Ventricular Refractoriness Research Articles

Abstract 15242: The Flipside of Flecainide: A Case of Flecainide Induced Loss of Capture

Introduction: Flecainide is a class 1c anti-arrhythmic agent that slows phase 0 of the fast inward sodium (Na) channels in a rate-dependent fashion leading to decreased conduction velocity in the His-Purkinje and ventricular myocardium. Its high affinity and slow unbinding prolong QRS duration on electrocardiogram (EKG). Partial renal excretion and a narrow therapeutic index of 0.2-1mcg/mL can cause drug toxicity. Case: A 72-year-old woman presented with palpitations and weakness. She had a history of non-ischemic cardiomyopathy, biventricular (BiV) implantable cardioverter defibrillator, frequent premature ventricular contractions on flecainide 100 mg twice a day, and chronic kidney disease. She was hypotensive and with acute kidney injury. EKG showed wide complex ventricular rhythm, QRS duration of 305 ms and intermittent ventricular pacing (Fig.1A), changed since EKG 6 months ago (Fig.1B). Device interrogation revealed normal sensing and impedances but failure to capture from all 3 leads. She had stable lead parameters and appropriate BiV pacing 6 months ago. Chest X ray showed stable lead positions. Flecainide toxicity was suspected, and Na bicarbonate infusion was started. Flecainide level was 2.4mcg/mL (normal <1mcg/mL). She went into an idioventricular rhythm which terminated spontaneously (Fig.1C). After 48 hours of Na bicarbonate infusion, lead capture was noted with narrower QRS (198 ms) (Fig.1D) and on day 6, EKG was back to effective BiV pacing with QRS duration 127 ms (Fig.1E). Discussion: This case highlights the EKG manifestations of flecainide toxicity including QRS widening, sine-wave pattern and loss of pacing capture due to prolonged ventricular refractoriness. It also underscores the reversibility of this condition with prompt treatment using Na bicarbonate. Conclusion: Early recognition and rapid treatment of the cardiac effects of flecainide toxicity is critical in managing a life threatening but reversible medical condition.

Autonomic neuro-cardiac profile of electrical, structural and neuronal remodeling in myocardial infarction-induced heart failure.

Heart failure is a clinical syndrome typified by abnormal autonomic tone, impaired ventricular function, and increased arrhythmic vulnerability. This study aims to examine electrophysiological, structural and neuronal remodeling following myocardial infarction in a rabbit heart failure model to establish its neuro-cardiac profile. Weight-matched adult male New Zealand White rabbits (3.2±0.1kg, n=25) were randomized to have coronary ligation surgeries (HF group, n=13) or sham procedures (SHM group, n=12). Transthoracic echocardiography was performed six weeks post-operatively. On week 8, dual-innervated Langendorff-perfused heart preparations were set up for terminal experiments. Seventeen hearts (HF group, n=10) underwent ex-vivo cardiac MRI. Twenty-two hearts (HF group, n=7) were examined histologically. Electrical remodeling and abnormal autonomic profile were evident in HF rabbits with exaggerated sympathetic and attenuated vagal effect on ventricular fibrillation threshold, ventricular refractoriness and restitution curves, in addition to increased spatial restitution dispersion. Histologically, there was significant neuronal enlargement at the heart hila and conus arteriosus in HF. Structural remodeling was characterized by quantifiable myocardial scarring, enlarged left ventricles, altered ventricular geometry and impaired contractility. In an infarct-induced rabbit heart failure model, extensive structural, neuronal and electrophysiological remodeling in conjunction with abnormal autonomic profile provide substrates for ventricular arrhythmias.

Сardioprotective agents with biaromatic structure. Part 5. Potassium Kv1.5-channels blockers

The Kv1.5 potassium channel provides an ultra-rapid delayed rectifier potassium current, IKur, that acts selectively in human atrial cells. This makes selective Kv1.5 blockade a promising approach to control atrial arrhythmias without the adverse ventricular effects associated with classical hERG-subtype potassium channel blockers (Kv11.1). This review considers all currently known Kv1.5-channel blockers with a biaromatic structure and data on their biological properties. For many of the Kv1.5-selective compounds studied, the ability to prevent the development of atrial arrhythmias without affecting ventricular refractoriness was confirmed.

Optimizing electrophysiology studies to prevent sudden cardiac death after myocardial infarction.

This study assessed associations of minimum final extrastimulus coupling interval utilized within electrophysiology study (EPS) after myocardial infarction (MI) and possible site of origin of induced ventricular tachycardia (VT) with long-term occurrence of spontaneous ventricular tachyarrhythmia and long-term survival. This prospective study recruited consecutive patients with left ventricular ejection fraction (LVEF) ≤ 40% who underwent EPS days 3-5 after MI between 2004 and 2017. Positive EPS was defined as sustained monomorphic VT cycle length ≥200 ms for ≥10 s or shorter duration if haemodynamic compromise occurred. Each of the four extrastimuli was shortened by 10 ms at a time, until it failed to capture the ventricle (ventricular refractoriness) or induced ventricular tachyarrhythmia. Outcomes included spontaneous ventricular tachyarrhythmia occurrence and all-cause mortality. Shorter coupling interval length of final extrastimulus that induced VT was associated with higher risk of spontaneous ventricular tachyarrhythmia (P < 0.001). Significantly higher rates of spontaneous ventricular tachyarrhythmia (65.2% vs. 23.2%; P < 0.001) were observed for final coupling interval at EPS <200 ms vs. >200 ms. Right bundle branch block (RBBB) morphology of induced VT, with possible site of origin from the left ventricle, was associated with all-cause mortality [hazard ratio (HR) 3.2, P = 0.044] and a composite of spontaneous ventricular tachyarrhythmia recurrence or mortality (HR 1.8, P = 0.043). Ventricular tachycardia induced with shorter coupling intervals was associated with higher risk of spontaneous ventricular tachyarrhythymia on follow-up, indicating that the final extrastimulus coupling interval at EPS early after MI should be determined by ventricular refractoriness. Induced VT with possible origin from left ventricle was associated with increased risk of spontaneous ventricular tachyarrhythmia recurrence or death.

C23 ELECTROCARDIOGRAPHIC PREDICTORS OF PRIMARY VENTRICULAR FIBRILLATION DURING A FIRST ACUTE MYOCARDIAL INFARCTION

Abstract Introduction Few small studies evaluated electrocardiographic (ECG) predictors of ventricular fibrillation (VF) before reperfusion during a first acute myocardial infarction (AMI). None accounted for the time between symptom onset and ECG. Objectives To evaluate the ECG predictors of primary VF in the PREDESTINATION (PRimary vEntricular fibrillation and suDden dEath during a firST myocardIal iNfArcTION) population. Patients and methods: PREDESTINATION is an ongoing, prospective, multicenter, case–control study (1:2 match for sex and age) enrolling patients aged 18–80 with a first AMI, whether complicated (cases) or not (controls) by primary VF before reperfusion. For the present analysis, we matched 1:1 for age, sex, infarct site, and symptom–ECG time, the ECGs of cases before VF and those of controls revascularized at least 60 minutes after symptom onset. ECG traces were digitized in pdf and enlarged by 400%. Three blind analyzes were performed: on the entire population, on only anterior and only non–anterior AMI. Results PREDESTINATION currently includes 1478 patients (mean 59 years, 83% male), 533 of whom are cases. Among the cases, only 59 (58 ± 11 years, 10% females, 64% with anterior AMI, mean symptoms–ECG time 78±60 minutes, mean ECG–VF time 23±15 minutes) had a pre–VF ECG of adequate quality. Both in the general population (118 ECGs) and in anterior AMIs subgroup (76 ECGs), the presence of ventricular (VEB) or supraventricular ectopic beats (SVEB) was associated with an increased risk of developing VF (maximum OR 8.35 for VEBs in anterior AMIs). In the subgroup of anterior AMIs, the Tpeak–Tend interval in non–infarction leads, both corrected for the RR interval (Bazett) and for the QT interval (TpTe/QT) was significantly longer in cases compared to controls. A TpTe/QT ≥0.33 in non–infarction leads was associated with an OR of 4.6 (p=0.02) of developing VF. Conclusions the present analysis, aimed at identifying ECG predictors of primary VF, is the first to perform a rigorous case–control matching including symptom–ECG time. In addition to ectopic beats, a well–known marker and promoter of electrical instability, we identified, only for anterior AMIs, a single additional predictor (TpTe/QT), which correlates with an increased dispersion of repolarization and consequently of ventricular refractoriness.

48 A CASE OF RECURRENT VENTRICULAR TACHYCARDIA IN A PATIENT WITH GRANULOMATOSIS WITH POLYANGIITIS WITH A CHALLEGING IDENTIFICATION OF ARRHYTHMIC SUBSTRATE: THE ROLE OF MULTIMODALITY IMAGING

Abstract Background Granulomatosis with polyangiitis (GPA), previously known as Wegener's granulomatosis, is a pulmonary-renal syndrome affecting small and medium sized blood vessels. Cardiac involvement is rare and generally includes pericarditis, myocarditis and aortic valve disease. We report a case of recurrent sustained ventricular tachycardia (VTs) in a patient with GPA. Case summary A 67-year-old man with past medical history of GPA presented palpitations, chest pain and episodes of presyncope. Electrocardiographic tracing upon ED presentation showed sustained monomorphic VT (fig.1) associated with global hypokinesia of the left ventricle and moderately reduced ejection fraction at transthoracic echocardiography (TTE). As the patient was hemodynamically stable, prompt treatment with amiodarone was adopted with successful recovery of sinus rhythm. After a few hours, TTE was normal. However, as troponin I was markedly elevated, coronarography was performed and coronary disease was ruled out. Contrast-enhanced cardiac magnetic resonance imaging (ceCMR) revealed late gadolinium enhancement in basal anteroseptal mid wall, suggestive of myocardial scar tissue with non-ischemic pattern. No sustained ventricular arrhythmias were induced during electrophysiological study (EPS), even with an aggressive protocol (up to 4 extra stimuli and ventricular refractoriness) and electro-anatomical mapping of both ventricles failed to show any arrhythmic substrate. An implantable cardioverter defibrillator (ICD) was then implanted. After 4 months the patient was admitted for multiple episodes of sustained VT (with cycle length in the ICD monitoring window) refractory to drugs and three external defibrillations. Repeated EPS failed to induce sustained arrhythmias. High-density electroanatomical mapping of the right ventricle, however, showed fragmented potentials in the mid-posterior septal wall (fig. 2-3). After myocardial biopsy of the region of interest, radiofrequency catheter ablation of the area was performed with regression of the potentials. The results of endomyocardial biopsy demonstrated fibrosis. At 5 months of follow-up, the patient didn't relapse. Discussion Multimodality imaging is of paramount importance in identifying arrhythmogenic substrate and in characterizing the specific anatomical–functional components of VT circuits. In our patient high-density electroanatomical mapping was able to identify fragmented potentials and define the ablation target area, despite the mismatch with ceCMR.

Endurance training increases ventricular refractoriness and wavelength of the cardiac impulse without participation of parasympathetic postganglionic neurons. A study in isolated rabbit heart

Abstract Background Endurance physical training plays a protective role in against ventricular fibrillation (VF), but the exact underlying mechanisms are not completely understood. It is well-known that modifications in myocardial ventricular properties such as refractoriness, conduction velocity and wavelength are key in the initiation and maintenance of VF; furthermore, vagus nerve stimulation has prophylactic effects on malignant arrhythmias and VF. On the other hand, parasympathetic nervous system activity is increased in trained individuals, which in turn affects different ventricular electrophysiological properties. We hypothesized that physical training increases conduction velocity and wavelength, and that these changes are mediated by myocardial cholinergic neurons. Methods To test this hypothesis, ten rabbits were submitted to a six-week endurance training protocol and twenty controls were not trained (divided in control group, n=10 and sham group n=10). After training, rabbits were euthanized and their hearts excised, isolated and perfused in a Langendorff system. A pacing electrode and a plaque with 240 recoding electrodes acquiring at 1 KHz were positioned on the left ventricle (LV). Extraestimulus test using four different pacing cycle lengths (90% basal cycle length, 250, 200 and 150 ms) was performed before and after atropine (1μM, control and trained groups) or vehicle (tyrode, sham group) infusion. We studied 1) LV effective refractory period (ERP), 2) LV functional refractory period (FRP), 3) LV conduction velocity (CV), and 4) LV wavelength, determined as LV FRP x CV. Factorial ANOVA (mixed model) was used for statistical analysis (p&amp;lt;0.05). Results Before parasympathetic blockade, LV FRP increased in trained animals (Figure, B) whereas no difference was found in LV CV between trained and control animals at any pacing cycle length (Figure, A). In consequence, LV wavelength increased in trained animals (Figure, C). There were no changes in LV ERP, FRP, CV and wavelength when comparisons were made within groups before and after atropine infusion. In sham animals, vehicle infusion or time-course of the experiment did not modify LV FRP, ERP, CV and wavelength. Conclusion Physical training increases LV wavelength, which can be one electrophysiological mechanism by which endurance training could protect against VF. Since modifications of ventricular refractoriness and wavelength do not seem dependent of intrinsic parasympathetic nervous system activity, other intrinsic mechanisms could be implied and warrant further research. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Instituto de Salud Carlos III, Generalitat Valenciana

B-PO01-004 NOCTURNAL VENTRICULAR TACHYCARDIA STORM: A MAN-MADE PHENOMENON

Drug refractory, rapid AF can be treated by atrioventricular junction (AVJ) catheter ablation with use of an existing or coincident pacemaker. Increased risk of sudden cardiac death (SCD) related to VF or polymorphic VT (PMVT) has been described afterwards. This is likely secondary to increased dispersion of ventricular refractoriness & is bradycardia-dependent. Malignant ventricular arrhythmias are reduced by increasing the basal pacing rate for several weeks after ablation. We report a case of nocturnal PMVT storm due to the Sleep Rate feature in an ICD being inadvertently left on following AVJ ablation. N/A A 68-year-old male with a history of NICM, primary prevention biventricular ICD (2018), permanent AF, HTN, COPD, chronic kidney disease, acute COVID-19 infection, and recent AVJ ablation 2 weeks prior, presented with VT storm & 21 ICD shocks. No prior significant burden of VT or NSVT was noted. A device interrogation showed normal function and programming (VVIR 90). He was started on IV amiodarone for arrhythmia suppression, however, continued to experience PMVT overnight and IV lidocaine was added. During the daytime hours he was ectopy free, but the following night he again experienced PMVT with appropriate device therapy. COVID-related myocarditis was suspected to have precipitated the electrical storm and elective intubation was being considered to help avoid further events. With further scrutiny, however, the VT appeared to be PVC/bradycardia initiated and exclusively occurring at night. The ICD was interrogated again & a sleep rate was noted to be programmed on at 50bpm starting at 10pm every night. The device was reprogrammed to VVIR 90 & the sleep rate feature turned off. No further VT was noted after these programming changes & the antiarrhythmic drips were discontinued. This case illustrates the real risk of bradycardia-dependent PMVT after AVJ ablation. In this case, not recognizing a bradycardia feature, sleep rate, being left on after AVJ ablation contributed to VT storm. With the myriad of programming features & options in contemporary pacing devices, it is important to program sleep & hysteresis features off after AVJ ablations & potentially in patients initiated on QT prolonging medications.

Cardiohemodynamic and Arrhythmogenic Effects of the Anti-Atrial Fibrillatory Compound Vanoxerine in Halothane-Anesthetized Dogs.

While vanoxerine (GBR-12909) is a synaptosomal dopamine uptake inhibitor, it also suppresses IKr, INa and ICa,L in vitro. Based on these profiles on ionic currents, vanoxerine has been developed as a candidate compound for treating atrial fibrillation. To investigate electropharmacological profiles, vanoxerine dihydrochloride was intravenously administered at 0.03 and 0.3 mg/kg to halothane-anesthetized dogs (n = 4), possibly providing subtherapeutic and therapeutic concentrations, respectively. The low dose increased the heart rate and cardiac output, whereas it prolonged the ventricular refractoriness. The high dose decreased the heart rate but increased the total peripheral vascular resistance, whereas it delayed the ventricular repolarization and increased the atrial refractoriness in addition to further enhancing the ventricular refractoriness. The extent of increase in the refractoriness in the atrium was 0.8 times of that in the ventricle. The high dose also prolonged the early and late repolarization periods of the ventricle as well as the terminal repolarization period. Meanwhile, no significant change was detected in the mean blood pressure, ventricular contraction, preload to the left ventricle, or the intra-atrial, intra-ventricular or atrioventricular conductions. The high dose can be considered to inhibit IKr, but it may not suppress INa or ICa in the in situ heart, partly explaining its poor atrial selectivity for increasing refractoriness. The prolongation of early repolarization period may reflect enhancement of net inward current, providing potential risk for intracellular Ca2+ overload. Thus, vanoxerine may provide both trigger and substrate toward torsade de pointes, which would make the drug less promising as an anti-atrial fibrillatory drug.

Analysis of electropharmacological and proarrhythmic effects of donepezil using the halothane-anesthetized intact dogs and the conscious chronic atrioventricular block ones.

Donepezil, an inhibitor for acetylcholinesterase used for patients with Alzheimer's disease, has been shown to inhibit IKr, occasionally inducing torsade de pointes. In order to analyze the causal relationship between donepezil treatment and onset of lethal arrhythmias, we initially assessed electropharmacological effects of donepezil hydrochloride of 0.01, 0.1, and 1 mg/kg, i.v. over 10 min using the halothane-anesthetized intact dogs (n = 4), possibly providing subtherapeutic to supratherapeutic plasma concentrations. Although the low or middle dose did not exert any effect, the high dose transiently increased the ventricular refractoriness along with modest prolongation of the late repolarization period, indicating potential IKr inhibitory action in vivo. Moreover, the high dose induced the positive chronotropic, inotropic, and dromotropic actions along with the pressor effect and prolongation of early repolarization period, suggesting sympathicotonic condition in the central nervous system. Next, we examined proarrhythmic effects of donepezil hydrochloride of 0.1 and 1 mg/kg, i.v. over 10 min using the conscious chronic atrioventricular block dogs (n = 4). Although the low dose hardly affected the cardiovascular variables, the high dose increased the atrial and ventricular rate without significantly altering the repolarization period, possibly reflecting sympathicotonic condition. Importantly, the high dose induced non-sustained ventricular tachycardia in half of the animals. Thus, donepezil by itself did not induce torsade de pointes in vivo, which suggests that donepezil-induced sympathicotonic condition may induce Ca2+ overload, triggering the ventricular arrhythmias, but might indirectly attenuate its IKr inhibitory action, preventing excessive repolarization delay.

Age-dependent changes in electrophysiology and calcium handling: implications for pediatric cardiac research.

Rodent models are frequently employed in cardiovascular research, yet our understanding of pediatric cardiac physiology has largely been deduced from more simplified two-dimensional cell studies. Previous studies have shown that postnatal development includes an alteration in the expression of genes and proteins involved in cell coupling, ion channels, and intracellular calcium handling. Accordingly, we hypothesized that postnatal cell maturation is likely to lead to dynamic alterations in whole heart electrophysiology and calcium handling. To test this hypothesis, we employed multiparametric imaging and electrophysiological techniques to quantify developmental changes from neonate to adult. In vivo electrocardiograms were collected to assess changes in heart rate, variability, and atrioventricular conduction (Sprague-Dawley rats). Intact, whole hearts were transferred to a Langendorff-perfusion system for multiparametric imaging (voltage, calcium). Optical mapping was performed in conjunction with an electrophysiology study to assess cardiac dynamics throughout development. Postnatal age was associated with an increase in the heart rate (181 ± 34 vs. 429 ± 13 beats/min), faster atrioventricular conduction (94 ± 13 vs. 46 ± 3 ms), shortened action potentials (APD80: 113 ± 18 vs. 60 ± 17 ms), and decreased ventricular refractoriness (VERP: 157 ± 45 vs. 57 ± 14 ms; neonatal vs. adults, means ± SD, P < 0.05). Calcium handling matured with development, resulting in shortened calcium transient durations (168 ± 18 vs. 117 ± 14 ms) and decreased propensity for calcium transient alternans (160 ± 18- vs. 99 ± 11-ms cycle length threshold; neonatal vs. adults, mean ± SD, P < 0.05). Results of this study can serve as a comprehensive baseline for future studies focused on pediatric disease modeling and/or preclinical testing.NEW & NOTEWORTHY This is the first study to assess cardiac electrophysiology and calcium handling throughout postnatal development, using both in vivo and whole heart models.

P1602Basic electrophysiological modifications induced by carvedilol in unstrectched and stretched ventricular myocardium

Abstract Background Acute regional ventricular stretch (ARVS) is a pathophysiologic event that may occur in certain situations, originating arrhythmogenic effects through the mechanoelectrical feedback. Mechanical effects of stretch originate calcium-related changes as sarcoplasmic recticulum Ca2+ overload that can trigger Ca2+ diastolic leaks (store-overload-induced Ca2+ release, SOICR), mediated by the cardiac ryanodine receptor (RyR2). SOICR seems to be implicated in the mechanisms underlying stretch-induced arrhythmias. Carvedilol can inhibit the overload of Ca2+ through blocking of beta-adrenergic receptors, and also suppress the release of Ca2+ induced by the SOICR. Purpose The aim of this investigation was to study the effects of carvedilol on the changes in ventricular refractoriness produced by AVRS, directly related with reentrant phenomenon and life-threatening arrhythmias. Methods Eleven adult male New Zealand White rabbits (3–3.5 kg) were heparinized (2500 IU) and euthanized by intravenous injection of sodium thiopental (100 mg/kg), according to European Ethic Guidelines. The hearts were excised, isolated and perfused in a Langendorff system. A pacing electrode and a recording multielectrode (121 electrodes) were placed on the left ventricle epicardium. The ARVS was produced by an “ad hoc” device introduced into the left ventricle. The ventricular effective and functional refractory periods (VERP, VFRP) were determined by the ventricular extrastimulus test with a basic cycle length of 250 ms, previously and at the third minute of ARVS, in control conditions and under Carvedilol (1 μM) infusion. The pacing threshold was determined for each situation and the stimulus amplitude was twice the diastolic threshold. A Student's t-test was used. Significance was reached when p&lt;0.05. Results Myocardial stretch reduced VERP and VFRP with respect to pre-stretch values under control conditions (VERP: 110±13 vs 99±16 ms, VFRP: 119±13 vs 113±13 ms, p&lt;0.05; n=10). No stretch-induced modifications of refractoriness were observed under carvedilol action (VERP: 139±18 vs 140±17 ms, VFRP: 161±29 vs 157±15 ms, ns; n=8). Before stretching, there were differences between control and carvedilol conditions (VERP: 110±13 vs 139±18 ms, VFRP: 119±13 vs 161±29 ms, p&lt;0.001), and during stretch VERP and VFRP were significantly higher under carvedilol perfusion than in control conditions (VERP: 99±16 vs 140±17 ms, VFRP: 113±13 vs 157±15 ms, p&lt;0.001). Conclusion The beta-adrenergic blocker and ryanodine receptor antagonist, carvedilol, attenuates the intrinsic electrophysiological modifications on refractoriness produced by myocardial acute local stretch.

Proarrhythmic proclivity of left-stellate ganglion stimulation in a canine model of drug-induced long-QT syndrome type 1

BackgroundLeft-stellate ganglion stimulation (LSGS) can modify regional dispersion of ventricular refractoriness, promote triggered activity, and reduce the threshold for ventricular fibrillation (VF). Sympathetic hyperactivity precipitates torsades de pointes (TdP) and VF in susceptible patients with long-QT syndrome type 1 (LQT1). We investigated the electromechanical effects of LSGS in a canine model of drug-induced LQT1, gaining novel arrhythmogenic insights. MethodsIn nine mongrel dogs, the left and right stellate ganglia were exposed for electrical stimulation. ECG, left- and right-ventricular endocardial monophasic action potentials (MAPs) and pressures (LVP, RVP) were recorded. The electromechanical window (EMW; Q to LVP at 90% relaxation minus QT interval) was calculated. LQT1 was mimicked by infusion of the KCNQ1/IKs blocker HMR1556. ResultsAt baseline, LSGS and right-stellate ganglion stimulation (RSGS) caused similar heart-rate acceleration and QT shortening. Positive inotropic and lusitropic effects were more pronounced under LSGS than RSGS. IKs blockade prolonged QTc, triggered MAP-early afterdepolarizations (EADs) and rendered the EMW negative, but no ventricular tachyarrhythmias occurred. Superimposed LSGS exaggerated EMW negativity and evoked TdP in 5/9 dogs within 30 s. Preceding extrasystoles originated mostly from the outflow-tracts region. TdP deteriorated into therapy-refractory VF in 4/5 animals. RSGS did not provoke TdP/VF. ConclusionsIn this model of drug-induced LQT1, LSGS readily induced TdP and VF during repolarization prolongation and MAP-EAD generation, but only if EMW turned from positive to very negative. We postulate that altered mechano-electric coupling can exaggerate regional dispersion of refractoriness and facilitates ventricular ectopy.

Differential effects of sevoflurane and propofol on swine cardiac conduction system

ObjectiveTo compare the effects of sevoflurane and propofol on the porcine cardiac conduction system. Study designA prospective, comparative study of electrophysiological properties of anaesthetics agents in an experimental porcine model. AnimalsA total of 36 hybrid Landrace-Large White pigs. MethodsAfter premedication with 20 mg kg−1 of intramuscular ketamine, anaesthesia was induced with 4.5 mg kg−1propofol intravenously. In 18 consecutive animals, anaesthesia was maintained with propofol (13 mg kg−1 hour−1) and in the remaining 18 animals with 2.66% sevoflurane. The femoral artery and vein were canalized for invasive monitoring, analytical blood gas sampling and intracardiac catheter insertion. Following instrumentation and after a period of stabilization, a customary electrophysiological evaluation was performed. We compared the electrophysiology of the sinus and atrioventricular node (AV) node under sevoflurane or propofol anaesthesia, and the effects of both anaesthetics on atrial and ventricular refractoriness. ResultsThere was a significant difference in sinus node recovery time between sevoflurane and propofol (907 ± 231 versus 753 ± 146 ms, p = 0.02). Sevoflurane in comparison with propofol significantly prolonged specialized AV conduction times, represented by an increased Wenckebach cycle length (272 ± 54 versus 235 ± 40 ms, p = 0.03) and AV nodal refractoriness (327 ± 34 versus 287 ± 30 ms, p = 0.002). In addition, sevoflurane prolonged ventricular refractoriness (298 ± 27 versus 255 ± 38 ms, p = 0.007) and the QT corrected interval (0.50 ± 0.05 versus 0.46 ± 0.09 ms, p = 0.005). Conclusions and clinical relevanceSevoflurane in comparison with propofol, depresses several parameters of sinus and AV nodal function and prolongs the ventricular refractoriness of the porcine cardiac conduction system. These findings should be taken into consideration for the choice of anaesthetic agents in clinical and experimental settings.

Transgenic short-QT syndrome 1 rabbits mimic the human disease phenotype with QT/action potential duration shortening in the atria and ventricles and increased ventricular tachycardia/ventricular fibrillation inducibility.

Short-QT syndrome 1 (SQT1) is an inherited channelopathy with accelerated repolarization due to gain-of-function in HERG/IKr. Patients develop atrial fibrillation, ventricular tachycardia (VT), and sudden cardiac death with pronounced inter-individual variability in phenotype. We generated and characterized transgenic SQT1 rabbits and investigated electrical remodelling. Transgenic rabbits were generated by oocyte-microinjection of β-myosin-heavy-chain-promoter-KCNH2/HERG-N588K constructs. Short-QT syndrome 1 and wild type (WT) littermates were subjected to in vivo ECG, electrophysiological studies, magnetic resonance imaging, and ex vivo action potential (AP) measurements. Electrical remodelling was assessed using patch clamp, real-time PCR, and western blot. We generated three SQT1 founders. QT interval was shorter and QT/RR slope was shallower in SQT1 than in WT (QT, 147.8 ± 2 ms vs. 166.4 ± 3, P < 0.0001). Atrial and ventricular refractoriness and AP duration were shortened in SQT1 (vAPD90, 118.6 ± 5 ms vs. 154.4 ± 2, P < 0.0001). Ventricular tachycardia/fibrillation (VT/VF) inducibility was increased in SQT1. Systolic function was unaltered but diastolic relaxation was enhanced in SQT1. IKr-steady was increased with impaired inactivation in SQT1, while IKr-tail was reduced. Quinidine prolonged/normalized QT and action potential duration (APD) in SQT1 rabbits by reducing IKr. Diverse electrical remodelling was observed: in SQT1, IK1 was decreased-partially reversing the phenotype-while a small increase in IKs may partly contribute to an accentuation of the phenotype. Short-QT syndrome 1 rabbits mimic the human disease phenotype on all levels with shortened QT/APD and increased VT/VF-inducibility and show similar beneficial responses to quinidine, indicating their value for elucidation of arrhythmogenic mechanisms and identification of novel anti-arrhythmic strategies.

Effects of the Inhibition of Late Sodium Current by GS967 on Stretch-Induced Changes in Cardiac Electrophysiology.

Mechanical stretch increases sodium and calcium entry into myocytes and activates the late sodium current. GS967, a triazolopyridine derivative, is a sodium channel blocker with preferential effects on the late sodium current. The present study evaluates whether GS967 inhibits or modulates the arrhythmogenic electrophysiological effects of myocardial stretch. Atrial and ventricular refractoriness and ventricular fibrillation modifications induced by acute stretch were studied in Langendorff-perfused rabbit hearts (n = 28) using epicardial multiple electrodes and high-resolution mapping techniques under control conditions and during the perfusion of GS967 at different concentrations (0.03, 0.1, and 0.3μM). On comparing ventricular refractoriness, conduction velocity and wavelength obtained before stretch had no significant changes under each GS967 concentration while atrial refractoriness increased under GS967 0.3μM. Under GS967, the stretch-induced changes were attenuated, and no significant differences were observed between before and during stretch. GS967 0.3μM diminished the normal stretch-induced changes resulting in longer (less shortened) atrial refractoriness (138±26ms vs 95±9ms; p < 0.01), ventricular refractoriness (155±18ms vs 124±16 ms; p < 0.01) and increments in spectral concentration (23±5% vs 17±2%; p < 0.01), the fifth percentile of ventricular activation intervals (46±8ms vs 31±3ms; p < 0.05), and wavelength of ventricular fibrillation (2.5±0.5cm vs 1.7±0.3cm; p < 0.05) during stretch. The stretch-induced increments in dominant frequency during ventricular fibrillation (control = 38%, 0.03μM = 33%, 0.1μM = 33%, 0.3μM = 14%; p < 0.01) and the stretch-induced increments in arrhythmia complexity index (control = 62%, 0.03μM = 41%, 0.1μM = 32%, 0.3μM = 16%; p < 0.05) progressively decreased on increasing the GS967 concentration. GS967 attenuates stretch-induced changes in cardiac electrophysiology.

Unanesthetized Rodents Demonstrate Insensitivity of QT Interval and Ventricular Refractory Period to Pacing Cycle Length.

Aim: The cardiac electrophysiology of mice and rats has been analyzed extensively, often in the context of pathological manipulations. However, the effects of beating rate on the basic electrical properties of the rodent heart remain unclear. Due to technical challenges, reported electrophysiological studies in rodents are mainly from ex vivo preparations or under deep anesthesia, conditions that might be quite far from the normal physiological state. The aim of the current study was to characterize the ventricular rate-adaptation properties of unanesthetized rats and mice.Methods: An implanted device was chronically implanted in rodents for atrial or ventricular pacing studies. Following recovery from surgery, QT interval was evaluated in rodents exposed to atrial pacing at various frequencies. In addition, the frequency dependence of ventricular refractoriness was tested by conventional ventricular programmed stimulation protocols.Results: Our findings indicate total absence of conventional rate-adaptation properties for both QT interval and ventricular refractoriness. Using monophasic action potential recordings in isolated mice hearts we could confirm the previously reported shortening of the action potential duration at fast pacing rates. However, we found that this mild shortening did not result in similar decrease of ventricular refractory period.Conclusion: Our findings indicate that unanesthetized rodents exhibit flat QT interval and ventricular refractory period rate-dependence. This data argue against empirical use of QT interval correction methods in rodent studies. Our new methodology allowing atrial and ventricular pacing of unanesthetized freely moving rodents may facilitate more appropriate utility of these important animal models in the context of cardiac electrophysiology studies.

Analysis of Safety Margin of Lithium Carbonate Against Cardiovascular Adverse Events Assessed in the Halothane-Anesthetized Dogs.

Lithium is one of the classical drugs that have been widely used for treating bipolar disorder. However, several cardiac side effects including sick sinus syndrome, bundle branch block, ventricular tachycardia/fibrillation, non-specific T-wave abnormalities in addition to Brugada-type electrocardiographic changes have been noticed in patients who were given antidepressant, anticonvulsant, and/or antipsychotic drugs besides lithium. In this study, we assessed cardiohemodynamic and electrophysiological effects of lithium carbonate by itself to begin to analyze onset mechanisms of its cardiovascular side effects. Lithium carbonate in intravenous doses of 0.1, 1, and 10mg/kg over 10min was cumulatively administered with an interval of 20min to the halothane-anesthetized beagle dogs (n = 4), which provided peak plasma Li+ concentrations of 0.02, 0.18, and 1.79mEq/L, respectively, reflecting sub-therapeutic to toxic concentrations. The low and middle doses prolonged the ventricular effective refractory period at 30min and for 5-30min, respectively. The high dose decreased the heart rate for 45-60min, delayed the intraventricular conduction for 15-20min and the ventricular repolarization at 45min, and prolonged the effective refractory period for 5-60min. No significant change was detected in the other cardiovascular variables. Thus, lithium alone may have a wide safety margin against hemodynamic adverse events; however, it would directly and/or indirectly inhibit Na+ and K+ channels, which may synergistically increase the ventricular refractoriness from the sub-therapeutic concentration and decrease the heart rate at the supra-therapeutic one. These findings may partly explain its clinically observed various types of arrhythmias as well as electrocardiographic changes.

Termination of Vernakalant-Resistant Atrial Fibrillation by Inhibition of Small-Conductance Ca2+-Activated K+ Channels in Pigs.

Evidence has emerged that small-conductance Ca2+-activated K+ (SK) channels constitute a new target for treatment of atrial fibrillation (AF). SK channels are predominantly expressed in the atria as compared with the ventricles. Various marketed antiarrhythmic drugs are limited by ventricular adverse effects and efficacy loss as AF progresses. A total of 43 pigs were used for the studies. AF reversion in conscious long-term tachypaced pigs: Pigs were subjected to atrial tachypacing (7 Hz) until they developed sustained AF that could not be reverted by vernakalant 4 mg/kg (18.8±3.3 days of atrial tachypacing). When the SK channel inhibitor AP14145 was tested in these animals, vernakalant-resistant AF was reverted to sinus rhythm, and reinduction of AF by burst pacing (50 Hz) was prevented in 8 of 8 pigs. Effects on refractory period and AF duration in open chest pigs: The effects of AP14145 and vernakalant on the effective refractory periods and acute burst pacing-induced AF were examined in anaesthetized open chest pigs. Both vernakalant and AP14145 significantly prolonged atrial refractoriness and reduced AF duration without affecting the ventricular refractoriness or blood pressure in pigs subjected to 7 days atrial tachypacing, as well as in sham-operated control pigs. SK currents play a role in porcine atrial repolarization, and pharmacological inhibition of these with AP14145 demonstrates antiarrhythmic effects in a vernakalant-resistant porcine model of AF. These results suggest SK channel blockers as potentially interesting anti-AF drugs.

Role of abnormal repolarization in the mechanism of cardiac arrhythmia.

In cardiac patients, life-threatening tachyarrhythmia is often precipitated by abnormal changes in ventricular repolarization and refractoriness. Repolarization abnormalities typically evolve as a consequence of impaired function of outward K+ currents in cardiac myocytes, which may be caused by genetic defects or result from various acquired pathophysiological conditions, including electrical remodelling in cardiac disease, ion channel modulation by clinically used pharmacological agents, and systemic electrolyte disorders seen in heart failure, such as hypokalaemia. Cardiac electrical instability attributed to abnormal repolarization relies on the complex interplay between a provocative arrhythmic trigger and vulnerable arrhythmic substrate, with a central role played by the excessive prolongation of ventricular action potential duration, impaired intracellular Ca2+ handling, and slowed impulse conduction. This review outlines the electrical activity of ventricular myocytes in normal conditions and cardiac disease, describes classical electrophysiological mechanisms of cardiac arrhythmia, and provides an update on repolarization-related surrogates currently used to assess arrhythmic propensity, including spatial dispersion of repolarization, activation-repolarization coupling, electrical restitution, TRIaD (triangulation, reverse use dependence, instability, and dispersion), and the electromechanical window. This is followed by a discussion of the mechanisms that account for the dependence of arrhythmic vulnerability on the location of the ventricular pacing site. Finally, the review clarifies the electrophysiological basis for cardiac arrhythmia produced by hypokalaemia, and gives insight into the clinical importance and pathophysiology of drug-induced arrhythmia, with particular focus on class Ia (quinidine, procainamide) and Ic (flecainide) Na+ channel blockers, and class III antiarrhythmic agents that block the delayed rectifier K+ channel (dofetilide).