Monophasic Action Potential Duration Research Articles

Ivabradine Protects Against Ventricular Arrhythmias in Acute Myocardial Infarction in the Rat

Ventricular arrhythmias are an important cause of mortality in the acute myocardial infarction (MI). To elucidate effect of ivabradine, pure heart rate (HR) reducing drug, on ventricular arrhythmias within 24 h after non-reperfused MI in the rat. ECG was recorded for 24 h after MI in untreated and ivabradine treated rats and episodes of ventricular tachycardia/fibrillation (VT/VF) were identified. Forty-five minutes and twenty-four hours after MI epicardial monophasic action potentials (MAPs) were recorded, cardiomyocyte Ca(2+) handling was assessed and expression and function of ion channels were studied. Ivabradine reduced average HR by 17%. Combined VT/VF incidence and arrhythmic mortality were higher in MI versus MI + Ivabradine rats. MI resulted in (1) increase of Ca(2+) sensitivity of ryanodine receptors 24 h after MI; (2) increase of HCN4 expression in the left ventricle (LV) and funny current (IF) in LV cardiomyocytes 24 h after MI, and (3) dispersion of MAP duration both 45 min and 24 h after MI. Ivabradine partially prevented all these three potential proarrhythmic effects of MI. Ivabradine is antiarrhythmic in the acute MI in the rat. Potential mechanisms include prevention of: diastolic Ca(2+)-leak from sarcoplasmic reticulum, upregulation of IF current in LV and dispersion of cardiac repolarization. Ivabradine could be an attractive antiarrhythmic agent in the setting of acute MI.

Cardiac contractility modulation increases action potential duration dispersion and decreases ventricular fibrillation threshold via β1-adrenoceptor activation in the crystalloid perfused normal rabbit heart

Background/objectivesCardiac contractility modulation (CCM) is a new treatment being developed for heart failure (HF) involving application of electrical current during the absolute refractory period. We have previously shown that CCM increases ventricular force through β1-adrenoceptor activation in the whole heart, a potential pro-arrhythmic mechanism. This study aimed to investigate the effect of CCM on ventricular fibrillation susceptibility. MethodsExperiments were conducted in isolated New Zealand white rabbit hearts (2.0–2.5kg, n=25). The effects of CCM (±20mA, 10ms phase duration) on the left ventricular basal and apical monophasic action potential duration (MAPD) were assessed during constant pacing (200bpm). Ventricular fibrillation threshold (VFT) was defined as the minimum current required to induce sustained VF with rapid pacing (30×30ms). Protocols were repeated during perfusion of the β1-adrenoceptor antagonist metoprolol (1.8μM). In separate hearts, the dynamic and spatial electrophysiological effects of CCM were assessed using optical mapping with di-4-ANEPPS. ResultsCCM significantly shortened MAPD close to the stimulation site (Basal: 102±5 [CCM] vs. 131±6 [Control] ms, P<0.001). VFT was reduced during CCM (2.6±0.6 [CCM] vs. 6.1±0.8 [Control] mA, P<0.01) and was correlated (r2=0.40, P<0.01) with increased MAPD dispersion (26±4 [CCM] vs. 5±1 [Control] ms, P<0.01) (n=8). Optical mapping revealed greater spread of CCM induced MAPD shortening during basal vs. apical stimulation. CCM effects were abolished by metoprolol and exogenous acetylcholine. No evidence for direct electrotonic modulation of APD was found, with APD adaptation occurring secondary to adrenergic stimulation. ConclusionsCCM decreases VFT in a manner associated with increased MAPD dispersion in the crystalloid perfused normal rabbit heart.

Effects of intravenous amiodarone and ibutilide on action potential duration and atrial conduction kinetics in patients with persistent atrial fibrillation.

Class III antiarrhythmic drugs have been shown to be effective for termination of atrial fibrillation (AF). The aim of this study was to determine the steady state and non-steady state effects of amiodarone and ibutilide on the atrial monophasic action potential (MAP) duration (MAPD), effective refractory period (ERP), and intra-atrial conduction time (IACT) in human persistent AF.Fourteen patients with persistent AF who underwent internal atrial defibrillation were included in the study. The atrial MAP was recorded at the high right atrium. IACT was measured from the pacing spike to the distal coronary sinus. MAPD and IACT were assessed during the steady state and at the shortest diastolic interval (DI) at a basic cycle length (CL) of 600 msec and after a premature stimulus. Amiodarone did not affect MAPD or the ERP at the basic CL, but it increased MAPD at the shortest DI. Amiodarone increased IACT at both the basic CL and the shortest DI. Ibutilide increased the MAPD and ERP at the basic CL and at the shortest DI. Ibutilide did not affect IACT at the basic CL or the shortest DI.Ibutilide increases atrial MAPD not only in the steady state but also at the shortest DI, but it does not affect IACT in patients with persistent AF. Amiodarone does not affect MAPD or ERP, but it increases IACT in the steady state, and it increases MAPD and IACT at the shortest DI.

The Conventional Antihistamine Drug Cyproheptadine Lacks QT-interval–Prolonging Action in Halothane-Anesthetized Guinea Pigs: Comparison With Hydroxyzine

Antihistamines are known to belong to the chemical class that may induce long QT syndrome. Among them, cyproheptadine has been shown to exert multifaceted actions on the ventricular repolarization phase; namely, shortening of the action potential duration at supra-therapeutic concentrations of 2 - 8 μM and prolongation of the QT interval at ≥ 10 μM. Since information is limited regarding the in vivo electrophysiological effects of cyproheptadine, we assessed it using the halothane-anesthetized guinea-pig model, which was compared with effects of another antihistamine drug, hydroxyzine. Sub-therapeutic to therapeutic doses of hydroxyzine at 1 and 10 mg/kg, i.v. prolonged the QT interval and duration of monophasic action potential, whereas therapeutic to supra-therapeutic doses of cyproheptadine at 0.1 and 1 mg/kg, i.v. hardly affected the indices of ventricular repolarization. These results suggest that cyproheptadine may be categorized into antihistamines with little effect on the ventricular repolarization.

Cardiomyocyte-derived mitochondrial superoxide causes myocardial electrical remodeling by downregulating potassium channels and related molecules.

This study was designed to investigate the role of a primary hyperoxidative stress in myocardial electrical remodeling using heterozygous heart/muscle-specific manganese superoxide dismutase-deficient (H/M-Sod2(+/-)) mice treated with L-buthionine-sulfoximine (BSO). Both H/M-Sod2(+/-)and wild-type (WT) mice were treated with intra-peritoneal BSO or saline for 7 days, and divided into 4 groups: H/M-Sod2(+/-)+BSO, WT+BSO, H/M-Sod2(+/-)control, and WT control. The ventricular effective refractory period (ERP) and the monophasic action potential duration (MAPD) were determined. Levels of oxidative stress, potassium channel-related molecules, and K(+)channel-interacting protein-2 (KChIP2) were also evaluated. The H/M-Sod2(+/-)+BSO group exhibited markedly prolonged MAPD20, MAPD90 and ERP in comparison with the other groups (MAPD20: 14 ± 1 vs. 11 ± 1 ms, MAPD90: 77 ± 7 vs. 58 ± 4 ms, ERP: 61 ± 6 vs. 41 ± 3 ms, H/M-Sod2(+/-)+BSO vs. WT control; P<0.05). Mitochondrial superoxide and hydrogen peroxide formation in the myocardium increased in the H/M-Sod2(+/-)+BSO group in comparison with the WT+BSO group (P<0.05). Real-time RT-PCR and Western blotting revealed that Kv4.2 expression was downregulated in both BSO-treated groups, whereas KChIP2 expression was downregulated only in the H/M-Sod2(+/-)+BSO group (P<0.05). BSO treatment caused hyperoxidative stress in the myocardium of H/M-Sod2(+/-)mice. Changes in the expression and function of potassium channels were considered to be involved in the mechanism of electrical remodeling in this model.

Electromechanical Effects of 1,25‐Dihydroxyvitamin D with Antiatrial Fibrillation Activities

Treatment with 1,25-dihydroxyvitamin D (1,25[OH]2 D) has several cardiovascular benefits. 1,25[OH]2 D has direct cellular effects, but its effects on the atrium are not clear. We evaluated the effects of 1,25[OH]2 D on the atrial electrophysiology and atrial fibrillation (AF). Conventional microelectrodes were used to record action potentials (APs) and contractility in isolated rabbit left atrium (LA) tissue preparations before and after the administration of 0.01, 0.1, and 1 nM 1,25[OH]2 D with and without rapid atrial pacing (RAP) and acetylcholine (5 mM)-induced AF. Surface ECG and intracardiac electrograms were recorded before and after the intravenous administration of 4 units/kg of 1,25[OH]2 D in heart failure (HF) rabbits (4 weeks after coronary artery ligation) with RAP and acetylcholine-induced AF. 1,25[OH]2 D dose-dependently increased the AP duration in the LA, which was abolished by pretreatment with 0.1 μM ryanodine. RAP and 5 mM acetylcholine-induced fewer (64.3% vs 100%, P < 0.05) AF occurrences in the presence (n = 14) of 1,25[OH]2 D than those (n = 14) in the absence of 1,25[OH]2 D. The LA treated with 1,25[OH]2 D (n = 9) had a slower maximal AF rate (10.9 ± 2.4 Hz vs 13.3 ± 2.7 Hz, P < 0.05) than the LA (n = 14) without 1,25[OH]2 D. Moreover, 1,25[OH]2 D caused a lower AF inducible percentage (11.0 ± 1.9% vs 100 ± 0%, P < 0.001) and a shorter duration (4 ± 0.4 seconds vs 309 ± 26 seconds, P < 0.001) with a prolonged LA 90% monophasic AP duration (94.1 ± 0.2 milliseconds vs 98.5 ± 0.1 milliseconds, P < 0.05) in 5 rabbits with HF. 1,25[OH]2 D did not prolong the QT interval or 90% of the AP duration in isolated Purkinje fibers. 1,25[OH]2 D has direct electromechanical effects on the LA and can prevent or terminate AF.

Novel Parameters to Improve Quantification of Repolarization Reserve and Arrhythmogenesis Using a Dofetilide Challenge

<h3>Background</h3> In the canine complete AV block (AVB) model with bradycardia, inducibility of drug-induced torsades de pointes (TdP) is usually the primary outcome parameter, whereas short-term variability (STV) of the left ventricular monophasic action potential duration (LV MAPD) is used as primary surrogate parameter. The dichotomous parameter inducibility is cumbersome because it requires ≥3 TdP episodes and does not take into account (multiple) ectopic beats or severity of TdP episodes. In this study, we introduce arrhythmia score (AS) and T25, using dofetilide (D) to improve quantification of repolarization reserve. <h3>Methods</h3> Experiments performed under general anesthesia in unremodeled, acute AVB dogs (aAVB, n=13) and 3 groups of AVB dogs with chronic bradycardia but differences in remodeling due to alterations in chronic activation pattern were analyzed: spontaneous idioventricular rhythm (IVR, n=19), more physiologic high-septal pacing (HSP, n=10), and right ventricular apex pacing (RVA, n=8). AS was calculated as 1 + mean number of beats of the 3 most severe arrhythmias after D (0.025 mg/kg/5 min), with scores of 50, 75, and 100, for 1, 2, and ≥3 cardioversions, respectively. T25 was defined as the time required to obtain 25-ms increase of LV MAPD after D. <h3>Results</h3> For groups aAVB, IVR, HSP and RVA, TdP inducibility was 0%, 74% (<i>P</i> <.001 vs aAVB), 30%, and 75% (<i>P</i> <.01 vs aAVB), respectively, with a similar pattern in AS: 3.8 ± 6.5 (mean ± SD), 41 ± 28 (<i>P</i> <.001 vs aAVB), 14 ± 22 (<i>P</i> <.05 vs IVR), and 28 ± 24. Serial analysis in aAVB dogs revealed that AS was increased by D (from 1.3 ± 0.4 to 4.3 ± 7.4; n=10; <i>P</i> <.05), although 3 or more TdPs were not induced in any dog. T25 values were 2.1 ± 0.4 minutes 1.4 ± 0.4 minutes (<i>P</i> <.001 vs aAVB), 1.9 ± 0.4 minutes (<i>P</i> <.01 vs IVR), and 1.5 ± 0.3 minutes (<i>P</i> <.01 vs aAVB), respectively. Unexpectedly, STV before or after D was not significantly higher in any group vs aAVB. "Predicting" inducibility after pooling all data (n = 50) yielded areas under the receiver operating characteristics curves of 0.995 for AS and 0.792 for T25, and best cutoff values of 7.7 minutes and 1.6 minutes, respectively. <h3>Conclusions</h3> In anesthetized AVB dogs, AS is not inferior to inducibility and seems to be more detailed. T25 is a good surrogate for the arrhythmogenic outcome and is superior to STV.

Monophasic action potential duration alternans after abrupt shortening of the cardiac cycle in humans

BackgroundAction potential alternans may be important in causing ventricular arrhythmias. Methods and resultsWe recorded monophasic action potentials from the right ventricular endocardium in patients with persistent atrial fibrillation who underwent internal atrial defibrillation during rapid ventricular pacing. In 3 of 45 patients, monophasic action potential duration alternans was observed at a pacing cycle length ≤350ms. ConclusionAction potential alternans is not a rare phenomenon (6.6%) in humans.

Procainamide and lidocaine produce dissimilar changes in ventricular repolarization and arrhythmogenicity in guinea‐pig

Procainamide is class Ia Na(+) channel blocker that may prolong ventricular repolarization secondary to inhibition of IK r , the rapid component of the delayed rectifier K(+) current. In contrast to selective IN a blockers such as lidocaine, procainamide was shown to produce arrhythmogenic effects in the clinical setting. This study examined whether pro-arrhythmic responses to procainamide may be accounted for by drug-induced repolarization abnormalities including impaired electrical restitution kinetics, spatial gradients in action potential duration (APD), and activation-to-repolarization coupling. In perfused guinea-pig hearts, procainamide was found to prolong the QT interval on ECG and left ventricular (LV) epicardial monophasic APD, increased the maximum slope of electrical restitution, enhanced transepicardial APD variability, and eliminated the inverse correlation between the local APD and activation time values determined at distinct epicardial recording sites prior to drug infusion. In contrast, lidocaine had no effect on electrical restitution, the degree of transepicardial repolarization heterogeneities, and activation-to-repolarization coupling. Spontaneous episodes of monomorphic ventricular tachycardia were observed in 57% of procainamide-treated heart preparations. No arrhythmia was induced by lidocaine. In summary, this study suggests that abnormal changes in repolarization may contribute to pro-arrhythmic effects of procainamide.

A study of the proarrhythmogenic effect of acute left ventricular afterload increase: insights from a novel closed chest/pericardium model

Purpose: To determine whether acute LV afterload increase is an additive risk factor in sudden cardiac death. Prior studies of mechano-electric coupling during acute afterloading were limited to open chest/pericardium preparations or ex vivo models. The aim of this study was to determine the interrelationships of an acute LV afterload challenge with the induction, presence and disappearance of delayed after depolarizations (DADs). Methods: Systolic blood pressure was raised by 30% during 5 to 10 beats by acute balloon inflation (2-3ml) in the mid-descending aorta. Echo guidance was used to position a contact electrode catheter to record monophasic action potentials (MAPs). Concomitant 12 lead ECG was recorded. Endocardial MAP registration was performed during 30 pressure challenges in 3 consecutive pigs. Results: In all cases MAP duration and MAP amplitude slightly decreased during the acute pressure challenge (242±6 to 237±6 ms, p<0.001 ; 21.8±0.9 to 21.3±0.8 mV, p<0.05) with a concomitant lengthening of the RR interval (521±9ms to 570±13ms, p<0.001). With balloon release these changes normalized over several beats. Moreover, acute afterloading caused beat-to-beat appearance of DADs during 16/30 pressure challenges (figure A, asterisks). In 10/30 these DADs caused premature ventricular complexes (PVCs) (figure B) and in 1/30 short non-sustained ventricular tachycardia. Conclusion: The feasibility of MAP registration in a near to physiological closed chest/pericardium model of acute LV pressure overload was demonstrated. Furthermore, a beat-to-beat development of DADs was demonstrated during acute pressure overload giving rise to PVCs, with immediate disappearance during pressure release.

GW24-e1851 An increase of CO2 levels, enhancing late sodium current, is an independent factor of proarrhythmia in the heart

ObjectivesIncreased CO2 levels in the myocardium may be global due to inadequate ventilation/circulation or local due to myocardial ischaemia/infarction (by 4 times higher than the normal), and are associated with...

GW24-e1863 The influence of benazepril hydrochloride on hypertensive left ventricular hypertrophy transmural heterogeneity of ventricular repolarisation

ObjectivesTo study the relationship of Benazepril on hypertensive left ventricular hypertrophy transmural repolarisation heterogeneity effects and inhibit ventricular arrhythmiasMethodsMaking hypertensive left ventricular hypertrophy model in rabbits, and to give Benazepril...

Spatial correlation of action potential duration and diastolic dysfunction in transgenic and drug-induced LQT2 rabbits

Enhanced dispersion of action potential duration (APD) is a major contributor to long QT syndrome (LQTS)-related arrhythmias. To investigate spatial correlations of regional heterogeneities in cardiac repolarization and mechanical function in LQTS. Female transgenic LQTS type 2 (LQT2; n = 11) and wild-type littermate control (LMC) rabbits (n = 9 without E4031 and n = 10 with E4031) were subjected to phase contrast magnetic resonance imaging to assess regional myocardial velocities. In the same rabbits' hearts, monophasic APDs were assessed in corresponding segments. In LQT2 and E4031-treated rabbits, APD was longer in all left ventricular segments (P < .01) and APD dispersion was greater than that in LMC rabbits (P < .01). In diastole, peak radial velocities (Vr) were reduced in LQT2 and E4031-treated compared to LMC rabbits in LV base and mid (LQT2: -3.36 ± 0.4 cm/s, P < .01; E4031-treated: -3.24 ± 0.6 cm/s, P < .0001; LMC: -4.42 ± 0.5 cm/s), indicating an impaired diastolic function. Regionally heterogeneous diastolic Vr correlated with APD (LQT2: correlation coefficient [CC] 0.38, P = .01; E4031-treated: CC 0.42, P < .05). Time-to-diastolic peak Vr were prolonged in LQT2 rabbits (LQT2: 196.8 ± 2.9 ms, P < .001; E4031-treated: 199.5 ± 2.2 ms, P < .0001, LMC 183.1 ± 1.5), indicating a prolonged contraction duration. Moreover, in transgenic LQT2 rabbits, diastolic time-to-diastolic peak Vr correlated with APD (CC 0.47, P = .001). In systole, peak Vr were reduced in LQT2 and E4031-treated rabbits (P < .01) but longitudinal velocities or ejection fraction did not differ. Finally, random forest machine learning algorithms enabled a differentiation between LQT2, E4031-treated, and LMC rabbits solely based on "mechanical" magnetic resonance imaging data. The prolongation of APD led to impaired diastolic and systolic function in transgenic and drug-induced LQT2 rabbits. APD correlated with regional diastolic dysfunction, indicating that LQTS is not purely an electrical but an electromechanical disorder.

The “nervous” kidney and ventricular fibrillation: A possible game changer?

The “nervous” kidney and ventricular fibrillation: A possible game changer?

Renal denervation suppresses ventricular arrhythmias during acute ventricular ischemia in pigs

Increased sympathetic activation during acute ventricular ischemia is involved in the occurrence of life-threatening arrhythmias. To test the effect of sympathetic inhibition by renal denervation (RDN) on ventricular ischemia/reperfusion arrhythmias. Anesthetized pigs, randomized to RDN or SHAM treatment, were subjected to 20 minutes of left anterior descending coronary artery (LAD) occlusion followed by reperfusion. Infarct size, hemodynamics, premature ventricular contractions, and spontaneous ventricular tachyarrhythmias were analyzed. Monophasic action potentials were recorded with an epicardial probe at the ischemic area. Ventricular ischemia resulted in an acute reduction of blood pressure (-29%) and peak left ventricular pressure rise (-40%), which were not significantly affected by RDN. However, elevation of left ventricular end-diastolic pressure (LVEDP) during LAD ligation was attenuated by RDN (ΔLVEDP: +1.8 ± 0.6 mm Hg vs +9.7 ± 1 mm Hg in the SHAM group; P = .046). Infarct size was not affected by RDN compared to SHAM. RDN significantly reduced spontaneous ventricular extrabeats (160 ± 15/10 min in the RDN group vs 422 ± 36/10 min in the SHAM group; P = .021) without affecting coupling intervals. In 5 of 6 SHAM-treated animals, ventricular fibrillation (VF) occurred during LAD occlusion. By contrast, only 1 of 7 RDN-treated animals experienced VF (P = .029). Beta-receptor blockade by atenolol showed comparable effects. Neither VF nor transient shortening of monophasic action potential duration during reperfusion was inhibited by RDN. RDN reduced the occurrence of ventricular arrhythmias/fibrillation and attenuated the rise in LVEDP during left ventricular ischemia without affecting infarct size, changes in ventricular contractility, blood pressure, and reperfusion arrhythmias. Therefore, RDN may protect from ventricular arrhythmias during ischemic events.

Effects of hypokalemia on transmural dispersion of ventricular repolarization in left ventricular myocardium

ObjectiveTo observe effects of hypokalemia on transmural heterogeneity of ventricular repolarization in left ventricular myocardium of rabbit, and explore the role of hypokalemia in malignant ventricular arrhythmia (MVA). MethodsA total of 20 rabbits were randomly divided into control group and hypokalemic group. Isolated hearts in the control group were simply perfused with modified Tyrode's solution, and were perfused with hypokalemic Tyrode's solution in hypokalemic group. Ventricular fibrillation threshold (VFT), 90% monophasic action potential repolarization duration (APD90) of subepicardial, midmyocardial and subendocardial myocardium, transmural dispersion of repolarization (TDR) and C×43 protein expression in three layers of myocardium were measured in both groups. ResultsVFT in the control group and the hypokalemic group were (13.40±2.95) V, and (7.00±1.49) V, respectively. There was a significant difference between two groups (P<0.01). APD90 of three myocardial layers in the hypokalemic group were significantly prolonged than those in the control group (P<0.01). ΔAPD90 in the hypokalemic group and the control group were (38.10±10.29) ms and (23.70±5.68) ms, and TDR were (52.90±14.55) ms and (36.10±12.44) ms, respectively. ΔAPD90 and TDR in the hypokalemic group were significantly higher than those in the control group (P<0.05), and the increase in APD90 of midmyocardium was more significant in the hypokalemic group. Cx43 protein expression of all three myocardial layers were decreased significantly in the hypokalemic group (P<0.01), and ΔCx43 was significantly increased (P<0.05). Reduction of Cx43 protein expression was more significant in the midmyocardium. ConclusionsHypokalemic can increase transmural heterogeneity of C×43 expression and repolarization in left ventricular myocardium of rabbit, and decrease VFT and can induce MVA more easily.

Protective effects of ranolazine and propranolol, alone or combined, on the structural and functional alterations of cardiomyocyte mitochondria in a pig model of ischemia/reperfusion

Preventing the consequences of ischemia/reperfusion (I/R)-induced lesions in the clinic requires the administration of pharmacological agents prior to restoring coronary vascularization. The aim of this study was to evaluate the effects of ranolazine and propranolol when administered either alone or combined prior to I/R induction in a pig model. Thirty domestic pigs were randomly assigned to five groups of six animals including (i) sham animals; (ii) untreated animals with 45-min ischemia and 1-min reperfusion; animals administered intravenously with (iii) ranolazine, or (iv) propranolol, or (v) both combined, prior to 45-min ischemia and 1-min reperfusion. The heart rate (HR), duration of monophasic action potentials (dMAP), and peak of the time derivative of left ventricular pressure (LV dP/dt max) were measured during ischemia and after 1 min of reperfusion. Structural and functional parameters of mitochondria were analyzed in tissue samples taken from the left ventricle ischemic area at the end of the experiment. I/R induced expected effects, namely accelerated HR, decreased dMAP and LV dP/dt max, and altered mitochondrial structural and functional parameters including decreased oxygen consumption, increased reactive oxygen species (ROS) production, and reduced calcium retention capacity resulting in the opening of mitochondrial permeability transition pores (mPTP). Ranolazine and propranolol administered either alone or combined prior to I/R significantly decreased all of these deleterious consequences. The protective effects of ranolazine and propranolol are seemingly due to the prevention of calcium overload and resulting lesions in mitochondria.

The Effects of Kappa-Opioid Receptor on Stretch-Induced Electrophysiological Changes in Infarcted Rat Hearts

IntroductionKappa-opioid receptors (κ-OR) and mechanoelectric feedback seem to have common pathways that influence electrophysiological changes resulting from acute myocardial infarction (MI). This study aims to determine the effects of the κ-OR on stretch-induced electrophysiological changes after acute MI. MethodsMale Sprague-Dawley rats were randomly divided into 4 groups: sham operated, MI, U-50488H (a selective κ-OR agonist) -treated MI (MI+U-50488H) and nor-BNI (a selective κ-OR antagonist) -treated MI (MI+nor-BNI). After Langendorff perfusion to maintain stabilization, a transient stretch (5 seconds) was delivered early in diastole. Electrophysiological changes were recorded for 1 minute before and after stretch. Similarly, the 20%, 50% and 90% monophasic action potential duration (MAPD20, MAPD50 and MAPD90, respectively) and stretch-induced arrhythmias were recorded. ResultsMAPD90 significantly increased in all 4 groups. MAPD90 in the MI and MI+nor-BNI groups increased significantly before stretch (P<0.05) and after stretch (P<0.01) but was reversed in the MI+U-50488H group (P>0.05). MAPD90 in the MI group was increased compared with that of the MI+U-50488H group but decreased compared with that of the MI+ nor-BNI group after stretch (P<0.01). The arrhythmia score in the MI and MI+nor-BNI groups was higher than that of the sham-operated group (P<0.01), and the arrhythmia score in the MI+nor-BNI group was higher than that in MI group after stretch (P<0.01). The arrhythmia score of the MI+U-50488H group was lower than that of MI group after stretch (P<0.01). ConclusionsThe κ-OR could influence the stretch-induced electrophysiological changes and play an antiarrhythmic role in stretch-induced arrhythmias after acute MI.

The mechanical uncoupler blebbistatin is associated with significant electrophysiological effects in the isolated rabbit heart

Blebbistatin (BS) is a recently discovered inhibitor of the myosin II isoform and has been adopted as the mechanical uncoupler of choice for optical mapping, because previous studies suggest that BS has no significant cardiac electrophysiological effects in a number of species. The aim of this study was to determine whether BS affects cardiac electrophysiology in isolated New Zealand White rabbit hearts. Langendorff-perfused hearts (n= 39) in constant-flow mode had left ventricular monophasic action potential duration (MAPD) measured at apical and basal regions during constant pacing (300 ms cycle length). Standard action potential duration restitution was obtained using the single extrastimulus method with measurement of the maximal restitution slope. Ventricular fibrillation threshold was measured as the minimal current inducing sustained ventricular fibrillation with burst pacing (30 stimuli, at 30 ms intervals). Optical action potentials were recorded using the voltage-sensitive dye di-4-ANEPPS. Measurements were taken at baseline and after 60 min perfusion with BS (5 μm). Blebbistatin significantly prolonged left ventricular apical (mean ± SEM; from 129.9 ± 2.9 to 170.7 ± 4.1 ms, P < 0.001, n= 8) and basal MAPD (from 135.0 ± 2.3 to 163.3 ± 5.6 ms, P < 0.001) and effective refractory period (from 141.3 ± 4.8 to 175.6 ± 3.7 ms, P < 0.001) whilst increasing the maximal slope of restitution (apex, from 0.79 ± 0.09 to 1.57 ± 0.16, P < 0.001; and base, from 0.71 ± 0.06 to 1.44 ± 0.24, P < 0.001) and ventricular fibrillation threshold (from 5.3 ± 1.1 to 17.0 ± 2.9 mA, P < 0.001). In other hearts, blebbistatin significantly prolonged optically recorded action potentials (from 136.5 ± 6.3 to 173.0 ± 7.9 ms, P < 0.05, n= 4). In control experiments, the increase of MAPD with blebbistatin was present whether the hearts were perfused in constant-pressure mode (n= 5) or in unloaded conditions (n= 5). These data show that blebbistatin significantly affects cardiac electrophysiology. Its use in optical mapping studies should be treated with caution.

Quinidine elicits proarrhythmic changes in ventricular repolarization and refractoriness in guinea-pig

Quinidine is a class Ia Na(+) channel blocker that prolongs cardiac repolarization owing to the inhibition of I(Kr), the rapid component of the delayed rectifier current. Although quinidine may induce proarrhythmia, the contributing mechanisms remain incompletely understood. This study examined whether quinidine may set proarrhythmic substrate by inducing spatiotemporal abnormalities in repolarization and refractoriness. The monophasic action potential duration (APD), effective refractory periods (ERPs), and volume-conducted electrocardiograms (ECGs) were assessed in perfused guinea-pig hearts. Quinidine was found to produce the reverse rate-dependent prolongation of ventricular repolarization, which contributed to increased steepness of APD restitution. Throughout the epicardium, quinidine elicited a greater APD increase in the left ventricular chamber compared with the right ventricle, thereby enhancing spatial repolarization heterogeneities. Quinidine prolonged APD to a greater extent than ERP, thus extending the vulnerable window for ventricular re-excitation. This change was attributed to increased triangulation of epicardial action potential because of greater APD lengthening at 90% repolarization than at 30% repolarization. Over the transmural plane, quinidine evoked a greater ERP prolongation at endocardium than epicardium and increased dispersion of refractoriness. Premature ectopic beats and monomorphic ventricular tachycardia were observed in 50% of quinidine-treated heart preparations. In summary, abnormal changes in repolarization and refractoriness contribute greatly to proarrhythmic substrate upon quinidine infusion.