- Email: [email protected]
Comparison of single- versus seven-day Holter analysis for the identification of dilated cardiomyopathy predictive criteria in apparently healthy Doberman Pinscher dogs
Journal Pre-proof Comparison of single versus seven-day Holter analysis for the identification of dilated cardiomyopathy predictive criteria in apparently healthy Doberman Pinscher dogs Tamilselvam Gunasekaran, BVSc & AH, Nicholas B. Olivier, PhD, Robert A. Sanders, MS PII:
S1760-2734(20)30003-5
DOI:
https://doi.org/10.1016/j.jvc.2020.01.003
Reference:
JVC 606
To appear in:
Journal of Veterinary Cardiology
Received Date: 12 March 2019 Revised Date:
13 January 2020
Accepted Date: 22 January 2020
Please cite this article as: Gunasekaran T, Olivier NB, Sanders RA, Comparison of single versus seven-day Holter analysis for the identification of dilated cardiomyopathy predictive criteria in apparently healthy Doberman Pinscher dogs, Journal of Veterinary Cardiology, https://doi.org/10.1016/ j.jvc.2020.01.003. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Elsevier B.V. All rights reserved.
1
Comparison of single versus seven-day Holter analysis for the identification of
2
dilated cardiomyopathy predictive criteria in apparently healthy Doberman
3
Pinscher dogs.
4
Tamilselvam Gunasekaran BVSc & AH; Nicholas B Olivier PhD; Robert A Sanders MS.
5
Department of Small Animal Clinical Sciences, College of Veterinary Medicine,
6
Veterinary Medical Center, 736 Wilson Rd, East Lansing, Michigan 48824, United
7
States of America.
8 9 10
Short running title “Seven-day Holter monitoring in asymptomatic Doberman Pinscher dogs”
11 12
Address correspondence to Dr. Robert Sanders at [email protected].
13 14
Acknowledgements
15
This study was funded by Doberman Pinscher Health Foundation of America and
16
George Ward Fund for pure breed research – College of Veterinary Medicine, Michigan
17
State University Endowed Research Funds.
18 19 20 1
21
Abstract
22
Introduction: The primary objective of this study was to test whether seven-day Holter
23
recording improves the sensitivity of detecting dilated cardiomyopathy (DCM) predictive
24
criteria (DCMp) compared to 24-hour Holter in asymptomatic Dobermans Pinschers
25
(DP).
26
Animals: 28 asymptomatic DP with normal echocardiographic examinations.
27
Methods: Dogs with normal echocardiographic examinations underwent seven-day
28
Holter monitoring. The presence of ≥ 50 ventricular premature complexes and or ≥ one
29
couplet / one triplet / one episode of ventricular tachycardia per 24-hour period was
30
considered positive for DCMp.
31
Results: Five dogs were positive on the first day and an additional six dogs tested
32
positive from days two to seven of the Holter recording. The number of positive dogs
33
detected by four days was significantly different (p = 0.031) compared to the first day
34
Holter.
35
Conclusions: Seven-day Holter recording detected significantly more dogs with DCMp
36
compared to the first day Holter. Follow up studies are warranted to evaluate the long-
37
term accuracy of multiple-day Holter analysis in predicting the development of DCM in
38
DP.
39
Keywords
40
electrocardiography; arrhythmia; screening
41 2
42
Abbreviation Table DCM
dilated cardiomyopathy
DCMp DP
dilated cardiomyopathy predictive criteria Doberman Pinschers
ECG
electrocardiography
IQR
interquartile range
NT-proBNP
N-terminal pro B-type natriuretic peptide
VA
ventricular arrhythmia
VPC
ventricular premature complex
VT
ventricular tachycardia
43 44 45 46 47 48 49 50 51 52 53 3
54
Introduction
55
Dilated cardiomyopathy (DCM) is the most common primary myocardial disease
56
affecting Doberman Pinscher dogs (DP) [1, 2]. It is an inherited, slowly progressive
57
disease with reported prevalence as high as 58.8% and 63.2% in European and North
58
Americana DP dogs respectively [3]. The disease has a long preclinical phase during
59
which most dogs remain asymptomatic. Once clinical signs develop, it usually
60
progresses very quickly, and affected dogs die of congestive heart failure or experience
61
sudden cardiac death [1-3]. Sudden cardiac death, presumably due to ventricular
62
fibrillation, has been reported in about 25-30% of the dogs with DCM irrespective of the
63
echocardiographic findings [4]. Early detection of echocardiographic features of
64
preclinical DCM is important as therapies initiated during this stage can prolong the
65
symptom free survival duration in DP dogs [5,6]. A placebo controlled, multi-center
66
study in DP dogs has shown that therapy with pimobendanb during the preclinical DCM
67
stage can delay the onset of symptoms [5]. Treatment with the angiotensin converting
68
enzyme inhibitor, benazepril has also been shown to delay the progression of preclinical
69
DCM to overt clinical stage [6]. Additionally, early identification of affected dogs may
70
also help in modification of breeding programs [7]. Given the heritable nature of the
71
disease and positive response to drug therapy initiated before the onset of clinical signs,
72
early diagnosis during the preclinical stage of DCM is desirable, so that therapeutic and
73
breeding decisions can be made.
74
Various screening tools have been evaluated, aimed at early diagnosis during the
75
preclinical stage of DCM. A genetic test to detect a mutation of the pyruvate
76
dehydrogenase 4 gene, encoding for a mitochondrial protein involved in energy 4
77
metabolism has been developed in DP with DCM [8]. Dogs that are homozygous or
78
heterozygous for this gene mutation are considered to be at increased risk for
79
developing DCM [8]. However, the association between pyruvate dehydrogenase 4
80
gene mutation and DCM could not be replicated in a larger study performed in
81
European DP dogs [9]. Recently, a variant in the titin gene (DCM2) was reported to be
82
highly associated with the development of spontaneous model of canine DCM [10]. This
83
test is also commercially available for screening DP dogsc. However, due to variable
84
expression and incomplete penetrance of these genes, not all the dogs that have these
85
mutations will eventually develop DCM [7]. Additionally, having a negative genetic test
86
result does not preclude a dog from developing DCM in the future [7]. Biomarkers such
87
as cardiac troponin I and N-terminal pro B-type natriuretic peptide (NT-proBNP) have
88
been evaluated for screening healthy DP for the diagnosis of preclinical DCM [11-13].
89
These studies evaluated the diagnostic accuracy of biomarker levels to detect
90
preclinical DCM based on a pre-specified echocardiographic and or 24-hour ambulatory
91
ECG (Holter) cut-off criteria. Cardiac troponin I and NT-proBNP levels had a sensitivity
92
of 86.6% and 76.5% respectively to detect echocardiographic abnormalities during
93
preclinical DCM stage. But the sensitivity to detect abnormalities on 24-hour Holter
94
recordings was much lower (45.2% for NT-proBNP and 70.5% for cardiac troponin I),
95
limiting the use of these biomarkers as stand-alone screening tools for early diagnosis
96
of DCM [11-13]. Also, NT-proBNP and cardiac troponin I levels are not specific for DCM
97
as they can be elevated in association with other cardiac diseases and in various
98
systemic diseases [13].
99 5
100
Screening for preclinical DCM is also performed using trans-thoracic echocardiography.
101
Various cut off values have been proposed for M-mode obtained left ventricular
102
chamber dimensions for the diagnosis of echocardiographic features of preclinical DCM
103
[5-6]. However, volumetric measurements of the left ventricle obtained using Simpsons
104
method of discs was reported to have better sensitivity compared to M-mode
105
measurements for the diagnosis of echocardiographic features of preclinical DCM in DP
106
dogs [14]. Unfortunately, often the diagnostic yield of stand-alone echocardiography to
107
detect preclinical stage of DCM is low since not all dogs during this stage will have
108
echocardiographic abnormalities [3]. Various studies have shown that ventricular
109
arrhythmias (VA) can occur prior to development of echocardiographic changes during
110
preclinical DCM [1-3]. A study evaluating the prevalence of DCM in DP dogs of different
111
age groups reported that 13% of dogs have isolated echocardiographic abnormalities
112
without VA [3]. Twenty nine percent of dogs have both echocardiographic changes and
113
VA, while 37% of dogs only have VA (detected via 24-hour Holter monitoring) during the
114
preclinical stage of DCM [3]. Considering that a large proportion of dogs have VA during
115
the preclinical stage of DCM, screening for the VAs in an asymptomatic DP provides the
116
best opportunity for early diagnosis [15]. A study in DP with DCM concluded that five-
117
minute ECGs had high specificity to predict occult DCM, but they were highly insensitive
118
to detect ventricular premature complexes (VPCs) compared to a 24-hour Holter
119
monitoring [16]. Advanced high frequency short- term ECG recording may be helpful to
120
diagnose occult DCMd. This type of evaluation requires high fidelity ECG recorders and
121
custom software for high frequency ECG analysis that is not routinely available in the
122
clinical setting. Currently, yearly screening with a 24-hour Holter monitor in addition to 6
123
transthoracic echocardiography is recommended as the gold standard to screen during
124
preclinical stage of DCM [15]. A longitudinal study using 24-hour Holter monitoring in
125
healthy DP without echocardiographic evidence of DCM reported that 100% of dogs
126
with ≥ 50 VPCs in a 24-hour period and 94% of dogs with ≥ one couplet or one triplet or
127
one episode of ventricular tachycardia (VT) in a 24-hour period subsequently developed
128
DCM [17].
129
Despite having better sensitivity compared to short-term ECG to detect occult VA, the
130
diagnostic accuracy of a single 24-hour Holter could be affected by spontaneous day-to-
131
day variation in the frequency and complexity of VA [18,19]. A study in people has
132
demonstrated that seven-day Holter monitoring increased the sensitivity of detecting
133
non-sustained VT episodes compared to a 24-hour Holter recording due to spontaneous
134
day-to-day variability in VA [20]. A seven-day Holter study in boxer dogs diagnosed with
135
arrhythmogenic right ventricular cardiomyopathy reported similar spontaneous day-to-
136
day variability in VPC frequency and complexity [19]. In this study, Boxer dogs with
137
lower VPC frequencies had higher degree of spontaneous day-to-day variability as
138
compared to dogs with higher VPC frequencies [19]. Currently, no information is
139
available in DP dogs regarding the degree of spontaneous day-to-day variability of VA
140
during any stage of DCM. If spontaneous day-to-day variability in VPC frequency and
141
complexity exists in DP during preclinical stage of DCM, it could significantly impact the
142
diagnostic accuracy of a single 24-hour Holter recording. The objective of this study is to
143
evaluate the degree of day-to-day variation in DCM predictive criteria (DCMp) of
144
asymptomatic DP dogs by comparing the number of positive dogs identified by the first
145
24-hour period of the Holter recording to the entire seven-day Holter monitoring. 7
146
Animals, Materials and Methods
147
Client owned DP between 3 - 8 years of age were prospectively evaluated at College of
148
Veterinary Medicine, Veterinary Medical Center, Michigan State University, between the
149
years 2014 - 2017. After thorough review of medical history, dogs that did not have any
150
reported history of collapse, weakness, or other clinical signs suggestive of
151
cardiovascular disease were considered for enrollment. Dogs were excluded if they
152
were receiving any cardiac medications. Dogs were also excluded if they were receiving
153
fish oil, taurine, or L-carnitine on the possibility that these might affect VA frequency.
154
However, dogs were enrolled if a minimum of six weeks wash out period was followed
155
after stopping the above-mentioned supplementation. Lactating, pregnant and animals
156
in estrus were also excluded to avoid any potential effect of reproductive status on the
157
frequency and or complexity of VA [21]. After initial screening through history, dogs
158
underwent routine cardiology evaluation including physical examination, transthoracic
159
echocardiographic evaluation, and seven-day Holter monitoring.
160
Transthoracic echocardiographye was performed by a cardiology resident (TG) under
161
the supervision of a board-certified veterinary cardiologist (RAS) using standard views
162
as previously recommended for screening of DCM in DP dogs [15]. Left ventricular
163
internal end‐diastolic diameter ≥ 47mm and left ventricular internal end‐systolic diameter
164
≥ 38mm were considered to be abnormal [15]. Left ventricular end systolic and end
165
diastolic volume indices were calculated in dogs where appropriate echocardiographic
166
images were available for calculation using biplane Simpson’s method of discs [14].
167
Dogs that had normal echocardiographic measurements underwent seven-day Holter
168
monitoring. 8
169
Holter monitors were applied to the dogs using previously described techniques [22].
170
The Holter recordings were analyzed using an automated computer softwaref with
171
analyses verified by the cardiology resident (TG) under the supervision of a board-
172
certified veterinary cardiologist (RAS). This verification process involved detection of
173
VPCs that were identified as normal complexes by the automated system and vice
174
versa. For each 24-hour period of the Holter recording, mean heart rate per 24-hour
175
period, the frequency of VPCs, couplets, triplets, and number of VT episodes were
176
tabulated for each dog. For classification of ventricular origin complexes, ventricular
177
complexes occurring within ≤ 100% of prevailing RR interval were classified as VPCs
178
and ventricular complexes occurring at ≥ 150% of the prevailing RR interval were
179
considered as ventricular escape complexes. Ventricular complexes occurring between
180
100 - 150% of the prevailing RR interval were classified as non-premature ventricular
181
complexes. Non-premature ventricular complexes were not included in the analysis of
182
DCMp. Total VPC count per day included both isolated VPCs and VPCs in complex
183
forms. Ventricular tachycardia was defined as an episode of four or more consecutive
184
VPCs occurring at a rate of ≥ 160 beats per minute. Ventricular couplets and triplets
185
were defined as pairs and triples of VPCs that were initiated by a ventricular complex
186
occurring within ≤ 100% of prevailing RR interval respectively. Ventricular couplets and
187
triplets that were initiated by a ventricular complex occurring more than ≥100% of
188
prevailing RR interval were not included in couplet or triplet count. Dogs that had ≥ 50
189
VPCs, and or ≥ one couplet and or ≥ one triplet and or ≥ one VT in a 24-hour period
190
were considered as having positive test for DCMp [14]. Dogs that had < 50 VPCs, no
191
couplets, no triplets or no episodes of VT in a 24-hour period were considered as having 9
192
negative test for DCMp for each day of the Holter recording. For each dog the number of
193
positive DCMp days out of entire seven days were tabulated. Dogs that had positive
194
tests for DCMp on the first 24-hour period of the Holter recording were designated first-
195
day Holter positive. Dogs that had negative test on the first 24-hour period of the
196
recording but had positive test on any other day of the recording were designated as
197
seven-day Holter positive. Dogs that had negative tests for DCMp on all seven days of
198
the Holter recording were classified as seven-day Holter negative.
199
Statistical analysis was performed using a commercial software programg. Statistical
200
significance was set at alpha < 0.05. Normality was tested using Shapiro-Wilk test and
201
by visual inspection of histograms. Normally distributed continuous variables were
202
expressed as mean ± standard deviation. Non-parametric continuous variables were
203
expressed as median with range and or interquartile range (IQR; 25th percentile-75th
204
percentile) as applicable. Categorical variables were reported as frequency and
205
percentages. Wilcoxon rank sum test was used to compare body weight, age, left
206
ventricular internal diameter in diastole, left ventricular internal diameter in systole,
207
fractional shortening and mean heart rate / 24-hour period between the positive and
208
negative dogs for DCMp. The proportion of positive results between the first day and
209
seven-day Holter recording was compared using one tailed McNemar’s exact test.
210
Results
211
Signalment: Flow chart of dogs from study enrolment to Holter outcome in this study is
212
depicted in figure 1. A total of 28 dogs were initially recruited to the study. Two dogs
213
were excluded due to abnormal echocardiographic left ventricular chamber
214
measurements. Two additional dogs were excluded since the QRS morphology during 10
215
suspected ectopic beats could not be clearly differentiated between supraventricular
216
and ventricular origin beats. Twenty-four dogs completed the seven-day Holter study, of
217
which 19 were females (11 spayed) and five were males (one neutered). The median
218
age was 5.12 years (IQR = 4.4 - 6.2 years). The median body weight was 32.7 kg (IQR
219
= 29.75 - 39.5 kg).
220
Holter results: Ventricular premature complexes were detected in 17 of the 24 dogs
221
(71%) during the entire seven-day Holter recording. The maximum VPC frequency per
222
24-hour period ranged from 2 - 2862 (median = 6 VPCs / 24-hour period; IQR = 2 - 47
223
VPCs / 24-hour period). The percentage of dogs and their respective frequency of
224
maximum VPCs per 24-hour period is depicted in table 1. Ten out of 24 (42%) dogs and
225
seven out of 24 dogs (29%) dogs had at least one couplet and at least one triplet per
226
24-hour period of the recording respectively. The fastest instantaneous heart rate of
227
couplet / triplet for each dog ranged from 200 - 300 beats per minute. The median
228
number of couplets / 24 -hour period was three couplets (range = 1 - 225 couplets / 24-
229
hour period; IQR = 2 - 103 couplets / 24-hour period) and the median number of triplets
230
/ 24-hour period was two triplets (range = 1 - 91 triplets / 24-hour period; IQR = 1 - 4
231
triplets / 24-hour period) in dogs that had couplets and triplets respectively. Only two
232
dogs had episodes of VT with one dog having one episode and another dog having five
233
episodes of VT within 24-hour period.
234
Thirteen out of 24 dogs (54%) had negative tests for DCMp on all seven days of the
235
Holter recording. Of these 13 dogs, six dogs (46%) had VPCs and their maximum VPC
236
frequency per 24-hour period ranged from 2 - 46 VPCs (median = 5 VPCs / 24-hour
237
period; IQR = 2 - 13 VPCs / 24-hour period). Seven out of these 13 dogs (54%) did not 11
238
have any VPCs during the entire seven-day Holter recording. Eleven dogs had positive
239
tests for DCMp on at least one day of the seven-day Holter recording. Five out of 11
240
dogs (45%) were first day Holter positive. Of the 11 positive dogs, four dogs (36%) had
241
positive tests based on ≥ 50 VPCs / 24-hour period criteria. Seven dogs (64%) had
242
positive tests solely based on ≥ one couplet / triplet / VT criteria. These dogs did not
243
have ≥ 50 VPCs on any day of the seven-day Holter recording. All of the dogs that were
244
positive based on ≥ 50 VPC criteria also had couplets and triplets on at least one day of
245
the seven-day Holter recording. None of the dogs had positive tests based on VT
246
criteria alone. The relationship between the number of DCMp positive dogs and the
247
number of days positive for DCMp out of seven days of the Holter recording is depicted
248
in figure 2. Note that only one dog had positive test for DCMp criteria on all seven days
249
of the Holter recording. Table 2 provides a 2 x 2 contingency table with the number of
250
DP dogs meeting the DCMp criteria according to the results of single versus seven-day
251
Holter recording. Seven-day Holter recording detected significantly more dogs positive
252
for DCMp (p = 0.016) compared to the first day Holter recording. The probability of
253
obtaining a positive result for DCMp improves with longer duration of Holter recording
254
(Fig. 3). Four days of Holter recording detects significantly a greater number of positive
255
dogs for DCMp criteria compared to the first day of the Holter recording (p = 0.031) (Fig.
256
3). The number of dogs that had positive tests for DCMp criteria was not significantly
257
different between four days and seven days of Holter recording (Fig. 3). Supplementary
258
table A (table available in Supplementary Material online) provides the baseline data
259
comparison between the dogs that are positive and negative for DCMp criteria. Of all the
260
baseline variables compared, only left ventricular internal diameter in diastole (p = 0.04) 12
261
was significantly higher in dogs that were positive for DCMp compared to negative dogs
262
(see supplementary table A).
263
frequency was calculated using the formula previously reported for Boxer dogs with
264
arrhythmogenic right ventricular cardiomyopathy [19]. Table 3 provides the percent day
265
to day variation in the number of VPCs for each dog in the study.
266
Seven out of 11 positive dogs (64%) had ventricular escape complexes (range = 0 - 154
267
/ 24-hour period; median = 2 / 24-hour period; IQR = 0 -15 / 24-hour period) and ten out
268
of 11 positive dogs (91%) had non-premature ventricular ectopic complexes (range = 0 -
269
467 / 24-hour period; median = 3 / 24-hour period = IQR: 0 - 152 / 24-hour period). Out
270
of the 13 dogs that were negative for DCMp, one dog had ventricular escape complexes
271
(two total) and two dogs had non-premature ventricular complexes (three and eight
272
beats / 24-hour period). Addition of these late coupled ventricular complexes did not
273
change the total number of dogs positive for DCMp. However, in one dog the number of
274
positive DCM days increased from five to six days.
275
Discussion
276
Our results show that seven-day Holter recording detects a greater number of dogs with
277
DCMp criteria than a single 24-hour Holter assessment. This finding is consistent with
278
several human studies that showed longer duration Holter monitoring detects more
279
patients with arrhythmic events [20, 23]. The increased sensitivity of seven-day Holter
280
recoding is due to very high spontaneous day-to-day variation of VPC frequency and
281
complexity noted in the study dogs. For example, only one dog (one out of 11 dogs
282
positive for DCMp) had positive test for DCMp on all seven days of the Holter recording.
283
If a routine, single 24-hour Holter recording is performed, only the above-mentioned dog 13
Percent day to day spontaneous variability in VPC
284
will have a 100% probability of testing positive for DCMp, irrespective of the day when
285
the Holter recording is performed. The rest of the positive dogs (ten out 11 dogs positive
286
for DCMp) will have varying probabilities of testing falsely negative for DCMp. Also, note
287
that there is nearly 100% spontaneous day to day variation in VPC frequency even in
288
dogs with high VPC frequency / 24-hour Holter period.
289
Recently published screening guidelines for DCM in DP dogs classified dogs that have
290
50 - 300 VPCs / 24-hour Holter period as DCM suspects and recommended a recheck
291
Holter evaluation within one year of initial evaluation [15]. This recommendation was
292
based on a study that showed improved specificity of diagnosing preclinical DCM with
293
two Holter examination within one year showing ≥ 50 VPCs on a 24-hour Holter
294
recordingi. In this study even a single 24-Holter showing ≥ 50 VPCs had 100%
295
sensitivity for diagnosing preclinical DCM but the specificity was slightly lower (88.1%)
296
compared to two positive Holter examinations (98% specificity). However, the follow up
297
period was only one year, and it is possible that with longer follow up period the
298
specificity of a single positive 24-Holter (≥ 50 VPCs) may improve. The DCMp criteria
299
used in this study was based on a previous, longer duration (two years) longitudinal
300
study that evaluated the association between the initial 24-hour Holter findings and
301
development of overt DCM in healthy DP dogs [17]. In the aforementioned study, 100%
302
of dogs with ≥ 50 VPCs and 94% of dogs with at least one couplet or triplet developed
303
echocardiographic criteria for DCM [4]. It is noteworthy that, 42% of dogs (36 out of 89
304
dogs with known DCM status) in the above-mentioned study did not have any VPCs on
305
their initial Holter recording but they subsequently developed echocardiographic
306
features of DCM [4]. There are various possible explanations why these dogs did not 14
307
have VPCs on their initial Holter recording. One possibility is that some of these dogs
308
had isolated echocardiographic abnormalities during their initial Holter examination and
309
could have subsequently developed VA on follow up evaluations. It is also possible that
310
in some of these dogs, the 24-hour Holter recording was not sensitive enough to detect
311
VA and multiple day Holter screening could have improved the sensitivity of detecting
312
dogs with VA.
313
Our findings have important clinical implications for screening asymptomatic DP dogs
314
during the preclinical stage of DCM. Due to the presence of spontaneous variation in
315
VPC frequency and complexity, classifying DCMp status based on a single 24-hour
316
Holter recording may not actually represent the true arrhythmia status in these dogs.
317
This can impact therapy and breeding decisions. Our study also found that four days of
318
Holter recording detected significantly more positive dogs compared to the first 24-hour
319
period of the Holter recording. Further increase in the recording duration (from day four
320
to seven days) did not significantly increase the number of positive dogs for DCMp.
321
Considering the cost associated with longer duration Holter screening a total of four
322
days might be a more practical and economical option for owners screening DP dogs
323
for occult DCM.
324
In our study, ventricular escape complexes and non-premature ventricular complexes
325
were not included in the VPC frequency count. These complexes were predominantly
326
noted during times of slow heart rate periods. The classification of ventricular
327
complexes based on the prevailing RR interval in dogs could be affected by the
328
presence of significant sinus arrhythmia. Therefore, some of the non-premature
329
ventricular complexes could actually represent VPCs especially late diastolic VPCs. 15
330
Interestingly, these non-premature ventricular complexes and ventricular escape
331
complexes were noted almost exclusively in dogs that had positive tests for DCMp. Only
332
two of the negative dogs for DCMp had these non-premature ventricular complexes.
333
Further long-term follow-up studies are needed to evaluate the prognostic significance
334
of these non-premature ventricular complexes and their association to various stages of
335
DCM.
336
In our study, of the 11 dogs that were positive for DCMp, only four dogs tested positive
337
based on ≥ 50 VPCs / 24-hour period criteria. As previously reported 100% of dogs with
338
≥ 50 VPCs / 24-hour period on a Holter recording will go onto develop overt DCM [17].
339
However, this predictive value only applies to a 24-hour Holter recording and cannot be
340
directly extrapolated to a seven-day Holter recording. It is possible that not all the dogs
341
that had positive tests based on ≥ 50 VPCs on a seven Holter recording will go on to
342
develop DCM in the future. Additionally, seven dogs tested positive solely based on
343
couplet / triplet and VT criteria. These dogs did not have ≥ 50 VPCs on any day of the
344
seven-day Holter recording. The couplet / triplet / VT criteria have been shown to have a
345
slightly lower predictive value (94%) compared to the ≥ 50 VPCs criteria (100%
346
predictive value) [14]. Considering the lower predictive value for the couplet / triplet / VT
347
criteria, seven-day Holter monitoring could be overly sensitive in detecting VA
348
complexity, resulting in false positive results. However, recently published screening
349
guidelines for preclinical DCM in DP dogs recommended a recheck evaluation in any
350
dogs that show complexity in VA (couplet, triplet, or VT at high instantaneous rate)
351
irrespective of the number of VPCs, highlighting the importance of VA complexity in
352
occult DCM diagnosis [13]. At this time, it is unknown if all the dogs that tested positive 16
353
for DCMp on a seven-day Holter recording will go on to develop overt DCM, but it is
354
reasonable to consider more aggressive follow up of these dogs. Also, some the dogs
355
that tested negative for DCMp criteria in this study could have been evaluated prior to
356
development of arrhythmogenic or echocardiographic manifestations of DCM.
357
Therefore, long term follow-up studies are needed to risk stratify asymptomatic DP dogs
358
based on their DCMp status and number of positive DCMp days on a seven-day Holter
359
recording. In our study comprehensive diagnostic workup to screen for any systemic
360
cause for VA was not performed. Therefore, non-cardiac cause for these VAs due to
361
subclinical systemic disease is not completely ruled out in some dogs.
362
Conclusions
363
Multiple day Holter recording detects a greater proportion of DCMp positive dogs than
364
single 24-hour Holter assessment. The probability of obtaining a positive result for
365
DCMp is significantly improved with four days of Holter recording. Further long-term
366
follow-up studies are warranted to evaluate the accuracy of a multiple day Holter
367
recording in predicting the development of DCM in the future.
368
Conflicts of interest statement
369
The authors have no conflicts of interest to declare.
370 371 372 373 17
374
Footnotes
375
a. O'Grady M.R., Horne R. The prevalence of dilated cardiomyopathy in Doberman
376
Pinschers: A 4.5-year follow-up (abstract). J Vet Intern Med 1998; 12:199.
377
b. Pimobendan, Boehringer Ingelheim, St. Joseph, Minnesota, United States
378
c. Veterinary Genetics Laboratory at North Carolina State University webpage and
379
webinar on dilated cardiomyopathy: https://cvm.ncsu.edu/genetics/doberman-pinscher-
380
dilated-cardiomyopathy.
381
d. Spiljak MS, Petric DA, Wiberg M, et al. Advanced electrocardiography can identify
382
occult cardiomyopathy in Doberman pinschers. September 2011, 21st ECVIM-CA
383
Congress, Unpublished conference paper, 2011. Seville, Spain. Available online
384
through Veterinary Information Network at http://www.vin.com/doc/?id=5072308
385
e. Vivid E90, General Electric Medical System, Waukesha, Wisconsin, United States
386
f. Pathfinder SL, Spacelab’s Healthcare, Snoqualmie, Wisconsin, United States
387
g. Stata, StataCorp LP, College Station, Texas, United States
388
i. Geraghty N, Wess G. Vergleich verschiedener Holterkriterien zur Diagnose des
389
arrhythmischen Stadiums der dilatativen Kardiomyopathie beim Dobermann.
390
Tierärztliche, Facultät der LMU München; 2011. p. 1-107.
391
References
392
[1] O'Grady MR, O'Sullivan ML. Dilated cardiomyopathy: an update. Vet Clin North Am
393
Small Anim Pract 2004;34:1187–207.
18
394
[2] Tidholm A, Haggstrom J, Borgarelli M, Tarducci A. Canine idiopathic dilated
395
cardiomyopathy. Part I: aetiology, clinical characteristics, epidemiology, and pathology.
396
Vet J 2001;162:92–107.
397
[3] Wess G, Schulze A, Butz V, Simak J, Killich M, Keller LJ, Maeurer J, Harmann K.
398
Prevalence of dilated cardiomyopathy in Doberman pinschers in various age groups. J
399
Vet Intern Med 2010;24:533–8.
400
[4] Calvert CA, Jacobs G, Pickus CW, Smith DD. Results of ambulatory
401
electrocardiography in overtly healthy Doberman pinschers with echocardiographic
402
abnormalities. J Am Vet Med Assoc 2000;217:1328–32.
403
[5] Summerfield NJ, Boswood A, O'Grady MR, Gordon SG, Dukes-McEwan J, Oyama
404
MA, Smith S, Patteson M, French AT, Culshaw GJ, Braz-Ruvivo L, Estrada A,
405
O’Sullivan ML, Loureiro J, Willis R, Watson P. Efficacy of Pimobendan in the Prevention
406
of Congestive Heart Failure or Sudden Death in Doberman Pinschers with Preclinical
407
Dilated Cardiomyopathy (The PROTECT Study). J Vet Intern Med 2012;26:1337–49.
408
[6] O'Grady MR, O'Sullivan ML, Minors SL, Horne R. Efficacy of benazepril
409
hydrochloride to delay the progression of occult dilated cardiomyopathy in Doberman
410
Pinschers. J Vet Intern Med 2009;23:977–83.
411
[7] Dutton E, Lopez-Alvarez J. An update on canine cardiomyopathies - is it all in the
412
genes? J Small Anim Pract 2018;59:455-64.
413
[8] Meurs KM, Lahmers S, Keene BW, White SN, Oyama MA, Mauceli E, Lindblad-Toh
414
K. A splice site mutation in a gene encoding for PDK4, a mitochondrial protein, is
19
415
associated with the development of dilated cardiomyopathy in the Doberman pinscher.
416
Hum Genet 2012;131:1319-25.
417
[9] Owczarek‐Lipska M, Mausberg T, Stephenson H, Dukes‐McEwan J, Wess G, Leeb
418
T. A 16‐bp deletion in the canine PDK4 gene is not associated with dilated
419
cardiomyopathy in a European cohort of Doberman Pinschers. Anim Genet 2013:44;
420
239-49.
421
[10] Meurs KM, Friedenberg SG, Kolb J, Saripalli C, Tonino P, Woodruff K, Olby NJ,
422
Keene BW, Adin DB, Yost OL, DeFrancesco TC, Lahmers S, Tou S, Shelton GD,
423
Granzier H. A missense variant in the titin gene in Doberman pinscher dogs with familial
424
dilated cardiomyopathy and sudden cardiac death. Hum Genet 2019:138:515-24.
425
[11] Wess G, Butz V, Mahling M, Hartmann K. Evaluation of N-terminal pro-B-type
426
natriuretic peptide as a diagnostic marker of various stages of cardiomyopathy in
427
Doberman Pinschers. Am J Vet Res 2011;72:642-9.
428
[12] Singletary GE, Morris NA, O'Sullivan LM, Gordon SG, Oyama MA. Prospective
429
evaluation of NT-proBNP assay to detect occult dilated cardiomyopathy and predict
430
survival in Doberman Pinschers. J Vet Intern Med 2012;26:1330-6.
431
[13] Wess G, Simak J, Mahling M, Hartmann K. Cardiac troponin I in Doberman
432
Pinschers with cardiomyopathy. J Vet Intern Med 2010;24:843-9.
433
[14] Wess G, Maurer J, Simak J, Hartmann K. Use of Simpson's method of disc to
434
detect early echocardiographic changes in Doberman Pinschers with dilated
435
cardiomyopathy. J Vet Intern Med 2010;24:1069-76.
20
436
[15] Wess, O. Domenech, J. Dukes-McEwan, Haggstrom J, Gordon S. European
437
Society of Veterinary Cardiology screening guidelines for dilated cardiomyopathy in
438
Doberman Pinschers. J Vet Cardiol 2017;19:405-15.
439
[16] Wess G, Schulze A, Geraghty N, Hartmann K. Ability of a 5-Minute
440
Electrocardiography (ECG) for Predicting Arrhythmias in Doberman Pinschers with
441
Cardiomyopathy in Comparison with a 24-Hour Ambulatory ECG. J Vet Intern Med
442
2010;24:333–71.
443
[17] Calvert CA, Jacobs GJ, Smith DD, Rathbun SL, Pickus CW. Association between
444
results of ambulatory electrocardiography and development of cardiomyopathy during
445
long-term follow up of Doberman pinschers. J Am Vet Med Assoc 2000;216:34-9.
446
[18] Toivonen L. Spontaneous variability in the frequency of ventricular premature
447
complexes over prolonged intervals and implications for antiarrhythmic treatment. Am J
448
Cardiol 1987;60:608-12.
449
[19] Spier AW, Meurs KM. Evaluation of spontaneous variability in the frequency of
450
ventricular arrhythmias in Boxers with arrhythmogenic right ventricular
451
cardiomyopathy. J Am Vet Med Assoc 2004;224:538–41.
452
[20] Pastor-Perez FJ, Manzano-Fernandez S, Goya-Esteban R, Pascual-Figal DA,
453
Barquero-Perez O, Rojo-Alvarez JL, Martinez-Espejo MD, Chavarri MV, García-
454
Alberola A. Comparison of detection of arrhythmias in patients with chronic heart failure
455
secondary to non-ischemic versus ischemic cardiomyopathy by 1 versus 7-day Holter
456
monitoring. Am J Cardiol 2010;106:677-81
21
457
[21] Cordina R, McGuire MA. Maternal cardiac arrhythmias during pregnancy and
458
lactation. Obstet Med 2010;3:8-16.
459
[22] Sanders RA, Kurasowa TA, Sist MD. Ambulatory electrocardiographic evaluation
460
of the occurrence of arrhythmias in healthy Salukis. J Am Vet Med Assoc 2018;252:966-
461
9.
462
[23] Dagres N, Kottkamp H, Piorkowski C, Weis S, Arya A, Sommer P, Bode K, Gerds-
463
Li JH, Kremastinos DT, Hindricks G. Influence of the duration of Holter monitoring on
464
the detection of arrhythmia recurrences after catheter ablation of atrial fibrillation:
465
Implications for patient follow-up. Int J Cardiol 2010;139:305–6.
466 467 468 469 470 471 472 473 474 475 476 22
477
Figure 1
478
Flow chart of seven-day Holter study in healthy Doberman Pinschers with normal
479
echocardiographic parameters. DCM: dilated cardiomyopathy; VPC: ventricular
480
premature complex; DCMp: ≥ 50 VPCs and or ≥ 1 couplet and or ≥ 1 triplet and or ≥ 1
481
VT /24-hour periods of Holter recording; VT: ventricular tachycardia.
482
Figure 2
483
Depicts the number of dogs that are positive for dilated cardiomyopathy criteria based
484
on number of days that they are positive out of seven days of the Holter recording. Note
485
that only one dog is positive on all seven days of the Holter recording. DCM: dilated
486
cardiomyopathy.
487
Figure 3
488
Effect of increasing duration of Holter recording on obtaining positive dilated
489
cardiomyopathy predictive criteria in healthy Doberman Pinscher dogs with normal
490
echocardiographic examinations. Note the increasing probability of obtaining a positive
491
result with increasing duration of the Holter recording. * denotes statistical significance.
23
Table 1 Maximum VPC frequency Number of dogs
Percentage of dogs %
per 24-hour period 0
7
29
1-10
9
38
11-25
2
8
25-49
2
8
≥50
4
17
Maximum frequency of ventricular premature complexes per 24-hour period of the seven-day Holter recording in healthy Doberman Pinscher dogs with normal echocardiographic examinations. VPC: ventricular premature complex.
1
Table 2 Seven-day Holter positive
Seven-day Holter negative
Totals
First day Holter positive
5
0
5
First day Holter negative
6
13
19
Totals
11
13
24
p = 0.016; McNemar’s exact test.
Proportion of positive and negative Doberman Pinscher dogs for dilated cardiomyopathy predictive criteria as detected by single versus seven-day Holter recording.
1
Table 3 Dog
Max VPC
1 2 3 4 5 6 7 8 9 10 11
296 21 2231 5 2873 47 2 2 2 819 4
12 13 14 15 16 17 18 19 20 21 22 23 24
0 0 0 0 0 0 0 4 46 2 2 6 13
Min VPC Median VPC DCMp positive dogs 0 1 0 11 37 156 0 1 610 1262 9 12.5 0 0 0 0 0 0 0 138 0 0 DCMp negative dogs 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Variability %* 100 100 98 100 79 81 100 100 100 100 100 100 100 100 100 100 100
Spontaneous day to day variation in ventricular premature complex frequency in apparently healthy Doberman Pinscher dogs with normal echocardiographic measurements. DCMp: dilated cardiomyopathy predictive criteria; VPC = ventricular premature complex; Max VPC = maximum number of VPCs per 24 hours on a seven-
1
day Holter; Min VPC = minimum number of VPCs per 24 hours on a seven-day Holter; Median VPC = median number of VPCs per 24 hours on a seven-day Holter recording.
*variability % = Maximum VPCs/24 hours – Minimum VPCs/24 hours ----------------------------------------------------------------------Maximum VPCs/24 hours
2
1
1
1
S1760-2734(20)30003-5
DOI:
https://doi.org/10.1016/j.jvc.2020.01.003
Reference:
JVC 606
To appear in:
Journal of Veterinary Cardiology
Received Date: 12 March 2019 Revised Date:
13 January 2020
Accepted Date: 22 January 2020
Please cite this article as: Gunasekaran T, Olivier NB, Sanders RA, Comparison of single versus seven-day Holter analysis for the identification of dilated cardiomyopathy predictive criteria in apparently healthy Doberman Pinscher dogs, Journal of Veterinary Cardiology, https://doi.org/10.1016/ j.jvc.2020.01.003. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Elsevier B.V. All rights reserved.
1
Comparison of single versus seven-day Holter analysis for the identification of
2
dilated cardiomyopathy predictive criteria in apparently healthy Doberman
3
Pinscher dogs.
4
Tamilselvam Gunasekaran BVSc & AH; Nicholas B Olivier PhD; Robert A Sanders MS.
5
Department of Small Animal Clinical Sciences, College of Veterinary Medicine,
6
Veterinary Medical Center, 736 Wilson Rd, East Lansing, Michigan 48824, United
7
States of America.
8 9 10
Short running title “Seven-day Holter monitoring in asymptomatic Doberman Pinscher dogs”
11 12
Address correspondence to Dr. Robert Sanders at [email protected].
13 14
Acknowledgements
15
This study was funded by Doberman Pinscher Health Foundation of America and
16
George Ward Fund for pure breed research – College of Veterinary Medicine, Michigan
17
State University Endowed Research Funds.
18 19 20 1
21
Abstract
22
Introduction: The primary objective of this study was to test whether seven-day Holter
23
recording improves the sensitivity of detecting dilated cardiomyopathy (DCM) predictive
24
criteria (DCMp) compared to 24-hour Holter in asymptomatic Dobermans Pinschers
25
(DP).
26
Animals: 28 asymptomatic DP with normal echocardiographic examinations.
27
Methods: Dogs with normal echocardiographic examinations underwent seven-day
28
Holter monitoring. The presence of ≥ 50 ventricular premature complexes and or ≥ one
29
couplet / one triplet / one episode of ventricular tachycardia per 24-hour period was
30
considered positive for DCMp.
31
Results: Five dogs were positive on the first day and an additional six dogs tested
32
positive from days two to seven of the Holter recording. The number of positive dogs
33
detected by four days was significantly different (p = 0.031) compared to the first day
34
Holter.
35
Conclusions: Seven-day Holter recording detected significantly more dogs with DCMp
36
compared to the first day Holter. Follow up studies are warranted to evaluate the long-
37
term accuracy of multiple-day Holter analysis in predicting the development of DCM in
38
DP.
39
Keywords
40
electrocardiography; arrhythmia; screening
41 2
42
Abbreviation Table DCM
dilated cardiomyopathy
DCMp DP
dilated cardiomyopathy predictive criteria Doberman Pinschers
ECG
electrocardiography
IQR
interquartile range
NT-proBNP
N-terminal pro B-type natriuretic peptide
VA
ventricular arrhythmia
VPC
ventricular premature complex
VT
ventricular tachycardia
43 44 45 46 47 48 49 50 51 52 53 3
54
Introduction
55
Dilated cardiomyopathy (DCM) is the most common primary myocardial disease
56
affecting Doberman Pinscher dogs (DP) [1, 2]. It is an inherited, slowly progressive
57
disease with reported prevalence as high as 58.8% and 63.2% in European and North
58
Americana DP dogs respectively [3]. The disease has a long preclinical phase during
59
which most dogs remain asymptomatic. Once clinical signs develop, it usually
60
progresses very quickly, and affected dogs die of congestive heart failure or experience
61
sudden cardiac death [1-3]. Sudden cardiac death, presumably due to ventricular
62
fibrillation, has been reported in about 25-30% of the dogs with DCM irrespective of the
63
echocardiographic findings [4]. Early detection of echocardiographic features of
64
preclinical DCM is important as therapies initiated during this stage can prolong the
65
symptom free survival duration in DP dogs [5,6]. A placebo controlled, multi-center
66
study in DP dogs has shown that therapy with pimobendanb during the preclinical DCM
67
stage can delay the onset of symptoms [5]. Treatment with the angiotensin converting
68
enzyme inhibitor, benazepril has also been shown to delay the progression of preclinical
69
DCM to overt clinical stage [6]. Additionally, early identification of affected dogs may
70
also help in modification of breeding programs [7]. Given the heritable nature of the
71
disease and positive response to drug therapy initiated before the onset of clinical signs,
72
early diagnosis during the preclinical stage of DCM is desirable, so that therapeutic and
73
breeding decisions can be made.
74
Various screening tools have been evaluated, aimed at early diagnosis during the
75
preclinical stage of DCM. A genetic test to detect a mutation of the pyruvate
76
dehydrogenase 4 gene, encoding for a mitochondrial protein involved in energy 4
77
metabolism has been developed in DP with DCM [8]. Dogs that are homozygous or
78
heterozygous for this gene mutation are considered to be at increased risk for
79
developing DCM [8]. However, the association between pyruvate dehydrogenase 4
80
gene mutation and DCM could not be replicated in a larger study performed in
81
European DP dogs [9]. Recently, a variant in the titin gene (DCM2) was reported to be
82
highly associated with the development of spontaneous model of canine DCM [10]. This
83
test is also commercially available for screening DP dogsc. However, due to variable
84
expression and incomplete penetrance of these genes, not all the dogs that have these
85
mutations will eventually develop DCM [7]. Additionally, having a negative genetic test
86
result does not preclude a dog from developing DCM in the future [7]. Biomarkers such
87
as cardiac troponin I and N-terminal pro B-type natriuretic peptide (NT-proBNP) have
88
been evaluated for screening healthy DP for the diagnosis of preclinical DCM [11-13].
89
These studies evaluated the diagnostic accuracy of biomarker levels to detect
90
preclinical DCM based on a pre-specified echocardiographic and or 24-hour ambulatory
91
ECG (Holter) cut-off criteria. Cardiac troponin I and NT-proBNP levels had a sensitivity
92
of 86.6% and 76.5% respectively to detect echocardiographic abnormalities during
93
preclinical DCM stage. But the sensitivity to detect abnormalities on 24-hour Holter
94
recordings was much lower (45.2% for NT-proBNP and 70.5% for cardiac troponin I),
95
limiting the use of these biomarkers as stand-alone screening tools for early diagnosis
96
of DCM [11-13]. Also, NT-proBNP and cardiac troponin I levels are not specific for DCM
97
as they can be elevated in association with other cardiac diseases and in various
98
systemic diseases [13].
99 5
100
Screening for preclinical DCM is also performed using trans-thoracic echocardiography.
101
Various cut off values have been proposed for M-mode obtained left ventricular
102
chamber dimensions for the diagnosis of echocardiographic features of preclinical DCM
103
[5-6]. However, volumetric measurements of the left ventricle obtained using Simpsons
104
method of discs was reported to have better sensitivity compared to M-mode
105
measurements for the diagnosis of echocardiographic features of preclinical DCM in DP
106
dogs [14]. Unfortunately, often the diagnostic yield of stand-alone echocardiography to
107
detect preclinical stage of DCM is low since not all dogs during this stage will have
108
echocardiographic abnormalities [3]. Various studies have shown that ventricular
109
arrhythmias (VA) can occur prior to development of echocardiographic changes during
110
preclinical DCM [1-3]. A study evaluating the prevalence of DCM in DP dogs of different
111
age groups reported that 13% of dogs have isolated echocardiographic abnormalities
112
without VA [3]. Twenty nine percent of dogs have both echocardiographic changes and
113
VA, while 37% of dogs only have VA (detected via 24-hour Holter monitoring) during the
114
preclinical stage of DCM [3]. Considering that a large proportion of dogs have VA during
115
the preclinical stage of DCM, screening for the VAs in an asymptomatic DP provides the
116
best opportunity for early diagnosis [15]. A study in DP with DCM concluded that five-
117
minute ECGs had high specificity to predict occult DCM, but they were highly insensitive
118
to detect ventricular premature complexes (VPCs) compared to a 24-hour Holter
119
monitoring [16]. Advanced high frequency short- term ECG recording may be helpful to
120
diagnose occult DCMd. This type of evaluation requires high fidelity ECG recorders and
121
custom software for high frequency ECG analysis that is not routinely available in the
122
clinical setting. Currently, yearly screening with a 24-hour Holter monitor in addition to 6
123
transthoracic echocardiography is recommended as the gold standard to screen during
124
preclinical stage of DCM [15]. A longitudinal study using 24-hour Holter monitoring in
125
healthy DP without echocardiographic evidence of DCM reported that 100% of dogs
126
with ≥ 50 VPCs in a 24-hour period and 94% of dogs with ≥ one couplet or one triplet or
127
one episode of ventricular tachycardia (VT) in a 24-hour period subsequently developed
128
DCM [17].
129
Despite having better sensitivity compared to short-term ECG to detect occult VA, the
130
diagnostic accuracy of a single 24-hour Holter could be affected by spontaneous day-to-
131
day variation in the frequency and complexity of VA [18,19]. A study in people has
132
demonstrated that seven-day Holter monitoring increased the sensitivity of detecting
133
non-sustained VT episodes compared to a 24-hour Holter recording due to spontaneous
134
day-to-day variability in VA [20]. A seven-day Holter study in boxer dogs diagnosed with
135
arrhythmogenic right ventricular cardiomyopathy reported similar spontaneous day-to-
136
day variability in VPC frequency and complexity [19]. In this study, Boxer dogs with
137
lower VPC frequencies had higher degree of spontaneous day-to-day variability as
138
compared to dogs with higher VPC frequencies [19]. Currently, no information is
139
available in DP dogs regarding the degree of spontaneous day-to-day variability of VA
140
during any stage of DCM. If spontaneous day-to-day variability in VPC frequency and
141
complexity exists in DP during preclinical stage of DCM, it could significantly impact the
142
diagnostic accuracy of a single 24-hour Holter recording. The objective of this study is to
143
evaluate the degree of day-to-day variation in DCM predictive criteria (DCMp) of
144
asymptomatic DP dogs by comparing the number of positive dogs identified by the first
145
24-hour period of the Holter recording to the entire seven-day Holter monitoring. 7
146
Animals, Materials and Methods
147
Client owned DP between 3 - 8 years of age were prospectively evaluated at College of
148
Veterinary Medicine, Veterinary Medical Center, Michigan State University, between the
149
years 2014 - 2017. After thorough review of medical history, dogs that did not have any
150
reported history of collapse, weakness, or other clinical signs suggestive of
151
cardiovascular disease were considered for enrollment. Dogs were excluded if they
152
were receiving any cardiac medications. Dogs were also excluded if they were receiving
153
fish oil, taurine, or L-carnitine on the possibility that these might affect VA frequency.
154
However, dogs were enrolled if a minimum of six weeks wash out period was followed
155
after stopping the above-mentioned supplementation. Lactating, pregnant and animals
156
in estrus were also excluded to avoid any potential effect of reproductive status on the
157
frequency and or complexity of VA [21]. After initial screening through history, dogs
158
underwent routine cardiology evaluation including physical examination, transthoracic
159
echocardiographic evaluation, and seven-day Holter monitoring.
160
Transthoracic echocardiographye was performed by a cardiology resident (TG) under
161
the supervision of a board-certified veterinary cardiologist (RAS) using standard views
162
as previously recommended for screening of DCM in DP dogs [15]. Left ventricular
163
internal end‐diastolic diameter ≥ 47mm and left ventricular internal end‐systolic diameter
164
≥ 38mm were considered to be abnormal [15]. Left ventricular end systolic and end
165
diastolic volume indices were calculated in dogs where appropriate echocardiographic
166
images were available for calculation using biplane Simpson’s method of discs [14].
167
Dogs that had normal echocardiographic measurements underwent seven-day Holter
168
monitoring. 8
169
Holter monitors were applied to the dogs using previously described techniques [22].
170
The Holter recordings were analyzed using an automated computer softwaref with
171
analyses verified by the cardiology resident (TG) under the supervision of a board-
172
certified veterinary cardiologist (RAS). This verification process involved detection of
173
VPCs that were identified as normal complexes by the automated system and vice
174
versa. For each 24-hour period of the Holter recording, mean heart rate per 24-hour
175
period, the frequency of VPCs, couplets, triplets, and number of VT episodes were
176
tabulated for each dog. For classification of ventricular origin complexes, ventricular
177
complexes occurring within ≤ 100% of prevailing RR interval were classified as VPCs
178
and ventricular complexes occurring at ≥ 150% of the prevailing RR interval were
179
considered as ventricular escape complexes. Ventricular complexes occurring between
180
100 - 150% of the prevailing RR interval were classified as non-premature ventricular
181
complexes. Non-premature ventricular complexes were not included in the analysis of
182
DCMp. Total VPC count per day included both isolated VPCs and VPCs in complex
183
forms. Ventricular tachycardia was defined as an episode of four or more consecutive
184
VPCs occurring at a rate of ≥ 160 beats per minute. Ventricular couplets and triplets
185
were defined as pairs and triples of VPCs that were initiated by a ventricular complex
186
occurring within ≤ 100% of prevailing RR interval respectively. Ventricular couplets and
187
triplets that were initiated by a ventricular complex occurring more than ≥100% of
188
prevailing RR interval were not included in couplet or triplet count. Dogs that had ≥ 50
189
VPCs, and or ≥ one couplet and or ≥ one triplet and or ≥ one VT in a 24-hour period
190
were considered as having positive test for DCMp [14]. Dogs that had < 50 VPCs, no
191
couplets, no triplets or no episodes of VT in a 24-hour period were considered as having 9
192
negative test for DCMp for each day of the Holter recording. For each dog the number of
193
positive DCMp days out of entire seven days were tabulated. Dogs that had positive
194
tests for DCMp on the first 24-hour period of the Holter recording were designated first-
195
day Holter positive. Dogs that had negative test on the first 24-hour period of the
196
recording but had positive test on any other day of the recording were designated as
197
seven-day Holter positive. Dogs that had negative tests for DCMp on all seven days of
198
the Holter recording were classified as seven-day Holter negative.
199
Statistical analysis was performed using a commercial software programg. Statistical
200
significance was set at alpha < 0.05. Normality was tested using Shapiro-Wilk test and
201
by visual inspection of histograms. Normally distributed continuous variables were
202
expressed as mean ± standard deviation. Non-parametric continuous variables were
203
expressed as median with range and or interquartile range (IQR; 25th percentile-75th
204
percentile) as applicable. Categorical variables were reported as frequency and
205
percentages. Wilcoxon rank sum test was used to compare body weight, age, left
206
ventricular internal diameter in diastole, left ventricular internal diameter in systole,
207
fractional shortening and mean heart rate / 24-hour period between the positive and
208
negative dogs for DCMp. The proportion of positive results between the first day and
209
seven-day Holter recording was compared using one tailed McNemar’s exact test.
210
Results
211
Signalment: Flow chart of dogs from study enrolment to Holter outcome in this study is
212
depicted in figure 1. A total of 28 dogs were initially recruited to the study. Two dogs
213
were excluded due to abnormal echocardiographic left ventricular chamber
214
measurements. Two additional dogs were excluded since the QRS morphology during 10
215
suspected ectopic beats could not be clearly differentiated between supraventricular
216
and ventricular origin beats. Twenty-four dogs completed the seven-day Holter study, of
217
which 19 were females (11 spayed) and five were males (one neutered). The median
218
age was 5.12 years (IQR = 4.4 - 6.2 years). The median body weight was 32.7 kg (IQR
219
= 29.75 - 39.5 kg).
220
Holter results: Ventricular premature complexes were detected in 17 of the 24 dogs
221
(71%) during the entire seven-day Holter recording. The maximum VPC frequency per
222
24-hour period ranged from 2 - 2862 (median = 6 VPCs / 24-hour period; IQR = 2 - 47
223
VPCs / 24-hour period). The percentage of dogs and their respective frequency of
224
maximum VPCs per 24-hour period is depicted in table 1. Ten out of 24 (42%) dogs and
225
seven out of 24 dogs (29%) dogs had at least one couplet and at least one triplet per
226
24-hour period of the recording respectively. The fastest instantaneous heart rate of
227
couplet / triplet for each dog ranged from 200 - 300 beats per minute. The median
228
number of couplets / 24 -hour period was three couplets (range = 1 - 225 couplets / 24-
229
hour period; IQR = 2 - 103 couplets / 24-hour period) and the median number of triplets
230
/ 24-hour period was two triplets (range = 1 - 91 triplets / 24-hour period; IQR = 1 - 4
231
triplets / 24-hour period) in dogs that had couplets and triplets respectively. Only two
232
dogs had episodes of VT with one dog having one episode and another dog having five
233
episodes of VT within 24-hour period.
234
Thirteen out of 24 dogs (54%) had negative tests for DCMp on all seven days of the
235
Holter recording. Of these 13 dogs, six dogs (46%) had VPCs and their maximum VPC
236
frequency per 24-hour period ranged from 2 - 46 VPCs (median = 5 VPCs / 24-hour
237
period; IQR = 2 - 13 VPCs / 24-hour period). Seven out of these 13 dogs (54%) did not 11
238
have any VPCs during the entire seven-day Holter recording. Eleven dogs had positive
239
tests for DCMp on at least one day of the seven-day Holter recording. Five out of 11
240
dogs (45%) were first day Holter positive. Of the 11 positive dogs, four dogs (36%) had
241
positive tests based on ≥ 50 VPCs / 24-hour period criteria. Seven dogs (64%) had
242
positive tests solely based on ≥ one couplet / triplet / VT criteria. These dogs did not
243
have ≥ 50 VPCs on any day of the seven-day Holter recording. All of the dogs that were
244
positive based on ≥ 50 VPC criteria also had couplets and triplets on at least one day of
245
the seven-day Holter recording. None of the dogs had positive tests based on VT
246
criteria alone. The relationship between the number of DCMp positive dogs and the
247
number of days positive for DCMp out of seven days of the Holter recording is depicted
248
in figure 2. Note that only one dog had positive test for DCMp criteria on all seven days
249
of the Holter recording. Table 2 provides a 2 x 2 contingency table with the number of
250
DP dogs meeting the DCMp criteria according to the results of single versus seven-day
251
Holter recording. Seven-day Holter recording detected significantly more dogs positive
252
for DCMp (p = 0.016) compared to the first day Holter recording. The probability of
253
obtaining a positive result for DCMp improves with longer duration of Holter recording
254
(Fig. 3). Four days of Holter recording detects significantly a greater number of positive
255
dogs for DCMp criteria compared to the first day of the Holter recording (p = 0.031) (Fig.
256
3). The number of dogs that had positive tests for DCMp criteria was not significantly
257
different between four days and seven days of Holter recording (Fig. 3). Supplementary
258
table A (table available in Supplementary Material online) provides the baseline data
259
comparison between the dogs that are positive and negative for DCMp criteria. Of all the
260
baseline variables compared, only left ventricular internal diameter in diastole (p = 0.04) 12
261
was significantly higher in dogs that were positive for DCMp compared to negative dogs
262
(see supplementary table A).
263
frequency was calculated using the formula previously reported for Boxer dogs with
264
arrhythmogenic right ventricular cardiomyopathy [19]. Table 3 provides the percent day
265
to day variation in the number of VPCs for each dog in the study.
266
Seven out of 11 positive dogs (64%) had ventricular escape complexes (range = 0 - 154
267
/ 24-hour period; median = 2 / 24-hour period; IQR = 0 -15 / 24-hour period) and ten out
268
of 11 positive dogs (91%) had non-premature ventricular ectopic complexes (range = 0 -
269
467 / 24-hour period; median = 3 / 24-hour period = IQR: 0 - 152 / 24-hour period). Out
270
of the 13 dogs that were negative for DCMp, one dog had ventricular escape complexes
271
(two total) and two dogs had non-premature ventricular complexes (three and eight
272
beats / 24-hour period). Addition of these late coupled ventricular complexes did not
273
change the total number of dogs positive for DCMp. However, in one dog the number of
274
positive DCM days increased from five to six days.
275
Discussion
276
Our results show that seven-day Holter recording detects a greater number of dogs with
277
DCMp criteria than a single 24-hour Holter assessment. This finding is consistent with
278
several human studies that showed longer duration Holter monitoring detects more
279
patients with arrhythmic events [20, 23]. The increased sensitivity of seven-day Holter
280
recoding is due to very high spontaneous day-to-day variation of VPC frequency and
281
complexity noted in the study dogs. For example, only one dog (one out of 11 dogs
282
positive for DCMp) had positive test for DCMp on all seven days of the Holter recording.
283
If a routine, single 24-hour Holter recording is performed, only the above-mentioned dog 13
Percent day to day spontaneous variability in VPC
284
will have a 100% probability of testing positive for DCMp, irrespective of the day when
285
the Holter recording is performed. The rest of the positive dogs (ten out 11 dogs positive
286
for DCMp) will have varying probabilities of testing falsely negative for DCMp. Also, note
287
that there is nearly 100% spontaneous day to day variation in VPC frequency even in
288
dogs with high VPC frequency / 24-hour Holter period.
289
Recently published screening guidelines for DCM in DP dogs classified dogs that have
290
50 - 300 VPCs / 24-hour Holter period as DCM suspects and recommended a recheck
291
Holter evaluation within one year of initial evaluation [15]. This recommendation was
292
based on a study that showed improved specificity of diagnosing preclinical DCM with
293
two Holter examination within one year showing ≥ 50 VPCs on a 24-hour Holter
294
recordingi. In this study even a single 24-Holter showing ≥ 50 VPCs had 100%
295
sensitivity for diagnosing preclinical DCM but the specificity was slightly lower (88.1%)
296
compared to two positive Holter examinations (98% specificity). However, the follow up
297
period was only one year, and it is possible that with longer follow up period the
298
specificity of a single positive 24-Holter (≥ 50 VPCs) may improve. The DCMp criteria
299
used in this study was based on a previous, longer duration (two years) longitudinal
300
study that evaluated the association between the initial 24-hour Holter findings and
301
development of overt DCM in healthy DP dogs [17]. In the aforementioned study, 100%
302
of dogs with ≥ 50 VPCs and 94% of dogs with at least one couplet or triplet developed
303
echocardiographic criteria for DCM [4]. It is noteworthy that, 42% of dogs (36 out of 89
304
dogs with known DCM status) in the above-mentioned study did not have any VPCs on
305
their initial Holter recording but they subsequently developed echocardiographic
306
features of DCM [4]. There are various possible explanations why these dogs did not 14
307
have VPCs on their initial Holter recording. One possibility is that some of these dogs
308
had isolated echocardiographic abnormalities during their initial Holter examination and
309
could have subsequently developed VA on follow up evaluations. It is also possible that
310
in some of these dogs, the 24-hour Holter recording was not sensitive enough to detect
311
VA and multiple day Holter screening could have improved the sensitivity of detecting
312
dogs with VA.
313
Our findings have important clinical implications for screening asymptomatic DP dogs
314
during the preclinical stage of DCM. Due to the presence of spontaneous variation in
315
VPC frequency and complexity, classifying DCMp status based on a single 24-hour
316
Holter recording may not actually represent the true arrhythmia status in these dogs.
317
This can impact therapy and breeding decisions. Our study also found that four days of
318
Holter recording detected significantly more positive dogs compared to the first 24-hour
319
period of the Holter recording. Further increase in the recording duration (from day four
320
to seven days) did not significantly increase the number of positive dogs for DCMp.
321
Considering the cost associated with longer duration Holter screening a total of four
322
days might be a more practical and economical option for owners screening DP dogs
323
for occult DCM.
324
In our study, ventricular escape complexes and non-premature ventricular complexes
325
were not included in the VPC frequency count. These complexes were predominantly
326
noted during times of slow heart rate periods. The classification of ventricular
327
complexes based on the prevailing RR interval in dogs could be affected by the
328
presence of significant sinus arrhythmia. Therefore, some of the non-premature
329
ventricular complexes could actually represent VPCs especially late diastolic VPCs. 15
330
Interestingly, these non-premature ventricular complexes and ventricular escape
331
complexes were noted almost exclusively in dogs that had positive tests for DCMp. Only
332
two of the negative dogs for DCMp had these non-premature ventricular complexes.
333
Further long-term follow-up studies are needed to evaluate the prognostic significance
334
of these non-premature ventricular complexes and their association to various stages of
335
DCM.
336
In our study, of the 11 dogs that were positive for DCMp, only four dogs tested positive
337
based on ≥ 50 VPCs / 24-hour period criteria. As previously reported 100% of dogs with
338
≥ 50 VPCs / 24-hour period on a Holter recording will go onto develop overt DCM [17].
339
However, this predictive value only applies to a 24-hour Holter recording and cannot be
340
directly extrapolated to a seven-day Holter recording. It is possible that not all the dogs
341
that had positive tests based on ≥ 50 VPCs on a seven Holter recording will go on to
342
develop DCM in the future. Additionally, seven dogs tested positive solely based on
343
couplet / triplet and VT criteria. These dogs did not have ≥ 50 VPCs on any day of the
344
seven-day Holter recording. The couplet / triplet / VT criteria have been shown to have a
345
slightly lower predictive value (94%) compared to the ≥ 50 VPCs criteria (100%
346
predictive value) [14]. Considering the lower predictive value for the couplet / triplet / VT
347
criteria, seven-day Holter monitoring could be overly sensitive in detecting VA
348
complexity, resulting in false positive results. However, recently published screening
349
guidelines for preclinical DCM in DP dogs recommended a recheck evaluation in any
350
dogs that show complexity in VA (couplet, triplet, or VT at high instantaneous rate)
351
irrespective of the number of VPCs, highlighting the importance of VA complexity in
352
occult DCM diagnosis [13]. At this time, it is unknown if all the dogs that tested positive 16
353
for DCMp on a seven-day Holter recording will go on to develop overt DCM, but it is
354
reasonable to consider more aggressive follow up of these dogs. Also, some the dogs
355
that tested negative for DCMp criteria in this study could have been evaluated prior to
356
development of arrhythmogenic or echocardiographic manifestations of DCM.
357
Therefore, long term follow-up studies are needed to risk stratify asymptomatic DP dogs
358
based on their DCMp status and number of positive DCMp days on a seven-day Holter
359
recording. In our study comprehensive diagnostic workup to screen for any systemic
360
cause for VA was not performed. Therefore, non-cardiac cause for these VAs due to
361
subclinical systemic disease is not completely ruled out in some dogs.
362
Conclusions
363
Multiple day Holter recording detects a greater proportion of DCMp positive dogs than
364
single 24-hour Holter assessment. The probability of obtaining a positive result for
365
DCMp is significantly improved with four days of Holter recording. Further long-term
366
follow-up studies are warranted to evaluate the accuracy of a multiple day Holter
367
recording in predicting the development of DCM in the future.
368
Conflicts of interest statement
369
The authors have no conflicts of interest to declare.
370 371 372 373 17
374
Footnotes
375
a. O'Grady M.R., Horne R. The prevalence of dilated cardiomyopathy in Doberman
376
Pinschers: A 4.5-year follow-up (abstract). J Vet Intern Med 1998; 12:199.
377
b. Pimobendan, Boehringer Ingelheim, St. Joseph, Minnesota, United States
378
c. Veterinary Genetics Laboratory at North Carolina State University webpage and
379
webinar on dilated cardiomyopathy: https://cvm.ncsu.edu/genetics/doberman-pinscher-
380
dilated-cardiomyopathy.
381
d. Spiljak MS, Petric DA, Wiberg M, et al. Advanced electrocardiography can identify
382
occult cardiomyopathy in Doberman pinschers. September 2011, 21st ECVIM-CA
383
Congress, Unpublished conference paper, 2011. Seville, Spain. Available online
384
through Veterinary Information Network at http://www.vin.com/doc/?id=5072308
385
e. Vivid E90, General Electric Medical System, Waukesha, Wisconsin, United States
386
f. Pathfinder SL, Spacelab’s Healthcare, Snoqualmie, Wisconsin, United States
387
g. Stata, StataCorp LP, College Station, Texas, United States
388
i. Geraghty N, Wess G. Vergleich verschiedener Holterkriterien zur Diagnose des
389
arrhythmischen Stadiums der dilatativen Kardiomyopathie beim Dobermann.
390
Tierärztliche, Facultät der LMU München; 2011. p. 1-107.
391
References
392
[1] O'Grady MR, O'Sullivan ML. Dilated cardiomyopathy: an update. Vet Clin North Am
393
Small Anim Pract 2004;34:1187–207.
18
394
[2] Tidholm A, Haggstrom J, Borgarelli M, Tarducci A. Canine idiopathic dilated
395
cardiomyopathy. Part I: aetiology, clinical characteristics, epidemiology, and pathology.
396
Vet J 2001;162:92–107.
397
[3] Wess G, Schulze A, Butz V, Simak J, Killich M, Keller LJ, Maeurer J, Harmann K.
398
Prevalence of dilated cardiomyopathy in Doberman pinschers in various age groups. J
399
Vet Intern Med 2010;24:533–8.
400
[4] Calvert CA, Jacobs G, Pickus CW, Smith DD. Results of ambulatory
401
electrocardiography in overtly healthy Doberman pinschers with echocardiographic
402
abnormalities. J Am Vet Med Assoc 2000;217:1328–32.
403
[5] Summerfield NJ, Boswood A, O'Grady MR, Gordon SG, Dukes-McEwan J, Oyama
404
MA, Smith S, Patteson M, French AT, Culshaw GJ, Braz-Ruvivo L, Estrada A,
405
O’Sullivan ML, Loureiro J, Willis R, Watson P. Efficacy of Pimobendan in the Prevention
406
of Congestive Heart Failure or Sudden Death in Doberman Pinschers with Preclinical
407
Dilated Cardiomyopathy (The PROTECT Study). J Vet Intern Med 2012;26:1337–49.
408
[6] O'Grady MR, O'Sullivan ML, Minors SL, Horne R. Efficacy of benazepril
409
hydrochloride to delay the progression of occult dilated cardiomyopathy in Doberman
410
Pinschers. J Vet Intern Med 2009;23:977–83.
411
[7] Dutton E, Lopez-Alvarez J. An update on canine cardiomyopathies - is it all in the
412
genes? J Small Anim Pract 2018;59:455-64.
413
[8] Meurs KM, Lahmers S, Keene BW, White SN, Oyama MA, Mauceli E, Lindblad-Toh
414
K. A splice site mutation in a gene encoding for PDK4, a mitochondrial protein, is
19
415
associated with the development of dilated cardiomyopathy in the Doberman pinscher.
416
Hum Genet 2012;131:1319-25.
417
[9] Owczarek‐Lipska M, Mausberg T, Stephenson H, Dukes‐McEwan J, Wess G, Leeb
418
T. A 16‐bp deletion in the canine PDK4 gene is not associated with dilated
419
cardiomyopathy in a European cohort of Doberman Pinschers. Anim Genet 2013:44;
420
239-49.
421
[10] Meurs KM, Friedenberg SG, Kolb J, Saripalli C, Tonino P, Woodruff K, Olby NJ,
422
Keene BW, Adin DB, Yost OL, DeFrancesco TC, Lahmers S, Tou S, Shelton GD,
423
Granzier H. A missense variant in the titin gene in Doberman pinscher dogs with familial
424
dilated cardiomyopathy and sudden cardiac death. Hum Genet 2019:138:515-24.
425
[11] Wess G, Butz V, Mahling M, Hartmann K. Evaluation of N-terminal pro-B-type
426
natriuretic peptide as a diagnostic marker of various stages of cardiomyopathy in
427
Doberman Pinschers. Am J Vet Res 2011;72:642-9.
428
[12] Singletary GE, Morris NA, O'Sullivan LM, Gordon SG, Oyama MA. Prospective
429
evaluation of NT-proBNP assay to detect occult dilated cardiomyopathy and predict
430
survival in Doberman Pinschers. J Vet Intern Med 2012;26:1330-6.
431
[13] Wess G, Simak J, Mahling M, Hartmann K. Cardiac troponin I in Doberman
432
Pinschers with cardiomyopathy. J Vet Intern Med 2010;24:843-9.
433
[14] Wess G, Maurer J, Simak J, Hartmann K. Use of Simpson's method of disc to
434
detect early echocardiographic changes in Doberman Pinschers with dilated
435
cardiomyopathy. J Vet Intern Med 2010;24:1069-76.
20
436
[15] Wess, O. Domenech, J. Dukes-McEwan, Haggstrom J, Gordon S. European
437
Society of Veterinary Cardiology screening guidelines for dilated cardiomyopathy in
438
Doberman Pinschers. J Vet Cardiol 2017;19:405-15.
439
[16] Wess G, Schulze A, Geraghty N, Hartmann K. Ability of a 5-Minute
440
Electrocardiography (ECG) for Predicting Arrhythmias in Doberman Pinschers with
441
Cardiomyopathy in Comparison with a 24-Hour Ambulatory ECG. J Vet Intern Med
442
2010;24:333–71.
443
[17] Calvert CA, Jacobs GJ, Smith DD, Rathbun SL, Pickus CW. Association between
444
results of ambulatory electrocardiography and development of cardiomyopathy during
445
long-term follow up of Doberman pinschers. J Am Vet Med Assoc 2000;216:34-9.
446
[18] Toivonen L. Spontaneous variability in the frequency of ventricular premature
447
complexes over prolonged intervals and implications for antiarrhythmic treatment. Am J
448
Cardiol 1987;60:608-12.
449
[19] Spier AW, Meurs KM. Evaluation of spontaneous variability in the frequency of
450
ventricular arrhythmias in Boxers with arrhythmogenic right ventricular
451
cardiomyopathy. J Am Vet Med Assoc 2004;224:538–41.
452
[20] Pastor-Perez FJ, Manzano-Fernandez S, Goya-Esteban R, Pascual-Figal DA,
453
Barquero-Perez O, Rojo-Alvarez JL, Martinez-Espejo MD, Chavarri MV, García-
454
Alberola A. Comparison of detection of arrhythmias in patients with chronic heart failure
455
secondary to non-ischemic versus ischemic cardiomyopathy by 1 versus 7-day Holter
456
monitoring. Am J Cardiol 2010;106:677-81
21
457
[21] Cordina R, McGuire MA. Maternal cardiac arrhythmias during pregnancy and
458
lactation. Obstet Med 2010;3:8-16.
459
[22] Sanders RA, Kurasowa TA, Sist MD. Ambulatory electrocardiographic evaluation
460
of the occurrence of arrhythmias in healthy Salukis. J Am Vet Med Assoc 2018;252:966-
461
9.
462
[23] Dagres N, Kottkamp H, Piorkowski C, Weis S, Arya A, Sommer P, Bode K, Gerds-
463
Li JH, Kremastinos DT, Hindricks G. Influence of the duration of Holter monitoring on
464
the detection of arrhythmia recurrences after catheter ablation of atrial fibrillation:
465
Implications for patient follow-up. Int J Cardiol 2010;139:305–6.
466 467 468 469 470 471 472 473 474 475 476 22
477
Figure 1
478
Flow chart of seven-day Holter study in healthy Doberman Pinschers with normal
479
echocardiographic parameters. DCM: dilated cardiomyopathy; VPC: ventricular
480
premature complex; DCMp: ≥ 50 VPCs and or ≥ 1 couplet and or ≥ 1 triplet and or ≥ 1
481
VT /24-hour periods of Holter recording; VT: ventricular tachycardia.
482
Figure 2
483
Depicts the number of dogs that are positive for dilated cardiomyopathy criteria based
484
on number of days that they are positive out of seven days of the Holter recording. Note
485
that only one dog is positive on all seven days of the Holter recording. DCM: dilated
486
cardiomyopathy.
487
Figure 3
488
Effect of increasing duration of Holter recording on obtaining positive dilated
489
cardiomyopathy predictive criteria in healthy Doberman Pinscher dogs with normal
490
echocardiographic examinations. Note the increasing probability of obtaining a positive
491
result with increasing duration of the Holter recording. * denotes statistical significance.
23
Table 1 Maximum VPC frequency Number of dogs
Percentage of dogs %
per 24-hour period 0
7
29
1-10
9
38
11-25
2
8
25-49
2
8
≥50
4
17
Maximum frequency of ventricular premature complexes per 24-hour period of the seven-day Holter recording in healthy Doberman Pinscher dogs with normal echocardiographic examinations. VPC: ventricular premature complex.
1
Table 2 Seven-day Holter positive
Seven-day Holter negative
Totals
First day Holter positive
5
0
5
First day Holter negative
6
13
19
Totals
11
13
24
p = 0.016; McNemar’s exact test.
Proportion of positive and negative Doberman Pinscher dogs for dilated cardiomyopathy predictive criteria as detected by single versus seven-day Holter recording.
1
Table 3 Dog
Max VPC
1 2 3 4 5 6 7 8 9 10 11
296 21 2231 5 2873 47 2 2 2 819 4
12 13 14 15 16 17 18 19 20 21 22 23 24
0 0 0 0 0 0 0 4 46 2 2 6 13
Min VPC Median VPC DCMp positive dogs 0 1 0 11 37 156 0 1 610 1262 9 12.5 0 0 0 0 0 0 0 138 0 0 DCMp negative dogs 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Variability %* 100 100 98 100 79 81 100 100 100 100 100 100 100 100 100 100 100
Spontaneous day to day variation in ventricular premature complex frequency in apparently healthy Doberman Pinscher dogs with normal echocardiographic measurements. DCMp: dilated cardiomyopathy predictive criteria; VPC = ventricular premature complex; Max VPC = maximum number of VPCs per 24 hours on a seven-
1
day Holter; Min VPC = minimum number of VPCs per 24 hours on a seven-day Holter; Median VPC = median number of VPCs per 24 hours on a seven-day Holter recording.
*variability % = Maximum VPCs/24 hours – Minimum VPCs/24 hours ----------------------------------------------------------------------Maximum VPCs/24 hours
2
1
1
1