{'fraction_non_alphanumeric': 0.024181634398569317, 'fraction_numerical': 0.009641551978850789, 'mean_word_length': 4.97954439795444, 'pattern_counts': {'":': 0, '<': 2, '<?xml version=': 0, '>': 1, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Prevalence of sudden cardiac death in dogs with atrial fibrillation

Abstract Background Atrial fibrillation (AF) is associated with increased risk of sudden cardiac death (SCD) in humans, independent of secondary risk factors such as thrombogenic disorders. In dogs, SCD is described in a number of heart diseases, but an association between AF and SCD is unreported. Hypothesis (a) A higher proportion of dogs with AF will experience SCD, and (b) SCD will be associated with complex ventricular arrhythmias. Animals One‐hundred forty‐two dogs with AF, and 127 dogs without AF. Methods Retrospective, multicenter, case‐control study. Dogs included in the AF group were compared to a control group of dogs in sinus rhythm, matched for echocardiographic diagnosis. Descriptive statistics were used to identify proportions of each group suffering SCD, compared using chi‐squared testing. Risk factors for SCD in dogs with AF were evaluated at the univariable and multivariable level using binary logistic regression. Significance was P < .05. Results A significantly higher proportion of dogs with AF suffered SCD than dogs in the control group (14.8% vs 5.5%; P = .01). Younger age at diagnosis, larger left atrial size, and a history of syncope all were independent predictors of SCD in dogs with AF (χ 2, 16.3; P = .04). Conclusions and Clinical Importance Atrial fibrillation was associated with a higher prevalence of SCD in dogs. A history of syncope may be a useful predictor of SCD risk.

or "lone" AF. [1][2][3][4][5][6][7] Atrial fibrillation itself may trigger cardiac remodeling and, particularly at higher heart rates, systolic dysfunction in dogs. 8 The presence of worse structural heart disease identified using echocardiography and higher mean, Holter-derived heart rate previously have been reported to be associated with shorter survival time after diagnosis, 1,2 and AF itself confers shorter survival time for dogs diagnosed with myxomatous mitral valve disease (MMVD) 9 and dilated cardiomyopathy (DCM). 10 Most dogs with AF are treated using antiarrhythmic medication to control ventricular response rate, such as digoxin, diltiazem, or both in combination. 2,11 Electrical cardioversion may be performed with the intent of restoring sinus rhythm, but has variable long-term success rates. 12,13 In humans with AF, an increased risk of mortality 14 and, particularly, sudden cardiac death (SCD) [15][16][17] has been identified by largescale studies. In addition, people with AF have a higher risk of thrombogenic stroke, 18 presumably owing to decreased atrial function promoting a hypercoagulable state as well as various other tissue factors. 19 This may account for a proportion of the risk, as might complications associated with medication, or a predisposition to other arrhythmias. 16 In dogs with AF, sudden cardiac death is poorly described. One study reported that 4 of 46 (9%) dogs with AF died suddenly, 2 but further analysis was beyond the scope of that study.
Our aims were to identify the prevalence of SCD in a large population of dogs diagnosed with AF, comparing this prevalence to that of dogs without AF, matched for echocardiographic diagnosis. In addition, we aimed to evaluate possible risk factors for SCD in dogs with AF. Our hypotheses were: first, that dogs with AF would have a higher prevalence of SCD than the control group and, second, that complex ventricular arrhythmias on Holter ECG would be associated with SCD. In addition to the AF group, a control population of dogs in sinus rhythm was recruited in a similar manner, from 1 center only (Langford Vets). Inclusion criteria were the presence of signalment, echocardiographic and outcome data. There was no requirement for Holter data to be available in control dogs. Dogs surviving <7 days were excluded, so as to better match the control dogs to the AF dogs, which all were stable enough to undergo 24-hour Holter ECG recording at home. Exclusion criteria were no outcome data available and insufficient echocardiographic data available to make a confident diagnosis of cardiac pathology, and otherwise as above. Recruitment to the control group was stratified to gather a population of dogs with a similar make-up of heart disease diagnoses to the AF group, so as to more fairly assess SCD prevalence. After the AF group was collected, echocardiographic diagnoses were grouped as follows: DCM, MMVD, arrhythmogenic cardiomyopathy, congenital heart disease, and no detectable pathology using echocardiography ("normal" echocardiogram). Initially, control dogs were recruited and then the proportion of dogs in each of these groups was compared statistically between the AF and control groups. Where the overall group composition was significantly different, dogs were excluded from an overrepresented stratum of the control group (selected using a random number generator) so as to balance the group composition ( Figure 1). No dogs from the AF group were excluded at this stage. The control group was not stratified for body weight, sex, or age.

| MATERIALS AND METHODS
The definition of SCD used to classify status of death was as follows: if found dead, without cause and had been seen to be apparently well in the preceding 24 hours; or, if witnessed, had no apparent signs within the preceding hour. 20

| Dogs with atrial fibrillation
Most common breeds in dogs with AF were German shepherd   Figure 2). times more likely to experience SCD than those without, and younger age and increased left atrial size were associated with a higher risk of SCD (Table 4).

| DISCUSSION
In this retrospective study, the prevalence of SCD in dogs with AF was significantly higher than in a control group of dogs in sinus rhythm, matched for echocardiographic diagnoses (14.8% vs 5.5%). Younger age at diagnosis, larger left atrial size and history of syncope were independently associated with increased risk of SCD in dogs with AF. Analysis did not support our hypothesis that ventricular arrhythmias detected on 24-hour Holter ECG would be associated with SCD.
The reason for SCD in dogs AF is unknown. In humans, >20% of people with established AF treated using anticoagulants die suddenly, 16 and the association is independent of other risk factors such as heart failure, hypertension, or QT-prolonging antiarrhythmic medication. 22 Similar to our finding in dogs, some studies report that younger people with AF are at higher risk of SCD. 23 Dogs diagnosed with heart disease and AF at a younger age may have a more aggressive disease phenotype and therefore faster progression of disease (leading to earlier death). In addition, younger dogs may be exercised more or behave more excitably, thus increasing the risk from catecholamine surges, which could potentiate underlying arrhythmic foci or detrimentally alter vascular resistance.
The relationship between AF and SCD in humans may represent an intrinsic electrophysiologic link, where AF itself somehow predisposes to VT or ventricular fibrillation. Ventricular ectopy was certainly common among dogs with AF in our population, but none of the dogs died while wearing a Holter monitor, so we have no information to suggest that it relates to death. In fact, our results did not identify any association between Holter arrhythmia variables and SCD. However, the independent association between syncope and SCD in dogs with AF suggests that a relationship may exist between episodic arrhythmias, alterations in vascular tone, or activation of cardiac reflexes, or some combination of these, and increased risk. In humans with dualchamber implantable cardioverter defibrillator devices, atrial tachyarrhythmias (including AF) may increase susceptibility to ventricular arrhythmias. 24 An experimental study in dogs also supports this hypothesis. Programmed ventricular stimulation did not induce VT in dogs in sinus rhythm, but when AF was induced, 25/26 dogs did develop VT in response to the same stimulus. 25 This may be the case in dogs with naturally occurring cardiac disease, but we did not design our study to evaluate this factor.
One case report of a dog with AF that experienced SCD while wearing a Holter ECG has been published. In this report, the dog developed complex ventricular arrhythmias, followed by an episode of R-on-T phenomenon, which was followed by ventricular fibrillation and asystole. 26 This observation supports the idea that ventricular arrhythmias underlie SCD in dogs with AF. In contrast, a recent retrospective study reporting dogs that experienced transient loss of consciousness while undergoing ambulatory ECG described 7 cases of AF (out of 230 episodes; 3.3%) where loss of consciousness was associated with progressive slowing of AF rate followed by ventricular arrest. 27  In humans, the use of or requirement for antiarrhythmic drug treatment has been associated with increased risk of mortality in patients with AF for over 30 years. 29 Because use of digoxin is associated with a higher risk of hospitalization 30 and death in humans with AF, 31 and a high proportion of the dogs with AF in our population were receiving treatment with digoxin, we performed some basic analysis to compare the proportion of dogs receiving digoxin in the SCD group vs dogs dead from other causes, but no significant difference was found. Class III antiarrhythmic drug use may be another potential risk factor for QT prolongation and a proarrhythmic effect, triggering malignant ventricular ectopy which could be associated with SCD. 32 Both sotalol and amiodarone have been associated with increased risk of death in human patients when used to maintain sinus rhythm after successful cardioversion. 33 We chose not to analyze any association between class III drugs and SCD in dogs with AF owing to a relatively small number of dogs receiving amiodarone or sotalol in our cohort.
Our group of dogs with AF had larger left atrial size and a higher proportion of dogs with a history of congestive heart failure. This association was not addressed by our method of control group recruitment matching, and other factors associated with more advanced heart disease (eg, pulmonary hypertension) may contribute One limitation of our study is that the control and AF groups were not perfectly matched, specifically the proportion of dogs with current or previous heart failure signs was higher in the AF group. In humans, heart failure itself is associated with an increased risk of SCD in AF. 17 Although we did our best to match the control group for disease process, it was impossible to also match for heart failure status with the available data.
Limitations of our study are related to its retrospective, observational nature. Cases were managed in a nonstandardized manner by numerous clinicians at several different centers. Although all dogs in the AF group underwent Holter monitoring, it was not an inclusion criterion for the control group. Dogs with AF were heavier and had larger left atrial size, which means that the control and AF groups were not perfectly matched, but this difference may be more related to the pathophysiology of AF than to the study methods. Some dogs were euthanized because of poor quality of life, and some of these dogs may have gone on to suffer SCD had they lived longer. We did not evaluate causes of SCD in the control group as a comparison. In addition, the circumstances of death were not always clear, and some cases of SCD may have been mis-classified. No necropsies were performed. We have tried to be conservative and use previously reported criteria for SCD in veterinary studies, 20,21 which are comparable to those used in humans. The recruitment of a control group from only 1 center, as compared to AF dogs from 7 separate centers may be considered a weakness, but because all clinics were located within 200 miles of each other, the extent of genetic, environmental or geographic variation among populations is likely minimal and likely does not represent an important confounding factor. Finally, the lack of a standard treatment protocol by veterinarians managing the cases means that the effects of treatment cannot be evaluated, and the study was not designed to evaluate possible treatment effects.
Despite its weaknesses, this multicenter retrospective casecontrol study identified that a significantly higher proportion of dogs with AF died suddenly than dogs with sinus rhythm, matched for heart disease type. Younger age at diagnosis, larger left atrial size and history of syncope were independent risk factors for SCD in dogs with AF in our study. Prospective studies will be required to better understand these risk factors and any potential benefit of treatment.

ACKNOWLEDGMENT
Funding provided by a grant from The Langford Trust. We thank Dave Dickson (HeartVets) for helping to facilitate data collection.