty acid-producing bacteria, including the genera Blautia (p&lt;0.01) and Roseburia (p&lt;0.01). In addition, caecal butyrate levels were decreased in MI mice (p=0.029). These changes were largely comparable to microbial changes observed in HF patients and CRC patients. Interestingly, faecal transplantation with faeces from MI mice resulted in faster growth of CRC tumours in mice treated with AOM/DSS. This was demonstrated by a higher endoscopy score (7.9 ±2.5 vs. 10 ±2.4, p=0.038), indicative of worse disease progression, increased tumour counts (22 ±5.3 vs. 29 ±6, p&lt;0.01), and a higher percentage of Ki67 positive cells in tumour tissue (p=0.012), relative to AOM/DSS treated mice transplanted with faeces from sham mice. Sequencing data revealed several differences in the microbial composition of mice transplanted with faeces from MI mice compared to mice transplanted with faeces from sham mice.

Conclusion
Our results demonstrate that HF induces microbial dysbiosis in mice. In addition, we show, for the first time, using a faecal transplantation model, that HF-induced microbial dysbiosis is causally involved in CRC tumour growth in a mouse model of CRC. Targeting the microbiome may present a tool to mitigate HF associated co-morbidities, especially cancer.Graphical abstract