bluuebunny/crossref_metadata_2025 huggingface dataset:
Developing endoscopic cell sheet delivery device using a beating human heart simulator and a pig model for minimally invasive cardiac regenerative therapy
Authors: Hori Y , Yamashita H , Murata K , Kuroda Y , Iida J , Hakamada K , Minatoya K , Masumoto H
Published: October 2024

Introduction

Recently, clinical trials have commenced for cardiac regenerative therapy utilizing stem cells in patients with heart failure. Among the various transplantation approaches, there is a growing demand for less invasive methods to transplant sheet/patch-shaped cell products onto the heart surface, rather than resorting to conventional open surgery. This is particularly important considering the need for immunosuppressants due to allogeneic cell transplantation.

Objective

This study aims to develop a device for endoscopic transplantation of cell sheets onto the beating heart surface.

Methods

Prototype devices, initially developed in our prior study using a static heart model (Regenerative Therapy, 2020), were refined to better suit the cell sheet transplantation procedure onto a beating heart. We constructed a three-dimensional (3D) model of a beating heart located inside a thoracic cavity model, based on human computed tomography data and a 3D printer dedicated to simulating endoscopic surgical procedures. Human mesenchymal stromal cell (MSC)-derived cell sheets were prepared using temperature-responsive culture dishes and transferred onto a beating heart model pulsating at 80 beats per minute. We assessed the technical feasibility (N=8). Furthermore, skeletal muscle tissue was harvested from the thigh of the Clawn miniature pigs, and skeletal myoblasts were cultured from enzymatically digested tissue to create a cell sheet for autologous transplantation (8.0×10⁶ cells/sheet). Subsequently, the cell sheets labeled with Hoechst 33342 were endoscopically transplanted onto the pig heart surface (N=2). The pigs were sacrificed one week later, and the engraftment of the cell sheet was histologically evaluated.

Results

Successful deployment of MSC sheets onto the beating heart model was achieved in all procedures with one trial (100% success rate). The procedure duration from device insertion to the completion of cell sheet transplantation averaged 142±19 seconds. In experiments on autologous transplantation of myoblast cell sheets, two cases were successfully accomplished, with the transplanted cell sheet positive for Hoechst 33342 observed on the heart surface.

Conclusion

We have developed an endoscopic cell sheet delivery device using a pulsating heart model and a pig model, which holds promise for minimally invasive cardiac regenerative therapy in the future. Further investigations into the safety of the procedure are warranted for the clinical application of this system.
Cardiac secreted-HSP90alpha in cardiomyocyte hypertrophy by N-Cadherin mediated signaling under pressure overload
Authors: Pan L , Huang C X , Jin X J , Lin J Y , Wang Y , Li J X , Wang X , Zhang L , Zhang G P , Dong H M , Dai Y X , Zou Y Z , Gong H
Published: October 2024

Background

Left ventricular hypertrophy (LVH) in response to pressure overload is strongly associated with adverse cardiovascular outcomes. Heat shock protein 90 (HSP90) has been reported to be involved in cardiac remodeling under stress.

Aims

Here, we evaluate whether serum HSP90α (an isoform of HSP90) increases and associates with cardiac hypertrophy in patients with hypertension or severe aortic stenosis (AS), and explore the potential mechanisms in experimental pressure overload mouse model.

Methods

Serum HSP90α levels in patients with hypertension or aortic stenosis (AS) were determined by ELISA. Pressure overload mouse model was built by a transverse aortic constriction (TAC). Cardiac function was assessed by echocardiography. Cardiac hypertrophy was examined by histology, western blot and RNA analysis.

Results

Serum levels of HSP90α were higher in patients with hypertension or AS than in the control group, respectively, and the levels positively correlated with LVH. HSP90α levels also increased in heart tissues of patients with obstructive hypertrophic cardiomyopathy (HCM), and mice after TAC, in parallel with the hypertrophic markers. TAC induced the enhanced expression and secretion of HSP90α from cardiomyocytes and cardiac fibroblasts. Knockdown of HSP90α or blockade of extracellular HSP90α (eHSP90α) prevent the development of LVH under pressure overload in vivo and in vitro. By Nano-HPLC-MS/MS analysis, we identified eHSP90α interacted with N-cadherin in cardiomyocyte surface, which induced the activation of β-catenin and promoted β-catenin to bind TCF7 (a member of TCF/Lef family) in nucleus, enhanced the transcription of hypertrophic genes, contributing to cardiac hypertrophy and dysfunction under pressure overload.

Conclusions

Our data demonstrated that cardiac secreted-HSP90α promoted myocardial hypertrophy by N-Cadherin mediated β-catenin/TCF7 signaling under pressure overload. It indicates the therapeutic potential of targeting HSP90α-initiated signaling against cardiac hypertrophy and dysfunction under pressure overload.
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

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

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

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<0.05), reduced MV E/A ratio (P<0.01) and IVRT (P<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<0.05). snRNA-seq analysis indicated preferential monocyte migration into diabetic hearts (P<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<0.05), which was correlated with worsening diastolic function (MV E/A ratio: r=-0.839, P<0.01) and LV hypertrophy (LVPW;d: r=0.861, P<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

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

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

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 <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

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

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.
Implantable cardioverter defibrillators among elderly survivors of out-of-hospital cardiac arrest
Authors: Marcus M , Chan P S , Chang A , Merritt R K , Mcnally B , Link M S , Girotra S
Published: October 2024

Background

Survivors of out-of-hospital cardiac arrest (OHCA) with a shockable rhythm are at increased risk of cardiac arrest, and clinical practice guidelines recommend placement of an implantable cardioverter defibrillator (ICD) in the absence of a reversible cause and an expected meaningful survival of at least one year. Contemporary data on the prevalence of secondary prevention ICD placement among OHCA survivors remain limited.

Purpose

Examine patterns of secondary prevention ICD implantation in survivors of OHCA due to a shockable rhythm in a large national registry.

Methods

Using 2013-2019 data from the Cardiac Arrest Registry to Enhance Survival (CARES) linked to Medicare files, we identified 3,226 patients aged >65 years who survived to discharge following OHCA due to an initial shockable rhythm from January 1, 2013 to December 31, 2019. Patients with severe neurological disability, prior history of cancer, and those discharged to hospice were excluded. We calculated cumulative prevalence of ICD implantation at discharge, 90 days, and 6 months post cardiac arrest. Multivariable hierarchical regression models with random hospital effects were used to determine the adjusted association of patient characteristics with ICD implantation and quantify the extent of variation in ICD implantation across sites, using a median odds ratio (OR) and 95% confidence interval (CI).

Results

Patients’ mean age was 72.2 years; 23.5% were women, 10% were Black and 4% Hispanic. Among 3,226 OHCA patients, 997 (30.9%) received an ICD before discharge; 1,266 (39.2%) received an ICD within 90 days of cardiac arrest, and 1,287 (39.9%) received an ICD by 6 months. After adjusting for differences in demographics and co-morbidities, the odds of receiving an ICD at discharge were significantly lower in patients aged 85 years and older, women, patients with prior history of stroke or diabetes, patients who presented with acute myocardial infarction (P<0.05 for all). There was no significant difference in ICD implantation by race and ethnicity (P=0.94) (Table 1). Even after adjusting for patient demographics, co-morbidities, and presentation with acute myocardial infarction, there was large variation in hospital rate of ICD implantation at discharge, with a median odds ratio of 1.65 (95% CI 1.41-1.86).

Conclusion

Fewer than 1 in 3 patients with OHCA due to a shockable rhythm are discharged with a secondary prevention ICD. Although implantation of ICD was associated with patient variables, there was no difference in ICD implantation by race and ethnicity. There was large variation across hospitals in ICD implantation even after adjusting for patient variables highlighting an opportunity for improving post-arrest management of cardiac arrest survivors.
Evaluating lesion integrity with diamond temp system
Authors: Siddiqui U , Khanani A
Published: October 2024

Background

Pulmonary vein (PV) isolation by temperature-controlled (TC) radiofrequency ablation (RFA) is regaining popularity due to tissue-temperature feedback from thermocouples attached at the distal tip. The Diamond Temp (DT) ablation catheter system is uniquely able to monitor real time tissue temp during RFAs.

The DT catheter tip has a 1.1 mm split tip electrode, allowing precise bipolar pacing during RFA. Loss of capture (LOC) with High output pacing (HOP) has been considered a surrogate to assess lesion transmurality [1]. This study evaluated the utility of DT catheter distal pacing to achieve durable lesions.

Standard guidelines for TC ablation recommend achieving target tissue-temperature of 60ºC to produce durable lesions. The purpose of this study was to assess whether LOC is achieved at target tissue-temperature of 60ºC.

Objective

Pacing during ablation from distal tip micro electrode of the DT catheter and observing the time it takes for LOC at different segments around pulmonary veins. First pass isolation (FPI) percentage was also collected.

Methods

While target enrollment for this prospective study is 50 patients, these preliminary findings are based on analysis of the first 15 patients enrolled, all of whom had symptomatic, drug-refractory paroxysmal AF.

Point-by-point RF lesions were delivered around ipsilateral PVs, divided into 4 segments: superior, inferior, anterior, and posterior. Ablation was performed in a TC mode with max temp setting of 60°C and max power of 50 watts. HOP was performed prior to start of ablation and discontinued once LOC was observed. Time taken to LOC around all 4 segments of PVs were recorded. Intracardiac echocardiography (ICE) was used to guide contact and monitor lesion formation.

Results

Overall mean time to LOC was 3.32 sec. Anterior sites exceeded this mean. Inferior, superior, and posterior sites generally had shorter times. 92.53% of locations achieved LOC within 2-5 sec of ablation. The right anterior PV had the longest time at 3.73 sec, exceeding the overall mean of 3.32 sec. All patient achieved FPI.

Conclusion

Reaching target therapeutic temp of 60°C alone may not be sufficient to achieve LOC around PVs. Ablation duration of 4 sec led to LOC in 92.53% of lesions. Certain anatomical regions like anterior locations required prolonged ablation time. Tissue thickness on ICE correlated directly with time required to LOC.

This analysis shows that TC ablation with DT is effective; however, a therapeutic stable temperature of 60°C for at least 4 sec may be needed to achieve durable lesions around PVs. Tissue thickness on ICE and stability of temperature appear to be independent variables affecting duration prior to LOC.
The connection site of the Bachmann bundle to the left atrium affects atrial electrical and anatomical remodeling
Authors: Mine T , Terao S , Sugitani M , Kogame T , Fukuhara E , Ishihara M
Published: October 2024

Background

A common route for the propagation of the conduction system from the right atrium to the left atrium (LA) is via the Bachmann bundle (BB) which is a parallel-aligned muscular structure. It is empirically known that the site of conduction from BB to LA differs depending on the patient.

Purposes

To clear the clinical significance of differences in the BB conduction sites in patients with atrial fibrillation (AF).

Methods

We studied 182 patients (90 non-paroxysmal AF, 121 males, and 68.2 ± 10.0 years) who received catheter ablation for AF. Clinical data, echocardiographic data, and blood samples were evaluated. High-density LA mapping during high right atrial pacing was constructed. The site of conduction from BB to LA, the global activation time, LA mean voltage, the abnormal conduction zone (ACZ), and the conduction block (CBZ) were evaluated. The conduction from BB was connected to the region surrounded by the left atrial roof line, the carina of the right pulmonary vein, and the base of the left atrial appendage in all patients (Figure 1). This area was divided into four regions (right-roof, mid-roof, right-anterior, and mid-anterior area), and BB conduction sites were classified into each area by three independent observers who did not know clinical data. Global activation time for the LA was calculated by subtracting the earliest from the latest activation within the LA. Isochronal activation maps were created at a 5-ms interval setting, and ACZ (Figure 2) and CBZ were identified on the activation map by locating a site with isochronal crowding of ≥3 isochrones and ≥8 isochrones, which were calculated as ≤27 cm/s and ≤10 cm/s.

Results

The conduction from BB was observed in 45 patients in the right-roof area, 24 in the mid-roof, 76 in the right-anterior, 23 cases in the mid-anterior, and 14 in multiple sites. Global activation time (right-roof 108±20, mid-roof 107±16, right-anterior 105±19, and mid-anterior 117±20ms, P=0.0781) was more prolonged and left atrium diameter was larger (42.1±6.6, 42.6±8.5, 42.5±6.6, and 46.4±6.6mm, P=0.0718) in patients with mid-anterior BB connections. LA mean voltage (4.90±1.94, 5.72±2.62, 4.13±1.58, and 4.88±1.96mV, P=0.0032) was higher and plasma brain natriuretic peptide level (139±138, 67±59, 128±139, and 164±197pg/mL, P=0.0861) was lower in patients with mid-roof BB connections. ACZ (41/45 91%, 20/24 83%, 73/76 96%, and 23/23 100%, P=0.0904) and CBZ (1/45 2%, 0/24 0%, 8/76 11%, and 2/23 9%, P=0.0850) appearance rates were lower in patients with mid-roof BB connections.

Conclusion

The connection site of the Bachmann bundle to the left atrium may affect atrial electrical and anatomical remodeling in patients with atrial fibrillation.
Incidence of silent brain injury in pacemaker implanted patients with atrial high-speed episodes (AHRE)
Authors: Cinar A , Gedikli O , Uyanik M , Avci B
Published: October 2024

Purpose

Atrial high rate episodes (AHRE) are tachyarrhythmia attacks that can be detected by implantable cardiac devices. In the European Society of Cardiology (ESC) 2020 AF guideline, AHRE is defined as ≥ 175 bpm for the device-programmed rate criterion and ≥ 5 minutes for the duration criterion. AHRE has been shown to be one of the predisposing factors of AF and stroke. However, the relationship between AHRE and SBI has not been clarified yet. Neuron spesific enolase (NSE) is a valid biomarker for quantifying the volume of neuronal damage. In this study, we aimed to evaluate the incidence of silent brain injury (SBI), defined as elevated NSE levels in AHRE detected patients.

Method

Between January 2021 and June 2022, 80 patients who underwent routine pacemaker control, met the inclusion and exclusion criteria, and had AHRE detected in their permanent pacemaker records were included in a university faculty of medicine cardiology arrhythmia polyclinic. For the control group, patients who had a permanent pacemaker and did not have AHRE or any other arrhythmia were included. Of patients with AHRE detected in the last 6 months and those who had an AHRE attack within the last 72 hours were examined.

Results

Individuals included in the study were divided into subgroups according to AHRE duration. Group 1 (non-AHRE) 80 (50.0%), Group 2 (AHRE lasting <5 min) 24 (15.0%), Group 3 (≥5 min - <1h) 33 (20.6%), 19 (11.9%) patients in Group 4 (lasting ≥1 h - <24 h) and 4 (2.5%) patients in Group 5 (lasting ≥24 h). There was a statistically significant difference in NSE median values between groups (p=<0.001). In Mann Whitney U test with Bonferronni correction, the median values of all other groups were significantly different from each other (p=<0.001). In the correlational analysis, there was a statistically significant positive relationship between AHRE duration and NSE values (r=0.842; p=<0.001). Additionally, there was correlation between AHRE duration and age (r=0.235; p=0.036), CHA2DS2-VASc score (r=0.226, p=0.044) and LA diameter (r=0.300; p=0.007). NSE levels were positively correlated with AHRE duration (r=0.842; p=<0.001) and LA diameter (r=0.242; p=0.030).

Conclusion

AHRE duration was longer in patients with advanced age, increased CHA2DS2-VASc score, and increased LA diameter. This may play a role in explaining the underlying pathophysiological changes in AHRE before AF develops. Since NSE levels are related to LA diameter as well as AHRE duration, it can be thought that increasing LA diameter contributes to the development of thrombus.
Blood pressure response to exercise in endurance athletes with and without paroxysmal atrial fibrillation.
Authors: Janssens K , Apelland T , Mitchell A , Enger S , Dausin C , Rowe S , D'ambrosio P , Foulkes S , Hawley J , Claessen G , Myrstad M , La Gerche A
Published: October 2024

Background

Atrial fibrillation (AF) is more prevalent among endurance-trained athletes when compared to non-athletes. The underlying pathophysiology and mechanisms for this phenomenon remain unknown but repeated exposure to an exaggerated blood pressure (BP) response during exercise may contribute to the development of AF in this population.

Purpose

We aimed to assess whether endurance athletes with AF have a higher maximal systolic BP (SBP) or a higher BP relative to exercise intensity compared to endurance athletes without AF.

Methods

Endurance athletes with paroxysmal AF (n=66, 96% male) from the ProAFHeart, NEXAF Detraining and Master@Heart studies were matched for age and sex to endurance athletes without AF (n=66, 96% male). Participants with a history of hypertension were excluded. All athletes underwent a maximal graded cardiopulmonary exercise test on a cycle ergometer to assess exercise BP using an automated auscultatory BP machine, maximal oxygen uptake (VO2peak) and peak workload. All athletes were in sinus rhythm at the time of testing and BP was measured pre-exercise seated on the bike and every 2 min throughout the test. Exercise BP measurements included the maximum exercise SBP (SBPmax) and the slopes of the relationships between SBP, diastolic BP (DBP) and workload (W) as determined from linear regression analysis (SBP/W-slope and DBP/W-slope, respectively). The resting SBP and DBP were measured in the supine position after 10min of rest. Independent T-test (parametric data) or the Mann-Whitney U-test (non-parametric data) assessed for the differences between the two groups.

Results

The 66 athletes with AF were of similar age and sex as the 66 athletes without AF, median age (55 [IQR 45, 61] vs 54 [IQR 44, 62] years, p=0.839), 4% female. There was no difference in (mean±SD) VO2peak (46 ±9 vs 49±10 mL/kg/min, p=0.114) and peak workload (365±67 vs 385±83 W, p=0.136), nor resting SBP (131±13 vs 128±13 mmHg, p=0.169) and resting DBP (76±9 vs 75±11 mmHg, p=0.465) between athletes with and without AF respectively (Table 1). Athletes with AF showed no significant difference to athletes without AF for exercise BP responses (Figure 1) including SBPmax (222±22 vs 219±28 mmHg, p=0.479), SBP/W-slope (0.22±0.07 vs 0.24±0.08 mmHg/W, p=0.310) and median DBP/W-slope (-0.01 [IQR -0.02, 0.01] vs -0.01 [IQR -0.03, 0.02] mmHg/W, p=0.703).

Conclusion

When comparing endurance athletes with and without paroxysmal AF, there were no differences in the maximal BP attained during exercise or in their BP response indexed to external workload (SBP/W-slope) suggesting that exercise-induced hypertension does not explain the athletic predisposition to AF.
Outcome and life expectancy associated with novel subgroups of atrial fibrillation: a data-driven cluster analysis
Authors: Wang N , Yu Y , Li J , Sun Y , Yu B , Tan X , Wang B , Lu Y
Published: October 2024

Background/Introduction

Atrial fibrillation (AF) presents a significant global health burden, affecting millions and associated with elevated risks of mortality, heart failure, and stroke despite current treatment strategies. The current diagnosis of AF relies on episode characteristics, yet its heterogeneity calls for personalized assessment incorporating clinical features, biomarkers, and substrate determination for improved classification and management.

Purpose

This study aimed to develop a refined classification of AF according to comprehensive risk factors to identify patients at high-risk for poor prognosis and their life expectancy, aiming to facilitate personalized interventions.

Methods

A total of 7,391 participants aged 40-69 with AF at baseline, from UK Biobank, were recruited in the main analyses. Firstly, LASSO regression with Cox model and factor analysis were adopted for identification and integration of principal risk factors. Second, Consensus clustering analysis was employed to estimate the optimal cluster number and group all 7,391 participants. Difference in the risk of death and major complications, as well as reductions in life expectancy, among clusters were estimated. Replication was done in 2,399 participants with newly diagnosed AF within two years after baseline.

Results

Risk factors for AF were categorized into seven aspects (metabolic factors, respiratory factors, cardiovascular factors, renal and immunity diseases, mental health, acute illness, age), based on the correlation between them. Five distinct AF clusters were identified according to these seven characteristics: acute illness-related (Cluster 1), mental health-related (Cluster 2), cardiovascular disease-related (Cluster 3), immune-and-renal disease-related (Cluster 4), and respiratory-and-metabolism disease-related AF (Cluster 5). Patients with respiratory-and-metabolism disease-related AF had the highest risk of death, acute myocardial infarction, heart failure, and cerebral ischemic stroke, while those with acute illness-related AF had the lowest corresponding risk. In addition, compared with individuals with acute illness-related AF, those with respiratory-and-metabolism disease-related and mental health-related AF had the top 2 greatest loss of life expectancy. Furthermore, genetic variants for AF had different effect among the five clusters. Replication analysis confirmed the result stability.

Conclusion

A novel AF classification was developed, which provided insights into varying life expectancy and risks of death and complications among AF subgroups with distinct characteristics. It offers a practical approach for identifying high-risk patients, which may help to tailor precise interventions for AF management.Graphic abstractCluster features