SEARCH

SEARCH BY CITATION

Keywords:

  • Electrocardiography;
  • VPC;
  • Dog;
  • ARVC

Abstract

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgments
  8. References

Background

Boxer dogs are reported to be predisposed to arrhythmogenic right ventricular cardiomyopathy (ARVC), but the natural history has not been well characterized and inconsistent diagnostic criteria have been applied to identify affected dogs. Echocardiographic examination findings are unremarkable in many affected Boxer dogs, and in these dogs, 24-hour ambulatory ECG (Holter) monitoring often is used for diagnostic and prognostic purposes, despite limited information available relating Holter findings to outcome.

Hypothesis/Objectives

Boxers with complex ventricular arrhythmias at initial presentation will have shorter survival times. The objective was to investigate the prognostic value of Holter monitoring in Boxer dogs.

Animals

One hundred and twenty-two Boxer dogs seen at 3 university referral hospitals.

Methods

Retrospective study. Survival times were obtained for Boxer dogs evaluated by echocardiography and a 24-hour Holter ECG. Kaplan-Meier survival analysis was used to estimate the median survival time and Cox proportional hazards analysis was used to identify variables independently associated with cardiac mortality.

Results

Outcome data were obtained for 122/163 dogs meeting the inclusion criteria. Of the 70 dogs that had died, 45 were considered to have suffered cardiac-related deaths. Median survival was significantly longer in dogs with a left ventricular systolic diameter (LVIDs) ≤ 35 mm compared with those with LVIDs > 35 mm (P < .001). Multivariable analysis in dogs with LVIDs ≤ 35 mm showed that the presence of ventricular tachycardia, age >4.5 years, and male sex were independent predictors of cardiac mortality.

Conclusions and Clinical Importance

Holter monitoring in Boxer dogs provides valuable prognostic information.

Abbreviations
2D

2-dimensional

Ao

aortic root dimension

Aovel

aortic flow velocity

APC

atrial premature contraction

ARVC

arrhythmogenic right ventricular cardiomyopathy

CHF

congestive heart failure

CI

confidence interval

ECG

electrocardiography

FS%

fractional shortening

HR

hazard ratio

IQR

interquartile range

LA

left atrial dimension

LA/Ao

left atrial to aortic root ratio

LV

left ventricle

LVIDd

left ventricular internal diameter in diastole

LVIDs

left ventricular internal diameter in systole

SVT

supraventricular tachycardia

VPC

ventricular premature contraction

VT

ventricular tachycardia

Arrhythmogenic right ventricular cardiomyopathy (ARVC) has been reported in Boxer dogs, but the diagnostic criteria and natural history of ARVC in this breed remain ill-defined.[1-5] A definitive diagnosis usually is based on necropsy findings of fibrofatty replacement of the right ventricular myocardium.[1-6] The antemortem diagnosis commonly is based on the presence of an arbitrary number of ventricular premature complexes (VPC) in a 24-hour Holter recording. Many cutoff values have been proposed for the number of VPC/24 h to differentiate between affected and nonaffected individuals (eg, 50,[4] 100,[6-9] 1,000[3, 10-12]). Syncope is one of the most common clinical signs in affected Boxers, but syncope also can be associated with other conditions such as aortic stenosis[13] or neurally mediated syncope.[14, 15]

Echocardiographic abnormalities are present in some affected dogs, and the association with these and prognosis in Boxer dogs diagnosed with ARVC is well recognized. Palermo et al showed that Boxers diagnosed with ARVC and systolic dysfunction (defined as left ventricular internal diameter in systole >35 mm) had shorter survival times than Boxers with ARVC and normal systolic function.[3] In the same study, the presence of syncope and increased frequency and complexity of ventricular arrhythmias also were associated with shorter survival times. In another study of 64 Boxers with ARVC, Meurs et al showed that the presence of congestive heart failure (CHF) or poor systolic function, but not the presence of syncope, was associated with shorter survival times.[1] These studies elected to limit their analysis to dogs diagnosed with ARVC based on Holter-based diagnostic criteria. Similar studies in a wider population of Boxers would be more applicable to Boxers seen in general practice, but have not been reported.

We hypothesized that in Boxers with normal systolic function, cardiac mortality would be increased in those with complex ventricular arrhythmias at initial presentation compared with those without. The aim of this study was to investigate the prognostic value of Holter monitoring in Boxers presenting to a referral institution and in the subpopulation of dogs with normal systolic function.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgments
  8. References

The Ethics and Welfare Committees of the participating institutions approved the protocol used in this study.

For this multicenter study, we reviewed the medical records from 2004 to 2011 of all Boxer dogs undergoing Holter monitoring and echocardiographic examination at 3 referral centers: the Queen Mother Hospital for Animals, The Royal Veterinary College; the Small Animal Teaching Hospital, University of Liverpool; and the Hospital for Small Animals, Royal (Dick) School of Veterinary Studies. All dogs were assessed either by a board-certified cardiologist or a resident in training under direct supervision of a board-certified cardiologist. Dogs were included in the study only if they were referred for investigation of clinical signs (such as congestive heart failure, syncope, exercise intolerance, episodic weakness, or arrhythmias noted on routine physical examination), and the study population did not include dogs presented for routine screening for breeding purposes. Data were obtained from medical records, echocardiographic images, and Holter reports.

Boxer dogs with at least 1 Holter recording with a minimum of 19 hours of valid data and an echocardiographic examination within 1 month of Holter recording were included in the study. Dogs with documented congenital heart disease were excluded from the study, including those with aortic blood flow velocities (Aovel) ≥ 2.25 m/s.[16]

Baseline clinical details obtained from medical records at the time of first Holter recording included age, sex, body weight, a history of syncope or episodic weakness or collapse that was believed to be consistent with syncope, the presence of congestive heart failure before presentation, and concurrent diseases. The diagnosis of CHF was based on radiographic evidence of pulmonary venous congestion or edema, or when thoracic radiographs were not available, the attending clinician's judgment was based on a combination of history, physical examination (the presence of tachypnea and crackles, or jugular distension and ascites), and ultrasound findings (atrial enlargement with pleural effusion, abdominal effusion, or both). The presence of syncope before Holter recording was determined based on the history recorded in the patient records.

All echocardiographic measurements were made off-line by 1 observer in each center by proprietary software.1234 None of the dogs was sedated for the echocardiographic examination. For calculation of LA/Ao, left atrial diameter (LA) and aortic root diameter (Ao) were measured by 2-dimensional (2D) echocardiography from the first frame after aortic valve closure.[17, 18] M-mode echocardiography was used to measure left ventricular (LV) LV internal diameters in systole (LVIDs) and diastole (LVIDd) and to calculate fractional shortening (FS%) using the leading-edge-to-leading-edge dimensions.[19, 20] Spectral Doppler echocardiography was used to measure subcostal aortic velocity (Aovel).[21] Dogs were classified as having systolic dysfunction based on LVIDs > 35 mm.[3]

Two centers used the same commercial Holter analysis service5 and in the 3rd center, raw Holter data were reviewed.6 One investigator in each center reviewed available Holter recordings using the definitions presented in the Table 1. The number of arrhythmia episodes was normalized to a 24-hour period.

Table 1. List of variables recorded from the Holter recordings and the respective definitions
Holter variables
Presence and total number of atrial premature contractions (APC)
Presence and total number of episodes of supraventricular tachycardia (SVT)
Presence of episodes of bradycardia
Maximal duration of bradycardia episode
Minimal average ventricular rate during bradycardia episode
Presence and total number of ventricular arrhythmias
Total number of ventricular premature contractions (VPCs)
Presence of polymorphic VPCs
Presence of bigeminy or trigeminy
Presence of couplets or triplets
Presence and total number of episodes of ventricular tachycardia (VT)
Longest duration of VT episode
Average ventricular rate of fastest VT episode
Minimal, mean, and maximal 1-minute average heart rate
Definitions
Pause >2.5 seconds
Bradycardia—minimum of 4 consecutive normally conducted sinus-beats at the rate of <60 beats per minute
SVT—minimum of 3 consecutive normally conducted sinus-beats at >160 beats per minute
APC—normally conducted sinus complex with RR interval of <45% of the preceding RR interval
Bigeminy—minimum of 2 VPCs alternated with 1 sinus complex
Trigeminy—minimum of 2 VPCs alternated with 2 sinus complexes
Couplet—2 consecutive VPCs
Triplet—3 consecutive VPCs
VT—more than 3 consecutive VPCs at the rate of >100 beats per minute

Survival information was obtained from a range of sources as necessary, starting with the medical records, a questionnaire mailed to owners, and finally telephone follow-up with owners who did not respond to the mailed questionnaire. If survival data were still incomplete, referring veterinarians were contacted. Outcome data included patient status (dead/alive), date of death or euthanasia, and whether the death was caused by deterioration of a cardiac condition. Sudden cardiac death was defined as an unexpected death without apparent clinical signs during the preceding 24-hour period.[1] Dogs that were still alive were right-censored at the time of last veterinary contact or the date of the interview with the owner.

Statistical analysis was performed by commercially available statistical software.7-9 Significance was set at the 5% level for all tests, apart from the univariable Cox proportional hazards analysis where variables with a P value of <.2 were included in the multivariable model. Continuous data were expressed as median and interquartile range (IQR). Binomial and categorical data were expressed as number and percentage. Categorical data were assessed by the Fisher's exact test. The Mann-Whitney U-test was used to compare nonnormally distributed data. Hartigan's dip test statistic was used for testing unimodality.

For survival analysis, the endpoint was defined as death or euthanasia related to heart disease (cardiac mortality). Dogs that died or were euthanized for other reasons, were alive at the end of the study, or were lost to follow-up were right-censored. Kaplan-Meier survival curves were constructed and analyzed by the log-rank test to identify factors that significantly influenced cardiac mortality, and to estimate median survival time. Survival analysis was carried out for the whole population, and separately for dogs with normal left ventricular systolic function (defined as LVIDs ≤ 35 mm)[3] and no evidence of CHF (LVIDs≤35 mm group).

The Cox proportional hazards analysis was used to detect the association between each variable and time to event in the LVIDs≤35 mm group. Results were expressed as the hazard ratio (HR) with 95% confidence intervals (95% CI). A multivariable model was constructed using a manual forward stepwise approach to identify variables that independently predicted outcome. Pair-wise interactions of the variables in the final model were evaluated, the proportional hazard assumption was assessed by log cumulative hazard plots and Schoenfeld residuals, and overall model fit by graphical assessment of Cox-Snell residuals.[22]

Results

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgments
  8. References

A total of 163 dogs were identified based on a search of the medical records of the 3 participating centers. Forty dogs were excluded for Aovel ≥ 2.25 m/s and 1 dog had insufficient duration of the Holter recording, leaving 122 dogs included in the study. Myocardial histopathology or necropsy information was not available for any of the dogs. Signalment, clinical findings (the presence of syncope and CHF), survival data, echocardiographic findings, and results of Holter monitoring are summarized in Table 2. Data are presented separately for the whole population, the LVIDs≤35 mm group, and the LVIDs>35 mm group. Age distribution, the presence of syncope, and CHF are shown in Figure 1.

image

Figure 1. Age distribution of the whole population suggests a bimodal age distribution. Young dogs were more likely presented for investigation of syncope (P = .040) (A), but VT occurred more frequently in older dogs (P = .015) (B).

Download figure to PowerPoint

Table 2. Signalment, clinical findings (presence of syncope and congestive heart failure), echocardiographic findings, and Holter results for dogs without left ventricular systolic dysfunction or congestive heart failure (LVIDs≤35 mm/no CHF); dogs with left ventricular systolic dysfunction, congestive heart failure (LVIDs>35 mm/CHF), or both; and the whole population of dogs (All dogs)
VariableLVIDs≤35 mm/no CHFLVIDs>35 mm/CHF P All Dogs
Median (IQR)n (%)Median (IQR)n (%)Median (IQR)n (%)
  1. IQR, interquartile range; CHF, congestive heart failure; LA, left atrial diameter; Ao, aortic diameter; FS%, fractional shortening; APC, atrial premature complex; SVT, supraventricular tachycardia; VPC, ventricular premature complex; VT, ventricular tachycardia; HR, heart rate.

  2. The P value refers to a comparison between the [LVIDs≤35 mm/no CHF] and [LVIDs>35 mm/CHF] subpopulations.

  3. a

    The number of the dogs in which the data were available.

Male 38 (42%) 28 (80%)<.001 63 (52%)
Age (years)6.5 (2.8–9.0) 91 (100%)7.7 (5.9–9.0)31 (100%).0546.9 (4.1–9.0)122 (100%)
Body weight (kg)28.2 (25.0–33.6)91 (100%)33.8 (29.0–37.9)31 (100%)<.00130.0 (25.6–34.8)122 (100%)
Syncope on presentation 69 (76%) 24 (77%).857 93 (76%)
Aortic velocity (m/s)1.81 (1.50–1.97)91 (100%)1.59 (1.28–1.87)31 (100%).0141.73 (1.42–1.95)122 (100%)
LA/Ao1.42 (1.31–1.55)84a (92%)2.21 (1.70–2.51)30 (97%)<.0011.49 (1.35–1.73)114a (93%)
LVIDs (mm)26.41 (23.3–29.6)91 (100%)41.9 (36.1–45.7)31 (100%)<.00128.2 (24.7–34.1)122 (100%)
FS%29 (24–32)89a (98%)16 (10–25)30a (97%)<.00126 (21–31)119a (98%)
Presence of APCs 43 (47%) 21 (68%).049 64 (52%)
Number of APC/24 h4 (2–32) 512 (5–2,152) .0048.5 (2–472) 
Presence of SVT 18 (20%) 11 (35%).038 27 (22%)
Number of SVT episodes2 (1–19) 53 (5–204) .0115 (2–62) 
Presence of VPCs 86 (95%) 31 (100%).183 117 (96%)
Average VPC/24 h36 (2.9–1,001) 967 (208–3,376) <.001199 (5.5–1,410) 
>50 VPC/24 h 44 (48%) 27 (87%)<.001 71 (58%)
>100 VPC/24 h 40 (44%) 26 (83%)<.001 66 (54%)
>1,000 VPC/24 h 23 (25%) 15 (48%).016 38 (31%)
Presence of polymorphic VPCs 32 (35%) 24 (77%)<.001 56 (46%)
Presence of bigeminy or trigeminy 36 (40%) 18 (58%).073 54 (44%)
Presence of couplets or triplets 54 (59%) 26 (84%).013 80 (66%)
Presence of VT 22 (24%) 14 (45%).027 36 (30%)
Number of VT episodes8.5 (3–24.3) 8 (1.75–69.25) .7618 (3.0–32.5) 
Minimum heart rate (bpm)50 (43–59)91 (100%)55 (46–73)31 (100%).06851 (44–61)122 (100%)
Mean heart rate (bpm)87 (77–100)91 (100%)97 (84–110)31 (100%).02690 (78–104)122 (100%)
Maximum heart rate (bpm)186 (171–206)91 (100%)192 (166–215)31 (100%).520190 (171–206)122 (100%)

The distribution of Holter variables among the 3 centers was not statistically significant, apart from maximum (P < .001) and minimum (P < .001) 1-minute heart rate. No syncope episodes were documented during Holter recording in any dog.

Twenty-eight dogs had LV systolic dysfunction (defined as LVIDs > 35 mm). Three dogs with LVIDs ≤ 35 mm had CHF at presentation, leaving 91 dogs in the LVIDs≤35 mm group available for statistical analysis. The 3 excluded dogs all had marked biatrial and right ventricular enlargement on 2D echocardiographic examination.

Dogs with LVIDs > 35 mm were more likely to have increased left atrial size, decreased FS%, and CHF. There were significant associations between LVIDs > 35 mm and FS < 25% (P < .001), LA/Ao > 1.5 (P < .001), the presence of CHF (P < .001), and >50 VPC/24 h (P < .001) as well as between FS < 25% and CHF (P = .002), and >50 VPC/24 h (P = .002). The presence of syncope, however, was not significantly associated with any of these indices.

Median follow-up period for the whole population was 500 days (IQR, 186–917 days). The follow-up period for dogs that were alive at the end of the study period was significantly longer than the follow-up period for dogs that had died, both in the whole population (P < .001) as well as in the LVIDs≤35 mm group (P = .005).

Kaplan-Meier survival curves were constructed separately to evaluate cardiac mortality in the whole population and the LVIDs≤35 mm group. Based on the Kaplan-Meier analysis of the whole population, median survival time was significantly shorter for dogs with LVIDs > 35 mm compared with the LVIDs≤35 mm group (242 versus 2,083 days, P < .001, Fig 2). The presence of syncope before presentation was not associated with decreased survival time.

image

Figure 2. Kaplan-Meier survival curves in overall population. Dogs in group (A) had significantly shorter median survival time (MST) (242 days, 95% CI 0–512 days) than dogs in LVIDs≤35 mm group (2,083 days, 95% CI 1,336–2,830 days), P < .001. The presence of syncope (B) did not significantly influence survival (P = .385). MST for dogs with syncope was 1,244 days (95% CI 737–1,750 days) versus >2,107 days in dogs without syncope.

Download figure to PowerPoint

In the LVIDs≤35 mm group, male sex, the presence of >50 VPC/24 h, the presence of polymorphic VPCs, and the presence of VT all were significantly associated with shorter survival. The presence of couplets or triplets, bigeminy or trigeminy, the presence of bradycardia episodes, and the presence of pauses did not reach statistical significance. Increased left atrial size (LA/Ao > 1.5), decreased fractional shortening (FS < 25%), the presence of syncope, APC, or SVT were not predictive of outcome in the LVIDs≤35 mm group (Table 3, Fig 3). The Kaplan-Meier analysis was used to assess the prognostic value of the 3 cutoff values commonly used in the literature to differentiate between Boxers affected and not affected by ARVC. Dogs with increased numbers of VPCs using any of the 3 previously suggested cutoff values (50, 100, and 1,000 VPC/24 h) had significantly shorter survival times (P = .002, .018, and .019, respectively, Fig 4).

image

Figure 3. Kaplan-Meier survival curves (cardiac mortality) in the LVIDs≤35 mm group. Male dogs (A), dogs with ventricular tachycardia (B), >50 VPC/24 h (C), and polymorphic VPCs (D) had shorter median survival times.

Download figure to PowerPoint

image

Figure 4. Kaplan-Meier survival curves (cardiac mortality) in the LVIDs≤35 mm group. Median survival was shorter for Boxers exceeding any of the cutoff values used for distinguishing between Boxers affected and not affected by ARVC (>50 VPC/24 h (A), >100 VPC/24 h (B), or >1,000 VPC/24 h (C)).

Download figure to PowerPoint

Table 3. Median survival time and 95% CI in the LVIDs≤35 mm group based on the Kaplan-Meier analysis. Variables in the table were significantly associated with median survival times. The presence of bigeminy or trigeminy, and couplets or triplets did not reach statistical significance
VariableMedian Survival Time (days; 95% CI)P (log-rank)
Sex
Male1,244; 852–1,635.035
Female>2,083 
VT
Yes1,244; 351–2,137.002
No>2,083 
Polymorphic VPC
Yes1,660; 681–2,638.019
No2,083; 893–3,272 
>50 VPC/24 h
Yes1,393; 895–1,890.003
No>2,083 
Age tertiles
>4.67 years>2,083.001
 1,393; 703–2,083 
4.67–8.07 years
>8.07 years1,086; 493–1,679 

Age distribution was bimodal with 2 peaks (P = .04) at approximately 1 and 8 years of age (Fig 1). There was no correlation between age at diagnosis and the presence of LVIDs > 35 mm (P = .612), sex (P = .953), the presence of APCs (P = .133), the presence of SVT (P = .772), or LA/Ao (P = .362). Younger dogs were more likely to be presented for investigation of syncope (P = .040), and were more likely to have <50 VPC/24 h (P = .001). Dogs presenting with polymorphic VPCs (P < .001), bigeminy or trigeminy (P = .008), couplets or triplets (P < .001), and VT (P = .015) were older.

Dogs in the youngest age tertile had significantly longer survival than the other 2 tertiles (P < .001). There was no significant difference in survival between the 2 higher age tertiles (P = .574; Fig 5). An age of 4.5 years consequently was used as a cutoff value in the multivariable statistical analysis between young and older dogs.

image

Figure 5. Kaplan-Meier survival curves in LVIDs≤35 mm group comparing effect of age by tertiles. The youngest tertile (<4.67 years) had significantly longer median survival than the rest of the population (T2, 4.67–8.07 years; T3, >8.07 years). No significant difference was present between the 2 oldest age groups.

Download figure to PowerPoint

Variables included in the multivariable Cox proportional hazards model for the LVIDs≤35 mm group included sex, age >4.5 years, LA/Ao, FS%, the presence of SVT, the presence of >50 VPC/24 h, the presence of polymorphic VPCs, the presence of bigeminy or trigeminy, the presence of couplets or triplets, and the presence of VT. Based on the multivariable Cox proportional hazard analysis, only age >4.5 years (HR, 28.82; 95% CI, 3.03–274.31; P = .003), the presence of VT (HR, 3.407; 95% CI, 1.37–8.45; P = .008), and male sex (HR, 2.73; 95% CI, 1.04–7.12) were independent predictors of survival times in the LVIDs≤35 mm group (Fig 6).

image

Figure 6. Multivariate Cox proportional hazard analysis indicates that male sex, the presence of ventricular tachycardia, and age over 4.5 years are independent predictors of worse long-term outcome.

Download figure to PowerPoint

Discussion

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgments
  8. References

Two previous studies describing outcome in Boxer dogs limited the population to dogs affected with ARVC.[1, 3] Because the criteria for diagnosis of ARVC are still poorly defined, we assessed the prognostic factors in a broader population of Boxer dogs that would better reflect a typical practice situation. Extensive investigations to rule out other causes of ventricular arrhythmias were not conducted in most dogs, and conditions other than ARVC may have been responsible for ventricular arrhythmias in some dogs. In our study, the most common reason for seeking a referral was a history of syncope. There are conflicting results for the association between the presence of syncope and cardiac morbidity or mortality in humans with ARVC.[23-26] Our results suggest that the presence of syncope is not associated with a worse prognosis, in contrast with Palermo's findings.[3] However, our population included Boxer dogs that did not meet the most common diagnostic criteria for ARVC, and may have included a larger proportion of young dogs with neurocardiogenic syncope; these cases would be expected to have a better prognosis. In addition, fewer dogs had LV systolic dysfunction than in Palermo's study. Only a small proportion of dogs in Palermo's study had a Holter recording available, making it difficult to draw conclusions on the association between syncope and severity or frequency of arrhythmias. Furthermore, the arrhythmias responsible for syncope are not necessarily the same as those responsible for sudden death.

The bimodal age distribution seen in our population may be explained by the hypothesis that young dogs are more likely to be referred for isolated fainting episodes associated with neurocardiogenic syncope, whereas older dogs are more likely to be presented for other signs of congestive heart failure, or syncope associated with arrhythmias attributable to ARVC. The effect of treatment was not assessed in our study, because treatment protocols were not standardized.

As with the studies by Palermo et al[3] and Meurs et al,[1] our results showed that left ventricular systolic dysfunction was associated with increased cardiac mortality. As expected, other factors that were significantly associated with worse outcome in our overall population were FS < 25%, LA/Ao > 1.5, the presence of congestive heart failure, and the presence of >50 VPC/24 h, because all of these factors were strongly correlated with one another. Boxer dogs with CHF and systolic dysfunction are well recognized to have a poor prognosis, and their management usually is very different from the management of Boxer dogs with normal echocardiographic findings diagnosed with ARVC, and thus, dogs with LVIDs > 35 mm or the presence of CHF were excluded from further statistical analysis. The Boxers with LVIDs≤35 mm were a diverse group with varied ages and etiologies. Referral to a second-opinion hospital often was sought because of syncope, detection of an arrhythmia during routine physical examination, episodic weakness, or exercise intolerance. Because the prognosis in Boxers with normal echocardiography is very variable, it is important to identify prognostic factors, because information on outcome in these dogs is scant in the current literature.

A bimodal age distribution in syncopal Boxers has been suggested by other authors.[2, 3, 6, 27] This finding also was noted in our population, and the age distribution pattern was similar to Palermo's findings.[3] In our population, there was no association between age at presentation and sex, the presence of APC, the presence of SVT, or the proportion of dogs with LA/Ao > 1.5. With increasing age, the proportion of dogs having polymorphic VPC, bigeminy or trigeminy, couplets or triplets, or VT increased. This, in combination with a larger proportion of young dogs having <50 VPC/24 h, suggests that older dogs have increased complexity and frequency of ventricular arrhythmias. Whether this finding is associated with more advanced disease in the older population or caused by the presence of a less malignant condition in younger dogs, such as vasovagal syncope,[14] was not determined. However, the fact that only 2 dogs in the 1st age tertile reached the primary endpoint later in life may support the latter hypothesis and is the most likely explanation of the bimodal age distribution.

It has long been suspected that the presence of VT in an echocardiographically normal Boxer is associated with an increased risk of cardiac death, and our findings supported this suspicion. Dogs in LVIDs≤35 mm group with VT had a median survival time of 1,244 days (95% CI, 351–2,136 days) versus >2,083 days in dogs without VT. In addition, the presence of polymorphic VPCs and >50 VPC/24 h were significantly associated with worse outcome in the Cox univariable model, whereas the presence of bigeminy or trigeminy, and couplets or triplets failed to reach statistical significance in predicting a worse outcome in our population. Classification of ventricular arrhythmias as “polymorphic ventricular ectopy” may not have been accurate in all cases, because changes in QRS morphology also can be the result of changes in body position; however, the association with worse survival is otherwise difficult to explain. The complexity of ventricular arrhythmias has not been clearly associated with increased mortality in veterinary studies, but is considered a negative prognostic factor in the human medical literature.[25] Neither the presence of APCs or SVT nor the presence of bradycardia episodes or pauses was associated with outcome in the LVIDs<35 mm group.

The reported sex distribution in ARVC Boxers in previous publications has varied from male predominance[3, 28] to female predominance.[29] In our total population, a very mild male predominance was documented, with a smaller proportion of male dogs in the LVIDs≤35 mm group. The Kaplan-Meier survival analysis of the LVIDs≤35 mm group showed that male dogs in this group have a significantly worse prognosis.

The bimodal age distribution and significant association between many variables and age suggest that the correlation between age and prognosis is not likely to be linear. The Kaplan-Meier survival analysis of age tertiles supported this conclusion, because the first tertile did significantly better than the older age groups, whereas there was no significant difference between the 2 older tertiles (Fig 5). This information is clinically important, as it suggests that young syncopal Boxers are more likely to present with benign disease, such as vagally mediated (neurocardiogenic) syncope and therefore carry a markedly better prognosis, whereas older dogs could present with ARVC or systemic diseases that carry a poorer long-term prognosis.

The definitive diagnostic criteria for ARVC have not been established. This makes it difficult to provide a cutoff age to distinguish dogs with benign syncope from dogs with ARVC. The number of VPC/24 h alone cannot be used to differentiate between dogs affected and not affected with ARVC, because exceeding any of the previously suggested cutoff values was associated with shorter survival times. A grading scheme based on frequency and severity of ventricular arrhythmias on ambulatory ECG monitoring has been suggested by Lown[30] for use in human cardiology. A modification in Lown grading has been used in veterinary studies, but we lack data on the association with such schemes and cardiac mortality.[1, 4, 31] The data presented in our study could form the basis for constructing a new arrhythmia-grading scheme that would ideally be tested in a validation cohort of Boxers before being used as a classification scheme for severity of arrhythmias in this breed.

On the basis of our results, we suggest a better prognosis in Boxer dogs under 4.5 years of age, with no echocardiographic abnormalities and <50 monomorphic VPC/24 h. The multivariable Cox model identified male sex, age >4.5 years, and the presence of ventricular tachycardia as independent predictors of a worse outcome.

Limitations

Several limitations may have affected the results of this study. The retrospective nature of the study may have influenced the results, such as the accurate documentation of syncope and congestive heart failure. The data were collected from 3 different centers, with 2 centers using the same commercial diagnostic laboratory for analyzing the Holter recordings, which may have resulted in differences in analysis, and errors of interpretation. Periods of Holter recording artifacts also may have led to false-negative and false-positive classification of arrhythmias. The use of an arbitrary cutoff value for the classification of dogs as having normal or abnormal systolic function may have led to misclassification of some patients. However, the chosen cutoff value allows comparison of our study with previous studies.[3] The effect of treatment on outcome was not assessed. Lastly, the small number of patients was also a limitation in our study.

Conclusions

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgments
  8. References

Despite these limitations, the results of this study confirm that valuable prognostic information can be gained from Holter monitoring in Boxer dogs that are presented for investigation of suspected ARVC. The presence of systolic dysfunction or congestive heart failure also is associated with a poor prognosis and shorter life expectancy. Syncope was not associated with outcome in our population. Boxer dogs <4.5 years of age, with normal echocardiographic examination findings and fewer than 50 monomorphic VPC/24 h, have a good long-term prognosis. The presence of ventricular tachycardia, older age, and male sex are associated with shorter survival times. Additional studies with a larger number of patients and including dogs presented for screening are required to formulate and validate an arrhythmia-grading scheme that could be used for screening purposes.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgments
  8. References

The authors thank Yu-Mei Chang for her help with statistical analyses. The study was done in London, UK. The study was not supported by a grant.

Conflict of Interest Declaration: Authors disclose no conflict of interest.

Footnotes
  1. 1

    Philips Sonos 5500; Philips Healthcare, Surrey, UK

  2. 2

    GE Vivid 5; GE Healthcare, Milwaukee, WI

  3. 3

    GE Vivid 7; GE Healthcare

  4. 4

    GE EchoPAC PC; GE Healthcare

  5. 5

    Laboratory Corporation of America, Ambulatory Monitoring Services, Burlington, NC

  6. 6

    Novacor Holter Soft, Novacor UK Ltd, Kent, UK

  7. 7

    PASW Statistics 18.0 for Windows; SPSS Inc, Chicago, IL

  8. 8

    Prism 5 for Mac OS X ver 5.0a, GraphPad Software, Inc. La Jolla, CA

  9. 9

    <diptest> package in R 2.15.2 software, R Foundation, Vienna, Austria

References

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgments
  8. References