Role of the Na/Ca exchanger in arrhythmias in compensated hypertrophy.

Sudden, presumably arrhythmic, death is common in heart failure patients. Although total mortality is highest in end-stage failure, the fraction of sudden death in total mortality is higher in the early stages. In each of these stages various, not necessarily identical, ionic mechanisms may contribute to arrhythmogenesis. Dogs with chronic complete atrioventricular block (6-8 weeks) have an increased risk for arrhythmias and sudden death and have compensated biventricular hypertrophy. In this animal model, Ca(2+) release from the sarcoplasmic reticulum (SR) is not reduced. For low frequencies of stimulation, the SR Ca(2+) content is increased, related to a higher activity of the Na/Ca exchanger. Spontaneous Ca(2+) release induces inward Na/Ca exchange current, which can lead to delayed afterdepolarizations (DADs) triggering a new action potential. Such arrhythmogenic DADs and ectopic beats also can be observed in vivo during monophasic action potential recording. They appear after pacing protocols, and/or administration of ouabain, which result in contractile potentiation, suggestive of a enhanced sarcoplasmic reticulum Ca(2+) content. Other arrhythmogenic mechanisms related to increased dispersion of repolarization also can be identified in vivo. Downregulation of delayed K(+) currents is an important factor in prolongation of action potentials. In conclusion, in this animal model of compensated hypertrophy, Ca(2+) handling is different from end-stage heart failure. It is possible that arrhythmogenic mechanisms related to a higher Ca(2+) load contribute to the high incidence of sudden death in stages of compensated hypertrophy before overt heart failure. However, more than one ionic remodeling process is likely to be present, and different cellular mechanisms of arrhythmias can coexist.

Chronic amiodarone evokes no torsade de pointes arrhythmias despite QT lengthening in an animal model of acquired long-QT syndrome.

BACKGROUND: Amiodarone is an effective antiarrhythmic drug rarely associated with torsade de pointes arrhythmias (TdP). The noniodinated compound dronedarone could resemble amiodarone and be devoid of the adverse effects. In the dog with chronic complete atrioventricular (AV) block (CAVB) and acquired long-QT syndrome, the electrophysiological and proarrhythmic properties of the drugs were compared after 4 weeks of oral treatment. METHODS AND RESULTS: Amiodarone (n=7, 40 mg. kg(-1). d(-1)) and dronedarone (n=8, 20 mg/kg BID) were started at 6 weeks of CAVB (baseline). Six dogs served as controls. Surface ECGs and endocardially placed monophasic action potential catheters in the left (LV) and right (RV) ventricles were recorded to assess QTc time, action potential duration (APD), interventricular dispersion (DeltaAPD=LV APD minus RV APD), early afterdepolarizations (EADs), ectopic beats, and TdP. Both amiodarone (+21%) and dronedarone (+31%) increased QTc time. Amiodarone showed no increase in DeltaAPD in 4 of 7 dogs, whereas dronedarone augmented DeltaAPD in 7 of 8 animals. After dronedarone, TdP occurred in 4 of 8 dogs with the highest DeltaAPD (105+/-20 ms). TdP was never seen with amiodarone, not even in the dogs that had DeltaAPD values comparable to those with dronedarone. Furthermore, a difference existed in EADs and ectopic activity incidence (dronedarone 3 of 8; amiodarone 0 of 7), which was also seen during an epinephrine challenge. CONCLUSIONS: In the CAVB dog model, both amiodarone and dronedarone prolong QT time (class III effect). The absence of TdP with amiodarone seems to be related to homogeneous APD lengthening in the majority of dogs and the lack of EADs and/or ventricular ectopic beats in all.

Electrophysiological parameters indicative of sudden cardiac death in the dog with chronic complete AV-block.

BACKGROUND: The dog model of chronic complete AV-block (CAVB) demonstrates a considerable incidence of (witnessed) sudden death (16/117 dogs). In this study we tried to: (1) elucidate the mechanisms of sudden death using an ECG telemetry device and (2) identify retrospectively the risk parameters indicative of this arrhythmogenic death. METHODS: Between 1994 and 1998, 78 anesthetized dogs underwent an extensive electrophysiological study including: (1) left- (LV) and right ventricular (RV) monophasic action potential (MAP) recordings to assess Delta MAPD (LV APD minus RV APD) and (2) pacing protocols (PES) to induce torsade de pointes arrhythmias (TdP) at 4--6 weeks CAVB. Eight animals experienced sudden cardiac death (SCD) during the follow-up period (mean 7+/-3 weeks CAVB). Since the response of the CAVB dog to class III drugs is not uniform we also made comparisons among the SCD group, TdP drug responders and non-responders. For this purpose we selected all animals which (1) received almokalant (n=15, 0.12 mg/kg/5 min) or ibutilide (n=9, 0.025 mg/kg/5 min) as an additional challenge to induce TdP and (2) had a follow-up period of at least 4 weeks. RESULTS: Six out of eight SCD dogs showed inducible TdP at baseline. Two of eight dogs had telemetric ECG surveillance and both revealed polymorphic VT as the cause of SCD. Baseline Delta MAPD of the SCD (90+/-15 ms) was significantly higher than the non-SCD group (n=70, 60+/-30 ms). Of the 24 dogs which received class III drugs, 12 belonged to the TdP responder group. Delta MAPD of the TdP responder group (80+/-15 ms) was similar to the SCD group and significantly higher compared to the non-responder group (n=12, 40+/-25 ms). QT-time and cycle length of idioventricular rhythm were not different. CONCLUSION: In the CAVB dog model, SCD is (1) most probably related to TdP while (2) inducible TdP and the measure of Delta MAPD at baseline indicate susceptibility to SCD.

Contractile adaptations preserving cardiac output predispose the hypertrophied canine heart to delayed afterdepolarization-dependent ventricular arrhythmias.

BACKGROUND: In dogs, chronic complete atrioventricular block (CAVB) results in structural (biventricular hypertrophy) and electrical (delayed repolarization) remodeling, which predisposes the heart to torsade de pointes arrhythmias. We assessed the contractile alterations in the CAVB dog and tested the hypothesis that these adaptations increase delayed afterdepolarization (DAD)-dependent triggered arrhythmias. METHODS AND RESULTS: Steady-state and dynamic (fast pacing: 1 to 68 stimuli) left and right ventricular systolic and diastolic parameters were determined by positive and negative inotropic interventions at acute AVB and CAVB. Concomitantly, left and right ventricular endocardial monophasic action potentials were registered. In CAVB, all systolic contractile parameters were markedly increased, resulting in preserved cardiac output. The increase was most pronounced at low heart rates, altering the force-frequency response. At both acute AVB and CAVB, the degree of potentiation of cardiac function with pacing was dependent on the number of stimuli and showed a maximum at 8 to 13 stimuli. With CAVB, this potentiation curve was shifted upward, and it was only then that pacing resulted in DADs (in 8 of 10 dogs) and ectopic beats (EBs, in 6 of 10 dogs). The incidence of EBs in relation to the number of stimuli also had a maximum at 8 to 13 stimuli. Ouabain increased the incidence of DADs and EBs, whereas the negative inotropic interventions prevented them completely. CONCLUSIONS: The alterations responsible for improvement in systolic contractile function in CAVB dogs predispose the hypertrophied heart to DAD-dependent triggered arrhythmias during positive inotropic interventions.

Enhanced Ca(2+) release and Na/Ca exchange activity in hypertrophied canine ventricular myocytes: potential link between contractile adaptation and arrhythmogenesis.

BACKGROUND: Ventricular arrhythmias are a major cause of sudden death in patients with heart failure and hypertrophy. The dog with chronic complete atrioventricular block (CAVB) has biventricular hypertrophy and ventricular arrhythmias and is a useful model to study underlying cellular mechanisms. We investigated whether changes in Ca(2+) homeostasis are part of the contractile adaptation to CAVB and might contribute to arrhythmogenesis. METHODS AND RESULTS: In enzymatically isolated myocytes, cell shortening, Ca(2+) release from the sarcoplasmic reticulum (SR), and SR Ca(2+) content were enhanced at low stimulation frequencies. Ca(2+) influx through L-type Ca(2+) channels was unchanged, but Ca(2+) influx via the Na/Ca exchanger was increased and contributed to Ca(2+) loading of the SR. Inward Na/Ca exchange currents were also larger. Changes in Ca(2+) fluxes were less pronounced in the right versus left ventricle. CONCLUSIONS: Enhanced Na/Ca exchange activity may improve contractile adaptation to CAVB but at the same time facilitate arrhythmias by (1) increasing the propensity to Ca(2+) overload, (2) providing more inward current leading to (nonhomogeneous) action potential prolongation, and (3) enhancing (arrhythmogenic) currents during spontaneous Ca(2+) release.

The dynamic behavior of the diastolic slope of monophasic action potential can be related to the occurrence and maintenance of delayed afterdepolarization dependent arrhythmias.

We have described the value of the diastolic slope of the MAP recording at the end of a pacing train as a qualifying marker for the induction of delayed afterdepolarization (DAD) dependent arrhythmias. In the present study (1) the behavior of the slope at different time points during a pacing train was quantified and related to the arrhythmogenic outcome (group A) and (2) termination of DAD dependent VT was related to changes in the slope steepness (group B). In dogs with chronic complete AV block, a MAP was recorded during (1) ventricular pacing, before and after ouabain administration (group A) and (2) 6 spontaneous and 6 lidocaine induced VT terminations (group B). During control (group A), the slope at the end of pacing train was 5 +/- 3 m V/s (mean +/- SD), independent of the pacing duration. During ouabain, this increased to 20 +/- 15 mV/s (P < 0.05), varying with the duration of pacing. The slope was steeper after pacing for 4 seconds, compared to 20 seconds (26 +/- 12 mV/s vs 16 +/- 13 mV/s, P < 0.05) which corresponded with more frequent VT induction. In spontaneously terminating VTs (group B), CL increased from 353 +/- 54 ms at the start to 434 +/- 78 ms (P < 0.05) before VT termination. This corresponded with a decreasing steepness of the slope from 19 +/- 10 mV/s to 6 +/- 5 mV/s (P < 0.05). In lidocaine induced VT termination, the CL and the steepness of the slope showed an identical behavior. There is a dynamic variation in the steepness of the diastolic slope during pacing, which depends on the duration of pacing and predicts arrhythmogenic outcome. Furthermore, a decrease in steepness of the slope during DAD dependent VT can be used to predict VT termination.

Enhanced susceptibility for acquired torsade de pointes arrhythmias in the dog with chronic, complete AV block is related to cardiac hypertrophy and electrical remodeling.

BACKGROUND: Chronic, complete AV block (CAVB) in the dog leads to ventricular hypertrophy, which has been described as an independent risk factor for arrhythmias. In this model, we examined (1) whether the short- and long-term electrical adaptations predispose to acquired torsade de pointes arrhythmias (TdP) and (2) the nature of the structural and functional adaptations involved. METHODS AND RESULTS: We determined (1) endocardial right (RV) and left (LV) ventricular APD, DeltaAPD (LV APD-RV APD), presence of EADs at 0 weeks (acute: AAVB), and CAVB (6 weeks) and inducibility of TdP by pacing and d-sotalol (n=10); (2) steady-state and dynamic LV hemodynamics at 0 and 6 weeks (n=6); (3) plasma neurohumoral levels in time (n=7); (4) structural parameters of the LV and RV of CAVB dogs (n=6) compared with sinus rhythm (SR) dogs (n=6); and (5) expression of ventricular mRNA atrial natriuretic factor (ANF) in CAVB (n=4) and SR (n=4) dogs. Compared with AAVB, CAVB led to nonhomogeneous prolongation of LV and RV APD and different sensitivity for d-sotalol, leading to EADs (4 of 14 versus 9 of 18, P<0.05), increased DeltaAPD (45+/-30 versus 125+/-60 ms, P<0.05), and induction of TdP in most dogs (0% versus 60%, P<0.05). CAVB led to biventricular hypertrophy, whereas LV function was similar in AAVB and CAVB. The neurohumoral levels were transiently elevated. The LV and RV collagen and the capillary/fiber ratio remained normal, whereas ventricular ANF mRNA was not detectable. CONCLUSIONS: The electrical remodeling occurring after CAVB predisposes the heart to acquired TdP, whereas the structural changes (hypertrophy) are successfully aimed at maintaining cardiac function.

Combining monophasic action potential recordings with pacing to demonstrate delayed afterdepolarizations and triggered arrhythmias in the intact heart. Value of diastolic slope.

BACKGROUND: In the intact heart, methodological difficulties hamper the direct visualization of delayed afterdepolarizations (DADs) responsible for triggered arrhythmias. Therefore, we tested the hypothesis that a combination of pacing and the recording of a monophasic action potential (MAP) could facilitate the recognition of ouabain-induced DADs and triggered arrhythmias by demonstrating an increase in the diastolic baseline slope (dV/dT) of the MAP recording at the end of a pacing train. METHODS AND RESULTS: In anesthetized dogs with chronic atrioventricular block, a right ventricular endocardial MAP was recorded during (1) control (n = 11), (2) 15 to 45 minutes after administration of ouabain (45 +/- 10 micrograms/kg, n = 11), (3) 10 minutes after administration of lidocaine (3 mg/kg, n = 5), and (4) during lidocaine washout (n = 3). Pacing was performed with the MAP catheter. Also, the protocol was performed in 3 dogs with conducted sinus rhythm during control and ouabain circumstances. During control, the slope value was 2 +/- 2 mV/s (mean +/- SD), the incidence of DADs after the stimulation train was 6%, and no ventricular tachycardias (VTs) were induced in dogs with atrioventricular block. During ouabain administration, the slope and DAD incidences increased to, respectively, 26 +/- 14 mV/s and 74% (P < .05 for both). VTs were induced frequently. Lidocaine prevented VT induction by decreasing the slope and the incidence of DADs. This effect disappeared after lidocaine washout. During conducted sinus rhythm, similar results were found. CONCLUSIONS: By combining pacing and MAP recordings, the diastolic slope observed on MAP recordings in ouabain-intoxicated hearts can be used as a marker for DADs and triggered arrhythmias. This finding may be helpful in identifying triggered activity in the intact heart.

Mechanism-specific antiarrhythmic effects of the potassium channel activator levcromakalim against repolarization-dependent tachycardias.

INTRODUCTION: The hypothesis that levcromakalim, a potassium channel (IK-ATP) activator with antihypertensive properties, has a mechanism-specific antiarrhythmic action against repolarization-dependent ventricular tachycardias (VTs) was tested in dogs. METHODS AND RESULTS: A low dose of levcromakalim (0.01 mg/kg) was selected, which decreased blood pressure by 25% but had almost no electrophysiologic effect on AV nodal or ventricular conduction or effective refractory period. In dogs with chronic AV block, the antiarrhythmic action of this dose of levcromakalim was evaluated in three models of abnormal impulse formation: (1) d-sotalol (2 mg/kg) induced torsades de pointes VT, initiated by early afterdepolarizations (EADs), (2) sustained ouabain-induced VTs, which are dependent on delayed afterdepolarizations (DADs), and (3) VT occurring 24 hours after left anterior descending coronary artery occlusion, which are likely based on abnormal automaticity. Levcromakalim abolished d-sotalol induced U waves, ventricular ectopic beats, and self-terminating bouts of torsades de pointes. Induction of torsades de pointes by pacing was also completely prevented. The cycle length of the idioventricular rhythm, which was lengthened after d-sotalol from 1490 +/- 515 to 1700 +/- 610 msec (P < 0.05), remained similar after levcromakalim (1655 +/- 580 msec). The QT(U) duration, which was increased after d-sotalol from 410 +/- 55 to 550 +/- 40 msec (P < 0.05), normalized to 405 +/- 70 msec (P < 0.05). Levcromakalim did not suppress but rather enhanced ouabain-induced VT by decreasing the cycle length slightly from 315 +/- 35 to 290 +/- 35 msec (P < 0.05). Pretreatment with a beta blocker prevented this acceleration in rate. Finally, levcromakalim had no effect on VT 24 hours after infarction. CONCLUSION: A low dose of levcromakalim has specific antiarrhythmic properties against repolarization-dependent arrhythmias, but it does not affect VTs based on other mechanisms of abnormal impulse formation.