Dunaliella salina Alga Protects against Myocardial Ischemia/Reperfusion Injury by Attenuating TLR4 Signaling.

Myocardial ischemia/reperfusion (I/R) injury is marked by rapid increase in inflammation and not only results in myocardial apoptosis but also compromises the myocardial function. Dunaliella salina (D. salina), a halophilic unicellular microalga, has been used as a provitamin A carotenoid supplement and color additive. Several studies have reported that D. salina extract could attenuate lipopolysaccharides-induced inflammatory effects and regulate the virus-induced inflammatory response in macrophages. However, the effects of D. salina on myocardial I/R injury remain unknown. Therefore, we aimed to investigate the cardioprotection of D. salina extract in rats subjected to myocardial I/R injury that was induced by occlusion of the left anterior descending coronary artery for 1 h followed by 3 h of reperfusion. Compared with the vehicle group, the myocardial infarct size significantly decreased in rats that were pre-treated with D. salina. D. salina significantly attenuated the expressions of TLR4, COX-2 and the activity of STAT1, JAK2, IκB, NF-κB. Furthermore, D. salina significantly inhibited the activation of caspase-3 and the levels of Beclin-1, p62, LC3-I/II. This study is the first to report that the cardioprotective effects of D. salina may mediate anti-inflammatory and anti-apoptotic activities and decrease autophagy through the TLR4-mediated signaling pathway to antagonize myocardial I/R injury.

Lumbrokinase regulates endoplasmic reticulum stress to improve neurological deficits in ischemic stroke.

Ischemic stroke is characterized by the loss of cerebral blood flow, which frequently leads to neurological deficits. Tissue plasminogen activator is the only therapeutic agent approved to treat ischemic stroke but increases the risk of intracranial hemorrhage and mortality. The fibrinogen-depleting agent lumbrokinase has been used to improve myocardial perfusion in symptomatic stable angina and to prevent secondary ischemic stroke. Lumbrokinase is highly fibrin-specific and only active in the presence of fibrin. Therefore, lumbrokinase has a low risk of hemorrhage due to excessive fibrinolysis. In this study, we aimed to clarify the neuroprotection of lumbrokinase in mice subjected to permanent middle cerebral artery occlusion. Lumbrokinase significantly attenuated infarct volume and improved neurological dysfunction. Lumbrokinase dramatically decreased the expressions of the endoplasmic reticulum (ER) transmembrane receptor protein inositol-requiring enzyme-1 (IRE1) and its downstream transcription factor, XBP-1, caspase-12, and NF-κB activity, thereby significantly inhibiting apoptosis and autophagy and decreasing the NLRP3 inflammasome. Our evidence indicates that post-stroke treatment with lumbrokinase protects against ischemic stroke, thereby regulating ER stress through the collective inhibitory effect of the IRE1 signaling pathways to decrease apoptosis, autophagy, and inflammatory responses. We suggest that lumbrokinase is potential as an adjuvant treatment for ischemic stroke.

CHA2DS2-VASc score as an independent outcome predictor in patients hospitalized with acute ischemic stroke.

PURPOSE: Atrial fibrillation (AF) is a significant independent risk factor for 1-year mortality in patients with first acute ischemic stroke (AIS). The CHA2DS2-VASc score was initially developed to assess the risk of stroke in patients with AF. Recently, this scoring system has been demonstrated to have clinical value for predicting long-term clinical outcomes in AIS but the evidence is insufficient. This large-scale prospective cohort study investigated the independent predictive value of the score in such patients. METHODS: We included patients with AIS from the Taiwan Stroke Registry (TSR) during 2006-2016 as the present study population. Patients were divided into those with high (≥2) and low (<2) CHA2DS2-VASc scores. We further analyzed and classified patients according to the presence of AF. The clinical endpoint was major adverse cardiac and cerebrovascular events (MACCEs) at 1 year after the index AIS. RESULTS: A total of 62,227 patients with AIS were enrolled. The median age was 70.3 years, and 59% of the patients were women. After confounding factors were controlled, patients with high CHA2DS2-VASc scores had significantly higher incidence of 1-year MACCEs (adjusted hazard ratio [HR] = 1.63; 95% confidence interval [CI] = 1.52, 1.76), re-stroke (adjusted HR = 1.28; 95% CI = 1.16, 1.42), and all-cause mortality (adjusted HR = 2.03; 95% CI = 1.83, 2.24) than those with low CHA2DS2-VASc scores did. In the comparison between AF and non-AF groups, the AF group had increased MACCEs (adjusted HR = 1.74; 95% CI = 1.60, 1.89), myocardial infarction (adjusted HR = 4.86; 95% CI = 2.07, 11.4), re-stroke (adjusted HR = 1.47; 95% CI = 1.26, 1.71), and all-cause mortality (adjusted HR = 1.90; 95% CI = 1.72, 2.10). The Kaplan-Meier curve revealed that both CHA2DS2-VASc scores and AF were independent risk predictors for 1-year MACCEs and mortality. CONCLUSIONS: The CHA2DS2-VASc score and AF appeared to consistently predict 1-year MACCEs of AIS patients and provide more accurate risk stratification. Therefore, increased use of the CHA2DS2-VASc score may help improve the holistic clinical assessment of AIS patients with or without AF.

Hydroxychloroquine Does Not Increase the Risk of Cardiac Arrhythmia in Common Rheumatic Diseases: A Nationwide Population-Based Cohort Study.

Objectives: Hydroxychloroquine (HCQ) is widely used to treat rheumatic diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and Sjögren's syndrome (SS). Cardiac arrhythmia has been concerned as important safety issue for HCQ. The aim of this study was to investigate whether hydroxychloroquine increases new-onset arrhythmia among patients with RA, SLE or SS. Methods: This was a retrospective cohort study that conducted from the longitudinal health insurance database of Taiwan. Patients with newly diagnosed RA, SLE or SS with age ≥20 years old were selected from 2000 to 2012. Patients who received HCQ and without HCQ treatment groups were matched by propensity score to minimize the effect of selection bias and confounders. The Cox proportional hazard model was used to analyze the risk of arrhythmia between the two groups after controlling for related variables. Results: A total of 15892 patients were selected to participate and finally 3575 patients were enrolled in each group after matching. There was no different risk of all arrhythmia in patients using HCQ than without HCQ (adjusted hazards ratio 0.81, 95% CI 0.61-1.07) and ventricular arrhythmia as well. The incidence of arrhythmia did not increase when HCQ co-administrated with macrolides. The arrhythmia risk was also not different regardless of daily HCQ dose <400mg or ≥400mg or follow-up duration of ≦4 months or >4 months. Conclusion: The administration of HCQ did not increase the risk of all cardiac arrhythmia and ventricular arrhythmia regardless of different duration of treatment (≦4 months or >4 months) or cumulative dose (<400mg or ≥400mg) in patients with common autoimmune diseases such as RA, SLE and SS.

Paeonol Protects Against Myocardial Ischemia/Reperfusion-Induced Injury by Mediating Apoptosis and Autophagy Crosstalk.

Many studies have shown that crosstalk exists between apoptosis and autophagy, despite differences in mechanisms between these processes. Paeonol, a major phenolic compound isolated from Moutan Cortex Radicis, the root bark of Paeonia × suffruticosa Andrews (Paeoniaceae), is widely used in traditional Chinese medicine as an antipyretic, analgesic and anti-inflammatory agent. In this study, we investigated the detailed molecular mechanisms of the crosstalk between apoptosis and autophagy underlying the cardioprotective effects of paeonol in rats subjected to myocardial ischemia/reperfusion (I/R) injury. Myocardial I/R injury was induced by occlusion of the left anterior descending coronary artery (LAD) for 1 h followed by 3 h of reperfusion. Paeonol was intravenously administered 15 min before LAD ligation. We found that paeonol significantly improved cardiac function after myocardial I/R injury and significantly decreased myocardial I/R-induced arrhythmia and mortality. Paeonol also significantly decreased myocardial infarction and plasma LDH activity and Troponin-I levels in carotid blood after I/R. Compared with vehicle treatment, paeonol significantly upregulated Bcl-2 protein expression and significantly downregulated the cleaved forms of caspase-8, caspase-9, caspase-3 and PARP protein expression in the I/R injured myocardium. Myocardial I/R-induced autophagy, including the increase of Beclin-1, p62, LC3-I, and LC3-II protein expression in the myocardium was significantly reversed by paeonol treatment. Paeonol also significantly increased the Bcl-2/Bax and Bcl-2/Beclin-1 ratios in the myocardium after I/R injury. The cardioprotective role of paeonol during I/R injury may be due to its mediation of crosstalk between apoptotic and autophagic signaling pathways, which inhibits apoptosis and autophagic cell death.

Characteristics and significance of very early recurrence of atrial fibrillation after catheter ablation.

INTRODUCTION: Early restoration of sinus rhythm following ablation of atrial fibrillation (AF) facilitates reverse atrial remodeling and improves the long-term outcome. The purpose of this study was to determine the predictors and outcome in patients with very early AF recurrences (< 2 days). METHODS AND RESULTS: Ablation was performed in 339 consecutive AF patients (paroxysmal AF = 262). Biatrial voltage was mapped during sinus rhythm. If recurrent AF occurred within 2 days following the ablation, electrical cardioversion was performed to restore sinus rhythm. Very early recurrences of AF occurred in 39 (15%) patients with paroxysmal AF and 26 (34%) with nonparoxysmal AF. Patients with very early recurrence had a higher incidence of nonparoxysmal AF (40% vs 18.6%, P< 0.001), requirement of electrical cardioversion during procedure, larger left atrial (LA) diameter (43 ± 7 vs 39 ± 6 mm, P< 0.001), lower left ventricular ejection fraction (54 ± 10% vs 59 ± 7, P< 0.001), longer procedural time, and lower LA voltage (1.5 ± 0.7 vs 1.9 ± 0.8 mV, P< 0.001). A multivariate analysis revealed that the independent predictors of a very early recurrence were a longer procedural time and lower LA voltage. During a follow-up of 13 ± 5 months, a very early recurrence did not predict the long-term outcome of a single procedure recurrence in the patients with paroxysmal AF, but was associated with a late recurrence in the nonparoxysmal AF patients. CONCLUSION: Very early recurrence occurred in patients with paroxysmal AF is not associated with long-term recurrence. Nonparoxysmal AF is an independent predictor of late recurrence of AF in patients with very early recurrence.

The electrophysiologic characteristics in patients with only ventricular-pacing inducible slow-fast form atrioventricular nodal reentrant tachycardia.

BACKGROUND: Atrioventricular nodal reentrant tachycardia (AVNRT) can be usually induced by atrial pacing or extrastimulation. However, it is less commonly induced only by ventricular pacing or extrastimulation. OBJECTIVE: The purpose of this retrospective study was to investigate the electrophysiologic characteristics in patients with slow-fast form AVNRT that could be induced only by ventricular pacing or extrastimulation. METHODS: The total population was 1497 patients associated with AVNRT. There were 1373 (91.7%) patients who had slow-fast form AVNRT included in our study. Group 1 (n = 45) could be induced only by ventricular pacing or extrastimulation, and Group 2 (n = 1328) could be induced by only atrial stimulation or both atrial and ventricular stimulation. The electrophysiologic characteristics of the group 1 and group 2 patients were compared. RESULTS: Group 1 patients had a significantly lower incidence of both antegrade and retrograde dual AV nodal pathways. The pacing cycle length (CL) of the antegrade 1:1 fast pathway (FP) and antegrade ERP of the FP were both significantly shorter in Group 1 patients. Mean antegrade FRP of the fast and slow pathways were significantly shorter in Group 1 patients. The differences of pacing CL of 1:1 antegrade conduction, antegrade ERP and FRP were much longer in Group 2 patients. CONCLUSION: This study demonstrated the patients with slow-fast form AVNRT that could be induced only by ventricular stimulation had a lower incidence of dual AV nodal pathways and the different electrophysiologic characteristics (shorter pacing CL of the antegrade 1:1 FP, antegrade ERP of the FP and the differences of pacing CL of 1:1 antegrade conduction, antegrade ERP and FRP) from the other patients. The specific electrophysiologic characteristics in such patients could be the reason that could be induced only by ventricular stimulation.

Double atrial potentials recorded in the coronary sinus in patients with Wolff-Parkinson-White syndrome: a possible mechanism of induced atrial fibrillation.

BACKGROUND: Double atrial potentials recorded in the coronary sinus are not an unusual phenomenon in patients with supraventricular tachyarrhythmias. They have been demonstrated to potentiate the occurrence of atrial tachyarrhythmias. METHODS: Two hundred and forty-eight patients were included for investigating the presence of double atrial potentials on the coronary sinus recordings during electrophysiologic study. Group 1 consisted of 136 patients with WPW syndrome and group 2 consisted of 112 patients with atrioventricular nodal reentrant tachycardia (AVNRT). Group 1 patients had a higher incidence of induced atrial fibrillation (AF) (27% vs. 15%, P = 0.045) than group 2 patients. In addition, the incidence of double atrial potentials was significantly higher in group 1 than in group 2 patients (14% vs. 2%, P = 0.001). In group 1, 19 patients with double atrial potentials had a significantly higher incidence of left lateral bypass tracts (79% vs. 39%, P = 0.001) and induced AF (47% vs. 22%, P = 0.01) than 117 patients without double atrial potentials. CONCLUSIONS: WPW syndrome, especially with a left lateral bypass tract, had a higher incidence of double atrial potentials and induced AF than AVNRT. WPW patients with double atrial potentials had a higher incidence of induced AF than those without double atrial potentials. These findings may contribute to understanding the mechanism of induced AF in WPW syndrome.

Predictors of early and late recurrence of atrial fibrillation after catheter ablation of paroxysmal atrial fibrillation.

INTRODUCTION: The outcome of patients with early recurrence of atrial fibrillation (AF) (within one month) after ablation procedure is controversial. Furthermore, the predictors of early and late (up to mean follow-up 30 months) recurrence of AF are not investigated in depth. AIMS OF THE STUDY: The aim of the present study was to investigate the predictors of early and late recurrence of AF after catheter ablation of arrhythmogenic foci initiating AF in patients with paroxysmal AF. METHODS AND RESULTS: The study included 207 patients (155 men; mean age 62 +/- 13 years) who received catheter ablation of paroxysmal AF. Eighty-one (39%) patients had early recurrence of AF. Five clinical variables were related to the early recurrence of AF: (1) old age (>/=65 years) ( P = 0.004); (2) presence of associated cardiovascular disease ( P = 0.01); (3) presence of multiple AF foci ( P = 0.004); (4) presence of AF foci from left atrial free wall ( P = 0.039); (5) left atrial enlargement ( P = 0.038). Multivariate analysis demonstrated that presence of multiple AF foci could predict early recurrence of AF ( P = 0.013; ratio = 2.24; 95% CI 1.18 to 4.25). During the follow-up period (30 +/- 11 months), 70 (34%) patients had late recurrence of AF, and two clinical variables were related to the late recurrence of AF: (1) presence of early recurrence of AF ( P = 0.025); (2) presence of multiple AF foci ( P = 0.034). Multivariate analysis found that presence of early recurrence of AF could predict late recurrence of AF ( P = 0.046; hazard ratio = 1.62; 95% CI 1.01 to 2.59). Late recurrence of AF happened in 35 (43%) of the 81 patients with early recurrence of AF, and in 35 (28%) of the 126 patients without early recurrence of AF. CONCLUSIONS: Early AF recurrence could predict late AF recurrence.

Use of fluoroscopic views for detecting Marshall's vein in patients with cardiac arrhythmias.

INTRODUCTION: Recently, several studies showed that focal atrial fibrillation (AF) can be initiated by ectopic beats from the vein of Marshall (VOM). However, the incidence and best fluoroscopic views of VOM have never been reported. METHODS AND RESULTS: 106 patients (Non-AF = 52, AF = 54) underwent balloon-occluded coronary sinus angiography using seven fluoroscopic views (PA, Lateral, RAO 30 degrees, RA 30 degrees + Caudal 20 degrees, LAO 30 degrees, LAO 60 degrees, LAO 60 degrees + Cranial 20 degrees ). The total incidence of VOM was 74.5% (79/106), without significant difference in age (81.1 vs. 71.0%, >65 vs.

Clinical outcome of very late recurrence of atrial fibrillation after catheter ablation of paroxysmal atrial fibrillation.

INTRODUCTION: High recurrence rate is still a major problem associated with ablation of paroxysmal atrial fibrillation (AF). Most of the recurrences occur within 6 months after ablation. The characteristics of very late recurrent AF (>12 months after ablation) have not been reported. METHODS AND RESULTS: Two hundred seven patients with drug-refractory AF underwent successful focal ablation or isolation of AF foci. After the first ablation procedure, Holter monitoring and event recorders were used to evaluate symptomatic recurrent AF. A second ablation procedure was recommended if the antiarrhythmic drugs could not control recurrent AF. During long-term follow-up (mean 30 +/- 11 months, up to 51 months), 70 patients had recurrent AF, including 13 patients (6%) with very late (>12 months) recurrent AF (group 1) and 57 patients (28%) with late (within 12 months after ablation) recurrent AF (group 2). Group 1 patients had a significantly lower incidence of multiple (> or = 2) AF foci (23% vs 63%, P = 0.02) than group 2 patients. In addition, the incidence of antiarrhythmic drugs use (38% vs 84%, P = 0.001) to maintain sinus rhythm after the first episode of recurrent AF was significantly lower in group 1 than group 2 patients, and the incidence of a second intervention procedure (8% vs 35%, P = 0.051) tended to be lower in group 1 than group 2 patients. CONCLUSION: The incidence of very late recurrent AF after ablation of paroxysmal AF is very low, and the clinical outcome of patients with very late recurrent AF is benign.

Catheter ablation of paroxysmal atrial fibrillation initiated by non-pulmonary vein ectopy.

BACKGROUND: Most of the ectopic beats initiating paroxysmal atrial fibrillation (PAF) originate from the pulmonary vein (PV). However, only limited data are available on PAF originating from the non-PV areas. METHODS AND RESULTS: Two hundred forty patients with a total of 358 ectopic foci initiating PAF were included. Sixty-eight (28%) patients had AF initiated by ectopic beats (73 foci, 20%) from the non-PV areas, including the left atrial posterior free wall (28, 38.3%), superior vena cava (27, 37.0%), crista terminalis (10, 3.7%), ligament of Marshall (6, 8.2%), coronary sinus ostium (1, 1.4%), and interatrial septum (1, 1.4%). Catheter ablation eliminated AF with acute success rates of 63%, 96%, 100%, 50%, 100%, and 0% in left atrial posterior free wall, superior vena cava, crista terminalis, ligament of Marshall, coronary sinus ostium, and interatrial septum, respectively. During a follow-up period of 22+/-11 months, 43 patients (63.2%) were free of antiarrhythmic drugs without AF recurrence. CONCLUSIONS: Ectopic beats initiating PAF can originate from the non-PV areas, and catheter ablation of the non-PV ectopy has a moderate efficacy in treatment of PAF.