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(Circulation. 2000;102:2145.)
© 2000 American Heart Association, Inc.

Basic Science Reports

Contractile Adaptations Preserving Cardiac Output Predispose the Hypertrophied Canine Heart to Delayed Afterdepolarization–Dependent Ventricular Arrhythmias

S. H. Marieke de Groot, MD, PhD; Marieke Schoenmakers, MD; Mirella M. C. Molenschot, MD; Jet D. M. Leunissen; Hein J. J. Wellens, MD, PhD; Marc A. Vos, PhD

From the Department of Cardiology, Cardiovascular Research Institute Maastricht, Academic Hospital Maastricht, Netherlands.

Correspondence to M.A. Vos, PhD, Department of Cardiology, Cardiovascular Research Institute Maastricht, Academic Hospital Maastricht, PO Box 5800, 6202 AZ Maastricht, Netherlands. E-mail m.vos{at}cardio.azm.nl

	Abstract

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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.

Key Words: tachycardia • hypertrophy • contractility • electrophysiology

	Introduction

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Delayed afterdepolarization (DAD)–induced triggered arrhythmias (TAs) have been described under conditions of intracellular calcium overload.^{1 2} Positive inotropic interventions favor their initiation. In anesthetized dogs with chronic complete AV block (CAVB), DAD-dependent ectopic beats (EBs) and ventricular tachycardia (VT) have been observed after the combination of ouabain and pacing.^{3 4 5} Also, we have described that CAVB is associated with electrical and structural remodeling, eg, prolonged repolarization times and biventricular hypertrophy.^{5 6} In this study, we tested the hypothesis that contractile alterations increase arrhythmogenic potential in this dog, especially in regard to DAD-dependent TAs. Therefore, using positive and negative inotropic interventions, we related the occurrence of TAs with left and right ventricular (LV and RV) contractile function of the dog in sinus rhythm (SR) directly after AV block (AAVB) and in CAVB under both steady-state and dynamic circumstances. In the accompanying study,⁷ the cellular changes underlying these contractile adaptations were assessed.

	Methods

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Under aseptic conditions, we performed 50 experiments in 34 anesthetized mongrel dogs of either sex (body weight 27.5±5 kg). All experiments were performed in accordance with the European directive for the protection of vertebrate animals used for experimental and other scientific purposes. The dogs were tested serially: in SR, at AAVB, and at 6 weeks of CAVB in 3 groups: (1) LV and RV steady-state hemodynamic studies were followed by force-frequency (FF) and cardiac output (CO) determinations, (2) LV and RV postextrasystolic potentiation (PESP) and poststimulus potentiation (PSP) assessment, and (3) determination of the relation between the inducibility of EBs to LV PSP with negative and positive inotropic interventions. Because of technical difficulties and sudden cardiac death, dogs were added to increase the number with CAVB. For the procedures to induce anesthesia, to create AVB, to place LV electrodes, and for perioperative measures, we refer to our previous publication.⁵ A 6-channel ECG was recorded. Under fluoroscopic guidance, catheters were introduced to register LV and RV monophasic action potentials (MAPs⁵ ) and pressure curves.⁸ CO was determined by thermodilution in the pulmonary artery.⁹ All signals were stored at 1 kHz.

Pacing Protocols, Interventions, and Data Analysis
At AAVB and CAVB, the FF protocols (3 minutes of steady state) consisted of cycle lengths (CLs) of 300, 575±25 (equal to SR), 750, 1000, and 1250 ms. The PESP protocol consisted of a basic rhythm of 600 ms, which was interrupted every 20 beats by extrastimuli with decreasing coupling intervals from 550 to 250 ms. The PSP trains were delivered with an interstimulus interval of 300 ms and 1 to 68 stimuli. Three interventions were performed, after which PSP was repeated: at AAVB and CAVB, (1) 20 µg/kg ouabain IV was given (n=6) and (2) fixed-rate pacing (FRP) with the SR CL (520±40 ms, n=5) was performed with constant recovery interval. The third intervention, ryanodine (10 µg · kg^-1 · 10 min^-1), was administered only to 4 DAD-susceptible CAVB dogs. Pacing was performed from either the LV electrode (FF and PESP) or the RV MAP (PSP). By use of a software program, data were analyzed offline: LV and RV end-systolic pressure (ESP), end-diastolic pressure (EDP), and +dP/dt_max. From the ECG, CL idioventricular rhythm, CL PP interval, and QT time were determined. To correlate the functional adaptations with TA, we measured (1) coupling interval of the first beat postpacing, (2) LV and RV action potential duration of the MAP at 100% repolarization (MAPD), and (3) LV and RV +dP/dt before each pacing train and of beats 1 to 3 postpacing, either spontaneous, ectopic, or paced. DADs were defined in the MAP as an afterpotential with a diastolic slope of 10 mV/s. EBs were defined as ventricular activations with a postpacing interval <600 ms. VT was defined as 5 consecutive EBs. We refer to inducible dogs as those that responded with either EBs or VT.

Heart Weight
We confirmed that the CAVB dogs had (biventricular) hypertrophy: the ratio of heart to body weight was 11.5±2.1 g/kg. Slicing the heart in a subset of dogs (n=6) revealed 5.8±1.2 and 2.4±0.3 g/kg for the LV and RV, respectively.

Statistics
Data are presented as mean±SD unless otherwise stated. Statistical tests included (P0.05) repeated ANOVA followed by Bonferroni’s t test, 2-tailed Student’s t test for unpaired events, ² testing, and logarithmic regression analysis.

	Results

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Despite an increase in stroke volume, CO was reduced (P<0.05) when hemodynamics at AAVB were compared with SR (Table 1). Both ventricles show an increase in EDP with comparable systolic function (ESP and +dP/dt_max). After 6 weeks of CAVB, the LV and RV systolic parameters are significantly increased (+dP/dt: +100%), resulting in an enhanced stroke volume compared with SR and return of the CO and EDP values. Steady-state pacing at slow rates showed similar increases for LV and RV +dP/dt between AAVB and CAVB (Figure 1, top). Increasing the rate resulted in a positive inotropic response at AAVB. At CAVB, however, the FF response was attenuated: the LV shows a decrease, whereas the RV curve is flat.

View this table: [in this window] [in a new window]   Table 1. Contractile Adaptations at Spontaneous Rhythm

View larger version (21K): [in this window] [in a new window]   Figure 1. FF relation (FFR) and PESP. Top, Contractile response (+dP/dtmax) of LV (top left) and RV (top right) to increases in heart rate is shown at AAVB and CAVB. Increasing frequency from 48 to 200 bpm (x axis) leads at AAVB to a positive inotropic response in both ventricles (*P<0.05 vs 104 bpm). CAVB values are all significantly higher. Response to pacing, however, is attenuated: LV shows a decrease, whereas RV curve is flat. Bottom, Positive inotropic response (PESP) for 2 ventricles when extrastimulus interval is decreased from 550 to 250 ms (x axis, *P<0.05 vs 600 ms) at AAVB and CAVB. Values at CAVB, however, are all significantly higher.

PESP and PSP at Baseline
At AAVB and CAVB, the PESP protocols resulted in an increase in +dP/dt_max when the extrastimulus interval was decreased. The values obtained were higher at CAVB (Figure 1, bottom). At all time points, a fast pacing train resulted in a clear potentiation of cardiac function, which disappeared within 3 to 5 beats (Table 2 and Figure 2). This PSP was dependent on the number of stimuli: +dP/dt_max increased up to a maximum at 10 beats (Figure 3) and declined with a further increase in the stimuli (for details see Figure 5). These LV and RV PSP curves were comparable between SR and AAVB but were clearly shifted upward at CAVB.

View this table: [in this window] [in a new window]   Table 2. Electrophysiological and Hemodynamic Adaptations Before and After PSP

View larger version (126K): [in this window] [in a new window]   Figure 2. Effect of pacing during baseline at AAVB and CAVB in same dog. In each panel, ECG lead aVR, LV and RV MAP, and LV pressure (LVp) curve are shown at paper speed of 25 mm/s. Pacing is performed with 8 stimuli (S) with an interstimulus interval (Vs-Vs) of 300 ms. At AAVB (1), pacing clearly increases +LV dP/dt (from 1270 to 1795 mm Hg/s), but this does not result in DADs or EBs. In subsequent beats postpacing, +LV dP/dt declines and returns to prepacing values. At CAVB (2), all inotropic parameters have increased considerably. Pacing now results in induction of 3 EBs, which are related to DADs in LV MAP (*).

View larger version (17K): [in this window] [in a new window]   Figure 3. Effect of number of stimuli (nVs) on LV and RV PSP. Prepacing inotropic state (dP/dtmax) is depicted on y axis for SR, AAVB, and CAVB (dotted lines). Pacing induces PSP in LV (top) and RV (bottom), which for all curves reaches significance at stimulus 1 or 3 (*P<0.05 vs prepacing dP/dt). Absolute values for CAVB curves are significantly higher than SR and AAVB. Increasing nVs from 1 to 35 results initially in an increase, with highest values obtained at 8 to 13 stimuli ($P<0.05 vs 1 stimulus).

View larger version (26K): [in this window] [in a new window]   Figure 5. Effect of increasing number of stimuli (nVs) on PSP and inducibility of EBs. Top left, PSP curves similar to those in Figure 3 at AAVB and CAVB are illustrated, but now nVs has been extended to 68. Again, with increasing nVs, there is an initial increase in PSP, reaching a maximum after 8 to 13 stimuli, which is followed by a decline. At CAVB, curve is significantly shifted upward. Bottom left, No EBs at AAVB are induced, whereas there is a considerable induction of EBs at CAVB. Their occurrence shows a distribution similar to that of PSP. Response to ouabain at CAVB (right) has been divided (top right) into a curve (1) describing all stimulation trains and (2) visualizing only PSP response of trains that were not followed by EBs. Note (1) sawtooth appearance in overall data, (2) fact that curve of nonarrhythmic trains is smooth and shifted upward, and (3) widening in number of trains that showed EBs postpacing after ouabain (bottom right).

Triggered Ventricular Arrhythmias at Baseline
At AAVB, pacing never resulted in the induction of DADs or EBs. In contrast, at CAVB, similar pacing trains induced EBs in 6 of 10 (P<0.05) and VT in 1 of 10 dogs, which coincided with DADs in the MAPs in 8 of 10 dogs (P<0.05). An example is shown in Figure 2. The number of induced EBs also varied depending on the number of stimuli (Figures 4 and 5). Most EBs were induced after 5 to 13 stimuli, which corresponded with the highest postpacing LV +dP/dt.

View larger version (110K): [in this window] [in a new window]   Figure 4. Effect of number of stimuli (nVs) on induction of DAD-dependent EBs. In each panel, ECG lead II and LV MAP are shown. Idioventricular rhythm at CAVB is interrupted by pacing with 1 to 33 stimuli (S), with an interstimulus interval (Vs-Vs) of 300 ms. Arrhythmic quantification is based on diastolic slope3 and appearance of DADs and EBs. 1, Application of 1 stimulus does not lead to an EB and hardly to changes in diastolic slope of DADs (7 mV/s). 2, There is an increase in slope after application of 5 stimuli, which remains subthreshold. After 10 stimuli (3), additional increase of slope (>20 mV/s) is related to occurrence of 4 triggered EBs. A further increase in nVs to 13 (4) and 33 (5) stimuli results in a decreased induction of EBs and decreased slope of subthreshold DADs.

Inotropic Interventions Modulating Arrhythmias
At AAVB, the positive inotropic effect of ouabain or FRP did not result in the induction of DADs or EBs (Table 3). At CAVB, in contrast, ouabain increased the induction of arrhythmias (Figures 5 and 6), which was accompanied by a sawtooth appearance in the potentiation curve (Figure 5, top right). The induction of EBs was broadened when the different numbers of stimuli were compared (bottom right), and the numbers of EBs were increased (Table 3), sometimes resulting in VT (Figure 6).

View this table: [in this window] [in a new window]   Table 3. Hemodynamic and Arrhythmic Effects of Ouabain (20 µg/kg) and Fixed-Rate Pacing

View larger version (124K): [in this window] [in a new window]   Figure 6. Effect of ouabain on inducibility of EBs at CAVB in a dog. Configuration similar to Figures 2 and 4. 1, Pacing with 8 stimuli (S) results in an increase in DAD slope (arrow) and 1 DAD-related triggered beat (*) under baseline. 2, After ouabain prepacing, +LV dP/dt is higher, and pacing now results in occurrence of VT (12 beats). In MAP, DADs are visible during VT and directly after tachycardia terminates.

At CAVB, the negative inotropic effects of FRP (Table 3) or ryanodine (data not shown) were accompanied by prevention of all DADs and triggered EBs.

To describe the PSP curve, we determined the postpacing LV +dP/dt of any first postpacing beat, independent of coupling interval or activation sequence. Figure 7 shows PSP of single pacing trains subdivided for AAVB and CAVB and for their responses (EB+ and EB-) in relation to the prepacing inotropic values. There was a positive relation (r²=0.57) between potentiation and prepacing LV +dP/dt. Importantly, the different arrhythmic responses could not be discriminated on the basis of absolute LV +dP/dt or PSP, suggesting interindividual differences.

View larger version (19K): [in this window] [in a new window]   Figure 7. Relationship between inotropic parameters and EBs. Top, All pacing trains performed as part of this study during AAVB and CAVB with or without inotropic interventions are depicted. PSP achieved is positively related to prepacing inotropic dP/dtmax and best described logarithmically (r2=0.57, P<0.05). It is not possible, however, to discriminate between trains that result (eb+) and those that do not result (eb-) in EBs at CAVB. Bottom, Relative group incidence of EBs was related to prepacing LV dP/dt. It is clear that a threshold in dP/dtmax has to be reached before EBs occur.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
At 6 weeks of CAVB, steady-state LV and RV systolic contractile function is increased to such an extent that CO can be maintained. This successful adaptation remains present under positive inotropic interventions but is then accompanied by the occurrence of DADs and DAD-dependent TAs.

The CAVB Dog: Biventricular Compensated Contractile Function
Cardiac hypertrophy is an adaptation to mechanical overload of any cause. Whether this adaptation is able to maintain its contractile performance in time or whether there will be degeneration to congestive heart failure is still not clear. To quantify heart failure, numerous parameters have been developed at the integrative, (multi)cellular, and molecular level. In the nonfailing myocardium, FF and PESP are well-known phenomena that are decreased in the early stages of heart failure.^{10 11 12 13 14}

In the CAVB dog, both ventricles perform adequately under baseline as well as more demanding conditions (Figures 1 and 3). The FF response in the CAVB dog is altered, however (Figure 1): increasing the rate is no longer associated with an increase in LV or RV +dP/dt_max. The FF curve, however, is always increased with regard to AAVB and never reaches the data obtained in canine heart failure.^{12 15 16} Interpretation of this finding is complex, but rate-dependent measurements of cell shortening and calcium transients in isolated myocytes confirm that this is an intrinsic property of the cells.⁷ The possible role of an increased Na-Ca exchange current for improved contractile performance at slow rates is discussed in the accompanying article.⁷

PESP is also maintained during CAVB (Figure 1). PSP was seen during SR, AAVB, and CAVB (Figure 3), and its magnitude was dependent on the number of stimuli (Figures 3 and 5) and on the prepacing inotropic state (Figure 7). The highest PSP values were obtained at CAVB after short pacing trains consisting of 5 to 13 stimuli. To the best of our knowledge, we are the first to describe PSP in vivo. Because this curve remained present under all conditions tested, including FRP, we can exclude alterations in ventricular filling secondary to variations in the interval as the underlying mechanism. It appears that this PSP curve is intrinsic to the myocardium. All these findings are indicative of compensated contractile function in the CAVB dogs at 6 to 10 weeks.

TAs and Potentiation of Contractile Function
Electrical remodeling in the CAVB dog^{5 6} consists of an increase in repolarization times that exceeds the expected lengthening on the basis of rate and that is not uniform, leading to an increase in interventricular dispersion (Table 2). This dissimilar MAPD lengthening is caused by specific ventricular alterations in ionic channel function.^{7 17} Potential stimuli may include bradycardia, hypertrophy, and/or the alterations in calcium homeostasis. Synergistic effects could explain why our MAPD increase exceeds those reported so far in canine LVH.¹⁸

The PESP protocols never proved to be arrhythmic. Short-lasting, fast pacing trains, however, resulted in EBs in the majority of CAVB dogs but not in those with AAVB (Tables 2 and 3). The occurrence of EBs coincided with DAD registration on the MAP (Figures 2, 4, and 6), thereby indicating triggered activity as the underlying mechanism. Curves of potentiation and of incidence of EBs were similar, suggesting a common origin. The dynamic changes in calcium handling may temporarily create an arrhythmogenic window of calcium overload in the CAVB dog, during which the DADs and EBs occur. This hypothesis was studied further by use of different interventions that modulate the inotropic state. At AAVB, 2 positive inotropic interventions (ouabain and FRP) did not lead to induction of any arrhythmia. The highest PSP obtained, however, was far less than the baseline CAVB value (Table 3). The same therapeutic dosage of ouabain in CAVB increased the number of pacing trains that responded with EBs, and VT even occurred (Figures 5 and 6). The negative inotropic interventions at CAVB (FRP and ryanodine) caused prevention of the induction of all DADs and EBs. The block of the sarcoplasmic reticulum calcium release channel by ryanodine has been described to abolish DAD-related EBs.¹⁹ Thus, the CAVB heart is more susceptible to DAD-dependent arrhythmias under circumstances that demand higher contractile performance, in which the increased Na-Ca exchange current can be of great importance.⁷ It is unclear whether this arrhythmogenic potential is related to the remodeling processes or whether it is purely due to the (maximal attained) inotropism. In the latter, individual parameters such as the basal inotropic state, maximal amount of potentiation, contractile reserve, and threshold at which the sarcoplasmic reticulum spontaneously releases calcium have to be included. Whereas the prepacing inotropic state has a relation with maximal PSP and the occurrence of EBs, single-train analysis (Figure 7) did not allow prediction of the occurrence of EBs, suggesting that the inotropic state is not the single determinant.

In vitro, an increased propensity of hypertrophied myocardium to DAD-dependent TAs has been described.^{20 21} In these studies, stimulation alone resulted rather infrequently in DADs, whereas combining pacing with adrenergic stimulation frequently induced TAs. Because we studied intact animals, local activity of the autonomic nervous system might be related to the observed occurrence of DADs and related EBs.

Clinical Implications
Extrapolation from animal data to humans must be done with great caution. Both hypertrophy²² and heart failure²³ are known to predispose the human heart to ventricular arrhythmias and sudden cardiac death. The exact mechanisms involved are not elucidated, although prolongation of the APD has been described consistently and changes in calcium handling have been implicated,²³ suggesting TA as a contributing mechanism. Whether DADs occur with maximal inotropism (hypertrophy) or when the function is severely depressed (heart failure) can only be answered when combined, detailed information about the contractile performance and the arrhythmias is available and possible confounding factors, like ischemia, are excluded. This is most easily obtained in animal models. However, arrhythmogenic information has been limited to only a few studies, performed predominantly in heart failure.^{16 18 24 25}

Limitations
Because we measured at only 2 time points, we cannot exclude a time-specific arrhythmogenic response. Moreover, AAVB and CAVB resemble 2 different neurohumoral situations that can influence the results. In AAVB, compensation mechanisms have been activated, whereas at 6 weeks of CAVB, all plasma neurohumoral parameters have returned to baseline.⁵ Second, we do not know to what extent the observed phenomena actually relate to the different remodeling processes. Other factors can also play a role in the alterations in contractile function, including the sensitivity of the cardiac contractile proteins and the interstitial tissue of the myocardium. Third, we have concentrated on the initiation of the arrhythmia by DADs, thereby excluding other mechanisms.

In conclusion, the alterations accompanying the improvement in contractile function in the CAVB dog predispose the heart to DAD-dependent TA.

	Acknowledgments

 
This study was supported by grants from the Netherlands Organization for Scientific Research (NWO 902–16-24) and the Netherlands Heart Foundation (NHS 98.042).

Received March 6, 2000; revision received May 31, 2000; accepted May 31, 2000.

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