Atrial fibrillation (AF) is the most common cardiac arrhythmia. However, the development of preventative therapies for AF has been disappointing. The infiltration of immune cells and proteins that ...mediate the inflammatory response in cardiac tissue and circulatory processes is associated with AF. Furthermore, the presence of inflammation in the heart or systemic circulation can predict the onset of AF and recurrence in the general population, as well as in patients after cardiac surgery, cardioversion, and catheter ablation. Mediators of the inflammatory response can alter atrial electrophysiology and structural substrates, thereby leading to increased vulnerability to AF. Inflammation also modulates calcium homeostasis and connexins, which are associated with triggers of AF and heterogeneous atrial conduction. Myolysis, cardiomyocyte apoptosis, and the activation of fibrotic pathways via fibroblasts, transforming growth factor-β and matrix metalloproteases are also mediated by inflammatory pathways, which can all contribute to structural remodelling of the atria. The development of thromboembolism, a detrimental complication of AF, is also associated with inflammatory activity. Understanding the complex pathophysiological processes and dynamic changes of AF-associated inflammation might help to identify specific anti-inflammatory strategies for the prevention of AF.
Aging plays a critical role in the genesis of atrial fibrillation (AF) and also increases the risks of cardiac dysfunction and stroke in AF patients. AF is caused by increased AF triggering from ...abnormalities of the thoracic vein and/or modulated substrate (atrial) with enhancement of AF maintenance. Clinical and laboratory evidence indicates that aging is significant in the creation of atrial electrical and structural remodeling that leads to increased susceptibility to AF occurrence. Aging is commonly associated with cardiovascular comorbidities, oxidative stress, calcium dysregulation, atrial myopathy with apoptosis, and fibrosis, which all contribute to the genesis of AF. This review updates the current understanding of the effects of aging on the pathophysiology of AF.
Background
Ceramide is involved in regulating metabolism and energy expenditure, and its abnormal myocardial accumulation may contribute to heart injury or lipotoxic cardiomyopathy. Whether ceramide ...can modulate the electrophysiology of pulmonary veins (PVs) remains unknown.
Materials and methods
We used conventional microelectrodes to measure the electrical activity of isolated rabbit PV tissue preparations before and after treatment with various concentrations of ceramide with or without H2O2 (2 mM), MitoQ, wortmannin or 740 YP. A whole‐cell patch clamp and fluorescence imaging were used to record the ionic currents, calcium (Ca2+) transients, and intracellular reactive oxygen species (ROS) and sodium (Na+) in isolated single PV cardiomyocytes before and after ceramide (1 μM) treatment.
Results
Ceramide (0.1, 0.3, 1 and 3 μM) reduced the beating rate of PV tissues. Furthermore, ceramide (1 μM) suppressed the 2 mM H2O2‐induced faster PV beating rate, triggered activities and burst firings, which were further reduced by MitoQ. In the presence of wortmannin, ceramide did not change the PV beating rate. The H2O2‐induced faster PV beating rate could be counteracted by MitoQ or wortmannin with no additive effect from the ceramide. Ceramide inhibited pPI3K. Ceramide reduced Ca2+ transients, sarcoplasmic reticulum Ca2+ contents, L‐type Ca2+ currents, Na+ currents, late Na+ currents, Na+‐hydrogen exchange currents, and intracellular ROS and Na+ in PV cardiomyocytes, but did not change Na+‐Ca2+ exchange currents.
Conclusion
C2 ceramide may exert the distinctive electrophysiological effect of modulating PV activities, which may be affected by PI3K pathway–mediated oxidative stress, and might play a role in the pathogenesis of PV arrhythmogenesis.
When assessing ischemic stroke risk in patients with atrial fibrillation (AF), the CHA2DS2-VASc score is calculated based on the baseline risk factors, and the outcomes are determined after a ...follow-up period. However, the stroke risk in patients with AF does not remain static, and with time, patients get older and accumulate more comorbidities.
This study hypothesized that the “Delta CHA2DS2-VASc score,” which reflects the change in score between baseline and follow-up, would be more predictive of ischemic stroke compared with the baseline CHA2DS2-VASc score.
A total of 31,039 patients with AF who did not receive antiplatelet agents or oral anticoagulants, and who did not have comorbidities of the CHA2DS2-VASc score except for age and sex, were studied. The Delta CHA2DS2-VASc scores were defined as the differences between the baseline and follow-up CHA2DS2-VASc scores. During 171,956 person-years, 4,103 patients experienced ischemic stroke. The accuracies of baseline, follow-up, and Delta CHA2DS2-VASc scores in predicting ischemic stroke were analyzed and compared.
The mean baseline CHA2DS2-VASc score was 1.29, which increased to 2.31 during the follow-up, with a mean Delta CHA2DS2-VASc score of 1.02. The CHA2DS2-VASc score remained unchanged in only 40.8% of patients. Among 4,103 patients who experienced ischemic stroke, 89.4% had a Delta CHA2DS2-VASc score ≥1 compared with only 54.6% in patients without ischemic stroke, and 2,643 (64.4%) patients had ≥1 new-onset comorbidity, the most common being hypertension. The Delta CHA2DS2-VASc score was a significant predictor of ischemic stroke that performed better than baseline or follow-up CHA2DS2-VASc scores, as assessed by the C-index and the net reclassification index.
In this AF cohort, the authors demonstrated that the CHA2DS2-VASc score was not static, and that most patients with AF developed ≥1 new stroke risk factor before presentation with ischemic stroke. The Delta CHA2DS2-VASc score, reflecting the change in score between baseline and follow-up, was strongly predictive of ischemic stroke, reflecting how stroke risk in AF is a dynamic process due to increasing age and incident comorbidities.
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Effects of Indoxyl Sulfate on Pulmonary Vein and Atrial Arrhythmogenesis
Background
Chronic kidney disease (CKD) is associated with a higher incidence of atrial fibrillation (AF) with unclear ...mechanisms. Indoxyl sulfate (IS) accumulates in CKD patients. IS increases oxidative stress, which contributes to the genesis of AF. The arrhythmogenic effect of IS is unclear.
Methods
Conventional microelectrodes recorded the action potentials (AP) of isolated rabbit left atrium (LA), right atrium (RA), pulmonary vein (PV), and sinoatrial nodes (SANs) before and after treatment with IS with and without an antioxidant (ascorbic acid). Confocal microscopy with fluorescence and whole‐cell patch clamp were used to evaluate intracellular calcium in isolated PV cardiomyocytes with and without IS.
Results
Compared to the control, IS induced more PV delayed afterdepolarizations at 0.1, 1, 10, and 100 μM, and induced more PV burst firings at 1, 10, and 100 μM. In contrast, IS (10 and 100 μM) reduced the SAN spontaneous beating rate. IS (100 μM) significantly shortened LA AP durations, but not RA. IS (100 μM)‐treated PV cardiomyocytes had a similar calcium transient and sarcoplasmic reticulum calcium content, but a larger calcium leak than control PV cardiomyocytes. Burst pacing and isoproterenol induced a greater AF occurrence (50% vs. 100%; P = 0.009) and a longer AF duration (26 ± 9 vs. 5 ± 3 seconds; P < 0.05) in the LA (n = 8) with IS (100 μM) than without IS. Moreover, ascorbic acid (1 mM) attenuated the effects of IS on the LA, PV, and SANs.
Conclusion
IS increases PV and atrial arrhythmogenesis through oxidative stress. They may contribute to the occurrence of AF in CKD patients.
Introduction
Acquired Wolff–Parkinson–White (WPW) syndrome can occur after congenital heart disease (CHD) surgery.
Methods and Results
A 27‐year‐old male with Ebstein's anomaly and manifest WPW ...syndrome received catheter ablation twice. The first electrophysiology study (EPS) induced orthodromic atrioventricular reentrant tachycardia and successfully eliminated the posteroseptal accessory pathway (AP). Six months after the Cone procedure, the patient suffered from palpitation. The second EPS was performed and abolished the right lateral AP.
Conclusion
The appearance of a new AP after the reconstruction of CHD is a rare finding and should raise suspicion of an acquired AP connection.
Chronic kidney disease (CKD) increases the risk of arrhythmia. The right ventricular outflow tract (RVOT) is a crucial site of ventricular tachycardia (VT) origination. We hypothesize that CKD ...increases RVOT arrhythmogenesis through its effects on calcium dysregulation. We analysed measurements obtained using conventional microelectrodes, patch clamp, confocal microscopy, western blotting, immunohistochemical examination and lipid peroxidation for both control and CKD (induced by 150 mg/kg neomycin and 500 mg/kg cefazolin daily) rabbit RVOT tissues or cardiomyocytes. The RVOT of CKD rabbits exhibited a short action potential duration, high incidence of tachypacing (20 Hz)‐induced sustained VT, and long duration of isoproterenol and tachypacing‐induced sustained and non‐sustained VT. Tachypacing‐induced sustained and non‐sustained VT in isoproterenol‐treated CKD RVOT tissues were attenuated by KB‐R7943 and partially inhibited by KN93 and H89. The CKD RVOT myocytes had high levels of phosphorylated CaMKII and PKA, and an increased expression of tyrosine hydroxylase‐positive neural density. The CKD RVOT myocytes exhibited large levels of Ito, IKr, NCX and L‐type calcium currents, calcium leak and malondialdehyde but low sodium current, SERCA2a activity and SR calcium content. The RVOT in CKD with oxidative stress and autonomic neuron hyperactivity exhibited calcium handling abnormalities, which contributed to the induction of VT.
Current American and European guidelines emphasize the importance of rate-control treatments in treating atrial fibrillation with a Class I recommendation, although data on the survival benefits of ...rate control are lacking. The goal of the present study was to investigate whether patients receiving rate-control drugs had a better prognosis compared with those without rate-control treatment.
This study used the National Health Insurance Research Database in Taiwan. There were 43 879, 18 466, and 38 898 patients with atrial fibrillation enrolled in the groups receiving β-blockers, calcium channel blockers, and digoxin, respectively. The reference group consisted of 168 678 subjects who did not receive any rate-control drug. The clinical end point was all-cause mortality. During a follow-up of 4.9±3.7 years, mortality occurred in 88 263 patients (32.7%). After adjustment for baseline differences, the risk of mortality was lower in patients receiving β-blockers (adjusted hazard ratio=0.76; 95% confidence interval=0.74-0.78) and calcium channel blockers (adjusted hazard ratio=0.93; 95% confidence interval=0.90-0.96) compared with those who did not receive rate-control medications. On the contrary, the digoxin group had a higher risk of mortality with an adjusted hazard ratio of 1.12 (95% confidence interval=1.10-1.14). The results were observed consistently in subgroup analyses and among the cohorts after propensity matching.
In this nationwide atrial fibrillation cohort, the risk of mortality was lower for patients receiving rate-control treatment with β-blockers or calcium channel blockers, and the use of β-blockers was associated with the largest risk reduction. Digoxin use was associated with greater mortality. Prospective, randomized trials are necessary to confirm these findings.
Abstract
Aims
Ventricular arrhythmia (VA) frequently occurs in fatty infiltrative cardiomyopathy or epicardial adipose tissue (EAT) abundant hearts. Right ventricular outflow tract (RVOT), commonly ...covered with EAT, is vital for VA genesis. This study explored whether EAT contributes to RVOT arrhythmogenesis.
Methods and results
Conventional microelectrodes and whole-cell patch clamp were used to record electrical activity and ionic currents in rabbit RVOT tissue preparation or isolated single cardiomyocytes with or without (control) connected EAT. Epicardial adipose tissue-connected (N = 6) RVOT had more portions of fibrosis than did control (N = 5) RVOT (160.3 ± 23.2 vs. 91.9 ± 13.4 μm2/mm2, P < 0.05). Epicardial adipose tissue-connected RVOT cardiomyocytes (n = 18) had lower negative resting membrane potential (−68 ± 1 vs. −73 ± 2 mV, P < 0.05); smaller action potential (AP) amplitude (108 ± 4 vs. 135 ± 6 mV, P < 0.005); and longer 90%, 50%, and 20% of AP duration repolarization (361 ± 18 vs. 309 ± 9 ms, P < 0.05; 310 ± 17 vs. 256 ± 13 ms, P < 0.05; and 182 ± 19 vs. 114 ± 24 ms, P < 0.05, respectively) than did control (n = 13) RVOT cardiomyocytes. Moreover, compared with control RVOT cardiomyocytes, EAT-connected RVOT cardiomyocytes had larger transient outward potassium currents, similar delayed rectifier potassium currents, smaller L-type calcium currents, and inward rectifier potassium currents. After ajmaline (10 μM, a sodium channel blocker) superfusion, high VA inducibility was observed through rapid pacing in EAT-connected RVOT but not in control RVOT.
Conclusions
Epicardial adipose tissue exerts distinctive electrophysiological effects on RVOT with a propensity towards VA induction, which might play a role in lipotoxicity pathogenesis-related ventricular arrhythmogenesis.
The right ventricular outflow tract (RVOT) is the major origin of ventricular arrhythmias, including premature ventricular contractions, idiopathic ventricular arrhythmias, Brugada syndrome, torsade ...de pointes, long QT syndrome, and arrhythmogenic right ventricular cardiomyopathy. The RVOT has distinct developmental origins and cellular characteristics and a complex myocardial architecture with high shear wall stress, which may lead to its high vulnerability to arrhythmogenesis. RVOT myocytes are vulnerable to intracellular sodium and calcium overload due to calcium handling protein modulation, enhanced CaMKII activity, ryanodine receptor phosphorylation, and a higher cAMP level activated by predisposing factors or pathological conditions. A reduction in
and
expression may lead to electrical uncoupling in RVOT. The purpose of this review is to update the current understanding of the cellular and molecular mechanisms of RVOT arrhythmogenesis.
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