Early Afterdepolarizations Amplitude Research Articles

Mechanisms of phase-3 early afterdepolarizations and triggered activities in ventricular myocyte models.

Early afterdepolarizations (EADs) are abnormal depolarizations during the repolarizing phase of the action potential, which are associated with cardiac arrhythmogenesis. EADs are classified into phase‐2 and phase‐3 EADs. Phase‐2 EADs occur during phase 2 of the action potential, with takeoff potentials typically above −40 mV. Phase‐3 EADs occur during phase 3 of the action potential, with takeoff potential between −70 and −50 mV. Since the amplitude of phase‐3 EADs can be as large as that of a regular action potential, they are also called triggered activities (TAs). This also makes phase‐3 EADs and TAs much more arrhythmogenic than phase‐2 EADs since they can propagate easily in tissue. Although phase‐2 EADs have been widely observed, phase‐3 EADs and TAs have been rarely demonstrated in isolated ventricular myocytes. Here we carry out computer simulations of three widely used ventricular action potential models to investigate the mechanisms of phase‐3 EADs and TAs. We show that when the T‐type Ca2+ current (ICa,T) is absent (e.g., in normal ventricular myocytes), besides the requirement of increasing inward currents and reducing outward currents as for phase‐2 EADs, the occurrence of phase‐3 EADs and TAs requires a substantially large increase of the L‐type Ca2+ current and the slow component of the delayed rectifier K+ current. The presence of ICa,T (e.g., in neonatal and failing ventricular myocytes) can greatly reduce the thresholds of these two currents for phase‐3 EADs and TAs. This implies that ICa,T may play an important role in arrhythmogenesis in cardiac diseases.

Big Ducks in the Heart: Canard Analysis Can Explain Large Early Afterdepolarizations in Cardiomyocytes

Early afterdepolarizations (EADs) are pathological voltage fluctuations that can occur in cardiac cells and are a potent source of potentially fatal arrhythmias. Recent works examining the mechanisms underlying EADs in minimal computational cardiac models have revealed that voltage-driven EADs are canard-induced mixed-mode oscillations whose properties are mediated by the rate at which these cells are paced. In this work, we analyze the mechanisms for the pacing-induced generation of different EAD behaviors in a reduced four-dimensional Luo--Rudy I model using slow-fast analysis. While previous explanations for EADs in this model have required manipulation of the underlying multitimescale structure, our approach does not and we find that the canard mechanism persists in generating EADs in this context. We also find that the canard mechanism gives a more complete explanation for the onset and properties of the EADs induced (e.g., EAD amplitude and number). In addition, we also find that the canards play an essential role in producing a richer set of behaviors than were seen in other minimal models, some of which have also been observed in experiments. These behaviors include pacing-induced termination of EADs, the periodic alternation of cardiac action potentials with and without EADs, as well as bistability between standard and EAD-containing action potentials at a fixed pacing rate. Finally, we show that this bistability can lead to hysteretic transitions between standard and arrhythmogenic action potentials under sufficiently slow oscillations in the pacing rate.

Determinants of early afterdepolarization properties in ventricular myocyte models.

Early afterdepolarizations (EADs) are spontaneous depolarizations during the repolarization phase of an action potential in cardiac myocytes. It is widely known that EADs are promoted by increasing inward currents and/or decreasing outward currents, a condition called reduced repolarization reserve. Recent studies based on bifurcation theories show that EADs are caused by a dual Hopf-homoclinic bifurcation, bringing in further mechanistic insights into the genesis and dynamics of EADs. In this study, we investigated the EAD properties, such as the EAD amplitude, the inter-EAD interval, and the latency of the first EAD, and their major determinants. We first made predictions based on the bifurcation theory and then validated them in physiologically more detailed action potential models. These properties were investigated by varying one parameter at a time or using parameter sets randomly drawn from assigned intervals. The theoretical and simulation results were compared with experimental data from the literature. Our major findings are that the EAD amplitude and takeoff potential exhibit a negative linear correlation; the inter-EAD interval is insensitive to the maximum ionic current conductance but mainly determined by the kinetics of ICa,L and the dual Hopf-homoclinic bifurcation; and both inter-EAD interval and latency vary largely from model to model. Most of the model results generally agree with experimental observations in isolated ventricular myocytes. However, a major discrepancy between modeling results and experimental observations is that the inter-EAD intervals observed in experiments are mainly between 200 and 500 ms, irrespective of species, while those of the mathematical models exhibit a much wider range with some models exhibiting inter-EAD intervals less than 100 ms. Our simulations show that the cause of this discrepancy is likely due to the difference in ICa,L recovery properties in different mathematical models, which needs to be addressed in future action potential model development.

Renal sympathetic stimulation and ablation affect ventricular arrhythmia by modulating autonomic activity in a cesium-induced long QT canine model

Our previous studies showed that renal sympathetic stimulation (RS) may facilitate ischemic ventricular arrhythmia (VA) by increasing left stellate ganglion (LSG) nerve activity, whereas renal sympathetic ablation (RA) may suppress VA. The purpose of this study was to investigate whether renal sympathetic interventions also can affect VA by modulating LSG activity in a cesium-induced long QT canine model. Twenty-four dogs were randomly divided into RS group (n = 8), RA group (n = 8), or control group (n = 8). Serum norepinephrine, LSG function, and LSG neural activity were measured before and 3 hours after RS or RA. Increasing doses of cesium chloride then were administered until a "threshold dose" produced sustained ventricular tachycardia or ventricular fibrillation. Early afterdepolarization amplitude, VA prevalence, and tachycardia threshold dose were compared among these groups. Nerve growth factor and c-fos protein expressed in the LSG also were examined. Serum norepinephrine, LSG function, and LSG neural activity were all significantly increased after 3 hours of RS and all were decreased 3 hours after RA. In addition, RS significantly decreased the tachycardia threshold dose, increased the early afterdepolarization amplitude, facilitated the incidence of VAs, and increased the expression of nerve growth factor and c-fos protein. In contrast, RA induced the opposite effects. RS promotes, whereas RA suppresses, the incidence of VAs in a canine model of cesium-induced long QT. Modulation of LSG neural activity by RS and RA may be responsible for these different effects.

Increased Susceptibility of Spontaneously Hypertensive Rats to Ventricular Tachyarrhythmias during the Early Stages of Hypertension

Hypertension is a risk factor for sudden cardiac death caused by ventricular tachycardia and fibrillation (VT/VF). We hypothesized that during the early stages of uncontrolled hypertension, the susceptibility to otherwise benign stress promotes VT/VF. To test this hypothesis we compared the susceptibility of 5-6-month-old male spontaneously hypertensive rats (SHR) and age/gender-matched normotensive rats (NR) to VT/VF during challenge with mild oxidative stress (H2O2, 0.15 mmol/L). H2O2 initiated spontaneous VT in all 30 SHR but none of the NR hearts. In 33% of SHR cases, focal VT degenerated to VF within 3 s. Simultaneous voltage-Ca optical mapping of Langendorff-perfused SHR hearts revealed that H2O2-induced VT/VF arose spontaneously from focal activations at the base and mid left ventricular epicardium. Microelectrode recording of SHR hearts showed that VT was initiated by early afterdepolarization (EAD)-mediated triggered activity. However, despite the increased susceptibility of SHR hearts to VT/VF, patch-clamped isolated SHR ventricular myocytes developed EADs and triggered activity to the same extent as NR ventricular myocytes, except that SHR myocytes had a relatively larger EAD amplitude. Histopathological and echocardiographic studies showed that compared to NR, SHR hearts exhibited increased left ventricular fibrosis and mild hypertrophy. We conclude that during the early stages of hypertension (i.e., prior to the development of overt heart failure) SHR hearts manifest increased susceptibility to VT/VF when challenged with mild oxidative stress that appears to be related to tissue remodeling (i.e., hypertrophy, fibrosis) moreso than cellular electrophysiological remodeling. Our findings highlight the need for aggressive treatment during the stages of early hypertension to minimize myocardial fibrosis, ventricular hypertrophy, and arrhythmias.

Increased susceptibility of spontaneously hypertensive rats to ventricular tachyarrhythmias in early hypertension.

Hypertension is a risk factor for sudden cardiac death caused by ventricular tachycardia and fibrillation (VT/VF). We hypothesized that, in early hypertension, the susceptibility to stress-induced VT/VF increases. We compared the susceptibility of 5- to 6-month-old male spontaneously hypertensive rats (SHR) and age/sex-matched normotensive rats (NR) to VT/VF during challenge with oxidative stress (H2 O2 ; 0.15 mmol l(-1) ). We found that only SHR hearts exhibited left ventricular fibrosis and hypertrophy. H2 O2 promoted VT in all 30 SHR but none of the NR hearts. In 33% of SHR cases, focal VT degenerated to VF within 3 s. Simultaneous voltage-calcium optical mapping of Langendorff-perfused SHR hearts revealed that H2 O2 -induced VT/VF arose spontaneously from focal activations at the base and mid left ventricular epicardium. Microelectrode recording of SHR hearts showed that VT was initiated by early afterdepolarization (EAD)-mediated triggered activity. However, despite the increased susceptibility of SHR hearts to VT/VF, patch clamped isolated SHR ventricular myocytes developed EADs and triggered activity to the same extent as NR ventricular myocytes, except with larger EAD amplitude. During the early stages of hypertension, when challenged with oxidative stress, SHR hearts showed an increased ventricular arrhythmogenicity that stems primarily from tissue remodelling (hypertrophy, fibrosis) rather than cellular electrophysiological changes. Our findings highlight the need for early hypertension treatment to minimize myocardial fibrosis, ventricular hypertrophy, and arrhythmias.

Selective Ablation of the Ligament of Marshall Reduces the Prevalence of Ventricular Arrhythmias Through Autonomic Modulation in a Cesium-Induced Long QT Canine Model.

The goal of this study was to investigate the effect of selective ablation of the ligament of Marshall (LOM) on ventricular arrhythmias (VAs). Previous studies have shown that selective stimulation of sympathetic elements of the LOM, the distalsegment of the ligament of Marshall that extends beyond the left superior pulmonary vein (LOMLSPV), might induceVAs. In protocol 1, the blood pressure and ventricular effective refractory period changes as a response to LOMLSPV stimulation and left stellate ganglion (LSG) stimulation were measured before and after LOMLSPV ablation in 8anesthetized dogs. In protocol 2, a total of 24 dogs were randomly divided into group 1 (cesium alone, n= 8), group 2 (cesium combined with LSG stimulation, n= 8), and group 3 (cesium combined with LSG stimulation after LOMLSPV ablation, n= 8). Early afterdepolarization amplitude, VA prevalence, and the tachycardia threshold (measured according to the dose of cesium administered) were compared among the groups. In protocol 1, both LOMLSPV stimulation and LSG stimulation significantly increased blood pressure and shortened the ventricular effective refractory period, both of which were significantly attenuated by LOMLSPV ablation. Inprotocol 2, compared with group 1, the prevalence of VAs and the early afterdepolarization amplitudes were significantly augmented in group 2 and were maintained at a comparable level in group 3. Furthermore, the tachycardia threshold in group 2 (0.625 mmol/kg) was significantly lower than that noted in groups 1 and 3 (both 1.000 mmol/kg; p< 0.05). LOMLSPV ablation reduced the prevalence of the VAs induced by cesium in combination with LSG stimulation, and the antiarrhythmic effect may involve the blockade of the sympathetic conduit between the LSG and the ventricles.

Tuning L-Type Ca2+ Current Properties to Suppress Early After depolarizations

Early afterdepolarizations (EADs) are highly arrhythmogenic transient depolarizations occurring during phase 2 or 3 of the cardiac action potential. We recently reported that EADs are highly sensitive to minimal shifts (by 1-5 mV) in the half activation/inactivation potentials (V1/2) of the L-type Ca2+ current (ICa,L), such that V1/2 modifications which reduce the window current voltage range were highly effective in suppressing EADs (Madhvani et al., 2011). To better understand the underlying mechanisms, we have further explored the relevance of ICa,L biophysical parameters to EADs formation. We took advantage of the dynamic clamp technique, a hybrid experimental-computational system permitting real-time introduction of a programmable conductance into a myocyte under current clamp. A consistent EAD regime was achieved by pacing ventricular myocytes at 0.2 Hz in the presence of 600 μM H2O2. The native ICa,L was abolished with 20 μM nifedipine, and replaced with the dynamic clamp-generated ICa,L to recapitulate EADs. We found that altering the slope of the steady-state activation curve had profound effects on EAD take-off potential and amplitude. For z = 3.2 e0, EAD amplitude was 22±1.7 mV (take-off potential to peak). Steepening the voltage dependence of activation (z = 5.7 e0) increased the take-off potential and reduced EAD amplitude to 5.6±0.6 mV. Steepening the voltage dependence of activation beyond z = 5 e0 resulted in small voltage oscillations (<1 mV) without frank EADs. In contrast, making the voltage dependence shallower increased EAD amplitude, especially when combined with a reduction of the non-inactivating component of ICa,L (pedestal). Combined with our previous findings, our results show how multiple ICa,L parameters affect EAD formation, providing a template for the development of therapeutic interventions.

Identification and physiological activity of survival factor released from cardiomyocytes during ischaemia and reperfusion

We carried out a screening of survival factors released from cells exposed to simulated ischaemia and reperfusion (sI/R) using the embryonic rat heart-derived cell line, H9c2 cells, and examined the physiological role of the identified factor. The culture medium supernatant of H9c2 cells exposed to sI/R was separated by column chromatography and the fractions examined for survival activity. The protein with survival activity was identified by mass spectrometry, and its physiological role was examined in the models of ischaemia. Cell survival activity was detected in at least three fractions of the cell supernatant collected during sI/R and subjected to a series of column chromatographic steps. Among the proteins measured by mass spectrometry and western blotting, a p36 protein identified as a glycolytic enzyme, lactate dehydrogenase muscle subunit (M-LDH), showed strong survival activity. H(2)O(2)-induced intracellular calcium overload in H9c2 cells and irregular Ca(2+) transients in adult rat cardiomyocytes were both found to be inhibited by pretreatment with M-LDH. M-LDH also lowered the frequency and amplitude of early afterdepolarizations induced by H(2)O(2) in adult rat cardiomyocytes and suppressed the ischaemia-reperfusion-induced reduction of cardiac output from mouse working heart preparations. M-LDH was found to increase the phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2), which plays a role in H9c2 cell survival. M-LDH released from cardiomyocytes after hypoxia and reoxygenation has a role in protecting the heart from oxidative stress-induced injury through an intracellular signal transduction pathway involving ERK1/2.

Contribution of L-Type Ca2+ Channels to Early Afterdepolarizations Induced by I Kr and I Ks Channel Suppression in Guinea Pig Ventricular Myocytes

Early afterdepolarizations (EADs) induced by suppression of cardiac delayed rectifier I (Kr) and/or I (Ks) channels cause fatal ventricular tachyarrhythmias. In guinea pig ventricular myocytes, partial block of one of the channels with complete block of the other reproducibly induced EADs. Complete block of both I (Kr) and I (Ks) channels depolarized the take-off potential and reduced the amplitude of EADs, which in some cases were not clearly separated from the preceding action potentials. A selective L-type Ca(2+) (I (Ca,L)) channel blocker, nifedipine, effectively suppressed EADs at submicromolar concentrations. As examined with the action potential-clamp method, I (Ca,L) channels mediated inward currents with a spike and dome shape during action potentials. I (Ca,L) currents decayed mainly due to inactivation in phase 2 and deactivation in phase 3 repolarization. When EADs were induced by complete block of I (Kr) channels with partial block of I (Ks) channels, repolarization of the action potential prior to EAD take-off failed to increase I (K1) currents and thus failed to completely deactivate I (Ca,L) channels, which reactivated and mediated inward currents during EADs. When both I (Kr) and I (Ks) channels were completely blocked, I (Ca,L) channels were not deactivated and mediated sustained inward currents until the end of EADs. Under this condition, the recovery and reactivation of I (Ca,L) channels were absent before EADs. Therefore, an essential mechanism underlying EADs caused by suppression of the delayed rectifiers is the failure to completely deactivate I (Ca,L) channels.

Suppression of cesium-induced ventricular tachyarrhythmias by atrial natriuretic peptide in rabbits

Background: Intravenous injection of cesium chloride (Cs) causes ventricular tachyarrhythmias in rabbits. We investigated whether these tachyarrhythmias were caused by increased pressure load and whether they could be suppressed by atrial natriuretic peptide (ANP). Methods and Results: Cs was injected in a bolus dose (1.5 mmol/kg), which was repeated 20 minutes later. Rabbits were then divided into 3 groups: control, ANP-treated, and hydralazine-treated groups. ANP or hydralazine was administered between the first and second Cs injections. The experiments were performed during intrinsic sinus rhythm (protocol A) or during ventricular pacing (protocol B). In protocol A, the second injection of Cs in the control group induced early afterdepolarizations and ventricular tachycardia, which were preceded by a marked increase in left ventricular end-diastolic pressure (LVEDP). Both ANP and hydralazine significantly suppressed Cs-induced increase in LVEDP. The arrhythmia score after the second injection of Cs was significantly lower in the ANP-treated and hydralazine-treated group compared with the control group (P <.005 and P <.05, respectively). In protocol B, the duration of left ventricular monophasic action potential and early afterdepolarization amplitude before and/or after the injections of Cs did not differ significantly between control and ANP-treated groups. Conclusions: Our results suggest that increased pressure load may play a role in the arrhythmogenic effect of Cs. The protective effect of ANP against Cs-induced ventricular tachycardia may be explained in part by a reduction in pressure overload. However, this effect might also be explained by the diverse action of ANP on the cardiovascular system.

Sustained Left Ansae Subclaviae Stimulation for a 5-hour Period Inhibits Cesium-induced Ventricular Arrhythmogenesis in Rabbits

The acute stimulation of the left ansae subclaviae (LAS) augments cesium chloride (Cs)- induced early afterdepolarizations (EADs) and ventricular arrhythmias. However, the effect of sustained cardiac sympathetic nerve stimulation on Cs-induced arrhythmogenesis remains to be elucidated. Three protocols were used. In protocol A, seven rabbits received continuous LAS stimulation for 5 h (study group), and were then given bolus injections of Cs at 5-min intervals (initial dose 1.5 mmol/kg, followed by repetitive doses 1 mmol/kg). Another eight rabbits received the same dose of Cs after a 5-h observation period without LAS stimulation (control group). The effects of 2 h of LAS stimulation were also assessed in five rabbits of each group. In protocol B, a bolus injection of Cs (1 mmol/kg) was administered during atrial pacing (cycle length: 250 ms) after a 5-h period with (study group, n=5) or without (control group, n=5) LAS stimulation, and the amplitude of Cs-induced EADs was measured. In protocol C, a bolus injection of isoproterenol (0.05 mg/kg) was given after a 5-h period with (study group, n=5) or without (control group, n=5) LAS stimulation to assess the sensitivity to β-adrenergic stimulation. In protocol A, the cumulative doses of Cs required for the induction of ventricular tachycardia (VT) and fibrillation (VF) were significantly greater in the study group than in the control group (4.4±0.1v2.8±0.3 mmol/kg for VT,P<0.05; 5.8±0.3v4.1±0.4 mmol/kg for VF,P<0.05). However, 2 h of LAS stimulation did not influence the cumulative doses of Cs required for the induction of VT and VF. In protocol B, the amplitude of Cs-induced EADs was significantly lower in the study group than in the control group. In protocol C, the increase in rate-pressure product by isoproterenol was significantly less in study than in control groups (3492±612v6504±829,P<0.05). These results suggest that sustained LAS stimulation exerts a protective effect against Cs-induced arrhythmogenesis in the rabbit heart, which may be partially explained by desensitization to the β-adrenergic stimulation.

Electrophysiologic features of torsades de pointes: insights from a new isolated rabbit heart model.

The exact electrophysiologic mechanism of torsades de pointes (TdP) is under intense investigation. No isolated animal heart model of this particular arrhythmia exists. In isolated rabbit hearts, TdP was induced by means of bradycardia in the presence of a high concentration of d-sotalol (10(-4) M) and shortly after lowering the concentration of potassium and magnesium in the perfusate. Multiple simultaneous epicardial and endocardial monophasic action potentials (MAPs) and volume-conducted 12-lead ECGs were recorded. d-Sotalol prolonged repolarization and increased dispersion of ventricular repolarization compared to baseline recordings. With the onset of low potassium and magnesium concentrations, repolarization was further prolonged and dispersion of repolarization was further increased followed by the occurrence of early afterdepolarizations (EADs) in the majority of MAP recordings, i.e., at both endocardial and epicardial locations of both ventricles. Upon increase of EAD amplitude, triggered arrhythmias with TdP of up to 42 beats ensued in 10 of 11 hearts studied. MAP duration at 90% repolarization (APD90), dispersion of APD90, and the incidence of EADs as well as dispersion of the QT interval and T wave area were significantly higher in beats triggering bigemini, couplets, or runs of TdP. TdP observed in this new isolated heart model was associated with markedly increased dispersion of ventricular repolarization and the occurrence of EADs in multiple locations of the heart. TdP is initiated when the amplitude of an EAD reaches threshold for initiation of the first beat of an episode.

808-2 Sudden Heart Rate Speeding and Slowing Facilitates the Inducibility of Ventricular Tachycardia in Dogs

Clinically, torsades de pointes (TdP) often occurs when the heart rate suddenly slows (eg. atrial fibrillation to sinus rhythm). We investigated whether the dose of cesium chloride (CsCI) required to induce early afterdepolarizations (EADs), the putative mechanism of TdP. and ventricular tachycardia (VT) was different in dogs with a paced left ventricular cycle length (PCL) of 1,000 msec for a 1 week versus dogs with a PCL of 1,000 msec for 1 week and 500 msec for 1 hour prior to a PCL of 1,000 msec. All dogs had atrioventricular (AV) block induced by radiofrequency ablation and were studied closed chest. While recording surface ECG leads I.II.III and LV endocardlal monophasic action potential (MAP), CsCI was injected Incrementally (0.25, 0.5, 0.625, 0.75, 1.0 mM/kg) until sustained VT was induced. In group 1 (n = 6), CsCI was injected during PCL = 1,000 msec. In group 2 (n = 7), CsCI was injected during PCL = 1,000 msec after PCL = 500 msec for 1 hour. In group 1, VT was induced at 0.75 mM/kg in 3 dogs and at 1.0 mM/kg in 3 dogs. VT was induced at 0.75 mM/kg in all 7 dogs in group 2(p &lt; 0.05). The area of EAD as a percentage of LV MAP area (%EAD) in group 2 dogs exceeded that of group 1 at 0.5, 0.625, 0.75 mM/kg CsCI (mM/kg) 0.25 0.5 0.625 0.75 Group 1 (%EAD) 108 ± 2.4 115 ± 39 119 ± 5.4 129 ± 5.1 Group 2 (%EAD) 108 ± 3.6 118 ± 2.1 127 ± 3.9 135 ± 5.4 p ns &lt;0.05 &lt;0.01 &lt;0.05 We conclude that only 1 hour of rapid pacing after 1week of bradycardia is sufficient to produce a change in myocardial responsiveness to the K + channel blocker, CsCI, and increases the susceptibility of VT induction, possibly via an increase in EAD amplitude

Effects of vagal stimulation on cesium-induced early afterdepolarizations and ventricular arrhythmias in rabbits.

Previous evidence has shown that increased sympathetic tone enhances the cesium chloride (Cs)-induced early afterdepolarizations (EADs) and ventricular tachycardias (VTs). We assessed the effects of vagal stimulation on Cs-induced EADs and ventricular arrhythmias in the rabbit heart. Monophasic action potentials (MAPs) of the left ventricular endocardium were recorded simultaneously with surface ECG. Two protocols were used: 1) While in their intrinsic sinus rhythm, 11 rabbits were given three intravenous Cs injections (1 mM/kg) 20 minutes apart, and the effects of vagal stimulation on the ventricular arrhythmias thus induced were examined. 2) Under constant atrial pacing (cycle length, 250 msec), EAD amplitude was measured after Cs injection (1 mM/kg) without (five rabbits, control group) or with (four rabbits, vagal stimulation group) vagal stimulation. We observed the following. 1) Cs produced EADs and VTs of polymorphic (PVT) and monomorphic (MVT) types. During PVT, the take-off potential of repetitive premature action potentials in MAP recordings was about the same as the peak level of EADs, and during MVT, the take-off potential was the level of full repolarization. Vagal stimulation suppressed PVT but not MVT. Vagal stimulation after spontaneous termination of MVT restarted MVT of the same morphology at a rate much slower than the preceding sinus rate. 2) EAD amplitude was significantly smaller in the vagal stimulation group than in the control group. The results suggest that PVT originated from triggering by EADs, whereas MVT was of different origin, and that vagal stimulation suppressed PVT by decreasing the amplitude of EADs.

Early afterdepolarizations and triggered activity induced by cocaine. A possible mechanism of cocaine arrhythmogenesis.

Cocaine may produce life-threatening cardiac arrhythmias, but it is not clear whether this is an indirect effect of coronary vasoconstriction and ischemia or a direct myocardial effect of the substance. Except for its effects on the Na+ current as a local anesthetic, little is known about the direct electrophysiological actions on cardiac cells. Therefore, we studied the effects of cocaine on action potentials and membrane currents in isolated feline ventricular myocytes to test the hypothesis that cocaine-induced arrhythmogenesis may be based on cellular and ionic mechanisms. Action potentials and membrane currents were recorded using the patch clamp technique. Single cells were isolated from feline left ventricles by enzymatic digestion. Exposure to cocaine (10 or 50 microM) depressed the plateau phase of the action potential and prolonged action potential duration. Action potential duration measured at 90% repolarization (APD90) was increased from 280 +/- 12 msec to 325 +/- 17 msec (p less than 0.01) by 5-minute exposure to 10 mumol cocaine, when the cells were stimulated at 1 Hz. During exposure to 50 mumol cocaine, APD90 was markedly increased from 298 +/- 13 msec to 437 +/- 35 msec (p less than 0.01) in seven of 16 cells, and early afterdepolarizations (EADs) developed in these cells. The take-off potential and the amplitude of EADs were -28.3 +/- 2.3 mV and 16.8 +/- 1.2 mV, respectively. Triggered activity arising from EADs was induced in four of the seven cells. Addition of 1 nmol isoproterenol augmented EADs and induced sustained triggered activity, whereas they were suppressed by exposure to 2 microM verapamil. Whole-cell voltage clamp experiments revealed that cocaine (50 microM) reduced the peak L-type Ca2+ current from 1.03 +/- 0.13 nA to 0.79 +/- 0.11 nA (23% reduction, p less than 0.05). Cocaine also reduced the peak delayed rectifier K+ current from 362 +/- 51 pA to 113 +/- 32 pA (69% reduction, p less than 0.01). However, cocaine did not affect activation and inactivation kinetics of these channels. Cocaine had no effect on the inward rectifier K+ current. We conclude that cocaine can prolong action potential duration and induce EADs and triggered activity by blocking the delayed rectifier K+ current, and that cocaine-induced abnormalities of repolarization, modulated by its inhibitory effects on catecholamine reuptake, may play a role in the potential of cocaine for induction of acute fatal arrhythmias.

Modulation of drug effects by regional sympathetic denervation and supersensitivity.

Regional sympathetic denervation, such as that produced by a myocardial infarction, causes electrophysiological heterogeneity in the ventricles. The purpose of this study was to test the hypothesis that such denervation could cause drugs to exert heterogeneous myocardial effects. Sympathetic stimulation increases the amplitude of cesium chloride-induced early afterdepolarizations (EADs). The amplitude of these induced EADs was used to determine whether drug responses were different in innervated versus denervated areas of the heart. A canine model of sympathetic denervation was created at the cardiac apex by either transmural myocardial infarction (n = 19) or phenol application (n = 11). Cesium chloride (84 mg/kg) was infused while monophasic action potential recordings were simultaneously obtained from the base and apex of the left ventricle using an epicardial contact electrode. We found that control (innervated) dogs (n = 17) showed no difference in the EAD amplitude recorded from the apex compared with the base. In dogs with apical sympathetic denervation, the EAD amplitude was greater at the innervated base during ansae subclaviae stimulation than at the denervated apex (25.8 +/- 6.6% at base versus 18.8 +/- 6.7% at apex, p less than 0.001). However, during norepinephrine infusion, the EADs recorded from the denervated apex were greater than those recorded from the innervated base (23.3 +/- 7.6% at apex versus 20.6 +/- 6.0% at base, p less than 0.02) due to denervation supersensitivity. These data show that regional myocardial denervation creates autonomic and electrophysiological heterogeneity and the substrate for heterogeneous drug actions. This drug-induced electrophysiological heterogeneity may be another mechanism for proarrhythmia.

Effects of lidocaine and verapamil on early afterdepolarizations in isolated rabbit sinoatrial node.

The effects of local anaesthetic anti-arrhythmic agents (lidocaine) and Ca antagonists (Verapamil) have been examined on the early afterdepolarizations (EADs) in isolated rabbit sinoatrial (SA) node. In a nominally calcium free and magnesium free solution, strontium (0.5-4.5 mM) produced an EAD in small pieces isolated from the SA node. The additional presence of 0.02-0.6 mM lidocaine did not abolish the strontium (0.5 mM)-induced EAD. 0.6 mM lidocaine produced an increase in EAD amplitude and then abolished a prolonged action potential (AP) associated with repetitive EADs. On the other hand, the addition of 4 micro M verapamil abolished the strontium (0.5 mM)-induced EAD but did not abolish the AP.It is concluded that under conditions when the AP is not abolished, EAD blockade by lidocaine is less effective than that by verapamil.

Brady Cardie‐Dependent Early Afterdepolarizations in a Patient with QTU Prolongation and Torsade de Pointes in Association with Marked Bradycardia and Hypokalemia

Endocardial monophasic action potentials (MAPs) were recorded at the right ventricular apex in a patient with QTU prolongation and torsade de pointes (TdP) in association with marked bradycardia and hypokalemia. There was a distinct hump on phase 3 repolarization of the MAPs characteristic of early afterdepolarizations (EADs), which was associated with marked prolongation of the QTU interval on the surface electrocardiogram. EAD amplitude was bradycardia dependent, and there was a strong correlation (r = 0.91) between the preceding RR interval and the amplitude of the EAD (percent of MAP amplitude). Intravenous administration of lidocaine or right ventricular pacing suppressed the ventricular premature complexes and TdP in association with the suppression of the EADs on the MAPs. Furthermore, these EADs were not recorded on the MAPs 1 month later when the QTU prolongation and TdP had disappeared. These findings suggest that the TU abnormality and QTU prolongation responsible for TdP were due to bradycardia-dependent EADs.

Monophasic action potentials in the diagnosis of triggered arrhythmias

ECHANISMS responsible for cardiac arrhythmias are generally divided into three major categories: disorders of impulse formation, disorders of impulse conduction, and combinations of both causes.‘-’ Although this classification is limited and contains some inconsistencies, it serves as a useful framework in which to discuss the pathogenesis of cardiac arrhythmias. Normal automaticity refers to the normal diastolic depolarization of pacemakers found in the normal sinus node, Purkinje fibers, and in other areas of the heart. Abnormal automaticity, a disorder of impulse formation, may occur in many of these fibers, as well as in atria1 and ventricular muscle subjected to a variety of pertubations. Triggered activity, another form of abnormal impulse formation, is a transient membrane oscillation triggered by cardiac depolarization. When this oscillation occurs early, before repolarization is completed, it is called an early afterdepolarization (Fig 1). When it occurs late, after repolarization is completed, it is called a delayed afterdepolarization (Fig 2).3 Slow heart rates generally increase the amplitude of early afterdepolarizations, whereas fast heart rates, within limits, increase the amplitude of delayed afterdepolarizations. Early afterdepolarizations result from a reduced repolarizing current in comparison with the depolarizing current. This may be caused by a reduced outward current, an increased inward current, or both mechanisms.3 Because a variety of interventions that affect different currents can abolish earIy afterdepolarizations (eg, calcium channel blockers,6 sodium channel blockers,7 increasing rate or increasing external potassium concentration) and because a variety of substances that can alter different currents can produce early afterdepolarizations (eg, quinidine7 and related drugs: a sea anemone polypeptide,’ calcium current agonists,’ acidosis,” low extracellular potassium concentration,” hypoxia, and catecholamines), a diversity of currents have been suggested as causes of early afterdepolarizations. These include a calcium current through L-type calcium channels,’ the sodium “window” or slowly inactivating current,” sodium channel exchange mechanisms,13 the transient inward current activated by elevated intracellular calcium,14 intracellular potassium accumulation,*2 and the I,, current.” Cesium blocks inward rectifying potassium currents and delays repolarizatio# to produce early afterdepolarizations. However, the ionic basis of cesium-induced afterdepolarizations is still unclear. Although some early afterdepolarizations may be due to electrotonic membrane events,” a calcium current through L-type calcium channels may be involved.“” Cesium produces early afterdepolarizations in canine cardiac Purkinje fibers’9‘21 and in the intact heart.21-23 Magnesium suppresses these early afterdepolarizations and associated ventricular tachyarrhythmias,“~21 possibly by blocking the calcium current,24 whereas ansae subclaviae stimulation, infusion of norepinephrine, and selective CY- and P-agonists augment early afterdepolarizations.