Number Of Ventricular Premature Beats Research Articles

Cardiovascular activity of the chiral xanthone derivatives

A series of 6 derivatives of xanthone were synthesized and evaluated for cardiovascular activity. The following pharmacological experiments were conducted: the binding affinity for adrenoceptors, the influence on the normal electrocardiogram, the effect on the arterial blood pressure, the effect on blood pressor response and prophylactic antiarrhythmic activity in adrenaline induced model of arrhythmia (rats, iv). Two compounds revealed nanomolar affinity for α1-adrenoceptor which was correlated with the strongest cardiovascular (antiarrhythmic and hypotensive) activity in animals’ models. They were enantiomers of previously described (R,S)-4-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propoxy)-9H-xanthen-9-one hydrochloride and revealed similar antiarrhythmic potential in adrenaline induced model of arrhythmia in rats after intravenous injection (ED50=0.53mg/kg and 0.81mg/kg, respectively). These values were lower than values obtained for reference drug urapidil. These compounds were more active in this experiment than urapidil (ED50=1.26mg/kg). The compound 5 administered iv at doses of 0.62–2.5mg/kg at the peak of arrhythmia prevented and/or reduced the number of premature ventricular beats in a statistically significant manner. The ED50 value was 1.20mg/kg. The S-enantiomer (6) given at the same doses did not show therapeutic antiarrhythmic activity in this model.These compounds significantly decreased the systolic and diastolic blood pressure throughout the whole observation period in anesthetized, normotensive rats. The studied enantiomers showed higher toxicity than urapidil, but imperceptibly higher that another cardiovascular drugs,that is, carvedilol or propranolol. They were also evaluated for mutagenic potential in the Ames (Salmonella) test. It was found that at the concentrations tested the compounds were non mutagenic when compared to solvent control.Results were quite promising and suggested that in the group of xanthone derivatives new potential antiarrhythmics and hypotensives might be found.

Effects of the Selective Stretch-Activated Channel Blocker GsMtx4 on Stretch-Induced Changes in Refractoriness in Isolated Rat Hearts and on Ventricular Premature Beats and Arrhythmias after Coronary Occlusion in Swine.

Mechanical factors may contribute to ischemic ventricular arrhythmias. GsMtx4 peptide, a selective stretch-activated channel blocker, inhibits stretch-induced atrial arrhythmias. We aimed to assess whether GsMtx4 protects against ventricular ectopy and arrhythmias following coronary occlusion in swine. First, the effects of 170-nM GsMtx4 on the changes in the effective refractory period (ERP) induced by left ventricular (LV) dilatation were assessed in 8 isolated rat hearts. Then, 44 anesthetized, open-chest pigs subjected to 50-min left anterior descending artery occlusion and 2-h reperfusion were blindly allocated to GsMtx4 (57 μg/kg iv. bolus and 3.8 μg/kg/min infusion, calculated to attain the above concentration in plasma) or saline, starting 5-min before occlusion and continuing until after reflow. In rat hearts, LV distension induced progressive reductions in ERP (35±2, 32±2, and 29±2 ms at 0, 20, and 40 mmHg of LV end-diastolic pressure, respectively, P<0.001) that were prevented by GsMTx4 (33±2, 33±2, and 32±2 ms, respectively, P=0.002 for the interaction with LV end-diastolic pressure). Pigs receiving GsMtx4 had similar number of ventricular premature beats during the ischemic period as control pigs (110±28 vs. 103±21, respectively, P=0.842). There were not significant differences among treated and untreated animals in the incidence of ventricular fibrillation (13.6 vs. 22.7%, respectively, P=0.696) or tachycardia (36.4 vs. 50.0%, P=0.361) or in the number of ventricular tachycardia episodes during the occlusion period (1.8±0.7 vs. 5.5±2.6, P=0.323). Thus, GsMtx4 administered under these conditions does not suppress ventricular ectopy following coronary occlusion in swine. Whether it might protect against malignant arrhythmias should be tested in studies powered for these outcomes.

Impact of reperfusion therapy and infarct localization on frequency of premature ventricular beats in acute myocardial infarction.

To determine the impact of infarct localization and types of reperfusion therapy on the frequency of ventricular premature beats (VPBs) in patients with acute myocardial infarction (AMI) and reduced left ventricular ejection fraction (LVEF). A total of 705 patients with acute ST elevation myocardial infarction (STEMI) were divided according to the infarct localization (anteroseptal, anterolateral, inferior and posterior) and reperfusion therapy (fibrinolysis or percutaneous coronary intervention with stenting) into two groups: LVEF<45% was an experimental group and LVEF>45% was a control group. The occurrence of VPBs<10 per hour was defined as a non-significant, and the occurrence of VPBs>10 per hour defined as a significant. In patients with fibrinolysis therapy and LVEF<45% significant number of VPBs were in anteroseptal (p=0.017), anterolateral (p<0.001) and posterior AMI (p<0.001), but in patients with percutaneous coronary intervention (PCI) and LVEF<45% significant number of VPBs were only in anteroseptal AMI (p=0.001) localization. In patients with reduced ejection fraction in AMI, treatment with PCI method has a better antiarrhythmic effect compared to fibrinolysis treatment.

Classic herbal formula Zhigancao Decoction for the treatment of premature ventricular contractions (PVCs): A systematic review of randomized controlled trials

To systematically assess the current clinical evidence of Zhigancao (ZGC) Decoction for premature ventricular contractions (PVCs). PubMed, the Cochrane Center Controlled Trials Register, EMBASE, Chinese National Knowledge Infrastructure, Chinese Scientific Journal Database, and Wanfang Med Online Database were searched until June 2014. We included randomized clinical trials testing ZGC Decoction against anti-arrhythmic drugs, ZGC Decoction combined with anti-arrhythmic drugs versus anti-arrhythmic drugs alone. Study selection, data extraction, quality assessment, and data analyses were conducted according to the Cochrane standards. A meta-analysis of improving total effects and reducing number of ventricular premature beats was performed to evaluate the effects of ZGC Decoction on PVCs. A total of 25 studies (involving 2441 patients) were included. The methodological quality of the included trials was evaluated as generally low. The results of the meta-analysis showed that ZGC Decoction combined with anti-arrhythmic drugs had significant effect on improving total effects (RR: 1.30 [1.22, 1.38]; P<0.00001) and relieving number of ventricular premature beats (MD: -6.66 [-12.94, -0.37]; P=0.04) compared with anti-arrhythmic drugs alone. Our review showed that ZGC Decoction was more effective in improving total effects (RR: 1.22 [1.08, 1.37]; P=0.0009), compared with anti-arrhythmic drugs alone. 13 trials reported adverse events, while the others did not mention them, indicating that the safety of ZGC Decoction remains uncertain. ZGC Decoction appears to have beneficial effects on improvement of total effects, reduction of number of ventricular premature beats in participants with PVCs. However, further thorough investigation, large-scale, proper study designed, randomized trials of ZGC Decoction for PVCs will be required to justify the effects reported.

Impact of ventricular arrhythmias on survival in patients after myocardial infarction

Introduction: Despite the continuous development of new methods of pharmacological and invasive treatment for patients with acute myocardial infarction (MI) the prognosis of long-term survival is still uncertain. Therefore, there is still need to look for new noninvasive predictors of death in patients after MI. Aim: To analyze the prognostic value of ventricular arrhythmias in predicting mortality following MI in long-term follow-up. Methods: We analyzed 390 consecutive patients (114 females and 276 males, aged 63.9 ± 11.15 years, mean EF: 43.8 ± 7.9%) with MI treated invasively. On the 5th day after MI 24-hour digital Holter recording was performed to assess the number of premature ventricular beats (VPB) and their sustained forms such as: salvos and nonsustained ventricular tachycardia (nsVT &lt; 30 s). The large numbers of ventricular extrasystoles: ≥ 10 VPB / hour were considered as abnormal. In echocardiography the size of heart cavities and cardiac contractile function were evaluated. Within 30.1 ± 15.1 months of follow-up 38 patients died. Results: In the group of patients with MI the mean value of ventricular ectopy during the day was: 318.8 ± 1447.6. Large numbers of ventricular extrasystoles were observed in 75% patients, while nsVT in 6% patients. Significant differences in the incidence of death after MI were observed in patients with nsVT and ventricular salvos. In the group of patients who died in comparison to the group of patients who survived in long-term follow-up, a significantly less ventricular ectopic incidence was noted (9.83% vs 90.17%, p &lt; 0.01). In patients who died after MI more premature ventricular beats (≥ 10 VPB / h) and a greater nsVT incidence were observed; however not significant. Moreover, in patients with MI the systolic and diastolic LV dimension, decreased values of hemoglobin, salvos and nsVT incidence are the independent risk factors of death. The strongest independent risk factor of death after MI is salvos (HR: 1.32, P &lt; 0.01). Conclusions: In long term follow-up the largest differences in death were observed in patients with ventricular salvos and nsVT. Furthermore, ventricular salvos are the strongest independent risk factor of death in patients with AMI.

Efficiency and safety of allapinin in short- and long-term treatment of patients with normal heart and ventricular premature beats

Allapinin, class 1C antiarrhythmic drug, is highly effective in treatment of patients with ventricular premature beats (VPB). The purpose of work was retrospective assessment of efficacy and safety of allapinin in patients with benign ventricular arrhythmias. 73 patients with VPB and no structural heart disease were selected from a database. In short course allapininin in dose of 75-150 mg per os daily decreased the number of VPB for more than 90% in 46,6% of patients. In 34,4% cases tolerable drug side effects were observed. Among patients with VPB burden of 10% and higher allapinin reduced this quantity below the indicated value in 76% of cases with tolerable drug side effects in 38,6% of cases. In long treatment study antiarrhythmic effect of allapinin persisted and no other side effects of the drug were documented. Allapinin is highly effective in treatment of patients with VPB without structural heart disease.

Electrocardiographic findings during marathon running in healthy athletes using a new telemedical approach

Objective: Despite the beneficial effects of regular endurance exercise on cardiovascular mortality and morbidity, complex ventricular arrhythmias and atrial fibrillation seem to be common in elite and amateur endurance athletes. Nevertheless, data on arrhythmias during endurance exercise is sparse. Our goal was to proof the feasibility for recording electrocardiogram (ECG) during marathon running, and to compare the first hour with the last hour of running. Methods: 11 healthy, male recreational athletes were equipped with a long-term Tele-ECG with continuous recording of the heart rhythm during running a marathon. All ECG data were directly transferred via mobile network from the device to the Telemedicine center (Campus, Berlin, Germany) for a subsequent online diagnosis (Streaming-Telemedtechnology) The recorded data was analyzed offline. Results: One runner had to be excluded due to artifact superimposed recording quality. Therefore 10 male runners were included in our study and completed a full or a half marathon. No episodes of atrial fibrillation could be detected. Two participants showed less than 10 ventricular premature beats (VPB) during running (Lown classification I). In another two athletes 15 polymorphic VPB (Lown classification IIIa) and 117 VPB (Lown classification IV b), including 8 couplets and one triplet were observed, respectively. There was no significant difference between the first and last hour of running concerning the number of ventricular premature beats (3.4±10.8 vs. 1.6±4.4, P = ns), mean heart rate (139.8±32.6 vs. 130.6±39.2 bpm, P = ns), maximal heart rate (150.0±32.3 vs. 149.4±37.1 bpm, P = ns), rate corrected QT-interval (444.3±35.7 vs. 439.2±25.2 ms, P = ns). Concerning heart rate variability (HRV), it remained unchanged during marathon running {HRV triangular index 11.2±9.9 vs. 10.9±8.5, P = ns; Standard deviation of all NN intervals (SDNN) 85.4±67.0 vs. 109.0±62.7 ms, P = ns}. Conclusion: We showed that ECG recording and immediate transmission of the signal by telemedicine during marathon running is feasible. In general, ventricular and supraventricular arrhythmias were rare during endurance sport in our athletes. In addition, there were no significant changes in ECG parameters during marathon running.

Heart Rate Turbulence Analysis Based on Photoplethysmography

The goal of this paper is to determine whether the photoplethysmography (PPG) can replace the ECG-based detection of heart rate turbulence. Using the PPG, classification of ventricular premature beats (VPBs) is accomplished with a linear classifier. The two conventional parameters turbulence onset and slope are studied together with a recently introduced parameter characterizing turbulence shape. Performance is studied on a dataset with 4131 VPBs, recorded from a total of 27 patients in different clinical contexts (hemodialysis treatment, intensive care monitoring, and electrophysiological study). The sensitivity/specificity of VPB classification was found to be 90.5/99.9%, with an accuracy of 99.3%, suggesting that classification of VPBs can be reliable made from the PPG. The main difference between the two types of turbulence analysis stems from the fact that the pulse transit time varies largely immediately after the VPB. Out of the 22 patients which had a sufficient number of VPBs, the outcome of the ECG- and PPG-based analysis was identical in 21. It is concluded that the PPG may serve as a surrogate technique for the ECG in turbulence analysis.

The involvement of gap junctions in the delayed phase of the protection induced by cardiac pacing in dogs

The present study has examined the role of GJ (gap junctions) in the delayed anti-arrhythmic effect of cardiac pacing, with particular reference to the time-course changes in Cx43 (connexin43) expression both after pacing (4×5min, at a rate of 240 beats/min) and 24h later, when the dogs were subjected to a 25min occlusion and reperfusion of the LAD (left anterior descending coronary artery). Compared with the SP (sham-paced) controls (n=20), in dogs paced 24h previously (n=16) there were reductions in arrhythmia severity [e.g. number of VPB (ventricular premature beats) during occlusion 294±78 compared with 63±25; survival from the combined ischaemia/reperfusion insult 20% compared with 78%], and in other ischaemic changes [epicardial ST-segment, TAT (total activation time) and tissue impedance]. Pacing also prevented the ischaemia-induced structural impairment of the intercalated discs, and preserved GJ permeability and Cx43 phosphorylation, without modifying Cx43 protein content. Following cardiac pacing the membrane and total Cx43 protein contents were unchanged up to 6h, but were significantly reduced 12h later (preceded by a down-regulation of Cx43 mRNA at 6h), and returned to normal by 24h. Interestingly, dogs that were subjected to ischaemia 12h after cardiac pacing showed increased arrhythmia generation. We conclude that cardiac pacing results in time-dependent changes in Cx43 expression, which may alter GJ function and influence arrhythmia generation during a subsequent ischaemia/reperfusion insult. This effect is manifested in protection 24h after pacing, but of potential clinical interest is the finding that there is a time interval after pacing during which an ischaemic event may generate severe ventricular arrhythmias.

Acute effects of granulocyte colony-stimulating factor on early ventricular arrhythmias after coronary occlusion in rats

Objectives:To evaluate the acute effects of colony-stimulating factor (G-CSF) on ventricular arrhythmias after coronary occlusion in rats.Materials and Methods:Male Wistar rats (10 weeks) received G-CSF (100 μg.kg-1) or vehicle. Thirty minutes later, animals were infarcted by coronary occlusion under artificial respiration. Electrocardiogram was monitored for 30 min to evaluate ventricular arrhythmias.Results:G-CSF treatment reduced the number of premature ventricular beats and the number and duration of ventricular tachycardia. The incidence of ventricular fibrillation was significantly reduced by G-CSF (MI-Cont: 11.2 ± 2.4 vs. MI-GCSF: 5.4 ± 1 events; P < 0.05). However, total duration of ventricular fibrillation was not altered (MI-Cont: 84 ± 16 vs. MI-GCSF: 76 ± 13 sec).Conclusions:Acute administration of G-CSF before coronary ligature in rats reduces the incidence of ventricular premature beats and ventricular tachycardia, suggesting a possible direct electrophysiological effect of this cytokine independently of its genomic effects. However, the data suggest that G-CSF treatment may affect the spontaneous recovery from ventricular fibrillation. Acute G-CSF administration acts directly on cardiac electrophysiology, different from chronic treatment.

Effect of long-term application of Crataegus oxyacantha on ischemia and reperfusion induced arrhythmias in rats.

The effect of long-term application of Crataegus oxyacantha on ischemia and reperfusion induced arrhythmias was investigated in Wistar rats on the heart in situ and on Langendorff preparations. Seventeen rats were fed for 8 weeks with 0.5 g/kg b.w. Crataegus extract per day, standardised to 2.2% flavonoids. Twenty age-matched untreated rats served as controls. In the hearts in situ as well as in the Langendorff preparations the left anterior descending coronary artery (LAD) was ligated for 20 min and subsequently reperfused for 30 min. ECG was continuously recorded and the time spent between start of ischemia and onset of arrhythmias was measured. In addition, during ischemia and reperfusion the number of ventricular premature beats and bigemini and the duration of salvos and ventricular flutter and fibrillation were determined. The ischemic area was evaluated in all experiments and coronary flow was measured in Langendorff preparations. In the present experiments, no cardioprotective effects of Crataegus oxyacantha could be detected, neither in the heart in situ nor in the Langendorff preparations. Although the ischemic areas were identical, arrhythmias occurred even earlier in the Crataegus collectives than in the controls. Also the number and duration of ischemia and reperfusion induced arrhythmias tended to occur longer and more frequently in the Crataegus collectives, whilst coronary flow remained unchanged. The phenomenon that Crataegus rather aggravates than prevents arrhythmias may be reduced to a Crataegus induced increase in intracellular Ca(2+)-concentration proven true for the positive inotropic effects of Crataegus.

Abstract 9583: Remote Preconditioning Has a Powerful Antiarrhythmic Effect Independent of the Reperfusion Injury Salvage Kinase Pathways

Background: There is continuing need for non pro-arrhythmic antiarrhythmic therapies for life threatening ventricular arrhythmias associated with myocardial ischemia/reperfusion. A new form of endogenous cardio-protection, remote ischemic preconditioning (RPC) showed promise for reducing myocardial infarct size, but its effect on ventricular arrhythmias is largely unknown. The purpose of this study was to determine the effects of RPC on arrhythmias in a non-infarct producing model. Methods: Anesthetized open chest rats were exposed to 5 minutes of proximal left coronary artery occlusion and 10 minutes of reperfusion. Rats were either untreated controls (Ctrl, n=17) or received RPC (n=14) with 5 minutes bilateral femoral occlusions followed by 5 minutes of reperfusion times 3, started 30 minutes before coronary occlusion. Reperfusion arrhythmias were quantitated and in some rats Western Blot Analysis for pAKT and p-p70S6 kinase were studied. Results: Ischemic risk zone (blue dye technique) was similar in Ctrl (35% of LV) and RPC (32%) as were heart rate and blood pressure throughout the study. At reperfusion, onset of ventricular tachycardia (VT) was delayed in RPC group (45.8 ± 17.1 sec; mean + SEM) versus Ctrl (11.5 ± 3.3 sec; p=0.04). The number of episodes of VT was 18.1 ± 5.1 in Ctrl versus 5.2 ± 1.7 in the RPC group (p=0.01) and duration of VT was 67.2 ± 13.2 sec in Ctrl versus 24.9 ± 11.1 sec in RPC (p=0.019). Sustained VT (≥ 10 sec) occurred in 12 controls and 4 RPC rats (p=0.03); and duration of sustained VT was 40.2 ± 9.9 sec in Ctrl versus 14.6 ± 7.2 sec in RPC (p=0.03). Ventricular fibrillation occurred in 3 controls and 1 RPC rat. Mean number of ventricular premature beats was 38.2 ± 11.4 in Ctrl and 14.1 ± 3.1 in RPC rats (p=0.04). At the end of reperfusion p-Akt level in the risk area in control hearts was 2 times higher compared to the non-ischemic area, and was not different from its level in the risk area in the RPC hearts. In addition, the risk area in both Ctrl and RPC hearts demonstrated no difference in the p-p70S6 kinase level. Conclusion: Remote ischemic preconditioning of the lower limbs induced a powerful delay in/and reduction in ischemia/reperfusion induced ventricular arrhythmias, but without evoking the reperfusion injury salvage kinase pathway.

IKs reduces ventricular arrhythmia during cardiac ischemia and reperfusion in rabbits by enhancing the repolarisation reserve

ObjectivesTo understand the function of the repolarisation reserve provided by slowly activated delayed rectifier potassium current (IKs) in the prevention of ventricular arrhythmias during cardiac ischemia/reperfusion.MethodsThe responses of monophasic action...

Chronic ischemia suppressed the expression of KCNQ1 protein and compromised the repolarisation reserve

ObjectivesTo explore the impact of chronic or transient ischemia on slowly activated delayed rectifier potassium current (IKs) channel subunit expression and its subsequent effect.MethodsIKs channel subunit expression was examined following...

Effects of Postectopic Heart Rate Turbulence on Measures of Heart Rate Variability in Patients after an Acute Myocardial Infarction

Heart rate (HR) turbulence lasting up to 15 beats after ventricular premature beats (VPBs) may have profound effects on HR variability measures. Aim of this study was to examine the effects of HR turbulence on HR variability measures. We developed an algorithm, which deletes 15 consecutive RR intervals after VPBs and examined the effects of the HR turbulence removal on the HR variability measures in patients after an acute myocardial infarction (AMI). Two hundred and sixty seven patients with left ventricular ejection fraction (LVEF) ≤ 0.40 and occurrence of VPBs were included in the study. Differences (%) between original HR data and HR turbulence edited data were compared. HR turbulence editing had variable effects on different HR variability indexes. Ultra low (ULF) and very low frequency (VLF) spectral components were mostly affected by the HR turbulence removal. Both ULF and VLF decreased significantly both at baseline Holter recordings (ULF: P = 0.006, VLF: P = 0.031) and at 6 weeks from AMI (ULF: P < 0.001, VLF: P = 0.001). The number of VPBs had a marked influence on results, e.g., when the number of VPBs exceeded the highest decile (≈50 VPBs/hour), the ULF and VLF spectral component were >30% lower after removal of turbulence. In addition, the prediction of arrhythmic events by ULF component improved after turbulence removal (AUC: 0.69 ->0.74). HR turbulence affects HR variability measures, especially the ULF and VFL spectral components. Editing of the HR turbulence should be considered when HR variability is measured from Holter recordings.

First Direct Comparison of the Late Sodium Current Blocker Ranolazine to Established Antiarrhythmic Agents in an Ischemia/Reperfusion Model

There are few safe antiarrhythmics for ischemic heart disease. Whereas ranolazine is a promising late INa blocker with antiarrhythmic effects, and devoid of pro-arrhythmic properties, there are no direct comparisons between ranolazine and other antiarrhythmic agents in an ischemia/reperfusion setting. HYPOTHESIS AND METHODS: To determine whether ranolazine was as effective as sotalol and lidocaine to reduce ischemia/reperfusion-induced arrhythmias, anesthetized rats were subjected to 5 minutes of proximal left coronary artery occlusion plus 5 minutes of reperfusion, which causes severe ventricular arrhythmias. At 21 minutes prior to coronary occlusion, rats (n = 20 per group) were randomized to receive either sotalol (intravenous [IV] bolus 5 mg/kg, 10 mg/kg per hour infusion), lidocaine (IV bolus 2.5 mg/kg, 2.5 mg/kg/hr infusion), ranolazine (IV bolus 3.3 mg/kg, 3.2 mg/kg per hour infusion), or saline (control). The incidence of ventricular arrhythmias in the sotalol (S), lidocaine (L), ranolazine (R), and control (C) groups was 7/20, 10/20, 9/20, and 16/20, respectively (P = .01 S vs C, P = .10 L vs C, and P = .048 R vs C). Duration of ventricular tachycardia (VT) episodes was reduced from 15.5 seconds (mean) in C to 1.3 seconds in S, 1.4 sec in L and 0.09 sec in R (P < .05 for S vs C and R vs C by Wilcoxon test). The number of rats with any (≥ 10 seconds) sustained VT was 3 in C versus 1, 0, and 0 in the S, L, and R groups, respectively. Two rats in C had reversible ventricular fibrillation versus 0 in the S, L, and R groups. The number of ventricular premature beats (VPBs) per rat was 10.9 in C, 2.3 in S, 4.9 in L, and 5.7 in R (P < .05 for S, L, or R vs C). P = NS for R versus L or S for all analyses. In this first head-to-head comparison of R vs other antiarrhythmic agents at therapeutic doses in an ischemia/reperfusion model, ranolazine (which lacks pro-arrhythmic effects) was as effective as either sotalol or lidocaine to reduce reperfusion-induced ventricular arrhythmias.

The Antianginal Agent Ranolazine is a Potent Antiarrhythmic Agent that Reduces Ventricular Arrhythmias: Through a Mechanism Favoring Inhibition of Late Sodium Channel

The antianginal agent ranolazine (R) has shown some promise as an antiarrhythmic agent but its mechanism of action is not known. Previously, we have shown that R suppresses ventricular arrhythmias at a concentration >10 μM that may affect multiple ion currents including IKr. The present study was carried out to determine the effects of low dose (4 μM) of R that primarily inhibits late I(Na) on ischemia/reperfusion induced ventricular arrhythmias. We subjected 20 anesthetized rats to 5 min of proximal left coronary artery occlusion followed by 5 min of reperfusion. Rats were randomized to vehicle control (C; n = 10) versus low dose R (n = 10; 3.33 mg/kg i.v. bolus plus 3.2 mg/kg/h R started 20 min prior to occlusion, which yields a concentration of 4 μM, within the known level that blocks late Na channels but well below the level that has effect on IKr or peak I(Na)). Reperfusion-induced arrhythmias were quantitated by electrocardiographic monitoring. In the C group 9/10 rats developed any arrhythmias versus 3/10 in the R group (P = 0.02); 6/10 developed ventricular tachycardia (VT) in the C group versus 0/10 in the R group (P = 0.01). The median number of episodes of VT were 1.5 in the C group versus 0 in the R group (P = 0.005). Sustained VT (>10 sec) occurred in 3/10 C and 0/10 in R (P = 0.21). The median duration of VT was 1.8 seconds in C versus 0 in R (P = 0.005). Ventricular fibrillation occurred in 1/10 in C and 0 in R. Ventricular premature beats (VPBs) occurred in 9/10 C and 3/10 R rats (P = 0.02). The median number of VPBs was 5.5 in the C group versus 0 in R group (P = 0.01). The ischemic risk zones were equivalent in the C and R groups (35 ± 3% and 32 ± 3% of the left ventricle, respectively). In conclusion, data show that the marked antiarrhythmic effect of R in the setting of acute ischemia/reperfusion occurs at low doses consistent with inhibition of late I(Na) .

Taxol, a microtubule stabilizer, prevents ischemic ventricular arrhythmias in rats.

Microtubule integrity is important in cardio-protection, and microtubule disruption has been implicated in the response to ischemia in cardiac myocytes. However, the effects of Taxol, a common microtubule stabilizer, are still unknown in ischemic ventricular arrhythmias. The arrhythmia model was established in isolated rat hearts by regional ischemia, and myocardial infarction model by ischemia/reperfusion. Microtubule structure was immunohistochemically measured. The potential mechanisms were studied by measuring reactive oxygen species (ROS), activities of oxidative enzymes, intracellular calcium concentration ([Ca2+]i) and Ca2+ transients by using fluorometric determination, spectrophotometric assays and Fura-2-AM and Fluo-3-AM, respectively. The expression and activity of sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) was also examined using real-time polymerase chain reaction, Western blot and pyruvate/Nicotinamide adenine dinucleotide-coupled reaction. Our data showed that Taxol (0.1, 0.3 and 1 μM) effectively reduced the number of ventricular premature beats and the incidence and duration of ventricular tachycardia. The infarct size was also significantly reduced by Taxol (1 μM). At the same time, Taxol preserved the microtubule structure, increased the activity of mitochondrial electron transport chain complexes I and III, reduced ROS levels, decreased the rise in [Ca2+]i and preserved the amplitude and decay times of Ca2+ transients during ischemia. In addition, SERCA2a activity was preserved by Taxol during ischemia. In summary, Taxol prevents ischemic ventricular arrhythmias likely through ameliorating abnormal calcium homeostasis and decreasing the level of ROS. This study presents evidence that Taxol may be a potential novel therapy for ischemic ventricular arrhythmias.

Effect of Hemidesmus indicus on ischemia–reperfusion injury in the isolated rat heart

The root extract of Hemidesmus indicus (Linn.) R. Br. (Asclepiadaceae) (HI) was studied for its cardioprotective effect in Langendorff-perfused rat hearts. HI was perfused for 15 min at a concentration of 0.09 g/L prior to 30 min global ischemia/120 min reperfusion (I/R). Recovery of functional parameters, reperfusion arrhythmias, and infarct size (TTC staining) served as the end-points. After 15 min of perfusion with HI, the left ventricular developed pressure (LVdevP) and HR (heart rate) were not altered significantly (p > 0.05), as compared with the pre-drug values. During R, HI showed a significantly higher (p < 0.05) recovery of LVdevP at nearly all time points. The recovery of maximal rate of pressure development (+dP/dtmax) and left ventricular end-diastolic pressure (LVEDP) at 40 min of R were significantly better than in non-treated controls. There was also a significant reduction in the total number of ventricular premature beats (VPB) and duration of ventricular tachycardia (VT). HI can protect ischemic myocardium against contractile dysfunction and reperfusion-induced arrhythmias and reduce the extent of irreversible tissue damage following I/R in rat hearts.

Activation of cardiac muscarinic M3 receptors induces delayed cardioprotection by preserving phosphorylated connexin43 and up‐regulating cyclooxygenase‐2 expression

Activation of muscarinic M(3) mucarinic acetylcholine receptors (M(3)-mAChRs) has been previously shown to confer short-term cardioprotection against ischaemic injuries. However, it is not known whether activation of these receptors can provide delayed cardioprotection. Consequently, the present study was undertaken to investigate whether stimulation of M(3)-mAChRs can induce delayed preconditioning in rats, and to characterize the potential mechanism. Rats were pretreated (24 h), respectively, with M(3)-mAChRs agonist choline, M(3)-mAChRs antagonist 4-DAMP or M(2)-mAChRs antagonist methoctramine followed by the administration of choline. This was followed by 30 min of ischaemia and then 3 h of reperfusion. Ischaemia-induced arrhythmias and ischaemia-reperfusion (I/R)-induced infarction were determined. The phosphorylation status of connexin43 (Cx43) after 30 min ischaemia, and the expression level of Hsp70, cyclooxygenase-2 (COX-2) and iNOS effected by administration of choline were also measured. Compared to the control group, pretreatment with choline significantly decreased ischaemia-induced arrhythmias, reduced the total number of ventricular premature beats, the duration of ventricular tachycardia episodes and markedly reduced I/R-induced infarct size. Furthermore, choline attenuated ischaemia-induced dephosphorylation of Cx43, and up-regulated the expression of Hsp70 and COX-2. Administration of 4-DAMP abolished these changes, while methoctramine had no effect. Our results suggest that stimulation of M(3)-mAChRs with choline elicits delayed preconditioning, which we propose is the result of up-regulation of the expression of COX-2 and inhibition of the ischaemia-induced dephosphorylation of Cx43. Therefore, M(3)-mAChRs represent a promising target for rendering cardiomyocytes tolerant to ischaemic injury.