bluuebunny/crossref_metadata_2025_split huggingface dataset:
Recruited macrophages incorporate into the resident cardiac macrophage pool and converge into a common phenotype in the healing infarct, but not in the failing heart exposed to pressure overload
Authors: Vico T , Taglinger M , Haacke V , Zehender C , Heinz B , Von Ehr A , Dederichs T , Ehlert C , Dufner B , Westermann D , Hilgendorf I 
Published: November 2023

Abstract

Introduction
Resident macrophages account for 5% of the cells in the healthy heart. In response to cardiac injury, monocytes infiltrate and differentiate into recruited macrophages which function distinctly from the resident subset of primarily embryonic origin. In this work, we aim to identify the extent to which macrophage origin, tissue location and type of cardiac injury determine macrophage phenotypes in ischemic and non-ischemic cardiac injuries over time.

Results and methods
We use a tamoxifen inducible CX3CR1 Yfp CreER/+ :R26tdT/+ mouse line to visualize and quantify fluxes of resident and recruited macrophages, and their respective localizations within the heart following ischemia and reperfusion (I/R) injury and pressure overload after transversal aortic constriction (TAC), respectively.
Interestingly, macrophage numbers peaked during the first week post-surgery in both the local/acute and the global/continuous injury models. Initially, recruited macrophages outnumbered the resident macrophage pool within the infarct area but ultimately reached a 1:1 equilibrium at 4 weeks post I/R injury and at 8 weeks post TAC. In I/R injury, the 1:1 equilibrium established already during the first week in the remote myocardium. Gene expression profiles changed alongside shifts in macrophage ratios. For instance, in the infarct, recruited macrophages showed upregulation of cytokine production and cell chemotaxis pathways at early stage. By 4 weeks post MI their gene expression profiles have converged with those of resident macrophages. Likewise, in the remote myocardium, recruited and resident macrophages assimilated post MI, overexpressing genes associated adaptative immune response activation and cellular homeostasis.
Similar to the I/R injury setting, a 1:1 equilibrium of resident and recruited macrophages established in the hypertrophied and dilated hearts within 4 to 8 weeks post TAC surgery. However, transcriptional profiles remained differentially regulated between recruited and resident cardiac macrophages at all time points tested, and distinct from those observed post I/R injury: recruited macrophages behavior changed from a profibrotic into a proliferative phenotype, meanwhile resident macrophages featured prominently in tissue homeostasis.

Conclusion
Ischemic and non-ischemic, focal and global, acute and chronic cardiac injuries induce a transient peak of monocyte recruitment and macrophage differentiation in and around cardiac lesions which lead to a permanent integration of recruited monocyte-derived macrophages into the pool of tissue resident macrophages – albeit at different paces. The type of injury and macrophage localization within the remodeling tissue determine partial or complete override of ontogenic cell programs.
Platelet-derived microRNAs play a pivotal role in cardiac remodeling after myocardial ischemia and reperfusion
Authors: Schuette J , Manke M C , Hemmen K , Schoerg B , Ramos G , Pogoda M , Kollotzek F , Muenzer P , Pichler B , Lang F , Nieswandt B , Heinze K G , Gawaz M , Casadei N , Borst O 
Published: November 2023

Abstract

Background
Platelets can infiltrate ischemic myocardium and are increasingly recognized as critical regulators of inflammatory processes during myocardial ischemia and reperfusion (I/R). Platelets contain a broad repertoire of miRNAs, which, under certain conditions such as myocardial ischemia, may be transferred to surrounding cells or released into the microenvironment. Recent studies could demonstrate, that platelets contribute substantially to the circulating miRNA pool holding the potential for so far undiscovered regulatory functions.

Purpose
The present study aimed to determine the role of platelet-derived miRNAs in myocardial injury and repair following myocardial I/R.

Methods and Results
Combining an in vivo model of myocardial I/R, multimodal in vivo and ex vivo imaging approaches (LSFM, PET&MRI, speckle-tracking echocardiography), in vitro immune cell migration assays and Next-generation deep sequencing analysis of platelet miRNA expression pattern in mice with a MK/platelet-specific knockout of pre-miRNA processing ribonuclease Dicer, the present study discloses a key role of platelet-derived miRNAs in the tightly regulated cellular processes orchestrating LV remodeling after myocardial I/R following transient LCA ligation. Disruption of the miRNA processing machinery in platelets by deletion of Dicer resulted in increased myocardial inflammation, impaired angiogenesis, and accelerated development of cardiac fibrosis, culminating in an increased infarct size by d7 that persisted through d28 of myocardial ischemia and reperfusion. Worsened cardiac remodeling after myocardial infarction (MI) in mice with a platelet-specific Dicer deletion (Dicer Pf4Δ/PfΔ4) resulted in an increased fibrotic scar formation and distinguishably increased perfusion defect of the apical and anterolateral wall at d28 post-MI. Altogether, these observations culminated in an impaired LV function and hampered long-term cardiac recovery after experimental MI and reperfusion therapy. Treatment with the P2Y12 antagonist ticagrelor completely reversed increased myocardial damage and adverse cardiac remodeling observed in Dicer Pf4Δ/Pf4Δ mice.

Conclusions
The present study discloses a critical role of platelet-derived miRNA in myocardial inflammation and structural remodeling processes following myocardial ischemia and reperfusion.
Time-course of cardiac gene profiles post-acute lung injury
Authors: Wang H , Steven J Lisco S J L , Irving H Zucker I H Z 
Published: November 2023

Abstract
Patients suffering from acute lung injury (ALI) are at high risk of developing cardiac arrhythmias. In a recent study we demonstrated that bleomycin (Bleo)-induced ALI in rats exhibited significantly more spontaneous premature ventricular contractions (PVCs) from 1 to 3 weeks post induction. Although spontaneous PVCs disappeared at 4 weeks post ALI, PVCs were evoked again by electrical stimulation of the decentralized stellate ganglia in Bleo-exposed rats but not in normal rats. The molecular mechanisms underlying cardiac arrhythmia both post ALI and during the recovery of ALI remains unclear. In the current study, we aimed to utilize non-biased RNA-Seq analysis to discover the time-course changes in cardiac gene profiles both post ALI and during the recovery from ALI. We created an ALI rat model using a single tracheal instillation of bleomycin (2.5 mg/kg) with saline as a vehicle (Veh) control. Blood Troponin level was measured and compared between Veh- and Bleo-treated rats varied between W1 to Week 4 post Veh/Bleo. Cardiac tissues were harvested at W1 or W4 post Veh/Bleo for RNA-seq analysis and validation by real time RT-PCR. One week post ALI, cardiac Troponin was significantly increased in Bleo-treated rats whereas it was undetectable in Veh-treated rats. Cardiac Troponin was largely restored at W2 and was undetectable at W4 post ALI. RNA-seq analysis of the left ventricle (LV) indicated 85 downregulated and 147 upregulated genes at 1 W post ALI vs. Veh. Gene Ontology (GO) enrichment analysis demonstrated that genes related to chronic inflammatory signaling, cell adhesion signaling, and extracellular matrix (ECM) signaling pathways were upregulated at W1 post ALI, suggesting cardiac inflammation. Furthermore, genes related to oxygen carrier activity, oxygen binding and oxygen transport signaling were also significantly altered, which may be due to acute hypoxia caused by ALI. In contrast to W1, RNA-seq analysis at W4 post ALI detected a smaller number of altered genes, including 11 downregulated and 13 upregulated genes between ALI and Veh groups. Comparing these two RNA-Seq databases, 4 genes (i.e., Phactr3, Tgm1, Drd4, Selplg) were identified as changed in both the post ALI state and during the recovery from ALI. Following real time RT-PCR validation confirmed significant changes in these four gene mRNA expressions in both post ALI and during the recovery from ALI. Phactr3 was downregulated while Tgm1, Drd4 and Selplg genes were upregulated in cardiac tissues at w1 and w4 post ALI. Phactr3 gene encodes a member of the phosphatase and actin regulator protein family. Tgm1 plays an important role in stabilizing intercellular junctions in myocardial microvascular endothelial cells, by modulating β-actin filaments. Drd4 gene encodes the D4 subtype of the dopamine receptor. Selplg gene encodes a glycoprotein that regulates T lymphocytes. Future studies are needed to examine the functional roles of these genes in cardiac injury post ALI.
Implantable loop recorder monitoring in inherited cardiomyopathies: yield of clinically relevant arrhythmias
Authors: Trancuccio A , Kukavica D , Zvielli G , Marino M , Gambelli P , Memmi M , Bloise R , Napolitano C , Mazzanti A , Priori S G 
Published: November 2023

Abstract

Background
Implantable loop recorders (ILRs) are a minimally invasive tool for the diagnosis of arrhythmias in patients with unexplained syncope or asymptomatic arrhythmias. Their use in patients with inherited arrhythmia syndromes has been recommended in the recent 2022 ESC Guidelines (1). However, the clinical utility of ILRs in patients with inherited cardiomyopathies remains unexplored.

Purpose
The purpose of this study was to evaluate the yield of ILR monitoring in detecting clinically relevant events in a single cohort of patients with inherited cardiomyopathies.

Methods
We prospectively collected demographic, clinical, and follow-up data from patients with inherited cardiomyopathies (Arrhythmogenic Cardiomyopathy, ACM; Hypertrophic Cardiomyopathy, HCM; Dilated Cardiomyopathy, DCM; Left Ventricular Non-Compaction, LVNC) who were implanted with an ILR and were followed with telemedicine. The primary endpoint was a clinically significant event recorded with the ILR that required an update to an implantable cardioverter defibrillator (ICD).

Results
The study cohort included 53 consecutive patients (55% males; mean age at ILR implantation 35±14 years) with inherited cardiomyopathies: 33/53 (62%) with ACM, 9/53 (17%) with HCM, 7/53 (13%) LVNC, 4/33 (8%) DCM. None of the patients implanted had previously experienced life-threatening arrhythmias. During a median follow-up of 2.6 years (IQR 1.4-3.7 years) after ILR implantation, clinically relevant arrhythmic events were documented in 9/53 (17%) of patients. Specifically, sustained or non-sustained ventricular tachycardia episodes were detected in 8 patients (5 with ACM, 2 with LVNC, 1 with LMNA-related DCM), whereas one patient with HCM showed symptomatic pauses &gt; 3 seconds due to sick sinus syndrome. In all cases, the detection of such episodes led to the upgrade to ICD implantation.

Conclusions
ILR monitoring of patients with inherited cardiomyopathies identified clinically relevant events in almost one-fifth of patients, suggesting that the use of ILR may substantially improve the management of these patients.
Figure 1. Representative example of clinically actionable event detected by implantable loop recorder (ILR) in a patient with inherited cardiomyopathy. The patient, a 19-year-old male with a definitive diagnosis of Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) and a pathogenic PKP2 truncating variant, presented with palpitations and vertigo during physical exertion one year after the implantation of an ILR. ILR monitoring documented a rapid tachycardia with a mean frequency of 250 bpm lasting 3 minutes, prompting an indication for an implantable cardioverter defibrillator (ICD).Figure 1.
Cardiac extracellular matrix at microvascular obstruction area after reperfused myocardial infarction: a morphometric study
Authors: Rios Navarro C , Molina-Garcia T , Ortega M , Gavara J , De Dios E , Perez-Sole N , Marcos-Garces V , Merenciano-Gonzalez H , Chorro F J , Bodi V , Ruiz-Sauri A 
Published: November 2023

Abstract

Background
Extracellular matrix (ECM), a structural and biomechanical support to cardiomyocytes, suffers substantial alterations after myocardial infarction (MI). Despite a complete reopening at epicardial level, hypoperfusion within the infarcted myocardium, known as microvascular obstruction (MVO), occurs. Extensive clinical studies and meta-analysis reported the association between the magnitude of MVO and the appearance of adverse remodeling; thus, scrutinizing ECM composition within the infarcted areas with impaired tissue-level reperfusion could provide fundamental insight regarding MVO pathophysiology.

Purpose
To histologically compare ECM composition within the infarct zone regarding the presence or absence of MVO using an experimental swine model of reperfused MI.

Methods
MI was induced in swine (n=10) by transitory 90-min coronary occlusion followed by 7 days of reperfusion. Prior to euthanasia, intracoronary thioflavin-S was infused. Within the infarcted myocardium, regions displaying MVO (thioflavin-S-) or no MVO (thioflavin-S+) were isolated and stained to morphometrically compare ECM composition.

Results
Regarding cellularity, areas with MVO displayed an enlarged presence of neutrophils and lymphocytes, whilst no differences in the amount of macrophages and myofibroblasts were detected in comparison to no MVO-myocardium. Those regions with macroscopic MVO showed lower capillary density than those without MVO. According to the fibers and ground substance, a significant reduction in the extension of type I collagen, laminin, and fibronectin together with an augmentation of glycosaminoglycan were noted in areas showing MVO compared to those without microvascular injury. No changes in the amount of type III collagen was observed.

Conclusion
The ECM composition in infarcted regions with MVO displays a higher presence of inflammatory infiltrate and glycosaminoglycans as well as a reduced amount of microvessels and fibers compared to those areas without microvascular hypoperfusion. These characteristics might underlie the development of adverse ventricular remodeling in MI patients with extensive MVO.
The selective Rho Kinase 2 inhibitor Chroman-1, is a potent vasodilator but does not compromise left ventricular function in-vivo
Authors: Pearce L , Yusof L , He D , Davidson S M , Yellon D M 
Published: November 2023

Abstract

Background
In the field of cardioprotection, focus is turning to limiting microvascular obstruction (MVO) post myocardial infarction. The development of MVO carries a poor prognosis, which is independent of infarct burden [1]. Commonly used vasodilators in the treatment of MVO e.g., Ca2+ blockers, beta-blockers can induce negatively inotropic effects. This is a serious problem as hypotension and shock during acute MI are harmful. Rho kinase (ROCK) inhibitors induce vasodilation by inhibiting the phosphorylation of myosin light chain kinase (MLC2) in vascular smooth muscle (VSMC) [2]. ROCK1/2 inhibitors are known to cause transient negative inotropic effects [3]. However, the potential side-effects of the selective ROCK2i, Chroman-1 (Ch1) are unknown.

Purpose
We aimed to i) Confirm the expression of ROCK2 mRNA in aorta and coronary vasculature, ii) To investigate the vasodilatory properties of Ch1 iii) To confirm that Ch1 does not acutely impair left ventricular ejection fraction (LVEF%) and blood pressure in-vivo.

Methods
RNA scope in-situ hybridisation was performed with a fluorescent, multiplex assay for ROCK1/2 & VSMC mRNA in whole hearts, coronary vasculature and aorta from male SD rats. Thoracic aorta was dissected and 3mm segments suspended into a tissue bath. Vascular rings were constricted with 1µM PE and treated with [10-12]-[10-5]mM Ch1. In a separate set of in-vivo experiments, male SD rats 250-300g were anaesthetised with isoflurane, intubated and ventilated. LVEF% was measured in a closed chest model, following the addition of Ch1 (30-300µg/kg) or DMSO vehicle, administered i.p at 15-minute intervals. Mean arterial pressure (MAP, mmHg) and heart rate (BPM) were measured throughout.

Results
ROCK2 mRNA was localised to myocardium, aorta and coronary circulation VSMC. Figure 1 demonstrates that Ch1 induced dose dependent vasodilation of PE constricted aortic rings vs control (EC50 Ch1 95% CI [5.1e-008, 2.2e-007] n=6). In-vivo, Ch1 at all doses (30-300µg/kg) did not significantly affect LVEF% (p&gt;0.05, n=5) nor average MAP at doses 30-100µg/kg (p&gt;0.05, n=5). At the highest dose, i.e 300µg/kg, Ch1 decreased average MAP (mmHg) compared to control +/-SEM (76+/-7.1 vs 92+/-2.8, p=0.02, n=5), but not below 70mmHg threshold. Ch1 did not significantly affect mean heart rate at any dose (p&gt;0.05, n=5).

Conclusion
The selective ROCK2 inhibitor Ch1, induces potent arterial vasodilation, without compromising LVEF% or haemodynamics. It is therefore, a suitable drug for further preclinical studies of MVO in ischaemia/reperfusion (I/R).Figure 1:Ch1 induces dose dependent vasodilation of aortic rings, **p&lt;0.005, ***p&lt;0.001
S1P content as a characteristic of the cardioprotective properties of HDL in coronary heart disease and diabetes mellitus
Authors: Polzin A M I N , Benkhoff M A R C E L , Dannenberg L I S A , Barcik M A I K E , Schroeder N A T A L I , Weske S A R A H , Vogt J E N S , Wolnitzke P H I L I P , Mourikis P H I L I P , Keul P E T R A , Sarabhai T H E R E S , Zeus T O B I A S , Roden M I C H A E , Kelm M A L T E , Levkau B O D O 
Published: November 2023

Abstract

Background
Many basic science studies have demonstrated the cardioprotective effect of high-density lipoprotein (HDL). At the same time, several clinical studies in which plasma levels of HDL were pharmacologically increased showed no benefit in cardiovascular risk patients. Accordingly, HDL quantity seems to be less important than HDL quality. Many beneficial effects of HDL are attributed to the bioactive sphingolipid S1P in HDL (HDL-S1P).

Purpose
In this study, we are now investigating a) the cardioprotective properties of HDL of different patient groups and b) the possibility of loading S1P to restore cardioprotection that may be lacking.

Methods
HDL was extracted from plasma of diabetic (dmHDL), as well as CHD patients (CHD-HDL) and healthy subjects (healthy HDL) of the same age by ultracentrifugation and injected i.v. into the mouse five minutes before 30 minutes of ischemia (43 mg/KG). This was followed by 24 hours of reperfusion. Systolic cardiac function was determined by ultrasound, infarct size by TTC (2,3,5-triphenyltetrazolium chloride) staining, and S1P levels by mass spectrometry. The level of apolipoprotein M in HDL was determined by ELISA.

Results
Mice treated with healthy HDL showed smaller infarct size and improved ejection fraction (EF) after I/R than control mice (IS: control 42.95±7.40% [n=26] vs. healthy HDL 33.15±4.68% [n=16], p=0.0001; EF: control 33.68±4.49% vs. healthy HDL 40.00±5.74%, p=0.0016). Treatment with CHD-HDL or dmHDL showed no cardioprotective effects compared to control mice (IS: CHD-HDL 42.22±6.53% [n=16], p=0.9863; dmHDL 43.67±7.81% [n=12], p=0.9899). In both cases, the lack of cardioprotection is associated with lowered HDL-S1P levels (total HDL 210.6±32.6 pmol/mg; CHD-HDL 157.6±49.0 pmol/mg, p=0.0073; dmHDL 171.1±64.7 pmol/mg, p=0.0176). Loading the "sick" HDL with S1P restores cardioprotection only in CHD-HDL (IS: CHD-HDL 42.22±6.53% [n=16] vs. CHD-HDL loaded 32.03±6.45% [n=10], p=0.0023), but not in dmHDL (IS: dmHDL 43.67±7.81% [n=12] vs. dmHDL loaded 38.44±5.98% [n=7], p=0.5110). The very low level of apolipoprotein M (ApoM), responsible for S1P binding, could be a reason for this (total HDL 23.45±6.23 µg/mg [n=15] vs. dmHDL 13.79±4.72 µg/mg [n=14], p=0.0007).

Conclusion
We highlighted worsened cardioprotection as another characteristic of HDL dysfunction in CHD and in diabetes. This characteristic was based on a lower HDL-S1P content and could be therapeutically corrected by loading S1P in the case of CHD-HDL. A low content of ApoM in dmHDL may prevent successful restoration of cardioprotection by S1P loading.
New therapeutic strategy targeting regulation of the SERCA2 complex protects from myocardial ischemia-reperfusion injury
Authors: Calejo A , Ostensen E , Aronsen M , Lygren B , Skogestad J , Klaveness J , Sjaastad I , Tasken K 
Published: November 2023

Abstract
7 million people suffer every year from myocardial infarction. There is significant unmet medical need for cardioprotection during MI treatment. The beta-adrenergic receptor/cyclic AMP/protein kinase A (PKA) signalling pathway regulates heart rate and contractility. Activation of cAMP-dependent PKA causes phospholamban (PLB) phosphorylation and its ability to inhibit sarcoplasmic reticulum calcium ATPase (SERCA) is lost. Discrete control of PLB phosphorylation is facilitated by the A-kinase anchoring protein (AKAP) 18g/d, which holds PKA and PLB in close proximity. We are developing a novel drug candidate, named 13M, with a highly selective mechanism of action in cardioprotection currently in pre-clinical phase. Our drug candidate disrupts the AKAP18g/d-PLB protein-protein interaction (PPI) as this may protect from ischemia reperfusion injury (IRI). We used AlphaScreen assay to screen a library of 79,000 small molecular compounds for compounds that disrupted the AKAP18δ-PLB PPI. Following secondary and tertiary screens of sub-libraries, the resulting hits were further characterized and similarity searches carried out to delineate a compound structure for further derivatization. Newly synthesized compounds were further tested in a cell-line based assay to determine compound toxicity. A combination of biochemistry, electrophysiology and heart function experiments demonstrated that the compounds exclusively block the adrenergic effect on SERCA2 without affecting its basal activity. A 40% reduction in infarction size and improved long term cardiac function was observed in an animal disease model for ischemia-reperfusion injury.