Role of subpulmonary right ventricle in sudden cardiac death in adults with congenital heart disease.

Despite improved childhood survival of congenital heart disease (CHD) as a result of advances in management, late-onset sudden cardiac death (SCD) from malignant ventricular arrhythmias remains a leading cause of mortality in adults with CHD. Preventing SCD in these patients requires an understanding of the underlying pathophysiological mechanisms. Many CHD patients experience significant hemodynamic stress on the subpulmonary right ventricle (RV), leading to pathologic remodeling. Unlike acquired heart disease in which left ventricular pathology is prevalent, RV pathologies are crucial in the SCD pathogenesis in CHD patients. This review examines the mechanisms and management of SCD related to subpulmonary RV pathologies in CHD patients.

Long-Term Stimulation of the Left Dorsal Branch of the Thoracic Nerve Improves Ventricular Electrical Remodeling in a Canine Model of Chronic Myocardial Infarction.

PURPOSE: To evaluate the ventricular electrophysiologic effects of long-term stimulation of the left dorsal branch of thoracic nerve (LDTN) derived from the left stellate ganglion (LSG) in a canine model of chronic myocardial infarction (MI). METHODS: Seventeen adult male beagles were randomly divided into three groups: the sham group (sham operated, n = 6), the MI group (n = 6), and the MI + LDTN group (MI plus LDTN stimulation, n = 5). The canine model of chronic MI was induced by the occlusion of the left anterior descending artery (LADO). The LDTN was separated and intermittently stimulated immediately after LADO for 2 months. The heart rate variability (HRV) analysis, in vivo electrophysiology, the evaluation of LSG function and neural activity, histological staining, and western blotting (WB) assay were performed to evaluate the effect of LDTN stimulation on the heart. RESULTS: The canine MI model was successfully established by LADO, and the LDTN was separated and stimulated immediately after LADO. The HRV analysis showed that LDTN stimulation reversed the increased LF value and LF/HF ratio of the MI group. LDTN stimulation prolonged the shortening ERP and APD90, decreased the dispersion of ERP and APD90, and increased the VFT. Additionally, LDTN stimulation inhibits the LSG function and neural activity. Furthermore, LDTN stimulation suppressed the activation of Wnt/ß-catenin signaling, which contributed to the LSG neuronal apoptosis by upregulation of pro-apoptotic Bax and downregulation of anti-apoptotic Bcl-2. CONCLUSION: LDTN stimulation could attenuate cardiac sympathetic remodeling and improve ventricular electrical remodeling, which may be mediated by suppressing the activated Wnt/ß-catenin signaling pathway and then promoting the LSG neuronal apoptosis.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Unraveling the Role of K2P Channels in Atrial Fibrillation.

Atrial fibrillation (AF) is a condition in which the electrical signals in the upper heart chambers (atria) are rapid and disorganized, producing an irregular and chaotical heartbeat. The sinus rhythm should be between 60 to 100 bpm at rest, while the heart rhythm in AF patients may be over 140 bpm. Either structural and electro-mechanical remodeling of the atrial tissue underlies the perpetuation and evolution of AF from the paroxysmal to persistent form. Unravelling the different pathological pathways involved in AF that lead to arrhythmogenesis and atrial remodeling is needed to discovery new and effective therapeutic approaches. A variety of drugs are available to convert and maintain the AF patient in a normal sinus rhythm; however, these strategies have limited chances of success or fail with the progression of AF to more persistent/permanent forms. Consequently, it is necessary to find new therapeutic targets for the relief of persistent or chronic AF forms, as well as the development of new and more effective pharmacological tools. The atrial specific two-pore domain K+ channels (K2P) constitute the background K+ current on atrial cardiomyocytes and modulate cell excitability emerging as novel targets in this disease and avoiding ventricle side effects. Moreover, several antiarrhythmic drugs used in AF treatment exert their mechanism of action in part by modulation of K2P channels. Thus far, TWIK-1, TREK-1, TASK-1, TASK-2 and TASK-3 channel have been identified as responsible for background currents IK2P current in atrial cells; however, it is not excluded that other K2PX subunits or subfamilies have physiological roles in atria. To date, a great diversity openers, activators and blockers of K2P channel have been identified, particularly those targeting TASK and TREK channels. Several studies have demonstrated that the expression of TWIK-1, TREK-1, TASK-1, TASK-2 and TASK-3 are dysregulated in AF and their pharmacology rescue could suppose a novel therapy in AF. The main objective is to examine the regulation of K2P channels and the current K2P channels pharmacological modulators for AF treatment.

Pinocembrin ameliorates atrial fibrillation susceptibility in rats with anxiety disorder induced by empty bottle stimulation.

Background: Anxiety disorder (AD) is the most common mental disorder, which is closely related to atrial fibrillation (AF) and is considered to be a trigger of AF. Pinocembrin has been demonstrated to perform a variety of neurological and cardiac protective effects through its anti-inflammatory and antioxidant activities. The current research aims to explore the antiarrhythmic effect of pinocembrin in anxiety disorder rats and its underlying mechanisms. Methods: 60 male Sprague-Dawley rats were distributed into four groups: CTL group: control rats + saline; CTP group: control rats + pinocembrin; Anxiety disorder group: anxiety disorder rats + saline; ADP group: anxiety disorder rats + pinocembrin. Empty bottle stimulation was conducted to induce anxiety disorder in rats for 3 weeks, and pinocembrin was injected through the tail vein for the last 2 weeks. Behavioral measurements, in vitro electrophysiological studies, biochemical assays, ELISA, Western blot and histological studies were performed to assess the efficacy of pinocembrin. In addition, HL-1 atrial cells were cultured in vitro to further verify the potential mechanism of pinocembrin. Results: After 3 weeks of empty bottle stimulation, pinocembrin significantly improved the exploration behaviors in anxiety disorder rats. Pinocembrin alleviated electrophysiological remodeling in anxiety disorder rats, including shortening the action potential duration (APD), prolonging the effective refractory period (ERP), increasing the expression of Kv1.5, Kv4.2 and Kv4.3, decreasing the expression of Cav1.2, and ultimately reducing the AF susceptibility. These effects may be attributed to the amelioration of autonomic remodeling and structural remodeling by pinocembrin, as well as the inhibition of oxidative stress with upregulation of the nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) pathway. Conclusion: Pinocembrin can reduce AF susceptibility in anxiety disorder rats induced by empty bottle stimulation, with the inhibition of autonomic remodeling, structural remodeling, and oxidative stress. Therefore, pinocembrin is a promising treatment for AF in patients with anxiety disorder.

Assessment of proarrhythmic ventricular electrophysiological remodeling in patients with rheumatoid arthritis.

INTRODUCTION: Rheumatoid arthritis (RA) is related to cardiovascular disease and results in increased mortality rates. Ischemia, autonomic nervous system dysfunction, impaired cardiac ionic currents, and genetic predisposition may be the underlying mechanisms. Proarrhythmic ventricular electrophysiological remodeling detected on the basis of Tp­e interval, Tp-e/QT, and Tp-e/QTc ratios plays a key role in the prognosis. Our aim was to assess proarrhythmic ventricular electrophysiological remodeling in patients with RA, a well-known chronic inflammatory disorder. MATERIALS AND METHODS: A total of 163 patients with RA and 47 patients as a control group were included in this retrospective study. Proarrhythmic ventricular electrophysiological remodeling markers were evaluated in both groups along with baseline demographic and clinical variables. Patients using medication or with chronic disorders that can affect ventricular repolarization markers were excluded. RESULTS: The patients with RA had prolonged Tp­e interval (66 ms [44-80]; 80 ms [78-96], p < 0.001) and increased Tp-e/QT ratio (0.18 [0.12-0.22]; 0.22 [0.20-0.24], p < 0.001) and Tp-e/QTc ratio (0.16 [0.11-0.19]; 0.20 [0.17-0.22], p < 0.001) compared to the control group. CONCLUSION: The Tp­e interval and Tp-e/QT ratio, which may help to clarify the pathophysiological mechanisms of ventricular arrhythmias, were increased in patients with RA.

Atrial Remodeling in Atrial Fibrillation. Comorbidities and Markers of Disease Progression Predict Catheter Ablation Outcome.

Atrial fibrillation is the most common supraventricular arrhythmia affecting an increasing proportion of the population in which mainstream therapy, i.e. catheter ablation, provides freedom from arrhythmia in only a limited number of patients. Understanding the mechanism is key in order to find more effective therapies and to improve patient selection. In this review, the structural and electrophysiological changes of the atrial musculature that constitute atrial remodeling in atrial fibrillaton and how risk factors and markers of disease progression can predict catheter ablation outcome will be discussed in detail.

Electrophysiological Mechanisms of Bayés Syndrome: Insights from Clinical and Mouse Studies.

Bayés syndrome is an under-recognized clinical condition characterized by inter-atrial block (IAB). This is defined electrocardiographically as P-wave duration > 120 ms and can be categorized into first, second and third degree IAB. It can be caused by inflammatory conditions such as systemic sclerosis and rheumatoid arthritis, abnormal protein deposition in cardiac amyloidosis, or neoplastic processes invading the inter-atrial conduction system, such as primary cardiac lymphoma. It may arise transiently during volume overload, autonomic dysfunction or electrolyte disturbances from vomiting. In other patients without an obvious cause, the predisposing factors are diabetes mellitus, hypertensive heart disease, and hypercholesterolemia. IAB has a strong association with atrial arrhythmogenesis, left atrial enlargement (LAE), and electro-mechanical discordance, increasing the risk of cerebrovascular accidents as well as myocardial and mesenteric ischemia. The aim of this review article is to synthesize experimental evidence on the pathogenesis of IAB and its underlying molecular mechanisms. Current medical therapies include anti-fibrotic, anti-arrhythmic and anti-coagulation agents, whereas interventional options include atrial resynchronization therapy by single or multisite pacing. Future studies will be needed to elucidate the significance of the link between IAB and atrial tachyarrhythmias in patients with different underlying etiologies and optimize the management options in these populations.

Carnitine deficiency induces a short QT syndrome.

BACKGROUND: Short QT syndrome is associated with an increased risk of cardiac arrhythmias and unexpected sudden death. Until now, only mutations in genes encoding the cardiac potassium and calcium channels have been implicated in early T-wave repolarization. OBJECTIVE: The purpose of this study was to confirm a relationship between a short QT syndrome and carnitine deficiency. METHODS: We report 3 patients affected by primary systemic carnitine deficiency and an associated short QT syndrome. Ventricular fibrillation during early adulthood was the initial symptom in 1 case. To confirm the relationship between carnitine, short QT syndrome, and arrhythmias, we used a mouse model of carnitine deficiency induced by long-term subcutaneous perfusion of MET88. RESULTS: MET88-treated mice developed cardiac hypertrophy associated with a remodeling of the mitochondrial network. The continuous monitoring of electrocardiograms confirmed a shortening of the QT interval, which was negatively correlated with the plasma carnitine concentration. As in humans, such alterations coincided with the genesis of ventricular premature beats and ventricular tachycardia and fibrillation. CONCLUSION: Altogether, these results suggest that long-chain fatty acid metabolism influence the morphology and the electrical function of the heart.