Epicardial Tissue Research Articles

Echocardiographic assessment of epicardial adipose tissue thickness as independent predictor in coronary artery disease.

This study aimed to assess the utility of echocardiography-measured epicardial adipose tissue (EAT) thickness (EATT) as an independent predictor for coronary artery disease (CAD), examining its correlation with oxidative stress levels in epicardial tissue and the complexity of the disease in patients undergoing open-heart surgery. This study included a total of 25 patients referred for cardiac surgery with 14 in the CAD group and 11 in the non-CAD group. Epicardial fat was sampled from patients subjected to open-heart surgery. EATT was higher in the CAD group compared to the non-CAD group (8.15±2.09mm vs. 5.12±1.8mm, p=0.001). The epicardial reactive oxygen species level was higher in the CAD group compared to the non-CAD group (21.4±2.47nmol H2O2/g tisssue/h vs. 15.7±1.55nmol H2O2/g tisssue/h, p<0.001). EATT greater than 6.05mm was associated with CAD, with a sensitivity of 86% and specificity of 73%. Echocardiographically measured EATT is a significant, independent predictor of CAD. Its relationship with increased EAT oxidative stress levels suggests a potential mechanistic link between EATT and CAD pathogenesis. These findings highlight the importance of EATT as a diagnostic tool in assessing the complexity of CAD in patients undergoing cardiac surgery.

Characterisation and distribution of human coronary artery innervation.

A detailed understanding of the sympathetic innervation of coronary arteries is relevant to facilitate the development of novel treatment approaches. This study aimed to quantitatively examine periarterial innervation in human epicardial coronary arteries. Coronary arteries with adjacent epicardial adipose tissue were excised along the left main coronary artery (LMCA), left anterior descending artery (LAD), left circumflex artery (LCx), and right coronary artery (RCA) from 28 body donors and examined histologically. Immunofluorescence staining was performed to characterise sympathetic nerve fibres. A total of 42,573 nerve fibres surrounding 100 coronary arteries (LMCA: n=21, LAD: n=27, LCx: n=26, RCA: n=26) were analysed. The nerve fibre diameter decreased along the vessel course (median [interquartile range]): (proximal 46 μm [31-73], middle 38 μm [26-58], distal 31 μm [22-46]; p<0.001), with the largest nerve fibre diameter along the LMCA (50 μm [31-81]), followed by the LAD (42 μm [27-72]; p<0.001). The total nerve fibre density was highest along the RCA (123 nerves/cm² [82-194]). Circumferentially, nerve density was higher in the myocardial tissue area of the coronary arteries (132 nerves/cm² [76-225]) than in the epicardial tissue area (101 nerves/cm² [61-173]; p<0.001). The median lumen-nerve distance was smallest around the LMCA (2.2 mm [1.2-4.1]), followed by the LAD (2.5 mm [1.1-4.5]; p=0.005). Human coronary arteries are highly innervated with sympathetic nerve fibres, with significant variation in the distribution and density. Understanding these patterns informs pathophysiological understanding and, potentially, the development of catheter-based approaches for cardiac autonomic modulation.

Diabetic Cardiomyopathy: Role of Cell Death, Exosomes, Fibrosis and Epicardial Adipose Tissue.

Diabetic cardiomyopathy (DCM) represents one of the typical complications associated with diabetes. It has been described as anomalies in heart function and structure, with consequent high morbidity and mortality. DCM development can be described by two stages; the first is characterized by left ventricular hypertrophy and diastolic dysfunction, and the second by heart failure (HF) with systolic dysfunction. The proposed mechanisms involve cardiac inflammation, advanced glycation end products (AGEs) and angiotensin II. Furthermore, different studies have focused their attention on cardiomyocyte death through the different mechanisms of programmed cell death, such as apoptosis, autophagy, necrosis, pyroptosis and ferroptosis. Exosome release, adipose epicardial tissue and aquaporins affect DCM development. This review will focus on the description of the mechanisms involved in DCM progression and development.

Impact of wall thickness on tissue cooling effect of cryoballoon ablation: Investigation using an experimental heart model

Abstract Background Understanding of the tissue cooling properties of cryoballoon ablation during pulmonary vein isolation is lacking. Purpose To delineate the depth of the tissue cooling effect during cryoballoon freezing at the pulmonary venous ostium. Methods A left atrial-pulmonary vein model, produced by a 3-dimensional printer using CT data from a patient, was constructed so that porcine thigh muscles of various thicknesses could be fixed and thermocouples could be fixed at locations corresponding to the epicardial side of the pulmonary vein ostium. The model was placed in a 37-degree water bath with a pulmonary vein water flow at a rate that mimicked biological blood flow, and the cryoballoon was advanced into the left superior vein until the vein was completely occluded. Cryofreezing was performed 5 times each for a porcine thigh muscle of 2-, 4-, and 6-mm thickness, and epicardial tissue cooling was monitored as assessed by the mean temperature of 12 evenly distributed thermocouples covering the roof region of the left superior vein. Results Epicardial tissue cooling effects were more in the order of 2-mm, 4-mm, and 6-mm thickness (Figure) with a mean temperature of -41.4 ± 4.2 for 2 mm, -33.0 ± 4.0 for 4 mm, and 8.0 ± 8.7 °C for 6 mm at 180 sec (p for trend &amp;lt; 0.0001). In addition, tissue temperature drops were steeper in thin muscle (maximum temperature drop per 5 s: 5.2 ± 0.9, 3.9 ± 0.7, 1.3 ± 0.7 °C, p for trend &amp;lt; 0.0001). Conclusion The cooling effect is weaker in the deeper layers during cryobaloon freezing, and longer freezing duration would be recommended in case of thick myocardium.

Distinct Electrogram Features and Ventricular Arrhythmia Induction Modes Between Repolarization and Conduction Heterogeneities

BackgroundRecent clinical studies have indicated the presence of localized electrical abnormalities in idiopathic ventricular fibrillation and J-wave syndrome patients. ObjectivesThis study aims to characterize the specific electrical signatures of localized repolarization and conduction heterogeneities and their respective role in vulnerability to arrhythmias. MethodsOptical mapping was performed in porcine right ventricles with local: 1) repolarization shortening; 2) conduction slowing; or 3) structural heterogeneity induced by locally perfusing: 1) pinacidil (20 μmol/L, n = 13); or 2) flecainide (2 μmol/L, n = 13) via an epicardial catheter; or 3) by local epicardial tissue destruction (9 radiofrequency lesions n = 12). Electrograms were recorded (n = 5 in each group) and spontaneous and induced arrhythmias were quantified and optically mapped. ResultsElectrograms were normal in (1) but showed local fragmentation in 40% of preparations in (2) with greater effects observed at high pacing frequencies dependent on the wavefront direction. In (3), the structural substrate alone increased the width and number of peaks in the electrograms, and addition of flecainide induced pronounced fragmentation (≥3 peaks and ≥70 ms) in all cases. Occurrence of spontaneous arrhythmias was significantly increased in (1) and (2) (P < 0.0001 and 0.05, respectively, vs baseline) and were triggered by ectopies. Vulnerability to arrhythmias at high pacing frequencies (≥2 Hz) was the lowest in (1) and greatest in (2). ConclusionsMicrostructural substrates have the most pronounced impact on electrograms, especially when combined with sodium channel blockers, whereas local action potential duration shortening does not lead to electrogram fragmentation even though it is associated with the highest prevalence of spontaneous arrhythmias.

ALK1 Signaling in Human Cardiac Progenitor Cells Promotes a Pro-angiogenic Secretome.

Pro-angiogenic paracrine/autocrine signaling impacts myocardial repair in cell-based therapies. Activin A receptor-like type 1 (ACVRL1, ALK1) signaling plays a pivotal role in cardiovascular development and maintenance, but its importance in human-derived therapeutic cardiac cells is not well understood. Here, we isolated a subpopulation of human highly proliferative cells (hHiPCs) from adult epicardial tissue and found that they express ALK1, a high affinity receptor for bone morphogenetic protein-9 (BMP9), which signals via SMAD1/5 to regulate paracrine/autocrine signaling and angiogenesis. We show that in humans, circulating BMP9 level is negatively associated with the number of epicardial hHiPC and positively associated with endothelial cell (EC) number in the adult heart, implicating the potential importance of this signaling pathway in cardiac cell fate and vascular maintenance. To investigate BMP9/ALK1 signaling in hHiPCs, we selected a primary cell population of hHiPC from each of 3 individuals and studied their responses to BMP9 and BMP10 treatment in vitro. Proteins were collected in conditioned media (CM) for mass spectrometry and cell-based assays on human ECs and hHiPCs. Proteomic analysis of the hHiPC secretome following BMP9 or BMP10 treatment demonstrates that the secreted proteins, sclerostin (SOST), meflin/immunoglobulin superfamily containing leucine rich repeat (ISLR), and insulin-like growth factor binding protein-3 (IGFBP3), are novel regulated targets of BMP9/ALK1 signaling. Lentiviral shRNA and pharmacological inhibition of ALK1 in hHiPCs suppressed transcription and secretion of SOST, ISLR, and IGFBP3 following BMP9 treatment. Moreover, the BMP9-treated secretome of hHiPC increased capillary-like tube formation of ECs and hHiPCs. Treatment of hHiPCs with recombinant SOST increased VEGF-a expression, increased tube formation and enhanced expression of EC receptor marker annexin A2 (ANXA2). These data provide the first proteomic characterization of hHiPC, identifying BMP9/ALK1-mediated target protein secretion in hHiPCs, and underscore the complex role of BMP9/ALK1 signaling in paracrine/autocrine mediated angiogenesis. Data are available via ProteomeXchange with identifier PXD055302.

The Comparison of Apoptosis Anti-apoptosis and Autophagy Markers in Epicardial Tissue in Patients with Coronary Artery Disease and in Patients have Valvular Disease, HOCM, Ascending Aortic Aneurysm without Coronary Artery Disease

The Comparison of Apoptosis Anti-apoptosis and Autophagy Markers in Epicardial Tissue in Patients with Coronary Artery Disease and in Patients have Valvular Disease, HOCM, Ascending Aortic Aneurysm without Coronary Artery Disease

Epicardial tissue derived leptin promotes myocardial injury in metabolic syndrome rats through PKC/NADPH oxidase/ROS pathway

Abstract Background The epicardial adipose tissue (EAT) of metabolic syndrome (MetS) is abnormally accumulated with dysfunctional secretion of adipokines, closely relating to cardiac dysfunction. The adipokines leptin has been proven to induce cardiac fibroblasts collagen metabolism disorder in hypertensive left ventricular hypertrophy rats. Purpose The study was designed to identify the effects of EAT-derived leptin on the myocardium of MetS rats and explore the potential molecular mechanisms. Methods and results MetS rat model was established in eight-week-old male Wistar rats by 12 week high-fat diet. MetS rats exhibited increased leptin secretion from EAT, cardiac hypertrophy and diastolic dysfunction with preserved systolic function. The myocardium of MetS rats had abnormal structure and mitochondrial morphology, increased oxidative stress injury and inflammatory factors level, especially the subepicardial myocardium, which was correlated with the EAT-derived leptin level, but not the serum leptin (Figure 1). The EAT was separated from each group rats to prepare EAT-Conditioned Medium (EAT-CM). The H9C2 rat cardiomyoblasts were treated with EAT-CM or leptin, plus various signaling pathway inhibitors. EAT derived leptin from MetS rats promoted mitochondrial oxidative stress and dysfunction, induced mitochondrial pathway apoptosis and inhibited cell viability in H9C2 cardiomyoblasts via PKC/NADPH oxidase/ROS pathway. EAT derived leptin from MetS rats stimulated inflammation in H9C2 cardiomyocytes by promoting AP-1 nuclear translocation via PKC/NADPH oxidase/ROS pathway. Leptin promoted the interaction between p-p47phox and gp91phox in H9C2 cardiomyocytes via PKC, activating NADPH oxidase, increasing ROS generation, and inhibiting cell viability. Conclusions EAT derived leptin induces the MetS related myocardial injury though the following two cooperative ways via PKC/NADPH oxidase/ROS pathway: 1. Inducing mitochondrial pathway apoptosis by promoting mitochondrial oxidative stress and dysfunction; 2. Stimulating inflammation by promoting AP-1 nuclear translocation (Figure 2). The results reveal the potential molecular mechanisms of EAT in MetS related myocardial injury, providing novel insights for the further study of MetS related cardiovascular diseases.Figure 1Figure 2

Epicardial Adipose Tissue and Development of Atrial Fibrillation (AFIB) and Heart Failure With Preserved Ejection Fraction (HFpEF).

Epicardial adipose tissue (EAT) has been associated with the development of many cardiovascular abnormalities, of which the development of atrial fibrillation (AFIB) in this group of patients is not an uncommon finding. Several mechanisms have been proposed to explain the role of EAT in the development of AFIB. It involves cardiac remodeling owing to the underlying fatty infiltration and the subsequent inflammation and fibrosis. This leads to the formation of ectopic foci that can lead to AFIB. Some studies propose that structural and valvular heart disease and increased hemodynamic stress further augment the development of AFIB in patients with underlying EAT. The degree of development of AFIB is also related to EAT thickness and volume. Therefore, EAT quantification can be used as an imaging technique to predict cardiovascular outcomes in these patients. Obesity also plays an important role in the development of AFIB both as an independent factor and by leading to adipose tissue deposition on the epicardial tissue. Understanding the pathophysiology of EAT is important as it can lead to the development of therapies that can target obesity as a risk factor for preventingAFIB. Some promising therapies have already been investigated for decreasing the risk of AFIB in patients with EAT. Dietary changes and weight loss have been shown to reduce the deposition of fat on epicardial tissue. Antidiabetic drugs and statin therapy have also shown promising results. Bariatric surgery has been shown to decrease EAT volume on echocardiography in obese patients.

Single-cell and spatial heterogeneity landscapes of mature epicardial cells

Tbx18, Wt1, and Tcf21 have been identified as epicardial markers during the early embryonic stage. However, the gene markers of mature epicardial cells remain unclear. Single-cell transcriptomic analysis was performed with the Seurat, Monocle, and CellphoneDB packages in R software with standard procedures. Spatial transcriptomics was performed on chilled Visium Tissue Optimization Slides (10x Genomics) and Visium Spatial Gene Expression Slides (10x Genomics). Spatial transcriptomics analysis was performed with Space Ranger software and R software. Immunofluorescence, whole-mount RNA in situ hybridization and X-gal staining were performed to validate the analysis results. Spatial transcriptomics analysis revealed distinct transcriptional profiles and functions between epicardial tissue and non-epicardial tissue. Several gene markers specific to postnatal epicardial tissue were identified, including Msln, C3, Efemp1, and Upk3b. Single-cell transcriptomic analysis revealed that cardiac cells from wildtype mouse hearts (from embryonic day 9.5 to postnatal day 9) could be categorized into six major cell types, which included epicardial cells. Throughout epicardial development, Wt1, Tbx18, and Upk3b were consistently expressed, whereas genes including Msln, C3, and Efemp1 exhibited increased expression during the mature stages of development. Pseudotime analysis further revealed two epicardial cell fates during maturation. Moreover, Upk3b, Msln, Efemp1, and C3 positive epicardial cells were enriched in extracellular matrix signaling. Our results suggested Upk3b, Efemp1, Msln, C3, and other genes were mature epicardium markers. Extracellular matrix signaling was found to play a critical role in the mature epicardium, thus suggesting potential therapeutic targets for heart regeneration in future clinical practice.

Role of localized repolarization and conduction heterogeneities in ventricular arrhythmias and sudden cardiac death

Recent clinical studies have indicated the presence of localized tissue abnormalities in sudden cardiac death (SCD) survivors without apparent structural heart disease, including idiopathic ventricular fibrillation (VF) and J-wave Syndromes. The origin of these abnormalities, showing distinct electrical features on contact mapping, and mechanisms of associated arrhythmias are still a matter of debate. To determine the respective role of localized repolarization and conduction heterogeneities in vulnerability to arrhythmias and SCD, and to characterize their specific electrical signatures. Optical mapping was performed on porcine right ventricular models of either local (i) repolarization shortening, (ii) conduction slowing, or (iii) micro-structural heterogeneity which were created by locally perfusing (i) pinacidil (20 μM n = 13) or (ii) flecainide (2 μM n = 13) via an epicardial catheter (branch of right coronary artery), or (iii) by local epicardial tissue destruction through radiofrequency application (9 micro lesions 30W 1 sec n = 13). Pseudo-ECG were assessed and the number of induced and spontaneous arrhythmias were quantified and mapped in each preparation. An HD grid mapping catheter was used to record bipolar electrograms (n = 5 in each group). Electrograms were normal in model (i), but showed local fragmentation in 40% of preparations in model (ii) with greater effects observed at high pacing frequencies (3 Hz). In model (iii), the structural substrate alone increased the width and number of peaks in the electrograms, and addition of flecainide (2 μM) in this model induced pronounced fragmentation (≥ 3 peaks and ≥ 70ms duration) in 100% of the cases. Arrhythmogenicity was significantly increased in models (i) and (ii) which presented 82% and 45% more spontaneous arrhythmias (P < 0.0001 and 0.05 vs. baseline) and a reduced pacing frequency threshold to induce arrhythmias (−69% and −50%, P < 0.001 vs. baseline). In these models, the frequency of spontaneous activity was increased (+411% P < 0.01 and +181% P < 0.05 vs. baseline) and originated near the heterogeneous area. Microstructural substrates have the most pronounced impact on electrograms, especially when combined with sodium channel blockers, while repolarization heterogeneities do not lead to electrogram fragmentation but are associated with the highest prevalence of spontaneous arrhythmias. Both heterogeneities show increased ectopic activity.

Left atrial appendage exclusion using a stapler with thoracoscopic ablation of atrial fibrillation

Highlights. Stroke prevention in patients with atrial fibrillation is extremely important and difficult. Lifelong anticoagulant therapy is not always an effective way of preventing thrombosis in the left atrial appendage in this group of patients. In this regard, one of the most urgent problems of modern surgical arrhythmology and cardiac surgery is the search for new open and minimally invasive surgical methods of excluding the left atrial appendage from the blood flow.Aim. To investigate the safety and efficacy of using the left atrial appendage stapler for video-guided thoracoscopic ablation (TSA) of non-valvular atrial fibrillation (AF).Methods. The retrospective, single-center study included 100 patients with non-valvular AF who underwent video-guided thoracoscopic ablation of AF with single-stage left atrial appendage exclusion using an Endo GIA stapler (Medtronic, Minneapolis, Minnesota, USA).Results. The mean age of the patients was 56,2±8,8 years, the majority of the patients (73 patients, 73%) were male. Patients with persistent 50 (50%) AF and longstanding AF 50 (50%) were included in the study. The duration of atrial fibrillation was 4 (1,7–7) years. The median CHA2DS2-VASc and HAS-BLED scores were 2 (1–1,5) and 1 (0-1), respectively. The mean anticoagulation therapy-to-ablation time was 4,2±1,9 years. Thirty-eight (38%) patients were prescribed warfarin preoperatively. The completeness of left atrial appendage (LAA) exclusion was confirmed by intraoperative transesophageal echocardiography. The average length of the staple lines was 48 (35–75). A single left atrial appendage exclusion was performed using a 60 mm staples. In 12 (12%) patients, stapler exclusions were performed using two 45 mm staples due to insufficient staple length. None of the patients had ruptures, punctures along the staple lines or rupture of the surrounding epicardial tissue. Anticoagulant therapy was discontinued 6 months after TSA in 70 (70%) patients with sustained sinus rhythm observed on 24-h Holter Monitoring, satisfactory CHA2DS2-VASc scores and after confirmation of absence of left atrial thrombus by transesophageal echocardiography and contrast-enhanced MSCT. No strokes were reported within 1,2±0,7 years after discontinuing anticoagulation therapy.Conclusion. Exclusion of LAA using a stapler for TSA is a highly effective and safe technique for patients with non-valvular atrial fibrillation compared to alternative methods of excluding the LAA from the systemic blood flow.

Elevated Plasma Immunoglobulin Levels Prior to Heart Transplantation Are Associated with Poor Post-Transplantation Survival.

Cardiac allograft vasculopathy (CAV) and antibody-mediated rejection are immune-mediated, long-term complications that jeopardize graft survival after heart transplantation (HTx). Interestingly, increased plasma levels of immunoglobulins have been found in end-stage heart failure (HF) patients prior to HTx. In this study, we aimed to determine whether increased circulating immunoglobulin levels prior to transplantation are associated with poor post-HTx survival. Pre-and post-HTx plasma samples of 36 cardiac transplant recipient patients were used to determine circulating immunoglobulin levels. In addition, epicardial tissue was collected to determine immunoglobulin deposition in cardiac tissue and assess signs and severity of graft rejection. High levels of IgG1 and IgG2 prior to HTx were associated with a shorter survival post-HTx. Immunoglobulin deposition in cardiac tissue was significantly elevated in patients with a survival of less than 3 years. Patients with high plasma IgG levels pre-HTx also had significantly higher plasma levels after HTx. Furthermore, high pre-HTX levels of IgG1 and IgG2 levels were also significantly increased in patients with inflammatory infiltrate in CAV lesions. Altogether the results of this proof-of-concept study suggest that an activated immune response prior to transplantation negatively affects graft survival.

Effectiveness of intra-operative topical amiodarone for prevention of postcardiac surgery new-onset atrial fibrillation:A review of current evidence.

Postoperative atrial fibrillation (POAF) is one of the most common complications following cardiac surgery and is associated with increased morbidity. Intraoperative topical amiodarone application on epicardial tissue has been shown to reduce systemic concentrations while maintaining therapeutic myocardial concentrations, thereby, lowering the risk of extracardiac adverse effects associated with oral and intravenous amiodarone therapy. However, the efficacy and safety of topical amiodarone in preventing POAF is unclear. This study summarizes the clinical studies to-date that have investigated the efficacy and safety of topical amiodarone administration in preventing POAF following cardiac surgery. A database search was conducted using Medline, Embase, and Cochrane Library to identify relevant studies. Abstracts were screened and data were extracted from relevant full-text articles that met the inclusion and exclusion criteria. The search returned four studies with variable findings on the effect of topical amiodarone therapy on the incidence of POAF, cardiac effects, extracardiac effects, and hospital length of stay. Prophylactic topical application of amiodarone may be effective and safe for preventing post-operative new-onset atrial fibrillation. Further investigation is required to evaluate the efficacy and safety of topical amiodadrone therapy before it can be widely integrated into current practice.

Abstract 14509: A Rare Case of Cardiac Tamponade as an Initial Presentation of Native Aortic Valve Infective Endocarditis

Background: Pericardial involvement is a rare presentation of infectious endocarditis (IE). We present a case of septic cardiac tamponade, paravalvular abscess and fibrinous pericarditis secondary to native aortic valve (AV) IE. Presentation: A 50-year-old gentleman with a history of IV drug use presented with fever, dyspnea and pleuritic chest pain for one week. He was febrile, tachycardic and hypotensive on presentation. Examination revealed a new onset early diastolic murmur. Workup: EKG showed mild diffuse ST segment elevations and PR segment depressions suggestive of pericarditis. Blood cultures grew Serratia marcescens in 6 out of 6 bottles and IV cefepime was initiated. TTE revealed large effusion with right atrium and right ventricle diastolic collapse consistent with tamponade physiology (fig. A, B). A vegetation was seen on the right coronary cusp of AV along with aortic insufficiency and aortic root abscess. TEE confirmed the above findings (fig. C-F) Management: An emergency cardiac surgery was performed for acute aortic regurgitation and cardiac tamponade. Intraoperative findings revealed 600mL of purulent effusion. A large vegetative mass near left-to-right commissure covering an abscess cavity that extended into the aortic wall that destroyed the annulus and extended into the ventricular muscle. AV replacement with 21mm Inspiris pericardial AV and pericardial patching was done. Epicardial tissue as well as AV leaflet cultures revealed moderate to heavy growth of S. marcescens . He was discharged on cefepime for a total duration of 6 weeks. Follow up TTE revealed normal peak and mean transaortic gradients. Conclusion: Cardiac tamponade is a rare but life-threatening complication of IE. Pericardial involvement should prompt us further work up to exclude intra-cardiac abscess which carries poor prognosis due to high complication rates. Hence, early multidisciplinary team response is of paramount importance to reduce in-hospital mortality.

Procalcitonin mediates vascular dysfunction in obesity

AimsObesity is accompanied by a chronic low-grade inflammation associated with endothelial dysfunction and vascular complications. Procalcitonin is a marker of inflammation, secreted by adipose tissue and elevated in obese subjects. We here investigated whether visceral or perivascular fat-derived procalcitonin is a target to improve obesity-induced endothelial dysfunction. Materials and methodsProcalcitonin expression was identified by Western blot. Murine endothelial cells were isolated using CD31-antibody-coated magnetic beads and reactive oxygen species and nitric oxide (NO) determined by H2DCF- or DAF-FM diacetate loading. Endothelium-dependent vasorelaxation was analyzed using pressure myography of murine arterioles. Calcitonin gene-related peptide (CGRP) was used to activate the calcitonin receptor-like receptor (CRLR)/RAMP1 complex and olcegepant or the dipeptidyl-peptidase 4 (DPP4) inhibitor sitagliptin to block procalcitonin signaling or activation. Key findingsIn addition to visceral adipose tissue, procalcitonin was present in perivascular and epicardial tissue. In concentrations typical for obesity, procalcitonin doubled reactive oxygen species formation and decreased endothelial nitric oxide production in murine endothelial cells. Intravenous delivery of procalcitonin to mice in obesity-associated concentrations impaired endothelium-dependent vasorelaxation in a CRLR/RAMP1-dependent manner and antagonized CGRP-induced endothelial NO release in vitro. Use of CRLR/RAMP1-receptor antagonist olcegepant counteracted procalcitonin effects on vasodilation, nitric oxide production and reactive oxygen species formation. Similarly, blocking procalcitonin activation by the DPP4 inhibitor sitagliptin antagonized endothelial procalcitonin effects. SignificanceProcalcitonin, liberated either from visceral or perivascular adipose tissue, contributes to endothelial dysfunction by antagonizing CGRP signaling in obesity. Targeting hyperprocalcitonemia may be a means to preserve endothelial function and reduce comorbidity burden in obese subjects.

A transmurally heterogeneous model of the ventricular tissue and its application for simulation of Brugada Syndrome.

We present a transmurally heterogeneous phe-nomenological model of ventricular tissue that is designed to reproduce the most important features of action potential prop-agation of endocardial, midmyocardial, and epicardial tissue. Our model consists of only 3 variables and 20 parameters. Therefore, it is highly computational efficient and easy to fit to experimental data. We exploited our myocyte model to simulate action potential propagation in a 3D slab of cardiac tissue both in healthy conditions and in presence of Brugada syndrome. The results show that our model can accurately reproduce the transmural heterogeneity of the ventricular wall and the main characteristics of electrocardiographic pattern both in healthy and pathological conditions.

Diffuse fibrosis and repolarization disorders explain ventricular arrhythmias in Brugada syndrome: a computational study

In this work, we reported a computational study to quantitatively determine the individual contributions of three candidate arrhythmic factors associated with Brugada Syndrome. In particular, we focused our analysis on the role of structural abnormalities, dispersion of repolarization, and size of the diseased region. We developed a human phenomenological model capable of replicating the action potential characteristics both in Brugada Syndrome and in healthy conditions. Inspired by physiological observations, we employed the phenomenological model in a 2D geometry resembling the pathological RVOT coupled with healthy epicardial tissue. We assessed the insurgence of sustained reentry as a function of electrophysiological and structural abnormalities. Our computational study indicates that both structural and repolarization abnormalities are essential to induce sustained reentry. Furthermore, our results suggest that neither dispersion of repolarization nor structural abnormalities are sufficient on their own to induce sustained reentry. It should be noted how our study seems to explain an arrhythmic mechanism that unifies the classic repolarization and depolarization hypotheses of the pathophysiology of the Brugada Syndrome. Finally, we believe that this work may offer a new perspective on the computational and clinical investigation of Brugada Syndrome and its arrhythmic behaviour.

Insights into the intracardiac electrogram from analytical and numerical modelling

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): FWO-Flanders, KU Leuven internal starting grant Introduction and Purpose Cardiac electrograms (EGMs) are one of the most important recordings obtained during electroanatomical voltage mapping and lie at the basis for planning most clinical electrophysiological interventions. Despite its widespread use, the relation of EGM shape and amplitude to the underlying excitation patterns and properties of cardiac tissue is not completely understood. Recent clinical studies [1] have provided important new guidelines on the relation between EGM amplitudes and the thickness of myocardial walls. The aim of this study is to quantify the effect of the wall thickness on EGM amplitudes and duration using analytical and in-silico approaches. Methods We study bipolar EGMs both in-silico and analytically in a homogeneous slab of cardiac tissue (70 x 70 x L mm), where L = 2, 5, or 10 mm, with parallel fiber direction. Simulations were performed using the cardiac electrophysiology simulator openCARP [2]. Cardiac cells were described by the ten Tusscher-Panfilov 2006 model (TP06) [4] with epicardial tissue parameters. A plane wave propagating along the fiber direction was initiated. The extracellular voltage at 147 points arranged in a hemisphere around a point was measured to study the effect of bipolar electrode orientation (see Fig. 1A [3]). In addition, we developed an analytical approach to obtain an EGM, using an equivalent dipole representation of the depolarization wavefront and analytical evaluation of the corresponding integrals. Results Fig. 1B and 1C show the dependency of the EGM properties on the electrode orientation, as represented by the angles α (incidence angle) and β (angle between electrode and propagation direction) [3]. Solid lines represent data from a state-of-the-art numerical methodology, the dashed lines show our analytical estimations. Both the peak-to-peak amplitude and EGM width are well approximated by our theory for all orientations of the electrodes. Fig. 2 shows how the EGM is influenced by the myocardial wall thickness L. Both the amplitude and the duration are in good agreement with our theory. We observe that the amplitude as well as the width increase with the slab thickness, confirming the result in [1] but also delivering an accurate analytical expression for this change. It may thus allow to discriminate effects of thickness and other factors affecting the EGMs, such as substrate abnormalities, for example. Conclusion We developed an analytical approach which can correctly describe the amplitude, duration, and shape of the depolarization part of the EGM. Our theory agrees with the previous in-silico and clinical studies on the influence of catheter orientation [3,5], and wall thickness [1,3]. Subsequent work in this direction is expected to provide better guidelines for clinical interpretation of EGMs, accounting for the effects of the thickness of myocardial wall in the characterization of the substrate of cardiac arrhythmias.

Reentry in cardiac ventricular epicardial tissue due to SCN5A L812Q gene mutation: a computational study

Cardiovascular diseases are the major cause of sudden death. Brugada syndrome is an inherited rare disease, that leads to death due to ventricular fibrillation (VF). Brugada Syndrome is related to mutations in the genes that encode SCN5A, a subunit of sodium ion channel (NaV). This computational study investigates the mechanism of loss of function gene mutation (SCN5A L812Q) in sodium ion channel that leads to spiral wave and further develops into VF in an epicardial tissue with homozygous condition. Study was made on wild type, L812Q heterozygous mutated and homozygous mutated ventricular tissues. Ten Tusscher human ventricular cell model (TP06) was used for the simulation study. VF is developed when a spiral wave that causes ventricular arrhythmia breaks. This leads to the formation of multiple spiral waves that are activated on different regions of the ventricles called wave break. This is observed in the epicardial tissue with homozygous condition as the effect of SCN5A L812Q gene mutation. This indicates that VF occurs in the SCN5A L812Q gene mutated homozygous ventricular epicardial tissue that may further lead to Brugada syndrome.