Age dependence of the development of ventricular arrhythmias in a canine model of sudden cardiac death.

OBJECTIVES: The age-dependence of the development of ventricular arrhythmias was studied in German shepherd dogs with inherited ventricular arrhythmias and sudden death. BACKGROUND: A colony of German shepherd dogs has been established that exhibit inherited ventricular arrhythmias and sudden death. The incidence of arrhythmias increases with age. Because ventricular tachycardia is associated with bradycardia, it was hypothesized that the increased incidence of arrhythmias was related to age-dependent slowing of heart rate. METHODS: Arrhythmia counts and RR intervals were measured from serial ambulatory ECG recordings obtained in 71 dogs (1-48 weeks). In addition, 19 dogs were challenged with phenylephrine (10 micrograms/kg i.v.) at 15, 28, and 45 weeks of age, 10 dogs were challenged with epinephrine (1 microgram/kg i.v.) at 3, 5, 7, 9, 11, 18, and 28 weeks of age, and 10 dogs were challenged at 28 weeks with epinephrine (2.5 micrograms/kg i.v.), before and after propranolol (0.5 mg/kg i.v.). RESULTS: The incidence and severity of ventricular arrhythmias increased between 7 and 28 weeks of age and decreased between 28 and 44 weeks of age. The age-dependent increase in the incidence of ventricular tachycardia was associated with age-dependent reductions in sinus rate. Baroreflex-mediated slowing of the heart rate unmasked arrhythmias in young animals that did not spontaneously display arrthythmias and exacerbated existing arrhythmias in older animals. However, the magnitude of baroreflex-induced bradycardia was similar from 7-18 weeks of age, yet the incidence of arrhythmias increased progressively. Moreover, the waning of ventricular arrhythmias in older animals was not associated with more rapid sinus rates. CONCLUSION: The risk for sudden death in dogs with inherited ventricular arrhythmias increases with age in part because of age-dependent slowing of heart rate and in part because of other heart-rate-independent factors. The correspondence between the development of ventricular tachycardia and sinus pauses is consistent with the hypothesis that ventricular arrhythmias are initiated by early afterdepolarization-induced triggered activity.

Relationship of ventricular tachycardia to sleep/wakefulness in a model of sudden cardiac death.

Death from some childhood disorders such as sudden infant death syndrome and the congenital long QT syndrome are associated with specific behaviors such as sleep or emotional stress. We studied young German shepherd dogs that die suddenly during presumed sleep. These dogs have inherited ventricular tachycardia (VT) which is most frequent during sinus bradycardia and sinus arrhythmia. We hypothesized that the number of VT complexes (three or more consecutive ectopic complexes) would be greatest during sleep. Moreover, we hypothesized that pauses in the sinus rhythm of greater than 1000 ms would be greatest in the behavior with the most frequent VT. Behavioral states [excited, ambulatory, sitting, lying, rapid eye movement (REM) sleep] were quantified from 24-h video recordings of seven dogs. VT and pauses were quantified for each behavior using simultaneously recorded ECGs. A multivariate model was used to analyze the results. After controlling for time of day, lying, and REM sleep were significantly (p < 0.02) associated with VT, whereas more active behaviors were not. Time of day also independently affected the number of VT complexes. However, behavior and time of day did not account for all of the variability in the number of VT complexes. Pauses were significantly associated with behavior, with the highest number of pauses occurring during lying and REM sleep. However, pauses were not always associated with VT, indicating that a pause was a necessary, but not sufficient, condition for the development of VT. These results suggest that modulation of VT incidence in these animals is multifactorial and that the highest number of VT complexes is associated with the bradycardia that accompanies REM sleep.

Phenylephrine-induced ventricular arrhythmias in dogs with inherited sudden death.

INTRODUCTION: Dogs with an inherited predisposition to sudden death display ventricular arrhythmias having certain characteristics, such as pause dependence, that are suggestive of early afterdepolarization-induced triggered activity. We hypothesized that alpha-adrenergic stimulation may facilitate the development of these arrhythmias by inducing a reflex bradycardia and by exerting a direct myocardial effect. METHODS AND RESULTS: Twenty affected dogs and 7 unaffected dogs were studied. The incidence and severity of ventricular arrhythmias were determined after administration of phenylephrine (0.01 mg/kg IV), with or without pretreatment with propranolol (0.1 to 0.3 mg/kg IV), atropine (0.04 mg/kg IV), or prazosin (0.5 mg/kg IV). Third-degree heart block was induced by AV nodal ablation in 4 affected dogs. Phenylephrine increased ventricular arrhythmias in affected dogs, with or without pretreatment with propranolol, but did not induce ventricular arrhythmias in unaffected dogs. In dogs with intact AV nodal conduction, atropine increased sinus rate, which suppressed baseline and phenylephrine-induced arrhythmias. In dogs with heart block, arrhythmias were increased during baseline and after phenylephrine, with or without pretreatment with atropine. Prazosin and overdrive ventricular pacing suppressed phenylephrine-induced arrhythmias. CONCLUSION: Phenylephrine increases ventricular arrhythmias in dogs with inherited sudden death via both an induction of reflex bradycardia and a direct myocardial effect. Superimposition of heightened alpha-adrenergic and vagal tone may facilitate the development of sudden death in these animals.

Use of surgical intrauterine insemination to manage infertility in a colony of research German shepherd dogs.

A colony of German shepherd dogs with inherited ventricular arrhythmias and sudden death had infertility that was resolved by intrauterine insemination. Mating of German shepherd males to related German shepherd females (40 cycles) by vaginal artificial insemination resulted in a low pregnancy rate of 35% and a small median litter size of 3.5. When these same German shepherd males were bred to female beagles by vaginal artificial insemination, the pregnancy rate of 100% (P = 0.02) and median litter size of 7.0 were significantly (P = 0.04) greater. Therefore, inadequate fertility existed when the German shepherds were mated. Because matings between these dogs were necessary, surgical intrauterine insemination of fresh semen was instituted in eight German shepherd females over nine cycles. In bypassing the cervix with this method, German shepherd fecundity increased significantly, with a pregnancy rate of 100% (P = 0.002) and median litter size of 8.0 (P = 0.001). Surgical intrauterine insemination may be an important method for management of canine infertility in the research environment.

Inherited ventricular arrhythmias and sudden death in German shepherd dogs.

OBJECTIVES: This report describes a unique group of German shepherd dogs with inherited ventricular arrhythmias and sudden death. Before death, these dogs have no evidence of cardiovascular failure. BACKGROUND: There are few spontaneous animal models of sudden death that permit intensive investigation. METHODS: To determine the temporal evolution of ventricular arrhythmias and to characterize the syndrome of sudden cardiac death in these dogs, 24-h ambulatory electrocardiographic (ECG) monitoring, echocardiograms, electrophysiologic testing and breeding studies were conducted. RESULTS: The 24-h ambulatory ECGs from dogs that died showed frequent ventricular arrhythmias with rapid polymorphic ventricular tachycardia (rates > 480 beats/min). Affected dogs had a window of vulnerability for arrhythmias, with the highest incidence and severity of arrhythmias between 20 to 30 and 40 to 50 weeks of age. Affected dogs that died did not have prolongation of the QT interval over a spectrum of heart rates compared with unaffected dogs. The clinical arrhythmia was not induced in dogs during programmed electrical stimulation. Severely affected dogs monitored > 5 years did not develop any evidence of heart failure or cardiomyopathy, and no histopathologic abnormalities existed. Seventeen dogs died suddenly (age 4 to 30 months) and were either 1) found dead at first observation in the morning (n = 8), 2) observed to die during sleep (n = 4), 3) observed to die while resting after exercise (n = 3), or 4) observed to die during exercise (n = 2). All sudden deaths occurred between the end of September and April, with most (n = 11) during January and February. CONCLUSIONS: The cause of the inherited severe ventricular arrhythmias and sudden death in these young German shepherd dogs is still undetermined. A purely arrhythmic disorder is supported by the lack of cardiac pathology. Moreover, the window of vulnerability to ventricular arrhythmias and the age and circumstances of death invite speculation about the role of the autonomic nervous system.