Electrophysiological Remodeling Research Articles

Mechanisms and Implications of Electrical Heterogeneity in Cardiac Function in Ischemic Heart Disease.

A healthy heart shows intrinsic electrical heterogeneities that play a significant role in cardiac activation and repolarization. However, cardiac diseases may perturb the baseline electrical properties of the healthy cardiac tissue, leading to increased arrhythmic risk and compromised cardiac functions. Moreover, biological variability among patients produces a wide range of clinical symptoms, which complicates the treatment and diagnosis of cardiac diseases. Ischemic heart disease is usually caused by a partial or complete blockage of a coronary artery. The onset of the disease begins with myocardial ischemia, which can develop into myocardial infarction if it persists for an extended period. The progressive regional tissue remodeling leads to increased electrical heterogeneities, with adverse consequences on arrhythmic risk, cardiac mechanics, and mortality. This review aims to summarize the key role of electrical heterogeneities in the heart on cardiac function and diseases. Ischemic heart disease has been chosen as an example to show how adverse electrical remodeling at different stages may lead to variable manifestations in patients. For this, we have reviewed the dynamic electrophysiological and structural remodeling from the onset of acute myocardial ischemia and reperfusion to acute and chronic stages post-myocardial infarction. The arrhythmic mechanisms, patient phenotypes, risk stratification at different stages, and patient management strategies are also discussed. Finally, we provide a brief review on how computational approaches incorporate human electrophysiological heterogeneity to facilitate basic and translational research.

Adipocyte-Mediated Electrophysiological Remodeling of PKP-2 Mutant Human Pluripotent Stem Cell-Derived Cardiomyocytes

Adipocyte-Mediated Electrophysiological Remodeling of PKP-2 Mutant Human Pluripotent Stem Cell-Derived Cardiomyocytes

Abstract 4138733: Predictive Value of Serum Vasoactive Intestinal Peptide for Low-Voltage Areas in Atrial Fibrillation

Introduction: Identifying low-voltage areas (LVAs) within left atrium (LA) is crucial for predicting atrial fibrillation (AF) recurrence after pulmonary vein isolation (PVI). Animal studies have shown that the parasympathetic neurotransmitter vasoactive intestinal peptide (VIP) affects atrial electrophysiological remodeling. Hypothesis: Thus, we hypothesized that elevated serum VIP levels might contribute to the development of LVAs and that serum VIP concentrations could serve as a biomarker for LVA presence in AF patients. Aims: The aim of this study is to investigate the relationship between the blood levels of VIP and the presence of LVAs in AF patients with electroanatomical mapping (EAM). Methods: We conducted an observational, prospective cross-sectional study on AF patients undergoing PVI between 2021 and 2023. Blood samples for VIP were collected before atrial septal puncture, and EAM was performed using CARTO 3® before PVI. VIP concentrations were measured using an enzyme-linked immunosorbent assay kit. Patients were divided into two groups based on LVA presence (≥5% or <5%) as determined by EAM. Results: Among the 108 patients, 51 (47%) had LVA. VIP levels were significantly higher in patients with LVA compared to those without (median [interquartile range]: 335.1 [274.1-456.5] pg/mL vs. 247.7 [196.1-294.0] pg/mL, p<0.001). No difference was observed in VIP levels by LVA sites. Multivariate logistic regression identified VIP and sex as independent predictors of LVA (per 50 pg/mL, odds ratio [OR]: 1.44, 95% confidence interval [CI]: 1.13-1.83, p<0.001, OR: 4.67, 95% CI: 1.69-12.89, p=0.002, respectively). Females with high VIP had lower conduction velocity compared to other groups. (low VIP male: 0.9 [0.6-1.0] m/s, high VIP male: 0.9 [0.7-1.1] m/s, low VIP female: 0.8 [0.7-1.0] m/s, high VIP female: 0.7 [0.3-0.8] m/s, p=0.013). Incorporating VIP levels (≥288 pg/mL) into an existing predictive score (age ≥65 years, female, and LA volume index ≥57 mL/m 2 ) significantly improved LVA detection (area under the curve: 0.784 vs. 0.707, p<0.001). Conclusions: Serum VIP levels are higher in patients with LVAs, and VIP is a reliable predictor of LVA presence. Incorporating VIP levels into existing predictive models enhances the power for identifying LVAs in AF patients. Serum VIP measurement could be valuable for detecting LVAs, improving risk stratification, and tailoring strategies in AF management.

Sex Differences in Electrophysiology and Calcium Handling in Atrial Health and Fibrillation.

The importance of biological sex on disease etiology and outcomes has long been underinvestigated. While recent focus on characterizing sex differences in cardiac pathophysiology has led to improved inclusion of both sexes in scientific studies and clinical trials, much is still unknown about underlying differences in normal cardiac physiology. This is particularly true for the atria, where the most common arrhythmia, atrial fibrillation (AF), occurs. AF is associated with adverse structural, electrophysiological, and calcium handling remodeling that leads to patient morbidity and mortality. Differences in the onset, prevalence, presentation, and prognosis of AF are known to differ between males and females, yet the sex-specific baseline phenotypes from which AF arises are not well characterized. This review examines what is currently known about sex differences in atrial physiology, the alterations that occur in AF, potential mechanisms underlying sex divergence, and the need for sex-targeted therapeutic strategies.

Salidroside ameliorates hypoxic pulmonary hypertension by regulating the two-pore domain potassium TASK-1 channel

BackgroundHypoxic pulmonary vasoconstriction (HPV) is a reflex constriction of vascular smooth muscle. This study aims to investigate the role of Salidroside (Sal) in pulmonary arterial dilatation and the potential mechanism of Sal regulating hypoxic pulmonary hypertension in vitro and in vivo. MethodsA rat model of hypoxic pulmonary hypertension (HPH) was constructed using hypoxic chamber. The effect of Sal on HPH were evaluated using vascular ring, whole cell patch-clamp, WGA staining, HE staining, and Sirius Scarlet staining assays. ResultsSal treatment alleviated the injury of acute hypoxia on pulmonary circulation in SD rats. Meanwhile, Sal treatment reduced the pulmonary vascular tone of acute hypoxia in a concentration-dependent manner, which was involved in the TWIK-related acid-sensitive potassium channel 1 (TASK-1) mediating diastolic effect. We found that Sal treatment significantly increased the TASK-1 current of pulmonary artery smooth muscle cells (PASMCs) in a concentration-dependent manner, as well as reversed the inhibitory effect of acute hypoxia on the TASK-1 current. Moreover, Sal treatment improved the TASK-1 current density, suppressed the proliferation, and enhanced the apoptosis of PASMCs in SD rats under continuous hypoxic condition. In addition, we found that the electrophysiological remodeling and pulmonary vascular remodeling of PASMCs were improved by the treatment of Sal through the regulation of TASK-1 channel. ConclusionsSal could alleviate HPH by restoring the function of TASK-1 channel, which may provide a novel method for the treatment of HPH.

Neuro- and immuno-modulation mediated by the cardiac sympathetic nerve: a novel insight into the anti-ischemic efficacy of acupuncture.

Communication between sympathetic nerves and the immune system is a crucial and active process during myocardial ischemia (MI), as myocardial damage and inflammatory stimuli concurrently occur. Sympathetic nerves undergo structural and functional changes after MI, leading to adverse left ventricular (LV) remodeling and heart failure (HF). The complex inflammatory response to MI, including local myocardial anti-inflammatory repair and systemic immune reactions, plays a key role in adverse LV remodeling. Here, we review the progressive structural and electrophysiological remodeling of the LV and the involvement of sympathetic tone in complex and dynamic processes that are susceptible to MI pathological conditions. Acupuncture has been reported to effectively improve cardiac function, eliminate arrhythmia, and mitigate adverse LV remodeling via somatosensory regulation after MI. Moreover, acupuncture has an anti-inflammatory effect on the pathological process of myocardial ischemia. In this Review, we aim to summarize the involvement of sympathetic nerve activation in the neuro-immune modulation of structural and functional cardiac changes after MI. As a noninvasive method for sympathetic regulation, acupuncture is an ideal option because of its anti-ischemic efficacy. A better understanding of the neural circuitry that regulates cardiac function and immune responses following MI could reveal novel targets for acupuncture treatment.

Sympathetic structural and electrophysiological remodeling in a rabbit model of reperfused myocardial infarction.

Chondroitin sulfate proteoglycans (CSPGs) inhibit sympathetic reinnervation in rodent hearts post-myocardial infarction (MI), causing regional hypoinnervation that is associated with supersensitivity of β-adrenergic receptors and increased arrhythmia susceptibility. To investigate the role of CSPGs and hypoinnervation in the heart of larger mammals, we used a rabbit model of reperfused MI and tested electrophysiological responses to sympathetic nerve stimulation (SNS). Innervated hearts from MI and sham rabbits were optically mapped using voltage and Ca2+-sensitive dyes. SNS was performed with electrical stimulation of the spinal cord, and β-adrenergic responsiveness was tested using isoproterenol. Sympathetic nerve density and CSPG expression were evaluated using immunohistochemistry. CSPGs were robustly expressed in the infarct region of all MI hearts, and the presence of CSPGs was associated with reduced sympathetic nerve density in the infarct versus remote region. Action potential duration (APD) dispersion and tendency for induction of ventricular tachycardia/fibrillation (VT/VF) were increased with SNS in MI but not sham hearts. SNS decreased APD at 80% repolarization (APD80) in MI but not sham hearts, whereas isoproterenol decreased APD80 in both groups. Isoproterenol also shortened Ca2+ transient duration at 80% repolarization in both groups but to a greater extent in MI hearts. Our data suggest that sympathetic remodeling post-MI is similar between rodents and rabbits, with CSPGs associated with sympathetic hypoinnervation. Despite a reduction in sympathetic nerve density, the infarct region of MI hearts remained responsive to both physiological SNS and isoproterenol, potentially through preserved or elevated β-adrenergic responsiveness, which may underlie increased APD dispersion and tendency for VT/VF.NEW & NOTEWORTHY Here, we show that CSPGs are present in the infarcts of rabbit hearts with reperfused MI, where they are associated with reduced sympathetic nerve density. Despite hypoinnervation, sympathetic responsiveness is maintained or enhanced in MI rabbit hearts, which also demonstrate increased APD dispersion and tendency for arrhythmias following sympathetic modulation. Together, this study indicates that the mechanisms of sympathetic remodeling post-MI are similar between rodents and rabbits, with hypoinnervation likely associated with enhanced β-adrenergic sensitivity.

Abstract Or105: Constitutive Deletion of the Obscurin Ig58/59 Domains Induces Structural and Electrophysiological Remodeling in Atria

Introduction: Obscurin is a giant cytoskeletal protein that supports muscle development, tethers intracellular compartments and regulates contraction. In the ObscnΔIg58/59 mouse model, expressing obscurin lacking Immunoglobulin (Ig) domains 58 and 59, aging males exhibit irregular heart rhythm with prominent atrial fibrillation, atrial enlargement, and progressive remodeling of the ventricles. A mechanistic basis for the emergence of arrhythmia early on could not be identified in ObscnΔIg58/59 ventricles, suggesting that the atria are preferentially impacted by deletion of the obscurin Ig58/59 module prior to the ventricles. Hypothesis: We hypothesize that Ig58/59 deletion elicits unique structural, electrical, and functional consequences in the atria preceding ventricular maladaptation. Aims: I. Examine the structural organization of ObscnΔIg58/59 atria II. Assess Ca 2+ handling in isolated atrial cardiomyocytes and determine molecular alterations. Methods: Electron microscopy and super resolution microscopy were utilized to visualize sarcomeric ultrastructure and the transverse-axial tubule (TAT) network, respectively. Ca 2+ handling activity and synchrony were also resolved, while Phos-Tag gels were used to quantify T-cap phospho-species. Results: ObscnΔIg58/59 atria exhibited misalignment of Z-disks. Spontaneous and stimulated Ca 2+ cycling behavior were [AB1] differentially disrupted in atrial cardiomyocytes in 6- and 12-month ObscnΔIg58/59 males. Relatedly, atrial cells showed an age-dependent deterioration in TAT architecture. Finally, as a function of aging, ObscnΔIg58/59 atria displayed alterations in the expression and phosphorylation of T-cap, a Z-disk protein implicated in the integration of t-tubules with the sarcomeric cytoskeleton. Conclusions: The structural and electrical alterations that arise in ObscnΔIg58/59 atria precede ventricular dysfunction and coincide with the emergence of atrial fibrillation. Collectively, our work indicates that the atria are principally affected by Ig58/59 elimination, instigating arrhythmias and morphological alterations with age. The ObscnΔIg58/59 mouse model has thus emerged as a proxy for atrial cardiomyopathy.

The Role of KACh Channels in Atrial Fibrillation.

This manuscript explores the intricate role of acetylcholine-activated inward rectifier potassium (KACh) channels in the pathogenesis of atrial fibrillation (AF), a common cardiac arrhythmia. It delves into the molecular and cellular mechanisms that underpin AF, emphasizing the vital function of KACh channels in modulating the atrial action potential and facilitating arrhythmogenic conditions. This study underscores the dual nature of KACh activation and its genetic regulation, revealing that specific variations in potassium channel genes, such as Kir3.4 and K2P3.1, significantly influence the electrophysiological remodeling associated with AF. Furthermore, this manuscript identifies the crucial role of the KACh-mediated current, IKACh, in sustaining arrhythmia through facilitating shorter re-entry circuits and stabilizing the re-entrant circuits, particularly in response to vagal nerve stimulation. Experimental findings from animal models, which could not induce AF in the absence of muscarinic activation, highlight the dependency of AF induction on KACh channel activity. This is complemented by discussions on therapeutic interventions, where KACh channel blockers have shown promise in AF management. Additionally, this study discusses the broader implications of KACh channel behavior, including its ubiquitous presence across different cardiac regions and species, contributing to a comprehensive understanding of AF dynamics. The implications of these findings are profound, suggesting that targeting KACh channels might offer new therapeutic avenues for AF treatment, particularly in cases resistant to conventional approaches. By integrating genetic, cellular, and pharmacological perspectives, this manuscript offers a holistic view of the potential mechanisms and therapeutic targets in AF, making a significant contribution to the field of cardiac arrhythmia research.

Sympathetic structural and electrophysiological remodeling in a rabbit model of reperfused myocardial infarction.

Here we show that CSPGs are present in the infarcts of rabbit hearts with reperfused MI, where they are associated with reduced sympathetic nerve density. Despite hypo-innervation, sympathetic responsiveness is maintained or enhanced in MI rabbit hearts, which also demonstrate increased APD dispersion and tendency for arrhythmias following sympathetic modulation. Together, this study indicates that the mechanisms of sympathetic remodeling post-MI are similar between species, with hypo-innervation likely associated with enhanced β-adrenergic sensitivity.

Activation of Exchange Proteins directly Activated by cAMP (EPAC) promotes electrophysiological remodeling and arrhythmogenic activity in human atrial cardiomyocytes

Activation of Exchange Proteins directly Activated by cAMP (EPAC) promotes electrophysiological remodeling and arrhythmogenic activity in human atrial cardiomyocytes

Metabolic remodelling in atrial fibrillation: manifestations, mechanisms and clinical implications.

Atrial fibrillation (AF) is a continually growing health-care burden that often presents together with metabolic disorders, including diabetes mellitus and obesity. Current treatments often fall short of preventing AF and its adverse outcomes. Accumulating evidence suggests that metabolic disturbances can promote the development of AF through structural and electrophysiological remodelling, but the underlying mechanisms that predispose an individual to AF are aetiology-dependent, thus emphasizing the need for tailored therapeutic strategies to treat AF that target an individual's metabolic profile. AF itself can induce changes in glucose, lipid and ketone metabolism, mitochondrial function and myofibrillar energetics (as part of a process referred to as 'metabolic remodelling'), which can all contribute to atrial dysfunction. In this Review, we discuss our current understanding of AF in the setting of metabolic disorders, as well as changes in atrial metabolism that are relevant to the development of AF. We also describe the potential of available and emerging treatment strategies to target metabolic remodelling in the setting of AF and highlight key questions and challenges that need to be addressed to improve outcomes in these patients.

Bioenergetics and mitochondrial deregulation underlie self-sustained persistency of atrial fibrillation in an ovine model

Abstract Background Atrial fibrillation (AF) often transitions from paroxysmal to more sustained forms in a 4-15/100 person-year range(1). It is well-recognized from both clinical and animal studies that some individuals undergo this transition much more readily than others, but the underlying mechanisms remain unclear. Purpose To identify potential differences in atrial bioenergetics between animals developing stable AF (AF-S) versus those resistant to this transition (AF-R) in a sheep AF-model. Methods AF was induced through repeated bursts of atrial tachystimulation (2). Stability of AF was monitored with telemetry. In-vivo electrophysiological remodeling was assessed via contact mapping. Metabolic and bioenergetic remodeling were evaluated using frozen left atrial appendage (LAA) tissues and isolated LAA mitochondria. Results AF-S sheep developed stable (>24-hour self-sustained) AF after 13 (range 5-22) days on average, whereas AF-R sheep failed to develop stable AF despite 120-day tachystimulation. Contact mapping and histological analysis revealed similar electro-anatomical remodeling in AF-S and AF-R groups, with the only significant difference observed in the decrease of activation time and conduction velocity in the AF-S atria. Both AF-S and AF-R animals displayed a notable increase in mitochondrial mass. Proteomic analysis showed significant differences in metabolism-related proteins and pathways between AF-S and AF-R, in particular concerning the anaplerotic supplementation of the tricarboxylic acid cycle at the level of α-ketoglutarate. Furthermore, compared to AF-R, AF-S LAA exhibited a 45% increase in succinate content, and a 23% decrease in ATP and Creatine Phosphate (PCr) content, suggesting a pathological metabolic alteration linked to a bioenergetic default. AF-S mitochondria presented abnormal succinate-oxidation, associated with a significant 20% decrease in ATP-synthesis rate, 22% increase in ROS-production, mitochondrial-membrane hyperpolarization, and decreased Complex I/II specific activity ratio. AF-S mitochondria alterations were prevented by complex I inhibitor S1QEL1.1, hinting to a participation of mitochondrial ROS into the mechanism of AF stabilization. In vivo acute intravenous perfusion of succinate in rats made them more susceptible to more frequent (OR 35 CI=[1.63-449.80]) and longer AF episodes upon treansesophageal stimulation; this vulnerability to AF was prevented by intraperitoneal pretreatment with SQEL1.1. Conclusions Resistance to AF-stabilization is associated with specific bioenergetic remodeling. These findings provide new mechanistic insights into AF-resistance and might open avenues for novel therapeutic strategies for AF-management.

Bariatric surgery partially reverses subclinical proarrhythmic structural, electrophysiological, and autonomic changes in obesity

BackgroundObesity confers higher risks of cardiac arrhythmias. The extent to which weight loss reverses subclinical proarrhythmic adaptations in arrhythmia-free obese individuals is unknown. ObjectiveThe purpose of this study was to study structural, electrophysiological, and autonomic remodeling in arrhythmia-free obese patients and their reversibility with bariatric surgery using electrocardiographic imaging (ECGi). MethodsSixteen arrhythmia-free obese patients (mean age 43 ± 12 years; 13 (81%) female participants; BMI 46.7 ± 5.5 kg/m2) had ECGi pre–bariatric surgery, of whom 12 (75%) had ECGi postsurgery (BMI 36.8 ± 6.5 kg/m2). Sixteen age- and sex-matched lean healthy individuals (mean age 42 ± 11 years; BMI 22.8 ± 2.6 kg/m2) acted as controls and had ECGi only once. ResultsObesity was associated with structural (increased epicardial fat volumes and left ventricular mass), autonomic (blunted heart rate variability), and electrophysiological (slower atrial conduction and steeper ventricular repolarization time gradients) remodeling. After bariatric surgery, there was partial structural reverse remodeling, with a reduction in epicardial fat volumes (68.7 cm3 vs 64.5 cm3; P = .0010) and left ventricular mass (33 g/m2.7 vs 25 g/m2.7; P < .0005). There was also partial electrophysiological reverse remodeling with a reduction in mean spatial ventricular repolarization gradients (26 mm/ms vs 19 mm/ms; P = .0009), although atrial activation remained prolonged. Heart rate variability, quantified by standard deviation of successive differences in R-R intervals, was also partially improved after bariatric surgery (18.7 ms vs 25.9 ms; P = .017). Computational modeling showed that presurgical obese hearts had a larger window of vulnerability to unidirectional block and had an earlier spiral-wave breakup with more complex reentry patterns than did postsurgery counterparts. ConclusionObesity is associated with adverse electrophysiological, structural, and autonomic remodeling that is partially reversed after bariatric surgery. These data have important implications for bariatric surgery weight thresholds and weight loss strategies.

Proteomics couples electrical remodelling to inflammation in a murine model of heart failure with sinus node dysfunction.

In patients with heart failure (HF), concomitant sinus node dysfunction (SND) is an important predictor of mortality, yet its molecular underpinnings are poorly understood. Using proteomics, this study aimed to dissect the protein and phosphorylation remodelling within the sinus node in an animal model of HF with concurrent SND. We acquired deep sinus node proteomes and phosphoproteomes in mice with heart failure and SND and report extensive remodelling. Intersecting the measured (phospho)proteome changes with human genomics pharmacovigilance data, highlighted downregulated proteins involved in electrical activity such as the pacemaker ion channel, Hcn4. We confirmed the importance of ion channel downregulation for sinus node physiology using computer modelling. Guided by the proteomics data, we hypothesized that an inflammatory response may drive the electrophysiological remodeling underlying SND in heart failure. In support of this, experimentally induced inflammation downregulated Hcn4 and slowed pacemaking in the isolated sinus node. From the proteomics data we identified proinflammatory cytokine-like protein galectin-3 as a potential target to mitigate the effect. Indeed, in vivo suppression of galectin-3 in the animal model of heart failure prevented SND. Collectively, we outline the protein and phosphorylation remodeling of SND in heart failure, we highlight a role for inflammation in electrophysiological remodelling of the sinus node, and we present galectin-3 signalling as a target to ameliorate SND in heart failure.

Semaglutide attenuates pathological electrophysiological remodeling in diabetic cardiomyopathy via restoring Cx43 expression.

Semaglutide is a relatively new anti-hyperglycemic agent that was shown to carry cardioprotective potentials. However, the exact effects of semaglutide on diabetic cardiomyopathy (DCM) and their underlining mechanism remain unclear. This study aimed to evaluate the effects of semaglutide on myocardium injury and cardiac function in DCM mice and its potential mechanisms, with emphasis on its effects on Cx43 and electrophysiological remodeling. C57BL/6 mice were randomly divided into four groups: control group, semaglutide group, diabetes group, and diabetes + semaglutide treatment group. Type 1 diabetes were induced by intraperitoneal injection of streptozotocin. Mice in the semaglutide intervention group were injected subcutaneously with semaglutide (0.15 mg/kg) every week for 8 weeks. The blood glucose, cardiac function, oxidative stress markers, apoptosis, expression of Sirt1, AMPK, Cx43, and electrocardiogram of mice in each group were evaluated. Treatment with semaglutide alleviated glucose metabolism disorders and improved cardiac dysfunction in diabetic mice. In addition, semaglutide ameliorated the increase in oxidative stress and apoptosis in diabetic heart. Sirt1/AMPK pathway was activated after semaglutide treatment. Furthermore, diabetic mice showed reduced expression of Cx43 in the myocardium, accompanied by changes in electrocardiogram, including significantly prolonged RR, QRS, QT and QTc interval. Semaglutide treatment restored Cx43 expression and reversed the above-mentioned ECG abnormalities. Our research results showed that semaglutide protected against oxidative stress and apoptosis in diabetic heart, thereby improving cardiac function and electrophysiological remodelling in DCM mice, which may attribute to activation of Sirt1/AMPK pathway and restore of Cx43 expression.

Late Presentation of Pulmonary Hypertension Crisis Concurrent with Atrial Arrhythmia after Atrial Septal Defect Device Closure

Background: ASD occurs when there is a septal defect between the right and left atria, resulting in a left-to-right shunt that increases the volume of the right heart and pulmonary circulation. Increased pulmonary resistance can lead to pulmonary hypertension (PH), resulting in progressive deterioration of right ventricular function, leading to right heart failure and death. Prolonged elevation of atrial pressure induces progressive atrial dilatation and electrophysiological remodelling. Together with autonomic modulation, this leads to atrial arrhythmias (AAs). Patients with significant shunts leading to ventricular volume overload are considered for ASD closure. However, in some cases, PH occurs after ASD closure.  Case Presentation: We report a 21 yo man diagnosed with ASD Secundum Post Closure with Device (September 1th, 2023) and Pulmonary Hypertension Crisis. The left atria (LA), right atria (RA) and right ventricle (RV) were dilated. We also found moderate mitral regurgitation, severe tricuspid regurgitation, and mild to moderate pulmonary regurgitation. There was a decline in systolic function in the right ventricle, and grade III diastolic dysfunction in left ventricle. There was a well-seated device with no residual shunt on interatrial septal. The pulmonary arteries were confluence and dilated. From ECG we found atrial flutter with variable conduction. This patient was transferred to HCU. This patient treated with digoxin, furosemide, milrinon, ceftriaxone, miniaspi, sildenafil, electrophysiology, and 3D ablation.  Conclusion: Pulmonary hypertension can occur in cases of congenital heart defects, such as ASD. The operative management of ASD is closure of the ASD, but in some unique groups, this can lead to pulmonary hypertensive crisis after its closure.

Atrial cardiomyocytes contribute to the inflammatory status associated with atrial fibrillation in right heart disease.

Right heart disease (RHD), characterized by right ventricular (RV) and atrial (RA) hypertrophy, and cardiomyocytes' (CM) dysfunctions have been described to be associated with the incidence of atrial fibrillation (AF). Right heart disease and AF have in common, an inflammatory status, but the mechanisms relating RHD, inflammation, and AF remain unclear. We hypothesized that right heart disease generates electrophysiological and morphological remodelling affecting the CM, leading to atrial inflammation and increased AF susceptibility. Pulmonary artery banding (PAB) was surgically performed (except for sham) on male Wistar rats (225-275 g) to provoke an RHD. Twenty-one days (D21) post-surgery, all rats underwent echocardiography and electrophysiological studies (EPS). Optical mapping was performed in situ, on Langendorff-perfused hearts. The contractility of freshly isolated CM was evaluated and recorded during 1 Hz pacing in vitro. Histological analyses were performed on formalin-fixed RA to assess myocardial fibrosis, connexin-43 levels, and CM morphology. Right atrial levels of selected genes and proteins were obtained by qPCR and Western blot, respectively. Pulmonary artery banding induced severe RHD identified by RV and RA hypertrophy. Pulmonary artery banding rats were significantly more susceptible to AF than sham. Compared to sham RA CM from PAB rats were significantly elongated and hypercontractile. Right atrial CM from PAB animals showed significant augmentation of mRNA and protein levels of pro-inflammatory interleukin (IL)-6 and IL1β. Sarcoplasmic-endoplasmic reticulum Ca2+-ATPase-2a (SERCA2a) and junctophilin-2 were decreased in RA CM from PAB compared to sham rats. Right heart disease-induced arrhythmogenicity may occur due to dysfunctional SERCA2a and inflammatory signalling generated from injured RA CM, which leads to an increased risk of AF.

Loss of Cardiac PFKFB2 Drives Metabolic, Functional, and Electrophysiological Remodeling in the Heart.

Phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2) is a critical glycolytic regulator responsible for upregulation of glycolysis in response to insulin and adrenergic signaling. PFKFB2, the cardiac isoform of PFK-2, is degraded in the heart in the absence of insulin signaling, contributing to diabetes-induced cardiac metabolic inflexibility. However, previous studies have not examined how the loss of PFKFB2 affects global cardiac metabolism and function. To address this, we have generated a mouse model with a cardiomyocyte-specific knockout of PFKFB2 (cKO). Using 9-month-old cKO and control mice, we characterized the impacts of PFKFB2 on cardiac metabolism, function, and electrophysiology. cKO mice have a shortened life span of 9 months. Metabolically, cKO mice are characterized by increased glycolytic enzyme abundance and pyruvate dehydrogenase activity, as well as decreased mitochondrial abundance and beta oxidation, suggesting a shift toward glucose metabolism. This was supported by a decrease in the ratio of palmitoyl carnitine to pyruvate-dependent mitochondrial respiration in cKO relative to control animals. Metabolomic, proteomic, and Western blot data support the activation of ancillary glucose metabolism, including pentose phosphate and hexosamine biosynthesis pathways. Physiologically, cKO animals exhibited impaired systolic function and left ventricular dilation, represented by reduced fractional shortening and increased left ventricular internal diameter, respectively. This was accompanied by electrophysiological alterations including increased QT interval and other metrics of delayed ventricular conduction. Loss of PFKFB2 results in metabolic remodeling marked by cardiac ancillary pathway activation. This could delineate an underpinning of pathologic changes to mechanical and electrical function in the heart.

Adipocyte-mediated electrophysiological remodeling of human stem cell - derived cardiomyocytes

Adipocytes normally accumulate in the epicardial and pericardial layers around the human heart, but their infiltration into the myocardium can be proarrhythmic. Methods and resultsHuman adipose derived stem/stromal cells and human induced pluripotent stem cells (hiPSC) were differentiated, respectively into predominantly white fat-like adipocytes (hAdip) and ventricular cardiomyocytes (CMs). Adipocytes cultured in CM maintenance medium (CM medium) maintained their morphology, continued to express adipogenic markers, and retained clusters of intracellular lipid droplets. In contrast, hiPSC-CMs cultivated in adipogenic growth medium displayed abnormal cell morphologies and more clustering across the monolayer. Pre-plated hiPSC-CMs co-cultured in direct contact with hAdips in CM medium displayed prolonged action potential durations, increased triangulation, slowed conduction velocity, increased conduction velocity heterogeneity, and prolonged calcium transients. When hAdip-conditioned medium was added to monolayer cultures of hiPSC-CMs, results similar to those recorded with direct co-cultures were observed. Both co-culture and conditioned medium experiments resulted in increases in transcript abundance of SCN10A, CACNA1C, SLC8A1, and RYR2, with a decrease in KCNJ2. Human adipokine immunoblots revealed the presence of cytokines that were elevated in adipocyte-conditioned medium, including MCP-1, IL-6, IL-8 and CFD that could induce electrophysiological changes in cultured hiPSC-CMs. ConclusionsCo-culture of hiPSC-CMs with hAdips reveals a potentially pathogenic role of infiltrating human adipocytes on myocardial tissue. In the absence of structural changes, hAdip paracrine release alone is sufficient to cause CM electrophysiological dysfunction mirroring the co-culture conditions. These effects, mediated largely by paracrine mechanisms, could promote arrhythmias in the heart.