bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development of a minimally invasive technique to measure the interstitial fluid pressure for remote monitoring of heart failure
Authors: Zafar H , Passman J , Sandy R , Wright C , Wright F , Evans H , Hanumapura P , Sebastian S , Ebah L , Khalifa A , Rowe S , Schwartz R , French A , Rothman A 
Published: October 2024

Abstract

Background
Heart failure (HF) induces fluid interstitial retention, leading to oedema and elevated interstitial fluid pressure (IFP).1-3 There is a clinical need for remotely assessing IFP and understanding its correlation with cardiopulmonary haemodynamics for early treatment optimization in HF. IFP can be measured from a preserved fluid pocket formed by a subcutaneous perforated capsule in animals.4 However, the structural understanding of tissue neovascularization within a perforated capsule and the temporal relationship between altered cardiopulmonary haemodynamics and IFP remains unknown.

Purpose
To determine the neovascularisation of the perforated capsule over time and demonstrate the relationship between haemodynamic metrics of congestion (CVP, PAP, and LVEDP) and IFP during HF development.

Methods
Ten 45-55kg swine were implanted with subcutaneous perforated capsules. Perforated capsule characterisation included MicroCT using MicroFil cast (Fig. 1A) and microscopy initially at 3 and 6 weeks. A perforated capsule containing a PTFE (polytetrafluoroethylene) membrane was subcutaneously implanted in animals and chronic stability was studied at 90 using MicroCT and microscopy. After 3 weeks of perforated capsule implantation, HF was induced under general anaesthesia with 12-16 mg/kg/hour of esmolol (i.v.) and 0.9% NaCl (10% body weight, i.v.) and fluid was removed to euvolemia via ultrafiltration (Fig 2A). Concurrent measurements of IFP from perforated capsules and haemodynamic metrics of congestion were made using interventional techniques.

Results
MicroCT and microscopy have demonstrated perforated capsule neovascularization containing a central fluid pocket at 3 weeks and loss at 6 weeks due to continued tissue growth (Fig 1B-E). The perforated capsule at 90 days demonstrated fluid pocket preservation due to the PTFE membrane on MicroCT and microscopy (Fig. 1F-G). During the development of HF and offloading, there is a strong correlation between IFP and haemodynamic metrics of congestion (Fig. 2B).

Conclusion
We have developed a minimally invasive technique for continuous IFP measurement demonstrating a relationship between IFP and cardiac filling pressure in HF. IFP assessment offers a direct measure of fluid status and an indirect measure of haemodynamics, facilitating early treatment optimisation.
Computational modeling of cardiac electrophysiology applied to a swine model of Long QT Syndrome
Authors: Trancuccio A , Santiago D J , Tarifa C , Bongianino R , Mazzanti A , Priori S G 
Published: October 2024

Abstract

Background
Computational models are pivotal for understanding electrophysiological aspects of cardiac diseases. Despite pigs' increased use in research, limited in vitro porcine data impedes accurate mathematical modeling. In this context, we recently developed a novel knock-in porcine model of long QT syndrome type 8 (LQT8) [1].

Purpose
To develop a novel computational model for electrophysiology and Ca2+ handing in wild-type and LQT8 swine ventricular cardiomyocytes.

Methods
We designed a mathematical model of wild-type swine action potential (AP) based on a wide range of cellular electrophysiological data. Using the ORd model [2] as a foundation, we re-parametrized main ionic currents using the Nelder-Mead algorithm. We then modified the model to simulate LQT8, evaluating its utility in exploring arrhythmogenic mechanisms and pharmacological approaches. For the L-type Ca Channel (LTCC), we replaced the original HH formulation with a Markov model based on [3], which was subsequently modified to account for a population of mutant p.G406R channels. Selected biomarkers for validation were AP duration at 20, 50, and 90% of repolarization, maximum upstroke velocity, AP amplitude and resting membrane potential. To assess the robustness of the model, we generated a random population of 500 models accounting for biological variability by sampling key parameters in the range [-20 to +20%] of their original values, using the Latin Hypercube Sampling. Simulations were executed using MATLAB R2023a. Numerical integration was performed utilizing the MATLAB function ode15s.

Results
The mathematical model accurately reproduced a wide range of experimental data, including steady-state curves of the main ionic currents, kinetic properties of LTCC, APD rate dependency, maximum upstroke velocity and Ca2+transient morphology. The model successfully simulated AP prolongation in LQT8. Also, it replicated key features of the cellular phenotype such as steeper APD rate adaptation, increased duration and amplitude of the Ca2+ transients, increased CaMKII-mediated late Na+ current, pathologically decreased upstroke velocity with increasing pacing frequency, due to a CaMKII-mediated mechanism. As a proof-of-concept, the model was utilized to investigate arrhythmogenic mechanisms and pharmacological approaches for LQT8. According to model’s prediction, early afterdepolarizations (EADs) in LQT8 can stem from three distinct mechanisms: improper kinetics of late Na+ current, improper kinetics of LTCC, and enhanced late-systolic SR Ca release. Notably, the model also predicts that full CaMKII inhibition effectively eliminates EADs for all three mechanisms, showcasing the potential efficacy of this pharmacological intervention.

Conclusions
A novel mathematical swine ventricular myocyte model explores arrhythmogenic mechanisms and therapeutic interventions, aiding LQT8 research and clinical translation in cardiac disorders.
Signature of diabetic cardiomyopathy progression using high-fat diet and streptozotocin mouse model: from subclinical to clinical with three-hit mouse model
Authors: Karuna N , Kerrigan L , Edgar K , Tonry C , Grieve D , Watson C 
Published: October 2024

Abstract

Background
Diabetic cardiomyopathy (DbCM) is a pre-heart failure (pre-HF) condition that usually exhibits early diastolic dysfunction and evolving systolic dysfunction, along with left ventricular (LV) remodelling. Although DbCM shows distinct pathophysiology, the transition from the subclinical to the symptomatic stage is not straightforward and usually involves multifaceted processes which are not fully understood.

Purpose
To define the signature of DbCM progression in a novel mouse model using longitudinal echocardiography and multi-omics approaches.

Methods
Male mice (C57BL/6) were fed with high-fat diet (HFD) or control diet (CD) for 24 weeks, with single dose of streptozotocin (STZ) or vehicle injection at 8 weeks (n=10 each). Serial functional and metabolic parameters were measured prior to endpoint single nuclei RNA sequencing (snRNA-seq) and mass spectrometry-based proteomics analysis with comparison to cardiac remodelling to define detailed mechanisms underlying DbCM progression.

Results
HFD/STZ mice developed type 2 diabetes mellitus (T2DM) based on higher fasting blood glucose and HbA1C levels, insulin resistance and decreased beta-cell function (HOMA-IR and HOMA-beta, respectively) compared to controls. Progressive diastolic dysfunction was evident in HFD/STZ mice compared to CD mice based on enlarged LVPW;d from 12 weeks (P&lt;0.05), reduced MV E/A ratio (P&lt;0.01) and IVRT (P&lt;0.05) from 16 weeks, and increased cardiac filling pressure (Left atrial (LA) area and LA volume) at 24 weeks, with preserved systolic function. This was paralleled by elevated collagen deposition (Picrosirius red), myocyte cross-sectional area and Col1a1 expression in HFD/STZ versus CD mice (all P&lt;0.05). snRNA-seq analysis indicated preferential monocyte migration into diabetic hearts (P&lt;0.01) whilst inflammatory pathways were activated across all cardiac cell types. Proteomics analysis revealed elevated expression of the established inflammation marker, plasma C-reactive protein (CRP), in HFD/STZ versus CD mice (P&lt;0.05), which was correlated with worsening diastolic function (MV E/A ratio: r=-0.839, P&lt;0.01) and LV hypertrophy (LVPW;d: r=0.861, P&lt;0.01).

Conclusion
Our HFD/STZ mouse model offers a ‘three-hit’ approach which effectively captures key stages of clinical DbCM progression: 1) T2DM with insulin resistance, 2) progressive diastolic dysfunction with elevated chronic filling pressure and cardiac remodelling, and 3) systemic inflammation. This improved HFD/STZ mouse model is therefore appropriate to support a detailed study of mechanisms underlying DbCM progression and subsequent translation.
Identification of left ventricular flow features in healthy and pathological conditions
Authors: Wang H , Feng S , He X , Wang S , Pan X , He G 
Published: October 2024

Abstract

Background
In the presence of mitral valve diseases or following surgical interventions, the hemodynamics in the left ventricle (LV) are significantly altered [1]. These maladaptive intraventricular hemodynamic alterations can stimulate a cascade of events leading to progressive adverse LV remodeling and eventual heart failure [2]. Qualitative and quantitative evaluation of LV flow features may provide a potential for sensitive risk stratification of clinical cardiac function [3].

Purpose
The purpose of this study is to identifying LV flow features using in vitro experiments under both normal and pathological conditions, including mitral regurgitation (MR), mitral valve replacement with bioprosthetic/mechanical valve, and transcatheter mitral valve edge-to-edge repair (TEER).

Methods
We utilized a biohybrid approach to construct the in vitro experimental platform, where the native mitral valve (including chordae tendineae and papillary muscles) and aortic valve from porcine were combined with a 3D-printed silicon LV (figure 1). To ensure comparability across different conditions, we maintained consistency by utilizing the same native valve and 3D-printed LV. For pathological conditions, we cut the chordae tendineae in A2 zone to induce the severe degenerative MR, and TEER was performed on this prolapsed valve by placing two clips in A2-P2 zone. Then, the anterior leaflet of valve was cut, and a bioprosthetic valve and mechanical valve were sutured to mitral annulus to simulate surgical valve replacement, respectively. Left ventricular flow fields were measured using four-dimensional particle image velocimetry (4D-PIV) technique, with vector interval of 0.9 mm in all the spatial directions and temporal resolution of 10 ms.

Results
Significant differences in mean flow field were observed among healthy and pathological conditions (figure 2). Firstly, the vortex orientation was clockwise in healthy, MR, bioprosthetic valve replacement, and TEER conditions, which could accompany the redirection of blood flows towards the aortic valve. However, the replacement with a mechanical valve resulted in an alteration in vortex orientation from clockwise to counterclockwise. Secondly, the position of the center of the vortex changed in pathological conditions, with the center of the vortex closest to the apex and the left ventricle outflow tract in the healthy condition. Thirdly, the maximum Reynolds shear stress (RSS), which may be responsible for thrombus formation, significantly increased after TEER procedure and bioprosthetic valve replacement.

Conclusions
This study demonstrates significant changes in LV hemodynamics across different conditions. The flow features, including vortex orientations, vortex positions and the RSS, may potentially become crucial considerations for the optimization of artificial valves and mitral valve repair devices.Figure 1 Figure 2
Combined administration of atorvastatin and mesenchymal stem cells synergizes to attenuate inflammation and promote efferocytosis in atherosclerotic mice
Authors: Pan Q , Jiang Y , Song L , Yang Y J 
Published: October 2024

Abstract

Background
Atherosclerosis (AS), characterized by chronic systemic and lesional inflammation, is by far the most frequent underlying cause of cardio-cerebrovascular diseases. Recently, impaired efferocytosis, referring to defective removal of dead cells, was identified as another essential factor contributing to the development of AS, which is partly attributed to upregulation of CD47 and explain the benefits of atorvastatin (ATV). Mesenchymal stem cells (MSCs) were reported to protect against AS by inhibiting inflammation; while whether ATV and MSCs could synergize to attenuate inflammation and promote efferocytosis and consequently, reduce AS burden, remains unclear.

Methods
To establish the AS model, 6-week-old male ApoE-/- mice fed with Western diet for 12 weeks were used and grouped randomly (n=15 per group). The scheme of administration of ATV and human umbilical cord MSCs was shown in Figure 1A. After 6-week treatment, mice were sacrificed, and hearts and aortas were harvested. Oil Red O staining was used to evaluate the lesional burden. Immunofluorescence staining was used to assess the inflammation and efferocytosis in the plaque. A high level of CD11b+ cells (macrophages) infiltration was considered an indicator of inflammation; a high level of cleaved caspase 3 puncta unmerged with macrophages (Mac3+ area) was considered an indicator of impaired efferocytosis.

Results
Human umbilical cord MSCs were identified as CD73+CD90+CD105+CD45-CD14- cells. Evoked inflammation and defective clearance of apoptotic cells in the plaque were observed (Figure 1B, C). ATV and MSC treatment inhibited macrophage infiltration and activated efferocytosis. Given the mechanistic idea that upregulated CD47 blocks the Signal regulatory protein α (SIRPα) / src homology-2 (SH2)-domain-containing protein tyrosine phosphatases (SHP) signal and leads to efferocytosis impairment, we evaluated the expression levels of CD47 in plaque and phosphorylated SHP (p-SHP) in lesional macrophages (Figure 2A, B). The elevation of CD47 expression and consequent downregulation of p-SHP was reversed by both ATV and MSCs, with a lower lesion burden observed in NS+MSC, ATV+PBS and ATV+MSC groups. All benefits were more pronounced in the group received combined treatment (ATV+MSC).

Conclusions
The results indicated ATV and MSC administration could synergizes to attenuate inflammation and promote efferocytosis in AS plaque, and the combined treatment led to the lowest lesion burden. CD47/p-SHP signal plays an essential role in the activation of efferocytosis. The mechanisms underlying the inhibition of CD47 are currently under investigation.
Blockade of endothelial to mesenchymal transition (EndMT) by an inhibitor of histone methyltransferase EZH2 attenuates atherosclerosis in diabetes
Authors: Khan A W , Aziz M , Sourris K , Okabe J , Jandeleit-Dahm K A M 
Published: October 2024

Abstract

Background
Atherosclerosis is a major contributor to cardiovascular disease (CVD) related deaths in individuals with diabetes. Persistent endothelial cell activation caused by factors such as hyperglycaemia induces endothelial to mesenchymal transition (EndMT), which promotes both initiation as well as progression of atherosclerosis. Gene expression changes that occur during EndMT, are regulated by multiple factors including epigenetic modifiers such as the histone methyltransferase EZH2 (Enhancer of zest homolog 2). Recent studies have implicated the role of EndMT in cardiovascular complications of diabetes including atherosclerosis. However, the role of EZH2 in induction of EndMT in diabetes associated atherosclerosis is not known.

Methods
Aortae of atheroprone diabetic Apoe-/- mice were subjected to single cell RNA sequencing (scRNA-seq) analysis using 10X Genomics platform. In vitro model mimicking diabetes-induced EndMT was established in human aortic endothelial cells (HAECs) using high glucose (25mM) and TNF-α containing media for 72 hrs ± a small molecule inhibitor of EZH2, GSK126. RNA and Chromatin Immunoprecipitation (ChIP) sequencing was performed to identify EZH2-mediated epigenomic and corresponding transcriptomic changes in this setting. Complementary in vitro EZH2 knockdown experiments using shRNA were also performed. Moreover, Apoe-/- mice made diabetic with streptozotocin, were treated with GSK126 (50 mg/kg BW daily for 5 weeks) in an intervention study design. Aortic sections from treated and control mice were subjected to immunofluorescent staining specific for the EndMT pathway.

Results
scRNA-seq analysis identified an EndMT+ve endothelial cell sub-population with a diabetes specific proatherogenic transcriptomic profile. Comparison with the ENCODE dataset for EZH2 target genes using Harmonizome showed that indeed multiple repressed genes in diabetes were targets of EZH2. Methyltransferase activity of EZH2 was elevated in in vitro settings of EndMT. Interestingly, EZH2 inhibition by GSK126 attenuated EndMT. Gene expression analysis showed that GSK126 treatment rescued 76 of 242 differentially expressed genes in HAECs exposed to EndMT conditions. Several differentially expressed genes including COL1A2, MMP2, NOS3, COL4A1, and TGFB2 (FDR &lt;0.05, Log2 fold change (2x)) were targets of EZH2 validating integrated analysis of our scRNA-seq with the ENCODE dataset. EZH2 knockdown experiments validated experimental findings of EZH2 inhibition studies using GSK126 in HAECs. Importantly, GSK126 treatment blocked EndMT resulting in reduced atherosclerosis in diabetic Apoe-/- mice in intervention studies.

Conclusion
This study showed that the inhibition of EZH2 with GSK126 is a potential vasculoprotective treatment for the diabetes induced EndMT and associated atherosclerosis.
Quantification of hemolysis rates from pulsed field ablation
Authors: Mercado Montoya M , Gomez Bustamante T , Jessen M , Kulstad E , Mickelsen S , Overzet L 
Published: October 2024

Abstract

Introduction
Pulsed electric fields induce hemolysis of red blood cells as a dose-dependent effect of the electric field. Voltage pulsations induce a transmembrane potential across the cell membrane and either open up or create pores in the red cells. In isotonic conditions, the pores allow passage of potassium and sodium ions but not sucrose or hemoglobin, and leakage of ions leads to an osmotic imbalance which in turn causes a colloidal hemolysis of the red cells.

Objective
To quantify hemolysis rates during pulsed field ablation (PFA).

Methods
We created a computational model of PFA to determine the total volume of blood hemolyzed from each pulse during catheter ablation using pulsed field energy. The percentage hemolysis was calculated as a function of electric field intensity utilizing existing published experimental data. A single electrode delivering a single pulse of 100 microseconds duration was modeled at voltages of 1 kV, 1.5 kV, and 2 kV.

Results
The total volume of hemolyzed blood per pulse increased with increasing applied voltage (Figure). For 2 electrodes in direct tissue contact, the electrode surface exposed to the blood pool generated 19 microliters of hemolyzed red blood cells with a single pulse of a 2 kV field strength. In the case of a single pulse train consisting of 50 pulses, using a catheter configuration with 20 electrodes, an estimate of total volume per pulse train is approximately 9.5 mL of hemolyzed blood. In the case of electrodes not in direct contact with endocardial tissue, and exposed to the blood pool, up to double this volume could be anticipated per pulse train. Hemolyzed volume can be reduced with better tissue contact (reducing exposure to blood), or potentially with the use of irrigation to dilute the local red blood cell concentration. Increased tonicity of the irrigant fluid may also reduce the osmotic pressure increases that result in hemolysis.

Conclusions
Typical voltages utilized in pulsed field ablation can cause significant hemolysis, which is exacerbated by inadequate tissue contact. A greater number of electrodes and number of pulses delivered increases the risk, whereas better tissue contact, and the use of irrigation, may reduce it.
Drug eluting stents trigger the secretion of inflammatory proteins in an experimental in vitro study
Authors: Paar V , Feng X , Hoppe U , Lichtenauer M 
Published: October 2024

Abstract

Introduction
Ischemic cardiovascular diseases commonly appear following the occlusion of one or more of the coronary arteries. Drug eluting stents (DES) constitute the gold standard to help to keep open the arteries and maintain the blood flow. After their placement into the coronary arteries, they stay in direct contact with the blood stream, disturbing the physiological conditions and interacting with several cells and proteins within the surrounding blood and vessel wall. Besides the beneficial effects of DES, their clinical application is also associated with complications, such as (late) stent thromboses. Previous studies have shown that thrombosis and inflammation are tightly linked with each other by activating inflammatory cells and secreting cytokines and chemokines to further promote an inflammatory surrounding. However, the influence of DES and their components on the inflammatory cascade and their corresponding players was not investigated yet.

Methods
To investigate the inflammatory secretome in response to DES, we performed an in vitro study with isolated human peripheral blood mononuclear cells (PBMCs). Therefore, PBMCs were isolated from the whole blood of four healthy volunteers. In total, 63 stents were used in the study, including Medtronic Resolute Onyx (n=37), Abbott XIENCE Sierra (n=5), Boston Scientific SYNERGY (n=4), Terumo Ultimaster (n=3), and Biotronik Orsiro (n=14). We measured the secretion of cytokines and chemokines, including IL-1β, IL-6, TNF-α, IL-8, and IL-12, as well as ICAM-1, VCAM-1, and MCP-1 by commercially available enzyme-linked immunosorbent assay (ELISA).

Results
Our results showed that DES significantly increase the secretion of the cytokines IL-1β (p=0.0005), and IL-6 (p=0.0002), as well as the chemokine IL-8 (p=0.0010). Additionally, we also detected an elevation of the reaction product ICAM-1 (p=0.0003). Further analyses resulted in a reduced secretion of IL-1β, IL-6, TNF-α, IL-8, and ICAM-1 into the cells’ supernatants in response to Resolute Onyx stents, in comparison to the other stents. Moreover, multiple regression analysis revealed a high dependency of the inflammatory reaction on the elution drug, the polymer type and the stent’s length. Additionally, the material of the stent platform, as well as the polymer thickness further have impact on the cytokine and chemokine response of PBMCs.

Conclusion
Our study indicate that DES by themselves trigger an inflammatory reaction of blood cells by the secretion of cytokines and chemokines. Furthermore, we provided first insights into the composition of the inflammosome in response to DES. A triggered inflammation may increase the vulnerability for complications and the failure of the DES. As these complications were already observed in clinical studies, our results would potentially provide predictions about the application of certain DES designs and may help to choose the appropriate stents in the clinical setting.