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Combination therapy with mexiletine and sotalol suppresses inherited ventricular arrhythmias in German shepherd dogs better than mexiletine or sotalol monotherapy: a randomized cross-overstudy

Combination therapy with mexiletine and sotalol suppresses inherited ventricular arrhythmias in German shepherd dogs better than mexiletine or sotalol monotherapy: a randomized cross-overstudy

Author information

Gelzer A.R., Kraus M.S., Rishniw M., Hemsley S.A., Moïse N.S. Combination therapy with mexiletine and sotalol suppresses inherited ventricular arrhythmias in German shepherd dogs better than mexiletine or sotalol monotherapy: a randomized cross-overstudy // J Vet Cardiol. 2010 Aug;12(2):93-106.


OBJECTIVES: To determine the spontaneous variability of ventricular arrhythmias (VA) and evaluate anti-arrhythmic efficacy of mexiletine, sotalol, and a mexiletine-sotalol combination in German shepherd dogs (GSD) with inherited arrhythmias.

ANIMALS, MATERIALS AND METHODS: 12 affected GSD, median age 20 weeks, received mexiletine (8 mg/kg PO q8 h), sotalol (2.5 mg/kg PO q12 h), and combination therapy for 6 days in random order. Pre- and post-treatment 24 h Holter recordings were acquired, allowing determination of VA variability and reduction in 24 h VA for each treatment. Drug concentrations during each arm were measured.

RESULTS: An anti-arrhythmic effect could be inferred if ventricular premature complexes (VPC), ventricular couplets (V(cpl)), ventriculartachycardia runs (VT(runs)) and total ventricular ectopy (VE(tot)) frequency were reduced by 61%, 97%, 98%, and 63% (1 control Holter model), by 53%, 94%, 95%, and 54% (4 control Holter model) and by 54%, 95%, 96% and 56% (3 control Holter model). Combinationtherapy reduced VPC and VE(tot) in more dogs (5/12 and 6/12) than mexiletine (1/11 and 2/11) or sotalol (2/9 and 1/9) (p < 0.05). The combination therapy reduced the mean number of VPC, V(cpl), and VE(tot). Sotalol monotherapy produced an increase in VT(runs). Plasma mexiletine concentration was higher during combination therapy than with monotherapy.

CONCLUSIONS: Combination therapy reduced VPC in affected GSD. Sotalol monotherapy increased VT(runs). Combination therapyincreased plasma mexiletine concentrations.


Inherited predispositions to the development of ventricular arrhythmias (VA) and sudden death are well characterized features of some families of young German shepherd dogs (GSD).1 The prevalence of this disorder in the general GSD population is unknown but afflicted GSD have been documented in Europe and the United States. A colony of affected GSD was established at Cornell University in 1988. Affected German shepherd dogs (GSD) have up to 60% VA during a 24 h period, but there is a large variation in phenotype; some GSD show very few ventricular premature complexes (VPCs), but other GSD have rapid (rates greater than 350 bpm) polymorphic ventricular tachycardia (VT). Clinical signs other than sudden death are not common in thisdog population. Risk of sudden death in these dogs correlates with severity of VA.1 A window of vulnerability for the presence of VA and sudden death exists approximately between 12 and 50 weeks (wk) of age; peak affectedness is seen between 20 and 28 wk of age.2 However, if a dog survives beyond 2 yr of age, the frequency and severity of the ventricular arrhythmias markedly decrease and the risk of death becomes minimal. Sudden death is most common during sleep, at rest after exercise, or early in the morning shortly after awakening.3 The frequency of VT is most common during rapid-eye-movement sleep and after long pauses. Such characteristics support triggered activity as an initiating mechanism for the VT, and early after depolarizations (EADs) have been documented from the Purkinje fibers of affected GSD.4,5

Oral anti-arrhythmic drugs used most commonly for suppression of VA in veterinary medicine include mexiletine, sotalol, atenolol, procainamide and amiodarone.6,7 In affected German shepherd dogs (GSD), intravenous lidocaine effectively abolishes VA.8 Mexiletine is an orally available class Ib antiarrhythmic drug similar to lidocaine; mexiletine inhibits fast sodium channels and reduces arrhythmias in canine in vitro models of repolarization abnormalities with triggered activity9 as well as in humans with the LQT2 and LQT3 form of long QT syndrome.10,11 Previous anti-arrhythmic drug studies in boxer dogs found mexiletine to be effective for reduction of VA when combined with atenolol6 and potentially useful as monotherapy in both dogs12 and humans.13

D,l-sotalol is a non-selective beta blocker with class III anti-arrhythmic properties.14,15 Its antiarrhythmic efficacy has been demonstrated both in boxer dogs with spontaneous VA6 as well as human patients with VA that were refractory to class I antiarrhythmics.16,17 However, sotalol exacerbates EAD-induced triggered activity in isolated Purkinje fibers of affected GSD via its action potential prolonging effects.5

Electrophysiologic studies of the coadministration in isolated Purkinje fibers of normal dogs indicate that mexiletine counteracts the action potential prolongation produced by sotalol.18,19 Similarly, studies of isolated Purkinje fibers from affected GSD in our laboratory (unpublished observation) suggest that whereas mexiletine reduces—but sotalol increases the incidence of EAD, coadministration of the drugs produces a profound reduction of spontaneous and triggered activity.

Potential benefits of combination therapy of sotalol with mexiletine have been shown in human clinical trials20 as well as boxer dogs with arrhythmogenic right ventricular cardiomyopathy (ARVC).a,:21 However, no studies have evaluated the efficacy of these drugs (either as monotherapy or in combination) at reducing VA or preventing sudden death in affected German shepherd dogs (GSD). In affected GSD, antiarrhythmic strategies might rely on reducing the VA complexity or severity and on reducing factors that initiate EADs during the vulnerable period.

Twenty-four hour ambulatory electrocardiographic monitoring (Holter) is considered the gold-standard method of assessing arrhythmias and anti-arrhythmic therapy in veterinary medicine.6,22—24 Anti-arrhythmic response is typically determined by observing a percent reduction in mean 24 h VPC frequency that exceeds spontaneous VA variability for the specific patient population. Spontaneous day-to-day variability of VA frequency approaches 80—85% in dogs and humans (and approaches 100% in dogs with low arrhythmia counts),25,26 so an anti-arrhythmic response is assumed if the reduction in VA frequency >80%.27 On the other hand, the characteristics of VA in different dog populations highly predisposed to VA are very breed-specific with respect to age, purported triggers of VA (excitement vs. sleep) and presence or absence of underlying structural heart disease.28—31 Thus, it cannot be assumed that the day-to-day spontaneous variability in VA is comparable between these breeds, and breed/disease- specific limits of spontaneous VA variability should be established before assessing anti-arrhythmic responses.

The objectives of this study were to determine the spontaneous variability of VA in a colony of severely affected German shepherd dogs (GSD) in order to establish the percent reduction in VA frequency required to identify an anti-arrhythmic effect, and to prospectively evaluate the efficacy of orally available mexiletine, sotalol, and a mexiletine—sotalol combination to reduce VA in German shepherd dogs (GSD) with a propensity for inherited arrhythmias and sudden death.

Animals, materials and methods

Animals and study design

In this prospective, randomized cross-over design study, we investigated the anti-arrhythmic efficacy of 3 pharmacological protocols — mexiletine or sotalol monotherapy, or mexiletine—sotalol combination therapy — in GSD affected with inherited VA. The dogs were maintained on a standard diet. All dogs were treated humanely and the study was approved by the Cornell University Institutional Animal Care and Use Committee.

Twelve affected German shepherd dogs (GSD) (raised in a closed colony at Cornell University) were selected for inclusion in the study based on a 24 h Holter acquired at 17 wkof age. The dogs in this colony have been selected for a severe phenotype characterized by severe VA and sudden death. We used the following inclusion criteria: (1) >6000 VPC per 24 h (>250 VPC per hour) and (2) >5% ventricular ectopy per 24 h. Dogs were not allowed to receive any other anti-arrhythmic medication up to 5 days prior to, or during, the study. Qualifying dogs were randomly assigned to a specific drug treatment order, established by a random number generator.13

We were initially concerned about sotalol monotherapy because of known incidence of triggered activity and abnormal repolarization4 as well as previously reported increased incidence of arrhythmias following sotalol in affected GSD.5 Consequently, we did not initially assign dogs to sotalol monotherapy, but after failing to observe adverse events in the first 3 dogs receiving combination therapy, we included a sotalol monotherapy arm in the study. Therefore, only 9/12 dogs were randomized to receive sotalol monotherapy (2.5 mg/kg PO q12 h), while all dogs were randomly assigned to receive mexiletinec monotherapy (8 mg/kg PO q8 h) and combination therapy of mexiletine (8 mg/kg PO q8 h) with sotalold (2.5 mg/ kg PO q12 h).

One dog accidentally received an inappropriately low dose of mexiletine during the monotherapy arm of the study, so therefore only 11/ 12 dogs were included in the analysis of mexiletine monotherapy. All 12 dogs on combination therapy could be included in the analysis. Immediately prior to starting each treatment period a 24 h Holter recording was acquired to serve as a control. In addition, a 24 h Holter recording was acquired at the end of the study, after a washout period was completed to determine if there was an innate change of VA over time. After each control Holter recording, the dogs received the assigned treatment for 6 days (to ensure drugs reached steady- state). On day 6 of each treatment period a 24 h Holterwas acquired to evaluate the anti-arrhythmic drug effect. A washout period of 4—7 days was included between each treatment period, based on prior pharmacokinetic data in GSD obtained in our laboratory for mexiletine and sotalol (Table 1). In summary, 9 dogs had 7 Holter recordings (4 control Holters, 3 treatment Holters; totaling 7 Holters) and 3 dogs had 5 Holter recordings (3 control Holters, 2 treatment Holters; totaling 5 Holters).

Blood samples were obtained on day 6 of each treatment period to assess plasma or serum mexiletine and sotalol concentrations. The blood was drawn 3 h post-pill for both drugs (estimated peak concentration) and 8 h post-pill for mexiletine and 12 h post-pill for sotalol, (trough concentration, i. e., immediately before giving the next dose of each drug). Serum or plasma drug concentrations were measured by gas chromatography at a commercial laboratory.e In the first 3 dogs enrolled in the study we also obtained plasma and serum drug concentrations of mexiletine and sotalol on the 4th day after drug discontinuation to confirm that drugs were undetectable in the serum at that time (validating the washout period). The study design and subject allocation are illustrated in Table 1.

Data acquisition and analysis

Holter monitoring was performed using 3-channel digital recorders/ in an orthogonal lead arrangement. A small area of hair was clipped for each electrode (two per channel and one ground) and ECG electrodes were connected to the Holter recorder, which was fitted into a custom-made vest. During Holter monitoring all dogs were housed individually in runs, but were not exercised. We acquired electrocardiographic data at a sampling frequency of either 200 or 400 Hz, stored it on 350 MB removable PC flashcards, and transferred it to a hard drive for automated analysis by proprietary software.g Ventricular arrhythmias were classified using the following criteria (1) the number of single VPC per 24 h (VPC), (2) the number of ventricular couplets per 24 h (Vcpl), (3) the number of runs (>3 VPC) of ventricular tachycardia (VT) per 24 h and (4) total number of ventricular ectopic (VE) complexes per 24 h.

Table 1 Cross-over design of Holter acquisitions and blood sampling during drug study

Cross-over design of Holter acquisitions and blood sampling during drug study

Because of the polymorphic nature of VA, the rapid rates of non-sustained ventricular tachycardia and the typically large T waves of affected GSD, trained personnel comprehensively edited and corrected the automated data analysis without knowledge of the drug status for any of the Holters.

Statistical analyses

Arrhythmia association with time

To exclude the confounding possibility of age-dependent dynamics of VA in affected GSD that have been previously described,2 we calculated the within-dog regression over time for VPC, ventricular couplets, runs of VT and total VE from all the serial control Holters available in every dog. For each of these variables we tested whether the regression coefficients (slope) of our sample population differed significantly from 0 using a one- sample T-Test. A significant difference would indicate that there was a change in arrhythmia frequency over time in our population.

Spontaneous variability of ventricular arrhythmias between 24 h periods in GSD

We first examined the spontaneous within-dog variability of arrhythmias in our patient population by methods previously described in human cardi- ology.26 We used the serial control Holter recordings obtained on each dog (4 control recordings in 9 dogs, 3 control recordings in 3 dogs) to obtain estimates of the percent reduction in arrhythmia frequency required to demonstrate an anti-arrhythmic effect. Briefly, the frequency data were first transformed using a natural logarithmic function to more closely approximate a normal distribution. We then determined the within-dog variances for each of the 12 dogs on the natural logarithms of the frequency (f ) of each variable (specifically, we determined the variance on the function ln{f + l}, because some dogs had no runs ofVTin some 24 h periods, resulting in the non-calculable ln(0), so "f + 1” was used for logarithmic transformation), which yielded 12 estimates of the within-dog (between-days) variance. These 12 within-dog variances which were then pooled and the pooled between-days variance (Sbd) was used to calculate a 95% confidence interval of the variance estimate using the formula26:

variance (Sbd) was used to calculate a 95% confidence interval

where nc = number of control days recorded, and nt = number of treatment days recorded. Therefore, a situation where 1 control Holter recording and 1 treatment Holter recording were obtained on a patient would result in 1/nc + 1/nt = 2, while a situation where 4 control Holter recordings and 1 treatment Holter recording were obtained on a patient would result in 1/nc + 1/nt = 1.25. Because we had 9 dogs with 4 control Holters and 3 dogs with 3 control Holters, we calculated the reduction in arrhythmias necessary to demonstrate a treatment effect using both an nc = 4 (1/nc + 1/ nt = 1/4 + 1//1 = 1.25), and nc = 3 (1/nc + 1/ nt = 1/3 + 1/1 = 1.33) model. The minimum difference required to demonstrate a significant difference ("threshold”) between ln(treatment) and ln(control) at an a = 0.05 for a 2-sided test is D. Therefore:

minimum difference required to demonstrate a significant difference

This method allowed us to examine the percent reduction with varying quantities of information (nc = 1 vs. nc = 3 vs. nc = 4) and simultaneously to approximate the spontaneous variability of arrhythmias in our population. Appendix 1 details a sample calculation in a simulated data set to help clarify the methodology.

Assessment of anti-arrhythmic efficacy

We used several approaches to examine antiarrhythmic efficacy. First, we examined the proportion of dogs exhibiting an anti-arrhythmic effect for each treatment using the nc = 1 threshold. We performed this calculation for illustrative purposes only, to provide data that would be most commonly used clinically, where only a single control Holter and single treatment Holter are usually obtained. However, since our data set included multiple control Holters, we were able to determine the proportion of dogs exhibiting an anti-arrhythmic effect using the nc = 3 threshold for the 3 dogs with 3 control Holters, and the nc = 4 threshold for the remaining 9 dogs. With the nc = 1 method, we used the actual pre- and post-treatment Holter recordings (nc = 1, nt = 1) to calculate a percent reduction for each dog as follows:

calculate a percent reduction for each dog as follows

where C = variable of interest in the control Holter and T = variable of interest in the treatment Holter.

With the nc = 3/nc = 4 method, we obtained the within-dog averages for all the control Holter recordings and compared these within-dog averages with each of the post-treatment Holter recordings (nc = 3 or nc = 4, nt = 1) to calculate a percent reduction in arrhythmias for each dog h as follows:

to calculate a percent reduction in arrhythmias for each dog h as follows

where C = average of the variable of interest from the control Holters and T=variable of interest from the treatment Holter.

Then, using either the nc = 3 (in the 3 dogs with 3 control Holters) or nc = 4 (in the 9 dogs with 4 control Holters) threshold values, we determined the proportion of dogs exhibiting an anti-arrhythmic effect for each treatment, and compared these proportions using a Cochran’s Q test. Appendix 1 details the methodology required to determine anti-arrhythmic efficacy.

In addition to the proportional analysis described above, which examines the treatment effect based on a pre-determined threshold (derived from the spontaneous variability data), we also examined therapeutic response using a one-way ANOVAon the transformed data with treatment as fixed effect, and dog as random effect (i.e. blocked for dog). This method allows for detection of a difference between baseline and treatment, regardless of the magnitude of the change. Differences were determined using Tukey’s HSD (Honestly Significant Difference) test for multiple comparisons. The least-squared means of the treatment and control frequencies were then back-transformed to obtain the actual mean VA values, which were used to illustrate the % change produced by each treatment (both significant and non-significant).

Drug concentrations with monotherapy and combination therapy

We compared the peak and trough plasma and serum concentrations of mexiletine and sotalol when administered individually and when administered as combination therapy by Wilcoxon signed-rank test.

Statistical assessment of significance

Due to the small number of statistical comparisons in this study (and the preservation of test-wise error for the ANOVA with the Tukey’s HSD), we considered differences for every comparison statistically significant at p < 0.05. All statistical comparisons were performed using commercial statistical software.


Study population and characteristics

We studied 12 intact GSD (8 males, 4 females; median body weight 20 kg, range: 18—27 kg; median age at enrollment 20 wk, range 17—22 wk). h Moye LA III, personal communication.

Table 2 The % reduction in arrhythmia frequency required to establish a drug effect using 3 different models

The % reduction in arrhythmia frequency required to establish a drug effect using 3 different models

Arrhythmia frequency in GSD affected with inherited ventricular arrhythmias

During the study period, the 12 dogs had a population median of 25,520 VPCs per 24 h (based on within-dog median VPC counts), (within-dog median range: 15,428—91,661 per 24 h), 5924 ventricular couplets per 24 h (within-dog median range: 43—15,994 per 24 h) and 586 runs of VT per 24 h (range 0—10,732 per 24 h). The complete set of data is listed in the data supplement (Tables A—D) The dogs received no anti-arrhythmic medication during these recording periods, thus the data represent a spectrum of 96 h per dog (72 h in 3 of 12 dogs) of spontaneous variability in VA in this German shepherd dogs (GSD) population.

Arrhythmia association with time

The median number of days required to complete the study for all dogs was 42 (range 30—49 days). We detected no effect of time on arrhythmia frequency for any of the measured variables, i.e., the regression coefficients were not statistically different from 0 (VPC p = 0.8; ventricular couplets p = 0.2, VT runs p = 0.54, total VE p = .49).

Characterization of spontaneous variability of arrhythmias

Using the ANOVA method described previously by Morganroth and Pratt,26,32 we calculated the % reduction in arrhythmia frequency necessary to document a drug effect, which is equivalent to estimating the spontaneous variability in arrhythmia frequency. Because we had 4 control Holter recordings available for 9 dogs, 3 control Holter recordings available for 3 dogs, and 1 treatment Holter recording for each treatment per dog, we first determined efficacy using an nc = 1 model (we examined this model for illustrative purposes, because in clinical practice, typically only 1 control and 1 treatment 24 h Holter recording are available for interpretation) and then a combined nc = 3/ nc = 4 model, which we used in statistical analysis and on which we based our conclusions about drug efficacy. Table 2 shows the percent reduction required for all the VA variables to demonstrate a drug effect with each model.

Drug efficacy assessed by 24 h Holter recording

When the data were analyzed by the second method (ANOVA), mexiletine—sotalol combination therapy, but not either monotherapy, resulted in a statistically significant reduction in all VPC, ventricular couplets and total VE (p = 0.008, p = 0.0179; and p < 0.0001, respectively). However, sotalol monotherapy increased VT runs (p = 0.05). After back-transforming the least- squared means, we calculated the % change for each treatment (Table 4). We found that VPC and total VE reductions determined by ANOVA using the mexiletine—sotalol combination therapy (55%) exceeded the spontaneous VA variability threshold using the nc = 3/nc = 4 model (54% and 53% respectively) (see Tables 2 and 4). Table 3 shows the proportion of dogs demonstrating a treatment effect with each treatment, using the nc = 1 and nc = 3/nc = 4 thresholds compared to mexiletine monotherapy, despite similar oral doses of mexiletine (trough [mexiletine] versus trough [mexiletinesotalol] p = 0.0068; peak [mexiletine] versus peak [mexiletinesotalol], p = 0.0098). Sotalol serum concentrations were not different between monotherapy and combination therapy with mexiletine, neither at trough nor peak levels ([sotalol] versus [sotalolmexiletine] peak and trough, p = 0.20 and p = 0.91, respectively).

Table 3 Treatment efficacy assessed by number of dogs reaching a percent reduction in arrhythmias below the threshold determined using either the nc = 1 model or nc = 3/nc = 4 model.

shows the proportion of dogs demonstrating a treatment effect with each treatment

A greater proportion of dogs achieved a reduction in VPC with combination therapy (5/12) than with either mexiletine (1/11) or sotalol (2/9) using the nc = 3/nc = 4 threshold (p < 0.05). Similarly, combination therapy reduced total VE in more dogs than either monotherapy (p < 0.05). However, no treatment reduced ventricular couplets, or VT runs more than any other treatment. The complete set of Holter recording data is listed in the data supplement (Tables E—H).

Concentrations of mexiletine and sotalol

The median and range for plasma and serum concentrations of [mexiletine] and [sotalol] are listed in Table 5. We found higher plasma concentrations of mexiletine (both at peak and a trough times) when the dogs received mexiletine in conjunction with sotalol (mexiletinesotalol), as


Our study demonstrates that GSD severely affected with inherited VA in the Cornell colony (median VPC count >25,000 per 24 h) have marked day-to-day variability in VA frequency between 17 and 26 wk of age. A combination of mexiletine at 8 mg/kg PO q8 h and sotalol at 2.5 mg/kg PO q12 h- but not either drug given alone- reduced VPC and total VE in this population. However, no antiarrhythmic protocol decreased the number of VT runs (although sotalol monotherapy increased the number of VT runs). Combination therapy increased plasma mexiletine concentrations by an undetermined mechanism.

Table 4 The % reduction in arrhythmia frequency achieved with anti-arrhythmic drugs (ANOVA)

The % reduction in arrhythmia frequency achieved with anti-arrhythmic drugs (ANOVA)

Spontaneous variability of VA in German shepherd dogs (GSD)

Spontaneous variability in our German shepherd dogs (GSD) population was substantial. When comparing two 24 h control Holter recordings, changes in VPC frequency of <61% were considered within the limits of spontaneous variability; however, when 3 or 4 control Holter recordings were assessed the spontaneous variability of VPC frequency decreased to 54% and 53% respectively. This is due to a narrowing of the 95% confidence intervals of the estimates of spontaneous variability as a result of increased numbers of Holter recordings per dog. Our results are similar to changes in thresholds for spontaneous VA variability proposed in humans with VA, where higher numbers of control Holter recordings reduce the spontaneous VA threshold required to demonstrate drug effect.26,32

Our findings further suggest that the percent reduction in VPC frequency necessary to document a therapeutic drug effect might be lower in affected German shepherd dogs (GSD) than that previously reported in boxers with ARVC (61% versus 83%).25 Similar findings have been described in humans with VA attributable to different cardiac disorders, which underscores the effect of heterogeneity of arrhythmogenic substrates on VA with different disorders and the need to establish disease- specific estimates of spontaneous VA variability when examining anti-arrhythmic efficacy.32,33 It is worth noting that Spier and colleagues performed a non-statistical evaluation of the spontaneous VA variability in 6 dogs—therefore, their thresholds might be conservative, and not comparable to those established for GSD in our study (in which a statistical approach was used in a larger sample size to establish the thresholds).25

Table 5 Plasma and serum concentrations of mexiletine (mg/ml) and sotalol (ng/ml)

Plasma and serum concentrations of mexiletine (mg/ml) and sotalol

Finally, estimates of spontaneous variability also depend on the frequency of the VA. Increased heterogeneity of spontaneous VA variability has been demonstrated in humans, with day-to-day VPC variability of 95% in post-myocardial infarction patients with relatively low VA counts.33 A different study revealed that patients with more severe, frequent VA (>1000 VPC/h) had lower day- to-day variability than those with less frequent arrhythmias (200—1000 VPC/h).26 The GSD population in our study included only markedly affected dogs with a median VPC count >25,000 per 24 h, which would decrease heterogeneity of spontaneous VPC variability. In patient populations with low frequencies of VA, alternate methods of determining drug efficacy are necessary.32

The spontaneous variability of complex VA (such as couplets and runs of VT) was very large in our GSD population; the change in runs of VT required to demonstrate efficacy of therapy was up to a 98% reduction when comparing one control and one therapy Holter, or up to a 95% reduction if 4 control recording periods were evaluated. This reflects the relative infrequency of couplets or runs of VT in several of the dogs in the study: some dogs had no VT on certain days and only a few runs on other days, while one dog had >10,000 runs of VT per 24 h. The clinical implications of this finding are important for several reasons. First, in affected German shepherd dogs (GSD) the risk of sudden death is associated with the presence and frequency of runs of VT,1 therefore suppression of VT is clinically desirable. However, an antiarrhythmic drug effect in an individual dog could only be inferred if the percent reduction in VT runs was greater than >95% (or even 98%, when only assessing two 24 Holter recording periods)—effectively a complete elimination of VT with treatment would be necessary to document a treatment effect in our patient population. Second, even though 11 of 12 dogs had runs of VT in at least two of their control recordings (see data supplement Table C), the large day-to-day variability of VT runs might render predictions for risk of sudden death potentially inaccurate if only one or two 24 h Holter recordings are available to a clinician. (One dog had a 190-fold difference in VT runs between 2 Holter recordings: 28 vs. 5432 runs; in most dogs, the numberofVT runs varied at least 10-fold between the 3 or 4 control Holter recordings.) On the other hand, the 1 dog in our study with no runs of VT during two of its 24 h recordings had only 2 and 6 runs of VT in the other two recordings and thus would likely have been considered at a low risk of sudden death based on any of the 4 recording periods evaluated.1 The variability in ventricular couplets and runs of VT as compared to single VPC in the German shepherd dogs (GSD) is greater than what is reported in several human studies, where variability in complex VA was found to be lower as compared to the variability in VPC.32,34,35 Low variability in complex VA as compared to single VPCs was also described in boxer dogs when using a grading scheme,36 rather than quantifying the absolute numbers.25 However, the boxer dogs in that study had no runs of VT with >4 VPCs, hence might represent a population with a milder form of VA than the GSD in this study.

The arrhythmogenic substrate of highly breed- specific VA in boxers with ARVC, German shepherd dogs (GSD) with inherited arrhythmias, Doberman Pinschers with dilated cardiomyopathy and other dogs with VA is clearly very different and warrants the establishment of breed-specific or disease-specific limits of spontaneous variability for investigation of antiarrhythmic efficacy. Additionally, as demonstrated in our study and also observed in boxer dogs with ARVC,25 the between-patient variability in VA frequency even within these 2 fairly "homogenous” patient populations is very large, so assessing antiarrhythmic responses in prospective clinical trials should examine within-patient responses, rather than between-patient comparisons.

Historically, GSD with sudden death do not display arrhythmias until after 12 wk of age and reach peak affectedness between 22 and 26 wk.2 However, due to the rigorous breeding involved in investigating the defect in our colony, the age of onset has decreased and dogs can be severely affected by 12 wk of age. Because we wanted to conduct the drug study during a period of peak affectedness, the age of the dogs at beginning of the study varied between 17 and 22 wk of age. The age-dependent development and regression of VA in affected German shepherd dogs (GSD) raises the concern that the duration of the drug study (median 42 days) could introduce a bias related to an inherent change in affectedness, rather than a true drug effect. Therefore, we examined the spontaneous VA frequency over the study period via regression analysis and found no consistent change in VA frequency over the period of investigation that would introduce unintended bias into the study.

Mexiletine—sotalol combination therapy reduces VA

Combination therapy with mexiletine and sotalol was well tolerated and produced a reduction in VPC frequency that exceeded spontaneous variability (>54% in the nc = 3/nc = 4 model or 61% in the nc = 1 model) in a significant proportion of German shepherd dogs (GSD). This effect of combination therapy was identified both by the proportion of dogs (5/12) exceeding the threshold VPC frequency reduction (i.e., 53% and 54%) and in the one-way ANOVA analysis, where the average difference between VPC number during combination therapy and VPC number at baseline also exceeded the 53% VPC threshold. Similarly, combination treatment reduced total VE in more dogs than either monotherapy and the average reduction in total VE, significant in the one-way ANOVA analysis, also exceeded the spontaneous VA variability threshold established in the first part of the study (54% & 56%). In contrast, no treatment reduced ventricular couplets, or VT runs below the required threshold for any of those variables in a significant proportion of dogs (we acknowledge that for ventricular couplets and VT runs, the thresholds were extremely high — 94% to 96% — and would have required an almost complete abolition of couplets and VT runs to detect a treatment effect). Indeed, two dogs on combination therapy had decreases in couplets and VT runs to within 1 —2% of the threshold value, but failed to achieve a reduction that exceeded the threshold value.

Combination therapy significantly reduced ventricular couplets (by 75%) but this did not exceed the spontaneous VA variability thresholds established in the first part of the study (94%). This discrepancy could be ascribed to the 2 dogs with borderline reductions in couplets and VT runs. The concordance in the reduction of VPC and VE demonstrated by 2 independent methods argues for the robustness of that result, while the discordance in the results for couplets requires that these data be interpreted cautiously. It is possible that a lack of differences in the proportion of dogs responding to combination therapy is a function of small sample size (lack of power), or it might simply be that no difference actually exists.

None of the treatment regimens reduced VT runs, but, ANOVA analysis showed that sotalol monotherapy increased the % VT runs. Because the proportional analysis was one-tailed, examining only a reduction, it was not possible to show a statistically significant increase. However, of the dogs exhibiting VT runs, 2/11 receiving mexiletine, 5/8 receiving sotalol and only 1/12 dogs receiving combination therapy had a net increase in VT runs when compared to the immediate preceding control Holter recording. This suggests a proarrhythmic effect of sotalol monotherapy in German shepherd dogs (GSD) with inherited VA. Additionally, while the combination therapy is more effective than either drug used as monotherapy in suppressing VPC, and total VE, the lack of effect on suppression of runs of VT might limit the clinical benefits of the combination therapy. However, the relatively low number of VT runs in some of the dogs in our study and the small sample population complicates the interpretation of these negative results. Furthermore, to definitively examine the efficacy of combination therapy on survival, prospective survival studies need to be performed to determine whether apparent lack of VT reduction translates into a lack of clinical benefit.

For this study we elected to test mexiletine, extrapolating from positive results seen in affected GSD with IV lidocaine, another Class Ib anti-arrhythmic drug similar to mexiletine. Mex- iletine has been shown to reduce arrhythmias in canine in vitro models of repolarization abnormalities with triggered activity.9 In our study, however, mexiletine monotherapy did not reduce VA in the German shepherd dogs (GSD), even though we administered mexiletine at a relatively high dose of 8 mg/kg PO q8 h. We attempted to increase the dose to 10 mg/kg PO q8 h in a pilot study in affected GSD, but induced adverse effects, mostly gastrointestinal disturbances and inappetence. This is analogous to observations in human patients where effective therapeutic concentrations of mexiletine exceeded the concentrations at which it induced intolerable adverse effects.37

Combining mexiletine with other anti-arrhythmics, such as beta blockers or potassium-channel blockers, improves efficacy over mexiletine monotherapy in humans,37 and has been suggested in boxer dogs, although mexiletine monotherapy was not attempted in that study.6 We chose to investigate the combination therapy of mexiletine with sotalol, based on in vitro evidence in our laboratory of a potential synergistic effect between these drugs, resulting in suppression of EAD in isolated Purkinje fibers from affected GSD. Several studies have investigated the potential mechanisms leading to improved efficacy of combining sotalol with other anti-arrhythmic drugs. The reverse use-dependence of sotalol is considered a limiting factor for its antiarrhythmic efficacy for treatment of rapid VT, and combination with class 1a drugs was shown to improve the efficacy by elimination of this factor.38 More recently, studies in isolated rabbit Purkinje fibers with sotalol-induced repolarization prolongation and EAD, similar to affected GSD, identified a protective action of lidocaine and mexiletine, in part via their ability to inhibit late (inward) sodium currents during repolarization, thereby reducing EAD and arrhythmia formation.39 Other in vitro studies have shown similar ameliorating effects of mexiletine on changes in action potential duration induced by sotalol,18’19’40 or the ability of class I anti- arrhythmics to substantially augment the effective refractory period when combined with sotalol.41 Additionally, mexiletine augmented the antiarrhythmic effects of sotalolin dogs with induced VT and in a canine model of torsade de pointes.42,43 Mexiletine—sotalol combination therapy did indeed produce a significant reduction in the frequency of VPCs in our study, indicating that drug concentrations were within the therapeutic range. Importantly, despite our initial concerns of proarrhythmia in GSD with sudden death, sotalol did not elicit any proarrhythmic effects when administered in combination with mexiletine.

It is well known that abnormalities in repolarizing currents are present in GSD with inherited arrhyth- mias.5,44,45 Reduced outward repolarizing currents are thought to be responsible for the prolongation of action potential duration and development of EAD in left ventricular Purkinje fibers of affected dogs4 and sotalol has been shown to exacerbate EAD in isolated Purkinje fibers of affected GSD.5 After initial reservations about sotalol monotherapy exacerbating VA in affected GSD, we ultimately decided to testsotalol monotherapy, because we felt it necessary to demonstrate that any effect seen with mexiletine—sotalol combination therapycould not be attributed to either drug separately. Additionally, our experience in the first 3 dogs with combination therapy failed to demonstrate aggravation of VA. During the study no German shepherd dogs (GSD) suffered sudden death with sotalol monotherapy, however, our study showed an increase in VT with sotalol monotherapy, with 5/8 dogs having a net increase in VT runs, underscoring that our initial concern was indeed warranted. Based on these limited observations, we would advise avoiding sotalol monotherapy in affected GSD. We were surprised when we failed to observe an increase of the frequency of VPCs. The reason for this is unknown, but might be due to the beta-blocking effects of sotalol (which would shorten action potential duration and thus reduce EAD) counteracting the potassium-channel blocking effects (which would lengthen action potential duration and increase EAD). Alternatively, the smaller sample population in the sotalol arm might have had insufficient power to detect a small increase.

Mexiletine and sotalol were well tolerated both as monotherapy and in combination with each other at the doses administered. Sotalol showed no significant anti-arrhythmic effects at the dose administered, but exhibited proarrhythmic effects by increasing runs of VT. Sotalol metabolism was not influenced by co-administration of mexiletine in GSD, as evidenced by similar serum concentrations when administered alone and with mexiletine. In contrast, we found a higher plasma concentration of mexiletine when co-administered with sotalol than when administered alone. This interaction has not been previously reported. Possible mechanisms of interaction between mexiletine and sotalol include decreased intrahepatic metabolism of mexiletine (by inhibition of the cytochrome P450 isoenzyme CYP2D6), or decreased hepatic mexiletine delivery, due to reduced hepatic blood flow. Plasma concentrations of mexiletine did not change significantly when co-administered with propranolol in 4 human patients,37 despite strong CYP2D6 inhibition by propranolol.46 Sotalol does not inhibit CYP2D6,46 so a decrease in hepatic metabolism of mexiletine due to CYP2D6 inhibition by sotalol is unlikely. Reduced hepatic blood flow by propranolol has been shown to decrease lido- caine metabolism,47 but, to the best of our knowledge, similar hemodynamic drug interactions between mexiletine and beta blockers have not been reported. However, failure of propranolol to alter mexiletine concentrations37 would suggest that decreased hepatic blood flow might not play a role in altering mexiletine kinetics. Our preliminary observation of the mexiletine/sotalol interaction warrants additional confirmation. The plasma concentrations of mexiletine measured in GSD during monotherapy were lower than those considered therapeutic in humans (therapeutic range: 0.75 to 2.00 mg/ml).48 This might explain the lack of efficacy in affected German shepherd dogs (GSD) with mexiletine monotherapy. However, during combination therapy, the mexiletine plasma concentrations were significantly higher, with concentrations closer to the therapeutic levels reported for humans. This might, in part, explain the enhanced antiarrhythmic efficacy of the combination therapy as compared to monotherapy of either drug; higher concentrations of mexiletine could (by themselves) have increased anti-arrhythmic effects, and could additionally counteract the proarrhythmic effects of sotalol, as observed in vitro.18,19,39-41


Our study has several limitations, which should be considered when interpreting the results. First, the spontaneous variability analysis used data from 3 or 4 control Holter recordings that were not obtained on consecutive days. However, spontaneous variability increases when week-to-week or month-to-month (rather than day-to-day) comparisons are made in humans49,50 so this would tend to increase the threshold VA frequency required to detect a drug effect. Consequently, our finding of an anti-arrhythmic effect of combination therapy is strengthened by the use of 10- day intervals between Holter recordings.

Only 12 dogs were used in this study. A larger sample population might have revealed additional anti- or proarrhythmic effects, such as VT reduction, proarrhythmia with sotalol monotherapy, or differences in proportions of dogs responding. However, such studies are very labor-and costintensive, and we were limited by the number of suitable dogs available for inclusion into the study. Our cross-over study design allowed us to minimize the sample population required.

Importantly, these results apply at best only to GSD with inherited VA and sudden death, and possibly only to the inbred population in our colony at Cornell University. Because we have selected for highly affected individuals, the spontaneous variability of VA in our population might not reflect the spontaneous variability of VA in the global German shepherd dogs (GSD) population affected with inherited arrhythmias and sudden death. However, evaluation of Holter recordings in our laboratory from client-owned GSD with VA show a similar pattern of VA. Therefore, we suspect that our results may be more widely applicable. Additionally, because the arrhythmogenic substrate is different in dogs with different breed-predisposed arrhythmias, our findings should not be extrapolated to dogs other than German shepherd dogs (GSD) with inherited VA and sudden death. Finally, our study demonstrated certain acute anti-arrhythmic effects of mexiletine—sotalol combination therapy at standard oral doses. However, there was no change in the potentially most important factor: a reduction in number of VT runs. Thus, whether our findings translate into a reduction in sudden death in this patient population remains unknown.

We only examined the effect of sotalol, mexiletine and the combination of mexiletine and sotalol on the reduction of various forms of VA (VPCs, couplets, VT runs). However, cardiologists also examine the complexity of arrhythmias when attempting to demonstrate improvement following anti-arrhythmic drugs (e.g., a change from polymorphism to monomorphism, a decrease in the VT rate or length of runs, a reduction in R-on-T incidence). We did not consider these factors when examining the anti-arrhythmic effect. Thus, whether these therapies produced more subtle changes in VE is unknown.


Our study demonstrates that the combination of sotalol and mexiletine, when administered to young German shepherd dogs (GSD) with inherited VAand sudden death reduces the frequency of VPC and total VE as assessed by 24 h Holter monitoring. However, VPCs themselves might not be the ultimate target of treatment. Rather, the value of a given anti-arrhythmic therapy in reducing sudden death might be better determined by abolition of runs of VT. A reduction in the number of VPCs, as observed with combination therapy, suggests that despite concentrations of both drugs reaching a therapeutic range, the therapeutic threshold for suppression of runs of VT was not achieved. Nevertheless, our preliminary observations might warrant investigation as to whether this anti-arrhythmic combination reduces sudden death in German shepherd dogs (GSD) with inherited sudden death.

Conflict of Interest

No conflict of interest.


The authors acknowledge Drs. Hollis Erb and Giles Hooker for their comments and advice regarding the statistical analyses. We thank Mary Ellen Charter and Kristie Garcia, as well as Drs. Geri Lake Bakaar and Sheryl Kepping for their technical assistance.

Appendix 1. Sample calculation of spontaneous variability and anti-arrhythmic efficacy

In this example, 4 dogs are evaluated. 4 control Holters are obtained for each dog. 1. The hourly VPC frequency for each dog is recorded and transformed to a natural logarithm:

The hourly VPC frequency for each dog is recorded and transformed to a natural logarithm

2. The variance of the transformed data for each of the 4 dogs is calculated:

The variance of the transformed data for each of the 4 dogs is calculated

3. The variance is pooled:Where ni ¼ number of samples in the ith subject, S2 i ¼ variance for the ith subject and k ¼ total number of subjects. Therefore, in this instance,


4. The pooled variance is used to calculate the 95% CI around the variance:


The confidence intervals are dependent on the number of control and treatment Holters that will be used for a specific patient. A table of confidence intervals can be generated from the pooled variance:where Dx,y is the 95% CI of the variance for  control Holters and Y treatment Holters. Thus, D1,1 is the model used for 1 control and 1 treatment Holter. 5. The % reduction required to demonstrate an anti-arrhythmic effect is calculated using the appropriate value of D:

111411111 1114111111

Thus, in a patient from this population, where 1 control and 1 treatment Holter is obtained, a treatment effect can be assumed if the reduction in VPC frequency exceeds 47%. However, if that same patient has 4 control and 1 treatment Holter performed, then only a 39% reduction is required to demonstrate a treatment effect. 6. Let us assume that post-treatment Holters were obtained on our 4 test subjects, from which we determined the population variance. The treatment Holter results are recorded:


7. The % reduction for each dog can be determined. If only 1 Control Holter was available for each dog the % reduction would be: %reduction ¼ C  T C )100 However, if multiple control Holters are available, the % reduction is calculated from the average of the control Holters. Therefore, in our sample population, 4 Control Holters can be averaged for each dog. Using the D4,1 model, the % reduction must exceed 39% in order to ascribe an anti-arrhythmic effect in a particular subject.


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