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Am J Physiol Heart Circ Physiol 295: H2264-H2272, 2008. First published October 3, 2008; doi:10.1152/ajpheart.00680.2008 Free Article
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Pharmacogenomics of anesthetic drugs in transgenic LQT1 and LQT2 rabbits reveal genotype-specific differential effects on cardiac repolarization

Katja E. Odening,1 Omar Hyder,1 Leonard Chaves,1 Lorraine Schofield,1 Michael Brunner,2 Malcolm Kirk,1 Manfred Zehender,2 Xuwen Peng,3 and Gideon Koren1

1Cardiovascular Research Center, Division of Cardiology, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island; 2Innere Medizin III, Kardiologie, University of Freiburg, Germany; and 3Department of Comparative Medicine, Pennsylvania State University College of Medicine, Hershey, Pennsylvania

Submitted 30 June 2008 ; accepted in final form 28 September 2008


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Anesthetic agents prolong cardiac repolarization by blocking ion currents. However, the clinical relevance of this blockade in subjects with reduced repolarization reserve is unknown. We have generated transgenic long QT syndromes type 1 (LQT1) and type 2 (LQT2) rabbits that lack slow delayed rectifier K+ currents (IKs) or rapidly activating K+ currents (IKr) and used them as a model system to detect the channel-blocking properties of anesthetic agents. Therefore, LQT1, LQT2, and littermate control (LMC) rabbits were administered isoflurane, thiopental, midazolam, propofol, or ketamine, and surface ECGs were analyzed. Genotype-specific heart rate correction formulas were used to determine the expected QT interval at a given heart rate. The QT index (QTi) was calculated as percentage of the observed QT/expected QT. Isoflurane, a drug that blocks IKs, prolonged the QTi only in LQT2 and LMC but not in LQT1 rabbits. Midazolam, which blocks inward rectifier K+ current (IK1), prolonged the QTi in both LQT1 and LQT2 but not in LMC. Thiopental, which blocks both IKs and IK1, increased the QTi in LQT2 and LMC more than in LQT1. By contrast, ketamine, which does not block IKr, IKs, or IK1, did not alter the QTi in any group. Finally, anesthesia with isoflurane or propofol resulted in lethal polymorphic ventricular tachycardia (pVT) in three out of nine LQT2 rabbits. Transgenic LQT1 and LQT2 rabbits could serve as an in vivo model in which to examine the pharmacogenomics of drug-induced QT prolongation of anesthetic agents and their proarrhythmic potential. Transgenic LQT2 rabbits developed pVT under isoflurane and propofol, underlining the proarrhythmic risk of IKs blockers in subjects with reduced IKr.

repolarization reserve; long QT syndrome types 1 and 2; sudden cardiac death; ventricular fibrillation

COMMONLY USED ANESTHETIC AGENTS influence cardiac repolarization, with effects on surface ECG such as changes in QT interval duration and T-wave morphology (23, 26, 37, 41). Drug-induced QT prolongation is known to precede potentially lethal arrhythmias such as polymorphic ventricular tachycardia (pVT) (reviewed in Refs. 3 and 15). The risk for anesthesia-induced malignant pVT is particularly pronounced in individuals with congenital long QT (LQT) syndromes (LQTS) (2, 14, 17, 18, 31, 35, 40), a genetically heterogeneous disease characterized by impaired cardiac repolarization leading to QT prolongation, spontaneous torsade de pointes (TdP), and sudden cardiac death (SCD) (reviewed in Ref. 32). LQTS types 1 (LQT1) and 2 (LQT2) account for 90% of all genotyped LQTS (32). Loss-of-function mutations in K+ voltage-gated channel, KQT-like subfamily, member 1 [KCNQ1; KvLQT1, {alpha}-subunit of slow delayed rectifier K+ current (IKs)] (49) and K+ voltage-gated channel, subfamily H, member 2 [KCNH2; human ether-a-go-go related gene (HERG), {alpha}-subunit of rapidly activating K+ current (IKr)] (12) are responsible for the LQT1 and LQT2 phenotypes, respectively. Furthermore, subtle mutations in LQT-related genes can predispose healthy individuals to drug-induced QT prolongation and ventricular arrhythmia (20, 22, 29, 51). Therefore, anesthetic agents might have more serious implications for apparently healthy individuals in the general population.

In vitro patch-clamp experiments have revealed that several anesthetic drugs block cardiac repolarizing ion currents; isoflurane (47) and propofol (5, 9) were shown to block IKs [and transient outward K+ current (Ito)]. Thiopental blocks IKs and inward rectifier K+ current (IK1) (11, 16, 27, 38). Additionally, all three agents block the L-type Ca2+ current (ICa,L) (9, 10, 38), which shortens the action potential duration (APD) and hence reduces their QT prolonging effect. Although the sedative midazolam inhibits IK1 in vitro (9), changes in QT duration have not been detected in healthy humans (25, 26). Finally, ketamine, a commonly used veterinary anesthetic, has no effect on IKs or IKr (5) and affects IK1 only at high concentrations (5, 11). However, the effects of anesthetic drugs on cardiac repolarization in models with reduced repolarization reserve have yet to be explored.

We have recently generated transgenic LQT rabbits selectively overexpressing loss-of-function pore mutants of the human KCNQ1 (KvLQT1-Y315S, {alpha}-subunit of IKs, LQT1) or KCNH2 (HERG-G628S, {alpha}-subunit of IKr, LQT2) in the heart (8). These rabbits exhibit a LQT phenotype (LQT1 and LQT2) associated with SCD (LQT2) due to pVT. Cardiomyocytes derived from these hearts exhibit prolonged APD at 90% duration due to the elimination of IKs in LQT1 and IKr in LQT2 rabbits (8). We hypothesize that the administration of anesthetic drugs would result in additional QT prolongation only in rabbits that express ion currents that are sensitive to those drugs. Furthermore, LQT1 and LQT2 rabbits might prove particularly sensitive to substances that affect the remaining repolarizing currents. This likely sensitivity suggests the use of LQT rabbits as an in vivo screening model to detect QT prolonging properties of anesthetic agents (and other drugs) and might help in identifying the specific ion currents that are their targets.

Here we report for the first time systematic analyses of the pharmacogenomics of isoflurane, thiopental, midazolam, propofol, and ketamine in LQT1 and LQT2 rabbits. The results suggest that these rabbits could serve as a model system for simulating the effects of these drugs in human subjects with reduced repolarization reserve.


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
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All animal experiments were performed in accordance with the local guidelines of the institutions and only after approval by the Institutional Animal Care and Use Committee in accordance with the Institute for Laboratory Animal Research Guidelines for the Care and Use of Laboratory Animals published by the National Institutes of Health (NIH Publication No. 85-23, Revised 1996).

Genotype-Specific Heart Rate Correction Formula Based on QT/RR in Free-moving Rabbits

We have previously reported genotype differences in the QT/RR slope steepness in free-moving LQT1 and LQT2 rabbits compared with wildtype littermate controls (LMC) and have generated the following genotype-specific heart rate correction formula (as described in Ref. 8): LMC, expected QT (QTexp) = 86 + 0.22 * RR; LQT1, QTexp = 80 + 0.32 * RR; and LQT2, 35 + 0.50 * RR.

Briefly, male LQT1, LQT2, and LMC rabbits (n = 8, 6, and 11, respectively) were implanted with radiofrequency ECG transmitters (triple-lead ECG D70-EEE; Data Sciences International). The analog telemetric ECG signals were acquired by Dataquest A.R.T. data acquisition software (Data Sciences International) using a sampling frequency of 1 kHz and were analyzed offline semiautomatically at a speed of 50 mm/s using Ponemah ECG analysis software (Data Sciences International). The analyses were blindly reviewed and manually corrected, if necessary, by an experienced clinical electrophysiologist.

To calculate the QT/RR relationship of each individual rabbit, pairs of QT/RR intervals were averaged over 5 s every 20 min during a 24-h monitoring period. We calculated QT/RR using a linear regression formula for each individual animal and averaged these to obtain the genotype-specific heart rate correction formula (8). Similarly as described for male rabbits, female LMC, LQT1, and LQT2 (n = 5, 5, and 9, respectively) rabbits were monitored, and female heart rate correction formulas were obtained similar to that described in male rabbits. Since the QT/RR was significantly steeper in LQT2 females than in LQT2 males (Odening et al., unpublished observations), we applied this female LQT2 heart rate correction formula (QTexp = 0.74 * RR – 19) to calculate QT indexes (QTi) in female LQT2 rabbits. No significant gender difference was found in the QT/RR in free-moving LMC and LQT1 rabbits so that the male correction formula could be applied (Odening et al., unpublished observations).

The QT and RR data obtained by monitoring ECG telemetrically in free-moving male (as part of the study published in Ref. 238) and female LMC, LQT1, and LQT2 rabbits served as our baseline data to calculate the QTi in free-moving rabbits, which we then used to compare with QTi under anesthesia. The baseline QT and RR values in free-moving rabbits were as follows: for males (8), LMC, QT 152 ± 11.2 ms at RR 299.3 ± 26.4 ms; LQT1, QT 176.6 ± 17.3 ms at RR 302.3 ± 32.4 ms; and LQT2, QT 175.9 ± 15.78 ms at 280.7 ± 13.2 ms; and for females, LMC, QT 148 ± 4.8 ms at RR 273.52 ± 24.4 ms; LQT1, QT 163.5 ± 11.1 ms at RR 264.5 ± 23.9 ms; and LQT2, QT 184.2 ± 10.3 ms at 271.7 ± 8.7 ms.

12-Lead Surface ECG Under Anesthesia, QTi

The following groups of animals were analyzed: LMC (n = 5 males and n = 5 females; age, 19.3 ± 3 mo; and weight, 5.3 ± 0.2 kg), LQT1 (n = 6 males and n = 6 females; age, 11 ± 2 mo; and weight, 3.8 ± 0.2 kg), and LQT2 (n = 5 males and n = 4 females; age, 10.4 ± 1 mo; and weight, 3.7 ± 0.4 kg). The LQT2 group experienced a considerable dropout rate of three out of nine animals (1 male and 1 female) due to SCD from anesthesia-induced pVT degenerating into ventricular fibrillation (see Table 2).

The rabbits were exposed to the following anesthetic agents: isoflurane (isoflurane, USP; Hospira, Lake Forest, IL), thiopental (pentothal for injection, USP; Hospira, Lake Forest, IL), midazolam (midazolam HCL injection; Hospira, Lake Forest, IL), propofol (diprivan 1%; AstraZeneca Pharmaceuticals, Wilmington, DE), ketamine (ketamine hydrochloride, injection, USP; Hospira, Lake Forest, IL), and xylazine (AnaSed, injection; Akorn, Decatur, IL) (see Table 1 for dosage and route of administration). Each animal was exposed to one anesthetic agent or combination (in the case of ketamine-xylazine) during a given experiment. A period of 1 wk, which is longer than five half-lives for all drugs administered, was allotted for recovery between each anesthetic protocol. The order of the anesthetic agent administration varied in the individual rabbits. However, thiopental was the last anesthetic drug used in all rabbits, and due to the deaths of one LQT2 rabbit after isoflurane anesthesia and two LQT2 rabbits after propofol anesthesia, only six LQT2 rabbits were exposed to thiopental anesthesia.


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  		Table 1. Summary of anesthetic agents, dosage, and route of administration

 
Isoflurane was administered via mask using a Fortec vaporizer and a veterinary anesthetic ventilator (Hallowell Model 2000). A rabbit restrainer was used in the thiopental and propofol protocols to insert the intravenous catheter into an ear vein.

Once adequate sedation was achieved, rabbits were shaved, an arterial line was inserted into the ear artery for intra-arterial blood pressure monitoring, and oxygen was administered via facemask. Rabbits were then placed on their back, and 12-lead surface ECG was acquired using a sampling frequency of 1 kHz. The results were blindly analyzed manually at a speed of 200 mm/s using the LabSystem EP laboratory Bard electrophysiology system and software. The rabbits were continuously ECG-monitored for 15 min to assess the occurrence of arrhythmias: atrioventricular (AV) block, premature ventricular contractions (PVC), nonsustained ventricular tachycardia defined as lasting <30 s, and sustained ventricular tachycardia lasting >30 s. A second 12-lead ECG was obtained 10–15 min later. Measurements included RR, HR, PQ, QRS, QT, QT peak, and T-wave peak-end intervals (Tpe), which were averaged over all surface ECG leads. The QT interval was defined as the interval between the onset of QRS and the point at which the T wave crossed the isoelectric line. The QT peak interval (QTp) was defined as the interval between the onset of QRS and the peak of the positive T wave or the nadir of the negative T wave. The Tpe was defined as the interval between the peak of the T wave and the point at which the T wave crossed the isoelectric line.

We used a genotype-specific heart rate correction formula (described in Genotype-specific Heart Rate Correction Formula Based on QT/RR in Free-moving Rabbits) to calculate the expected QT interval at a given RR interval. The observed QT interval was then expressed as a percentage of the expected QT (QT observed/QT expected * 100), generating a QTi. Applying the appropriate genotype- (and gender-) specific heart rate correction formulas to the QT and RR values obtained in telemetrically monitored free-moving male (as part of the study in Ref. 8) and female rabbits resulted in QTi of 100% in all genotypes (Fig. 1D). We compared the QTi under different anesthetic drugs to those obtained in free-moving rabbits (Fig. 1D) to detect the effect of different anesthetic agents on the QT interval. These comparisons were made between animals of the same genotype and the same gender. A value significantly greater than 100% and significantly greater than the QTi in free-moving, telemetrically monitored rabbits was considered an anesthesia-induced QT prolongation. Additionally, differences in the absolute QT durations between different genotypes were assessed by comparing the QT duration of LQT1 and LQT2 with LMC rabbits of the same gender.


Figure 1
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  		Fig. 1. Effect of isoflurane on QT duration. A–C: comparison of QT duration in free-moving rabbits (telemetric ECG recordings, lead II; top) with QT duration under isoflurane anesthesia (surface ECG, chest leads V1–4; bottom) at comparable RR intervals. The axes of the representative ECG recordings were rescaled to the same temporal resolution. Hatched lines indicate QRS duration. D: heart rate-corrected QT indexes in free-moving rabbits calculated with the genotype- (and gender-) specific correction formula. Solid bars denote males; hatched bars denote females. E: absolute QT duration under isoflurane anesthesia in littermate control (LMC) and long QT syndromes type 1 (LQT1) and type 2 (LQT2) rabbits. Solid bars denote males; hatched bars denote females. The corresponding RR intervals are indicated below. All values are presented as means ± SD. *P < 0.05 vs. LMC; **P < 0.01 vs. LMC. F: heart rate-corrected QT indexes under isoflurane. The QT index of LQT2 females is calculated with a female-specific LQT2 heart rate correction formula. The dotted line represents the mean QT indexes in free-moving rabbits obtained with the genotype-specific correction formulas (100%). **P < 0.01 vs. free-moving rabbits of the same genotype. ns, Not significant.

 
To assess anesthesia-induced changes in the QTp duration, we applied the genotype-specific heart rate correction formulas described in Genotype-specific Heart Rate Correction Formula Based on QT/RR in Free-moving Rabbits.

Statistical Analysis

For normally distributed values, we used Student's t-test (paired and unpaired) to compare the means of two groups and the Mann-Whitney test to compare values not normally distributed. Fisher exact test was used for categorical variables. Analysis was performed with Prism 4 for Windows (Graphpad, San Diego, CA). All data are presented as means ± SD; a P value ≤0.05 was considered significant.


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Effect of Anesthetic Drugs on Cardiac Repolarization

QT interval. To determine whether LQT rabbits could be used as a model system to study the channel-blocking effects of frequently used anesthetic agents, we exposed LQT rabbits to a series of anesthetic agents with known ion channel-blocking properties. The IKs blocker isoflurane (47) prolonged the QT interval in LQT2 (Fig. 1A) and LMC rabbits (Fig. 1B), generating a drug-induced LQT1 phenotype in the latter. In contrast, the QT interval of LQT1 rabbits lacking IKs was not altered (Fig. 1C). Consequently, the difference in absolute QT interval duration between LQT1 and LMC in free-moving rabbits (8) was abolished under isoflurane (Fig. 1E). Heart rate correction of the QT interval under isoflurane revealed a significant increase in the QTi of male and female LQT2 and LMC rabbits but not in LQT1 rabbits (Fig. 1F).

Similar to the observations under the IKs blocker isoflurane, the IKs and IK1 blocker thiopental (11, 16, 27, 38) abolished the difference in absolute QT interval duration between LQT1 and LMC rabbits (Fig. 2A). Thiopental significantly increased the QTi in LQT2 and LMC rabbits. However, a less pronounced increase in QTi was also observed in LQT1 rabbits; in LQT1 females, we observed a significant increase in QTi (P = 0.04) and in LQT1 males a nonsignificant trend toward a QT prolongation (P = 0.055; Fig. 2B).


Figure 2
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  		Fig. 2. Effect of thiopental on QT duration. A: absolute QT duration under thiopental anesthesia in LMC, LQT1, and LQT2 rabbits. The corresponding RR intervals are indicated below. All values are presented as means ± SD. **P < 0.01 vs. LMC; ***P < 0.001 vs. LMC. B: heart rate-corrected QT indexes calculated with the genotype-specific correction formula. Solid bars denote males; hatched bars denote females. The dotted line represents the mean QT indexes in free-moving rabbits obtained with the genotype-specific correction formulas (100%). *P < 0.05 vs. free-moving rabbits of the same genotype; **P < 0.01 vs. free-moving rabbits; ***P < 0.001 vs. free-moving rabbits.

 
The IK1-blocking sedative midazolam (9) prolonged the absolute QT duration in both LQT1 and LQT2 rabbits compared with free-moving rabbits (Fig. 3A). Midazolam also increased the heart rate-corrected QTi (Fig. 3B). In contrast, midazolam did not alter the QTi in LMC rabbits. Of note, RR intervals varied pronouncedly in LQT2 males under midazolam (indicated by the large SD in Fig. 3A) since one of the LQT2 males presented an AV 2:1 conduction block throughout the whole experiment.


Figure 3
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  		Fig. 3. Effect of midazolam on QT duration. A: absolute QT duration under midazolam sedation (3 mg/kg im) in LMC, LQT1, and LQT2 rabbits. The corresponding RR intervals are indicated below. Of note, 1 of the LQT2 males presented an atrioventricular (AV) 2:1 block throughout the experiment (indicated by AV 2:1 in 1 LQT2m). All values are presented as means ± SD. *P < 0.05 vs. LMC; **P < 0.01 vs. LMC. B: heart rate-corrected QT index calculated with the genotype-specific correction formula. Solid bars denote males; hatched bars denote females. The dotted line represents the mean QT indexes in free-moving rabbits obtained with the genotype-specific correction formulas (100%). *P < 0.05 vs. free-moving rabbits of the same genotype; **P < 0.01 vs. free-moving rabbits.

 
The IKs and Ito blocker propofol (5, 9) significantly increased the QTi in all three genotypes (LQT1, LQT2, and LMC control rabbits; Fig. 4, A and B).


Figure 4
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  		Fig. 4. Effect of propofol on QT duration. A: absolute QT duration under propofol anesthesia in LMC, LQT1, and LQT2 rabbits. The corresponding RR intervals are indicated below. All values are presented as means ± SD. *P < 0.05 vs. LMC; **P < 0.01 vs. LMC; ***P < 0.001 vs. LMC. B: heart rate-corrected QT index calculated with the genotype-specific correction formula. Solid bars denote males; hatched bars denote females. The dotted line represents the mean QT indexes in free-moving rabbits obtained with the genotype-specific correction formulas (100%). *P < 0.05 vs. free-moving rabbits of the same genotype; **P < 0.01 vs. free-moving rabbits; ***P < 0.001 vs. free-moving rabbits.

 
Exposing LQT rabbits to the veterinary anesthetic ketamine, which does not affect IKs or IKr (5), did not change the QTi in any of the genotypes (Fig. 5B). Genotypic differences in the QT interval observed in free-moving transgenic and LMC rabbits persisted under ketamine (Fig. 5A).


Figure 5
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  		Fig. 5. Effect of ketamine on QT duration. A: absolute QT duration under ketamine-xylazine in LMC, LQT1, and LQT2 rabbits. The corresponding RR intervals are indicated below. All values are presented as means ± SD. *P < 0.05 vs. LMC; **P < 0.01 vs. LMC. B: heart rate-corrected QT index calculated with the genotype-specific correction formula. Solid bars denote males; hatched bars denote females. The dotted line represents the mean QT indexes in free-moving rabbits obtained with the genotype-specific correction formulas (100%).

 
QT peak interval. To further characterize the differential effects of anesthetic drugs on cardiac repolarization, we analyzed differences in the QTp, which reflects the earlier phase of cardiac repolarization (24), when IKs and IKr are of major importance (39). Applying the genotype-specific heart rate correction formula to the QTp durations in free-moving rabbits resulted in longer QTp indexes in LQT1 and LQT2 rabbits compared with LMC (P < 0.001 LMC vs. LQT1 or LQT2; Fig. 6A) as previously described (8). Isoflurane and propofol produced the same changes in QTp indexes as observed in the QTi measurement: an increase in LMC and LQT2 rabbits but not in LQT1 rabbits during anesthesia with the IKs blocker isoflurane and an increase in the QTp index in all genotypes under propofol (Fig. 6, A and D). In contrast, the changes in QTp indexes differed from those in QTi under exposure to the IKs and IK1 blocker thiopental or the IK1 blocker midazolam; a thiopental-induced prolongation of the QTp was detected only in LMC and LQT2 but not in LQT1 rabbits. Finally, midazolam prolonged the QTp only in LQT2 but not in LQT1 rabbits, although the QTi was prolonged in both (Fig. 6, B and C). Ketamine did not alter the QTp index in any genotype.


Figure 6
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  		Fig. 6. Effect of anesthetic agents on QT peak interval (QTp) indexes. A: isoflurane. B: thiopental. C: midazolam. D: propofol. E: ketamine. Solid bars denote free-moving rabbits (n = 4 LMC, 4 LQT1, and 4 LQT2 males. Note the genotype differences in QTp indexes between LMC and LQT rabbits, which are indicated in Fig. 6A); hatched bars denote rabbits under anesthesia with the different anesthetic agents (n = 10 LMC, 12 LQT1, and 9 LQT2, except for thiopental: n = 6; female and male rabbit data are pooled). ***P < 0.001.

 
We also investigated the effect of anesthetic drugs on the final phase of cardiac repolarization: the Tpe. The Tpe was significantly longer in LQT2 than in LQT1 rabbits under all anesthetic protocols, similar to what has been described in human LQTS patients (48). However, we observed no difference in Tpe duration among the different anesthetic protocols in any of the genotypes. Under ketamine anesthesia (data are representative of all the different anesthetic agents used), the Tpe durations were as follows: LQT2, 41.7 ms ± 8 vs. LQT1, 29.2 ms ± 6, P < 0.001; and LMC, 34.3 ms ± 4, P = 0.01 vs. LQT2.

All other ECG parameters (including PQ and QRS) did not differ between genotypes or anesthetic protocols (see representative ECG traces of free-moving vs. isoflurane-treated rabbits in which the QRS duration is indicated with hatched lines; Fig. 1, A–C).

Arrhythmias and Anesthesia-Related Death

During the short monitoring periods under anesthesia, we observed signs of altered repolarization and arrhythmias only in LQT2 rabbits. Namely, we observed second-degree AV block in LQT2 males under isoflurane (second-degree AV block, Wenckebach type), midazolam, and thiopental (AV 2:1 block). Furthermore, we observed changes in T-wave morphology and T-wave alternans in LQT2 rabbits during ketamine and midazolam exposure (Table 2 and Fig. 7A). Multiple PVCs occurred in nearly all LQT2 males and females under midazolam, ketamine, or thiopental. Importantly, despite the short monitoring period we detected ventricular bigeminy in several LQT2 rabbits (Fig. 7B and Table 2). Isoflurane and propofol were especially proarrhythmic in LQT2 rabbits. One LQT2 female died suddenly after isoflurane-induced polymorphic TdP ventricular tachycardia degenerating into ventricular fibrillation. Similarly, one LQT2 female and one LQT2 male died within 48 h of propofol anesthesia of TdP (Fig. 7C, initiation of TdP). There were no signs of proarrhythmic effects or overt arrhythmias in either LQT1 or LMC independent of the anesthetic agent used.


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  		Table 2. Arrhythmias and arrhythmic death during anesthesia in LQT2 rabbits

 

Figure 7
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  		Fig. 7. Arrhythmias during anesthesia in LQT2 rabbits. A: T-wave alternans in LQT2 male during midazolam. B: ventricular bigeminy in LQT2 male during thiopental. C: episode of polymorphic torsade de pointes tachycardia in LQT2 female No. 584 after anesthesia with propofol.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
Mechanistic Implications: Transgenic LQT Rabbit Model as a Useful Tool to Differentiate Ion Channel-Blocking Properties Of Drugs

We set out to test whether the changes in the QTi in transgenic LQT1 and LQT2 rabbits will accurately reflect the differential ion channel-blocking effects of anesthetic drugs. IKs-blocking drugs like isoflurane (47) prolong the QTi in LQT2 and to a lesser extent in LMC, producing a drug-induced LQT1 phenotype in the latter similar to the phenomenon in healthy humans (41). In contrast, isoflurane does not affect QT duration in transgenic LQT1 rabbits lacking IKs. We conclude that the blockade of IKs by isoflurane observed during patch-clamp experiments dominates the QT prolonging effect of the drug. In contrast, the blockade of ICa,L, also observed in vitro (47) and which shortens the cardiac plateau phase, seems to be of minor importance at clinically relevant dosages.

Consistent with IKs- and IK1-blocking properties of thiopental (11, 16, 27, 28, 38), we observed an increase in the QTi in LQT2 and LMC rabbits under thiopental. The QTi increase, although present, was less pronounced in LQT1 rabbits (P = 0.04 in females and P = 0.055 in males) than in LQT2 and LMC. Similar observations were documented in humans (36). Of note, the difference in absolute QT duration between free-moving LQT1 and LMC rabbits (8) was abolished under thiopental anesthesia, a phenomenon similar to that observed under isoflurane. Therefore, in LQT rabbits the IKs-blocking property of thiopental predominates, whereas its IK1-blocking properties play a small role in prolonging the QT. The heart rate-corrected QTp index might serve as an additional tool to further differentiate the IKs- and IK1-blocking properties of thiopental, since the QTp reflects the earlier phases of cardiac repolarization (24) in which IKs and IKr play a major role (39). We found a prolongation of the QTp index only in LQT2 and LMC but not in LQT1 rabbits. By contrast, the QT interval, which represents the complete cardiac repolarization including the terminal part of phase 3 repolarization, during which IK1 is of major importance (44), is also (slightly) prolonged in LQT1 rabbits.

In line with the IK1 (and Ito-)-blocking properties of midazolam in patch-clamp experiments (9), the QTi was increased in both LQT1 and LQT2 rabbits. However, we detected no change in QT duration in LMC under midazolam sedation. This finding is consistent with observations in healthy humans (25, 26). In rabbits, the most important repolarizing currents during the plateau phase are IKr and IKs (39), with IK1 being more important for the terminal phase 3 repolarization (44). Consequently, the QTi is not significantly affected in LMC rabbits with normal IKr and IKs currents. In contrast, both transgenic LQT models lack one of the predominant repolarizing currents (namely IKr or IKs). Hence these LQT rabbits have a markedly reduced repolarization reserve, which might make them more susceptible to any further impairment of cardiac repolarization, e.g., by IK1-blocking agents. Our data suggest that cardiac repolarization is much more dependent on IK1 in transgenic LQT rabbits than in LMC.

The effect of propofol on cardiac repolarization is more complex. Propofol increased the QTi in transgenic LQT rabbits and LMC rabbits. This finding correlates with reports of in vivo QT prolongation under propofol (23, 36, 37). However, some other in vivo and in vitro studies did not find that propofol had any QT- or APD prolonging effect (19, 30). Propofol has no effect on IKr (50) or IK1 (5, 9) but blocks Ito and IKs (9). In theory, blockade of Ito and IKs might be the source of this QT prolongation. The transient activity of Ito limited to very early repolarization (46) makes it unlikely that blockade of this current is responsible for an overall QT prolongation. Furthermore, IKs blockade would result in QT prolongation only in LQT2 and LMC. In contrast, we noted QT prolongation in all three genotypes, suggesting that additional factors might play a role.

Finally, ketamine, an anesthetic agent used in animal studies, did not affect the QT duration in transgenic LQT rabbits or in LMC. Patch-clamp experiments did not reveal an effect on IKr or IKs (5). A dose-dependent blockade of the IK1 current has been reported at a concentration of 100 µM (5). However, no effect was observed at clinically relevant concentrations between 0.5 and 10 µM (11). The observation that ketamine did not elicit any QT prolongation in LQT1 or LQT2 rabbits might be due to the fact that the IK1-blocking property of ketamine might not be important at clinical relevant doses. Therefore, ketamine may be an ideal anesthetic agent for assessing the in vivo effect of ion channel mutations or of drugs on the QT interval in animal models.

Limitations of the Study

Here we have used averaged linear QT/RR regression formulas obtained from several male LQT1, LQT2, and LMC rabbits (8) to generate genotype-specific heart rate correction formulas. However, since the QT/RR steepness differs among individual humans (4, 21) as well as among individual transgenic LQT or LMC rabbits (8), an ideal study protocol would be to calculate individual heart rate correction formulas. QT/RR data are available for several rabbits that we implanted with ECG transmitters. Using these individual heart rate correction formulas to calculate QTi revealed similar anesthesia-induced changes of the QTi compared with the QTi calculated with the averaged genotype formulas, demonstrating that an averaged heart rate correction formula is an appropriate simplification of the method.

In transgenic LQT2 rabbits, we demonstrate that anesthesia-induced blockade of repolarizing ion currents in individuals with impaired repolarization reserve can be proarrhythmic and potentially lethal. Several of our transgenic LQT2 rabbits developed various arrhythmias, including T-wave alternans and multiple PVCs during various anesthetic protocols. Isoflurane and propofol induced pVT with subsequent deterioration into ventricular fibrillation in three LQT2 rabbits. However, we are aware that the brief observation period and a limited number of animals preclude quantification of arrhythmogenic risk of each anesthetic drug. Further investigations are thus warranted.

Clinical Implications

Our transgenic LQT rabbit models reveal that rabbits with LQT2 genotype are exceedingly sensitive to the QT prolonging properties of IKs-blocking agents. Moreover, IKs-blocking agents are highly proarrhythmic in subjects with reduced repolarization reserve due to an impaired IKr current. Isoflurane and propofol induced pVT with subsequent deterioration into ventricular fibrillation in three out of nine LQT2 rabbits. There are no general guidelines regarding the optimal anesthetic regimen for human patients with an acquired or genetic prolonged QT interval. Since propofol has no demonstrated effect on the repolarizing currents IKr (50) and IK1 (5, 9), it is considered a relatively safe drug for anesthesia in patients with LQTS (reviewed in Refs. 6, 7, 13, and 33). Nevertheless, the death of two LQT2 rabbits from TdP induced by propofol anesthesia calls this recommendation into question, especially in the case of LQT2 mutations. Several case reports demonstrate the risk of anesthesia-induced malignant pVT in human LQT patients, particularly during anesthesia with IKs-blocking agents like halothane (2), sevoflurane (40), or propofol (18, 34). However, no data are available on the underlying genotype of these patients. We have observed IKs blocker-induced TdP only in LQT2 rabbits. Consequently, physicians should consider evaluating the genotype of LQT patients before selecting anesthetic agents.

Phenotypic penetrance is highly variable in LQTS patients, and individuals who have normal QT intervals at baseline but harbor clinically silent mutations can develop polymorphic TdP with subsequent SCD if given QT prolonging drugs (42). Additionally, subtle mutations have been discovered in LQT-related genes like KCNQ1 (29), KCNH2 (29), SCN5A (45), and KCNE2/MirP1 (1, 43) in various healthy humans with drug-induced LQTS (22, 51). Thus anesthesia-associated QT prolongation and arrhythmia might be of clinical significance even in apparently healthy patients, especially in the presence of other drugs and compounding factors like hypokalemia and bradycardia. It seems likely that not only the QT prolongation itself but rather the blocking mechanism of the anesthetic agent might be of special importance. The specific ion currents blocked by the drug will determine whether a particular patient's subclinical repolarization impairment will manifest as a detectable LQT interval or ventricular arrhythmia.

Conclusions

We report the first systematic analysis of the effect of different anesthetic agents on the QT interval in a model system with impaired repolarization reserve. Drugs that selectively block IKs prolong the QTi only in LQT2 and LMC rabbits, but not in LQT1 rabbits, which lack IKs. Drugs that block IK1 prolong the QTi in both LQT1 and LQT2 rabbits due to their reduced repolarization reserve. Our transgenic LQT1 and LQT2 rabbits could therefore serve as an in vivo model in which to assess the importance of different ion channel blockades in inducing QT prolongation. Additionally, the model may help to differentiate the arrhythmogenic risk of different ion channel-blocking agents. The development of pVT under isoflurane and propofol underlines the heightened risk of arrhythmia when using IKs blockers in patients with a reduced repolarization reserve due to decreased IKr currents. From a clinical standpoint, these data suggest genotyping LQT patients before deciding on an anesthetic regimen. Since ketamine does not alter cardiac repolarizing currents or the QT interval, ketamine could be considered an optimal anesthetic agent for studies of the in vivo effect of drugs on the QT interval in the LQT rabbit model.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
G. Koren is the recipient of a National Heart, Lung, and Blood Institute Grant RO1-HL046005-14, and K. E. Odening was supported in part by grants from the German Cardiac Society (St. Jude Medical Stipendium), the German Research Foundation (Deutsche Forschungsgemeinschaft Forschungsstipendium), and an American Heart Association postdoctoral fellowship.


   FOOTNOTES
 

Address for reprint requests and other correspondence: G. Koren, Cardiovascular Research Center, Cardiology Div., Rhode Island Hospital, Coro West 51031 Hoppin St., Providence, RI 02903 (Gideon_Koren{at}Brown.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

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