Presented in part at the 23rd ACVIM forum, Baltimore, MD, June 1–4, 2005.
Corresponding author: Kathyrn Meurs, DVM, PhD, ACVIM, Department of Clinical Sciences, Washington State University, 100 Grimes Way, Pullman, WA 99164; e-mail: email@example.com.
Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is prevalent in the Boxer. There is little information on the temporal variability of ventricular arrhythmias within affected dogs.
Objective: To evaluate ambulatory electrocardiograms (AECG) from Boxers with ARVC for hourly variation in premature ventricular complexes (PVC) and heart rate (HR).
Animals: One hundred and sixty-two Boxer dogs with ARVC.
Methods: Retrospective, observational study of 1,181 AECGs collected from Boxer dogs at The Ohio State University from 1997 to 2004 was evaluated. The proportion of depolarizations that were PVCs was compared across each hour of the day, during six 4-hour periods of day, to the time after AECG application, and to the maximum and minimum HR.
Results: A lower proportion of PVCs was noted during early morning (midnight to 0400 hours) as compared with the morning (0800–1200 hours) and late (1600–2000 hours) afternoon (P= .012). There was no increase in PVC proportion in the 1st hour after AECG application as compared with all other hours of the day (P= .06). There was poor correlation between maximum (ρ= 0.19) and minimum (ρ= 0.12) HR and PVC proportion.
Conclusions and Clinical Importance: The likelihood of PVC occurrence in Boxer dogs with ARVC was relatively constant throughout the day, although slightly greater during the hours of 0800–1200 and 1600–2000. A biologically important correlation with HR was not apparent. The role of autonomic activity in the modulation of electrical instability in the Boxer with ARVC requires further study.
Arrhythmogenic right ventricular cardiomyopathy (ARVC), also known as arrhythmogenic right ventricular dysplasia, is a well-described familial disorder of human beings associated with predominantly right ventricular myocyte loss and subsequent fibrofatty infiltrates, ventricular arrhythmias, and risk of sudden death.1,2 Several forms of ARVC have been described in human medicine, most with significant familial penetrance.3 ARVC is an important cause of sudden death, particularly in young athletic men,1,4 and occurrence of ventricular tachyarrhythmias has been associated with exercise and sympathetic stimulation.5 Furthermore, heart rate (HR) variability analysis has confirmed the influence of autonomic activity in the modulation of electrical instability in humans with ARVC.6
Syndromes similar to human ARVC have been described in the veterinary literature, in both cats7 and dogs.8,9 ARVC is an important cause of morbidity and mortality in Boxer dogs, where it is recognized to occur in 3 forms—concealed, overt, and with myocardial dysfunction.8,10 The concealed and overt forms of the disease are characterized by ventricular arrhythmias, with the concealed form being episodic premature ventricular complexes (PVC) in asymptomatic dogs and the overt form distinguished by tachyarrhythmias leading to syncope or exercise intolerance. As in the human form of the disease, affected dogs can first present with malignant ventricular tachyarrhythmias and sudden cardiac death.10
There is little known about the factors influencing the onset of ventricular arrhythmias in Boxer dogs with ARVC. Analysis of 3 Boxer dogs with ARVC suggested a circadian variability in the frequency of ventricular ectopy, with a peak of ectopy in the morning and a variable afternoon peak.a Similar circadian patterns in ventricular ectopy have been documented in human cardiology with such diseases as coronary artery disease,11,12 hypertension,13 and hypertrophic cardiomyopathy.14 Although circadian variation in ventricular ectopy of humans with ARVC is not documented, some human patients with idiopathic ventricular tachycardia from the right ventricular outflow tract have significant circadian variability in ventricular ectopy with peaks in the morning and afternoon hours, separated by a nadir at noon.15
An understanding of the factors contributing to the incidence of ventricular ectopy in the Boxer dog could yield a greater understanding of ARVC etiology and arrhythmic risk, while providing insight into more appropriate antiarrhythmic strategies. The purpose of the present study was to evaluate a large number of ambulatory electrocardiograms (AECG) from Boxer dogs with ARVC for hourly variation in PVC number and HR, with implications for the role of sympathetic stimulation in the occurrence of ventricular extrasystoles.
Materials and Methods
Boxer dogs over 1 year of age were prospectively recruited for participation in a study of the clinical aspects of ARVC. All dogs were evaluated with physical examination, electrocardiogram, echocardiogram, and a 24-hour AECG with a 3-channel transthoracic system.b Echocardiographyc was performed in unsedated dogs positioned in right lateral recumbency. Aortic velocity was obtained with a subcostal transducer position to exclude the presence of congenital valvular or subvalvular aortic stenosis.16 Two-dimensional and M-mode imaging in the parasternal right short and long axis views were obtained to assess cardiac dimensions and function. Dogs were excluded from the study if they had aortic velocities >2.25 m/s (pressure gradient >20 mmHg, suggestive of aortic stenosis), evidence of any other congenital lesions, significant acquired valvular disease, or systolic dysfunction consistent with the myocardial form of ARVC.
Each AECG was placed and the dog sent home in order to allow monitoring of the dog's cardiac electrical activity in its normal environment. The owners were encouraged to maintain the dog's normal activity level and routine while wearing the monitor. The AECG monitor was removed after 25 hours. The AECG tapes were analyzed by 1 of 2 technicians under the guidance of a veterinary cardiologist with an AECG analysis system.b Any tapes that did not have at least 20 hours of readable data were excluded. The total number of PVCs, as well as the maximum and minimum HR, was tabulated for each hour of the day.
Participating dogs that had AECGS with ≥100 PVCs per 24-hour period, a record containing a full 24 hours of recording, and a concurrent echocardiogram displaying normal systolic function (fractional shortening >25%) were selected from 1,181 AECGs performed over the 7-year study. Dogs with a history of current antiarrhythmic medication were excluded and those with multiple AECGs had only 1 recording included in the study, with selection based on the recording with the greatest number of PVCs. The proportion of PVCs during each hour was computed as the PVC number in that hour/total number of PVCs in the 24-hour period. The day was then subdivided into six 4-hour periods and the proportion of PVCs for each dog during each period was summed. The time of maximum HR was defined as the hour of the day with the highest recorded instantaneous HR, while the time of minimum HR was defined as the hour of the day incorporating the lowest instantaneous HR over the 24-hour period.
Summary statistics and analysis were performed with commercially available software.d,e The Kruskal-Wallis test, a nonparametric 1-way analysis of variance (ANOVA), was used to identify a statistical difference between PVC proportion and hour of the day, 4-hour period, and hour after AECG application. Dunn's posttest was used to compare hours or periods if a significant difference was detected. A Spearman's correlation was performed to determine if the hourly PVC proportion correlated to the minimum or maximum HR. An α of 0.05 was considered significant.
One hundred and sixty-two dogs were included in the final analysis. The range of PVCs for all dogs was 100–62,622 (median of 1,026; interquartile range of 364–4,016) in 24 hours. The range of maximum HR for all dogs was 111–312 (median of 171; interquartile range of 159–188), whereas the range of minimum HR was 30–90 (median of 45; interquartile range of 41–51). Graphical representation of the proportion of PVCs during each hour of the day displayed a trend toward a biphasic peak in ventricular ectopy in the morning and afternoon (Fig 1), although no significant differences were noted when comparing all hours of the day (P= .053). When the day was divided into six 4-hour periods, a significant difference was detected (P= .012) and posttest analysis revealed that the hours of 800–1200 and 1600–2000 contained a significantly higher proportion of ectopy than the period from midnight to 0400 (Fig 2). Evaluating the proportion of PVCs after the AECG was applied showed no significant difference (P= .06) in the proportion of ectopy during the 1st hour after application to any other hour of the day (Fig 3). Temporal analysis of HR revealed that 5% of dogs had their maximum 24-hour HR between the hours of midnight to 0400, 4% from 0400 to 0800, 22% from 0800 to 1200, 28% from 1200 to 1600, 25% from 1600 to 2000, and 15% from 2000 to 2400 (Fig 4). Conversely, 9% of dogs recorded a minimum HR from 000 to 0400, 43% from 0400 to 0800, 15% from 0800 to 1200, 14% from 1200 to 1600, 14% from 1600 to 2000, and 6% from 2000 to 2400 (Fig 4). A statistically significant correlation (P= .015) was detected between the maximum HR and the time of maximum PVC proportion (ρ= 0.19). No significant correlation (P= .12) was found between minimum HR and the time of maximum PVC proportion (ρ= 0.12).
The results of this study suggest that there is mild variation in ventricular ectopy in Boxer dogs with ARVC throughout the day. Specifically, there is a nadir of ectopy during the early morning hours of midnight to 0400 whereas a greater proportion of ventricular ectopic depolarizations are recorded during the hours of 0800–1200 and again during the afternoon hours of 1600–2000. This is comparable to a prior reporta demonstrating a circadian pattern of ventricular ectopic depolarizations in Boxer dogs with ARVC, albeit of a much less dramatic magnitude. Only 3 dogs were examined in the earlier study,11 in which a substantial increase in ectopy was noted during the hours of 0700–1100 and from 1500 to 1900. A morning increase in ectopy has also been shown in human studies of ventricular extrasystoles, with a minor peak in the afternoon being variably present.12,17–20
The strength of the present study is the large number of dogs analyzed, for which the overall circadian variability in ventricular ectopy was more subtle than that reported in previous Boxer dogs.a It is plausible that circadian variability in ventricular ectopy is individualized, with some dogs displaying much greater magnitudes of variation than others. This is the case in humans with ventricular ectopy in whom a circadian variation in PVC frequency is noted in 40% of patients.18
The proposed cause for circadian variation in ventricular ectopy is catecholamine release and increased sympathetic activity associated with waking.19,21 This theory is supported in human cardiology by the abolishment of circadian variation in ventricular ectopy with β-blocker administration22 as well as by a measurable increase in plasma epinephrine and norepinephrine concentration with waking.21 Circadian alterations in the electrophysiologic properties of ventricular myocytes have also been suggested as a cause for the morning peak in PVCs as ventricular refractoriness varies by the time of day, with the ventricular refractory period being shortest around the time of awakening.20 There are no data in Boxers to suggest that these physiologic phenomena occur in the same manner or to the same degree as they do in people; however, such factors might account for the slight peak in morning ectopy seen in this study. Although speculative, the afternoon peak in ectopy can also be explained by increased sympathetic activity as this is a common time for owners to come home as well as for the dogs to be fed in the evening. The underlying cause for the mild variation in ectopy seen in these Boxer dogs remains unknown.
Sympathetic stimulation in dogs would likely be high during a visit to the veterinarian's office. As such, the data were evaluated to see if the 1st hour after the AECG was applied carried a greater risk for PVC prevalence, but such an effect was not detected. It is unlikely that this finding means that Boxers are not stressed while at the veterinary clinic, but does suggest that the act of putting on the AECG does not appear to increase the risk for ventricular ectopy in dogs with an underlying arrhythmic substrate such as ARVC.
HR did not appear to have a biologically significant correlation to the frequency of ventricular ectopy in this study. A nadir in HR was present in the early morning hours. Despite this intraday variation in sympathetic tone, only a minimal correlation between maximum HR and PVC proportion was present. While the time of maximum instantaneous HR was chosen as a marker of peak sympathetic stimulation, it is possible that the maximum HR was brief and periods of constant high sympathetic stimulation may have occurred at another time. However, there is prior research to support the finding that autonomic influences on ventricular ectopy differ between humans and Boxers with ARVC.6,23 HR variability analysis, used to assess autonomic activity via measurement of beat-to-beat variation in cardiac cycles, indicated a significant correlation between autonomic activity and ventricular arrhythmias in human ARVC patients.6 However, similar analysis in Boxer patients was unable to elucidate a significant difference between affected and unaffected Boxer dogs, bringing into question the role of sympathetic stimulation in the initiation of ventricular ectopy in these dogs.23
The importance of chronocardiology has led to increased discussion in human cardiology as to the role of temporal strategies in the diagnosis and treatment of cardiovascular disorders, such as the timing of β-blockade to reduce early morning mortality.19 Similar strategies may be advantageous in the management of veterinary cardiovascular disease given the mild circadian variation seen in this study; further study is required, however, before currently accepted treatment strategies10 are altered.
This analysis, as well as the strong body of evidence in the human literature for autonomic influence on ventricular ectopy,17–20 suggests that some degree of sympathetic stimulation might be involved in the development of ventricular arrhythmias in Boxer dogs with ARVC. The present study's inability to elucidate any strong circadian patterns of ectopy could be a reflection of the study's inherent limitations. This study is limited by variation in AECG quality, individual dog variation in arrhythmogenesis, and a sample size that could still be too small to elucidate subtle patterns of biological rhythms. Furthermore, whereas the signalment, morphology of the ectopy, and lack of overt systemic illness were strongly suggestive of ARVC as the underlying cause for the ectopy, the diagnosis of ARVC in each dog was presumptive and extracardiac causes of ventricular ectopy such as splenic disease were not definitively excluded.
We conclude that the likelihood of PVC occurrence remains relatively constant throughout the day in Boxer dogs with ARVC, though a slight rise in prevalence occurs during the hours of 0800–1200 and from 1600 to 2000 as compared with a nadir from midnight to 0400. A biologically significant correlation between maximum or minimum instantaneous HR was not apparent. The role of autonomic activity in the modulation of electrical instability in the Boxer with ARVC requires further study.
aGoodwin JK, Cattiny G. Further characterization of Boxer cardiomyopathy. Proceedings American College of Veterinary Internal Medicine Forum (13th): Lake Buena Vista, FL, 1995; 300–302
bDelmar Accuplus 363 Holter analysis system, Delmar Medical Systems, Irvine, CA
cGE Vivid 7 Dimension, GE Medical, Milwaukee, WI
dPrism 5, Graph Pad Software Inc, San Diego, CA
eMicrosoft Office Excel 2003, Microsoft Corporation, Redmond, WA
Supported by grants from the American Boxer Charitable Trust and the American Kennel Club Canine Health Foundation.