inherited ventricular arrhythmias and sudden death …jaw vol. 24. no. i july 1994:233-43 23% common...

JAW Vol. 24. No. I July 1994:233-43 23%

common arrhythmia associated with sudden

identification of those at risk and the mechanisms that precipitate the arrhythmia that causes death (34. With the notion of predicting the fatal rhythm, numerous stuuies have

attempted to define the specific ~rodroma~ am (5-7).

cardiac arrhythmias and associated su in patients with ident organic

tJsually patients with cular arrhythmias and a structurally normal heart have a low risk of death. The well known exceptions are patients with torsades de pointes (1042). Torsades de pointes is commonly associated with prolongation of the QT Interval, although this restriction is not absolute. The development of lethal cardiac

the absence of overt heart

From the Departments of Clinical Sciences, Pathology and Physholog{ College of Vctcrinary Medicinr, Cornell Urriversity, Ithaca. New York. This study was funded in gart by National Institutes of Health Grants HD28936-01 and BRSG FO7RROS4G2, IBethesda, Maryland and the College of Veterinary Medicine Alumm Unrestricted Funds, Ithaca, New York.

Manuscrip: received May 10, 1993; revised manuscript received January 13, 4.

Dr. N. Sydney Moise, Department of Clinical Sciences, College cf Veterinary Medicine, Cornell University, Ithaca, New York 14853.

81994 by the American College of Cardiology

to contribute to some cases atb syndrome (13-16). The etiology of su ridrome is most likely multifactorial and may involve a

imbalance in the development of car (1446).

There are few spontaneous animal models of sudden death that permit intensive investigation (i7,lg). We have established a colony of German shepherd dogs with inherited

0735.1o97194/$7.o0

234 MOISEETAL. INHERITEDARRHYTHMIASANDSUDDENDEATHINDOCS

spontaneous cardiac arrhythmias and associated sudden death. This report details the results of our initial studies to answer two broad questions: I) What is the temporal evolu- tion of the ventricular ectopic activity and the characteristics of dogs that died? 2) What is the inheritance of ventricular ectopic activity and sudden death? To address the first question, ambulatory electrocardiographic (ECG) recordings were used to determine the frequency and severity of spontaneously occurring arrhythmias over time. The circumstances associated with death were documented, and the ;;pes of arrhythmias associated with sudden death were determined. The QT interval was evaluated for prolongation. In addition, inducibility of the arrhythmias W%S tested using progmmmed electrical stimulation. Finally, histopathologic examination of the myocardium and conduction system was performed to determine whether any structural lesions existed. To address the second question, pedigree analysis and breeding studies were performed to deter-mime whether the disease was inherited by simple Mendelhn inheritance.

l Four families of German shepherd dogs with a his ventricular arrhythmias or sudden death were identified. The propositus was identified in 1987 in central New York. Four siblings of this dog died within 2 weeks of one another in four different locations at 4 months of age. Three were observed to die during sleep, and the fourth died while resting after exercise. Necropsy examinations did not reveal a cause of death. The second family of dogs was identified in 1987 in upstate New York. Sudden death was not reported in this family of dogs, a!though ventri arrhythmias were found in a female dog (dog !%I (see during an examination before ovariohysterectomy. In a third family, identified in Illinois in 1%8, three siblings died suddenly, and a fourth (dog 87) had ventricular arrhythmias. In the fourth family, identified in ichignn in 1992, five

(5 to 11 months of age) died suddenly in two the same sire and dam. Three other siblings had

ventricular arrhythmias identified by ambulatory ECG monitoring, Subsequently, it was discovered that all four of these families shared a common ancestor,

The four& of the breeding colony described in this study were the female proposirus (dog 1) and her darn (dog 2) and sire (dog 3) ftom central New York, a female from upstate New York (dog 5g), a female from Illinois (dog 87), and two m&s (dogs 143 and 157) and one female (dog 161) from Michigan.

electrocardimphy using surface limb leads (I, II. III, aVR, aVL aVF) were performed, and standard measurements (p wave amplitude and duration, QRS amplitude and dura- Gon, PR and QT intervals) were obtained to determine whether conduction disturbances, enlargement patterns or QT prolongation existed (19). These limb lead recordings weE obtained with the dogs unsedated, hand restrained and

placed in right lateral recumbency. For comparison to est lished normal values, were evaluated. Two-d raphy were performed stmctura! ab~o~a~~t~es e Echocardiograph Sonos ness, interventricular 5

trations were also de serum

precordial leads were positioner to give at least o and one negative QRS deflection. Ambulatory was performed biweekly until the dogs were at least 10 to 12 months of age. Subs ly, ambulatory . obtained every I to 3 s in dogs 12 to I and every 3 to 6 months in those ~18 mom were considered affected if premature ventricular complexes were more frequent than 1001 for any hour monitored or if ventricular tacbycardia was identified at any time. Ventric- ular tachycardia was defined as three or t-e consecutive ventricularcomplexes f&21) with a rate =+ beats~mju (I9)-

Ati ambulatory EC@ recordings were haqd counte observers familiar with canine ECGs using the Del Heartscreen I1 or Del Mar 563 Holter Analyzer (Del Avionics). Analysis of the ambulatory ECG recordirngs included the characterization of ventricular arrythmias as singlef, coup&, bigeminy or runs of ventticufac tachycardia, with the total number and average hourly counts calcu- lated. The actual number of ventricular complexes in each run of ventricular tachycardia was tabulated. The shortest cycle length of the ventricular tachycardia with six or more complexes also was determined for each dog. Other EC6 features, such as supraventricular arrhythmias, heart block and sinus arrest or pauses, were identified. All ECG features were tabulated for ezch hour. To determine whether the QT interval was prolonged, 100 QT intervals and preceding RR intervals during sinus rhythm were measured from ambulatory ECG recordings over a spectrum of heart rates in seven dogs that died suddenly and in seven age- and sex-matched unaffected dogs. The QT intervals were grouped in 20-beat/ min intervals: 41 to 50,61 to SO,81 to 100, 101 to 120, 121 to

JACC Vol. 24. No. 1 July 19%:233-43

MOlSE ET AL. BNWERITEDARRHVTM[MI.QSANDSUDDENDEATBINDOGS 235

tas were const

nd a sibling had ventric

I-% electrograms (5F) catheter (SF) were intr

tive refractory periods of the right ventricle,

stant cycle lengths of 300 and 400 ms. Two programmed stimulation protocols were used in an atte,npt to induce ventricular arrhythmias. For the first protocol, a train of 10 stimuli (S,) delivered at an S,S, interval of 200 to 5 followed by up to three extrastimuli (S2 to S,) delivered first to the right atrium and then to the right ventricular apex or outflow tract. For the second programmed stimulation protocol, a train of IO stimuli at an S,S1 interval of 200 to 5OtI ms was followed by a postmature S, aud up to three additional extrastimuli (S, to S& The SISz interval was fixed at the longest interval that was not interrupted by sinus rhythm. The diastolic interval then was scanned by varying the S,S, intervat. Thereafter, the S&is interval was fixed at to ms greater than the effective refractory period, and the proce- dure was repeated for the S4 and S, stimuli. This sequence of stimuli was delivered only to the right ventricle.

22). with samples obta

s~noatr~al node an region of the AV node. Sam n. sectioned at 4 tc 6

As an initial step in determinirlg whether this disorder is inherited as a simple Mendelian trait (autosomal do autosomal recessive), two dogs with frequent ventricular tachycartiia were outcrossed to unaffected female beagle dogs to produce an F, generation. The number of affected offspring produced from these matings was compared with the number predicted by the hypothesis of simple autosomal dominant inheritance.

~~~~y~~s, Continuous data from the ECGs, echocar- di s and electrolyte levels were analyzed using the Wilcoxon rank-sum test. Categorized data (i.e., vent~cn~ar tachycardia with or without sudden deat using the Fisher exact test normally distributed, the Q unaffected dogs within each heart rate s pared using the paired t test. Breeding stu by &i-square analysis, and p < 0.05 wa statistical significance for all analyses.

236 MOISE ET AL. 1NHERITEDARRHYTHhllASANDSlJDDENDEATHLNDOGS

JACC Vol. 24. No. 1 My 1 :233-43

t!3

. Physical examinations of affected and unaffected dogs did not reveal cardiac murmurs or other indica- tions of structural or functional cardiac disease. All dogs were robust and energetic and did not have exercise intoler-

c measurements and r between affected and un

ranged from 24 to 355 h/dog. Unaffected dogs (n = 25) had no more than three premature ventricular complexes during any 24-h period. Twenty-six dogs were affected, with five having infrequent premature ventricular co.mplexes and a single run of monomorphic ventricular tachycardia, nine having frequent premature ventricular complexes and infrequent ventricular tachycardia and 12 having frequent ~rern~tMre ventricular complexes and frequent ventricular tachycardia (Table 2). An additional 24 German shepherd dogs were studied, but because the animals were immatu~, they were not included in the statistical evaluation. However, to date,

doQs are affected, with seven having ar premature co

E ventricular tachyc re ventricular complexes and infrequent ven-

tricular tachycardia and seven having frequent premature ventricular complexes and frequent ventricular tachycardia.

Polymorphic nonsustained ventricular tachycardia was present in the dogs that died suddenly (Fig. 1) and was associated with frequent ventricular arrhythmias (Fii. 2). Ventricular tachycardia and premature ventricular complexes were often associated with a preceding pause or bradycardia, although sinus pauses were not always accom- panied by a run of ventricular tachycardia, and ventricular tachycardia was not always preceded by a long pause. Most commonly, the inci nce of ventricular arrhythmias in- creased with a slow of the sinus rate. In addition to the rapid ventricular tachycardia seen in severely affected dogs, both severely aa?d mildly affected dogs had periods of slower

monomorphic ventricular tachycardia (Fig. 3). Ventricular arrhythmias were the predominant abnormal rhythm, although some dogs also had supraventricular arrhythmias (dogs ~11, ~12, ~18, ~30, ~31). Four dogs (dogs 87, ~18, ~24,

Tpb?e 1. Comparison of Ele~tr~~di~g~~~i~~ hit, Electrophysiologic and ELctrolyte Results for Un&ected Dogs ___

Arected ~n~e~te~

Electrocardiogram n = 25 n = i7 Hearl rate (beats/min) 140 (100,180) P wave amplitude (mV) 0.2 (0.l. 0.4) PR duration (ms) PR inhiCrW1 (ms)

Q wave amplitude (mV1 QRS duration (ms) @I (50,W QT interval (ms) ( 160,220~ K wave amplitude (mV 1 P[O.% 2.6)

~ch~~io~mrn n = 17 n = 14 Left ventricular wal thickness

Diastele (mm) IO.5 (8.0. 13.2) Systole (mm) 12.3 (9.4. 13.W IS.2 (10.9. IS.11

Interventricular septal thickness Diastole (mm) 9.0 (8.0. IO.51 Systole (mm) 1 I.3 (9.5. MO)*

Left ventricular chamber dimension

Diastok (mm) 39.5 (34.3.42.0) 35.2 (33.1.49.0) Systole (mm) 24 5 (18.0,26.0)* 22.0 (14.5.32.0)

Fractional shortening (61 38.0 (31.0.48.5) 41.7 (31.0,57.0) ~lect~physiol~i~ studies n-7 n=4

AH interval (ms) 10.5 (80. 140) 88 (63. 135)

HV interval (msb 21 (20. 301 27 (20. 30)

MAP duration

Basic cycle lenph 199 (160.218)

215 (186.123) 217 (198, 252)

n=8 n=8

Sodium (mEq&terb 146.8 (143, 150) 147.7 (145. 153)

Potassium (mEq!literl 5.0 (4.4, 5.9) 5.2 (4.5. 5.8)

Chloride (mEq/literl 111(IOS. 113) 110 (103, 113)

~~g~siurn (mEq/liter) 1.7 (1.4, 2.2) 1.5 (1.3. 1.8)

*Siiilkan~ly diierent from unaffected dogs (p c 0.05). Data presented are median (minimal, maxima!) values.

~61) developed intermittent heart block and long sinus pauses, necessitating escape complexes (Fig. 4).

The median age at onset of ventricular arrhythmias was 128 days (4.5 months, range 19 to 203 days). Four dogs (dogs sll, ~24, ~27, ~31) with frequent premature ventricular complexes and infreqbcnt ventricular tachycardia had ventricular arrhythmias only during a brief period or window of time; the remaining dogs with frequent ventricular arrhythmias continued to have ectopic activity throughout t monitoring period, although there were periods of time (age) during which ventricular tachycardia was more prevalent (Fig. 5). In dogs with frequent ventricular tachycardia, examination of the age at which ventricular tachycardia occurred revealed peaks of greater frequency between 20 and 30 weeks, 40 and 50 weeks and possibly between 80 and 90 weeks of age (Fig. 6).

The QT intervals over the six ranges of heart rate were

JAC63 Vol. 24, No. 1 MQISE ET AC. July 1994:?33-43 ~WIASANH)SWDE)ENDEATP(IN1B06S

237

2. ~~a~~c~~~~~~~~~ of German Shepherd Dogs \IVith Ventricular Tao ~~~~~~~~~ ~~e~~~~s~~~~~~~a~~~c onitoring

._ Shortest CL. of VT Longest

No. of Wirb 26 Run of VT Dog Ventrk uiar Vemricular Runs Complexes (no. of Maximal Total ECG No. Couplets Bigeminy of VT ms) CompErx~s) PVC/h onitoring ihr

Dogs With Frequent ~re~a~~rc Vc~~ric~lar Complexes and Frequent Ventricular Tachycardia”

Y Y Y

Y Y Y

K

K Y

Y

Y

Y

Y

Y

N Y “il

N Y

Y

Y

Y

Y Y

!I I.471 49 6 5.116 87

14 429 72 83 4,177 280

9 I .040 20 9 569 47

20 766 26 9 1,340 48

46 2.928 23s ig 2,x9 351 19 3,601 196

5 1,464 Rl

24 Y N 3 - 3 156 16 s?O Y Y ? - 5 1,136 188 S?2 Y Y 2 140 6 103 44

g7 Y N 3 210 53 249 158

s2.l Y Y 3 - 3 475 152

s31 N Y 0 - 0 298 64

27 N Y I 315 36 3,414 355

5g P! Y 0 - 0 513 2s

\II N N I 165 3 686 76

*An additional seven dogs (s7d. ~80, ~87, ~88. ~90. ~91, 592) have been identified whh this degree of ventricular ectopic aciivity: however. because the animals are still immarure. Hoher analysis is incomplete. Sudden death. i:An additional five dogs (~80. sP4, sg9. ~91. s93\ have been identified whh this degree of venlricular ectopic activity: however, Jecause the dogs arc Ml immature, Hoher analysis is incomplete. &CL = basic cycle leuath: N = not present; PVC = premature venrricular complexes; VT = venukular mchycardia; Y = present.

not different between the (Table 3).

ca

physiologic studies, only one affected dog (dog ~17) had spontaneous ventricular arrhytbm~as. The AH and HV intervals during spontaneous sinus rhythm and the monopha- sic action potential durations during ventricular pacing at basic cycle lengths of 300 and 400 ms were not different in

ffected dogs (Table 1). Dogs died between the ages of 4 and 30

months (Table 4). Deaths occurred most frequently in Janu- ary and February, with no deatbs occurring between the end of April and September. The circumstances of death were known in 17 dogs. Animals died during observed sleep (n = 4), were found dead in their beds or pens at first observation in the morning (n = 8) or died during observed rest after exercise (n = 3) or during exercise (n = 2). Dogs that died

while being obse were not resuscit because of tkeir tion in the dog. Owners re

with infrequent ventricular tachycardia (D = 0.005). The ‘cular complexes +ve;e not different s with frequent premature ventricular

complexes that died (median 1,190 premature ventricular r hour, range 429 to 5,116) and

hour, range 1,464 to 3,601). tachycardia (>I0 runs124 h) had significantly greater (p C 0.01) total premature ventricular complexes (median 1,458 premature ventricular complexes per hour, range 429 to

238 MOISE ET AL. INHERITED ARRHYTHMIAS AND SUDDEN DEATH IN DOGS

JACC Vol. 24, No. I July 1994:233-43

F 1, Electrocardiographic recordings from five German shepherd dogs (dogs ~12, ~13, ~17, ~28, I) that died suddenly. Each of these dogs had multiple runs of rapid ~lymo~hic ventricular tachycardia of aI least six consecutive ventricular complexes with a rate ~4130 beatslmin. Most frequently, the ventricular tachycardia was preceded by a long RR interval.

5,116) than dogs with infrequent ventricular tac~y~ and c 10 runsl24 h) (median 475 premature vent

cd dogs and in all three bundle of His were identi s. Then were no histo

within the conduction tissue or within the myo~~ium (atrium, left and right ventricle, interventricular septum) in any alfected or untiected dogs. No differences were identifie ed and unaffected dogs.

Pedigree analysis revealed that the Ger- man shepherd dogs’in all four families identified were related

(dogs 42 and 52; dogs

ventricular complexes during any 24-h period. Under the thesis of simple a~tosomal dominant inberita~ce, a

average of one-half of the F, offspring would be expected to be affected. The probability that all five F, dogs would be unaffected if the disorder was inherited as a simple autosomal dominant trait is sufficiently low (p = 0.03) to reject this hypothesis. However, the mating of affected dogs s27 and

Figure 4. Electrocardiogram from German shepherd dog s61 with polymorphic nonsustained ventricular tachycardia that developed second-degree heart block, sinus pauses, escape complexes and atrial tachycardia a? I4 months of age.

SACC Vol. 24, No. 1 July 1994:233-43

ied at 69 weeks of age, and dog ~28 died at 120 weeks of age. ave = average.

Age (weeks) 00 120 140 160

Age (weeks)

0 IO 20 30 40 50 60 70 80

Age (weeks)

0 10 20 30 40 50 60 70 80 90 100

225

200

17s

150

125

15

50

25

0

0 10 20 30 40 50 H-l 70 80 90 100

Age (weeks) Age (weeks)

0 10 20 30 40 50 60 70 80 Age (weeks)

~31 produced five un cted offspring. This result is into patible with a hypot s of simple autosomal recessive m- heritance (23) and suggests either a minant inheritance pattern with incomplete penetrance or ygenic inheritance.

ts report describes a unique erd dogs with inherited ventricular

death, these dogs are ardiovascular compro-

mise. Sudden death caused by a cardiac a~hytbmia without structural heart disease has not been reported En the general population of dogs or in the German shepherd breed, and ambient ectopic activity in such young animals is uncommon.

e young age at onset, lack of cardiac pathology and apparent window of vulnerability for ventricular arrbythmias invite speculation with regard to a developmental abnormality of autonomic innervation to the heart. Sympathetic innervation oi the heart is not complete at birth but contin-

until the sixth month of life in d month in the dog (25). An

autonomic innervation to the heart (i.e., left ) increases the frequency of c , in particular, torsades de pointes (26). Similarly,

it has been proposed that the right and left sympathetic netup: yatbways may, on occasion, develop at ditTerent rates (24). The latter has been proposed to underlie sudden death in some cases of sudden infant death syndrome (24,281. It is plausible that inequality or delay of autonomic innervation

MOISE ET ,iL. JACC Vol. 24. No. 1

INHERITED ARRHYTHMlAS AND SUDDEN DEATH IN DOGS July 1994:233-Q

Age (weeks)

lween the irequency of ventricular tachyca lar tachycardia (solid sym indicate dogs thar have t frequent between 20 and 30

weeks, 40 and 50 weeks and, possibly, between 80 and 90 weeks of e.

or function may be the mechanism of electrical instability in these dogs.

The cause of the ventricular arrythmias and sudden death in this group of dogs was not identified by surface electro- cardiography, echocardiography or analysis of serum elec- trolytes. The echocardiogram did reveal less thickening of the left ventricular wall and interventricular septum, with a resulting mild increase in left ventricular chamber size during systole in cd dogs. Using ech~a~iograpby, Nador et al. (29) d strated an unsuspected abnorm~ity in the ventricular contraction pattern of patients with long QT syndrome. Fu studies are needed to determine whether the lesser e of thickening of the interventric- ulu septum and left ventricular wall in affected dogs is similar. However, wall and chamber dimensions of affected dogs remained within accepted normal ranges, and severely affected dogs monitored >5 years have not developed any evidence of congestive heart failure or cardiomyopathy.

Comparison of QT Intervals Between Affected and ted German Shepherd Dogs

te RR Values No. of QT Duration (ms)

n) (ms) Pairs AfFected Unaffected

41-60 1463-I000 7 240.9 (+ 19.8) 242.8 (k24.3) 61-80 983-750 7 241.6 (kl8.7) 233.0 (k21.5) 81-100 741~6lJo 8 232.4 (2 19.5) 229.0 (221.6)

101-120 594-500 8 230.4 (k20.8) 222.9 (219.7)

IZI-140 496-429 8 219.7 (+16.5j 213.8 (k18.9)

141-160 426-375 3 201.6 (+1X0) 194.9 (Z4.3)

No sWistkalIy ~ignitican! differences were found in QT interval duration.

s2lM Jan 15. 1987

s3/M Jan 22. 1987

s4/M Jan 28, 1987

&IF Jan 29, 1987

IIF Feb 27, 1988

s13/F Feb 23, 1989

slUF Feb 28, 1989

SW Jan 5. 1 s171 0ct 23.

S?8/ Feb 28,

1621 Feb 10,

s211 Feb l5. 19991

164/F arch 17. 1891

1631

159/M

WF

143/M

F = fem;lle: M = male.

4 Sleeping 4 Resting after exercise

4 Sleeping

4

17

5 Found dead in morning





9 Sleeping

30 Found dead in morniag

10

11

5

7 exerclsmg

18 Resting after exercise

However, the correct means of dete~~~ing the QT, interval is controversial (33-35). Formulas de for humans for calculating the QT, interval were not opiate in these

dogs, nor was the formula developed for use only in anes- thetized dogs by Van de Water et al. (36). Therefore, we compared the QT/RR intervals within six heart rate ranges. Although we did not identify prolongation of the QT interval in affected dogs, the mean values of the QT interval were longer among affected than among unaffected dogs in five of the six comparisons (Table 3). Although these differences were not statistically significant (with a maximum of eig paired observations), it is possible that a significant differ- ence might emerge with a larger sample size. Additionally, it is possible that dogs that were classified as unaffected because of the absence of identifiable arrhythmias could still be tiected but be misclassified. It should be noted, bow- ever, that the QT intervals from the routine ECGs for all affected dogs were within the normal ranges for dogs.

The clinical arrhythmia identified in these dogs was not inducible with the programmed stimulation protocols used. Although it is not surprising that the arrhythmia was not induced during anesthesia and in a heart without structural

a56 SW 86 d!

s may be the needed

man shepherd dogs died between the end of September an mid-April. Whether these observations are coincidental or clue to understanding the mechanism of death is presently unclear. Sudden cardiac death secondary to ischemic heart disease in humans and after experimental myocardial infarc- tion in dogs is more frequent in the winter months (38,39). Although the reason for a seasonal susceptibility to sudden death is unknown, it has been suggested that e~ba~~~d sympathetic activity during the winter may play a role (39).

Fifteen of these dogs either ied during observed sleep or were found dead in the mornin or died during observed rest after exercise. From this study, the association betwee sleep and sudden death is also tenuous, altheugh current work supports this observation (37). Sleep most commonly is associated with a reduction in the frequency and complex- ity of ventricular arrhythmias (40,41), and the relative para-

associated sudden death.

to a single common ancestor (dog dogs are indicated by squares and female dogs by sk&s. s78,580, sg7, sgg, s90, ~91 and ~92 had frequent polymorphic ventricular tachycardia, but whether these dogs would have died or will die suddenly cannot be determined because dogs ~61 and ~80 received implantable cardio- verter-defibrillators (Cadence, Ventritex); dog $37 was killed for studies not described herein: and dogs ~78, ~8% ~90, ~91 and ~92 are voung and at risk. 0, Cl = not tested; 0, q = tested, unaffected: = tested, affected; 8, tZI = sudden death but no electrocardiographic data; + = sudden death.

pathetic dorni~a~~e that occurs duri garded as protective against fatal a~hytbmias wever, patients have been identifie wbo manifest an increase in the frequency and severity of ventricular ar sleep (44). The major diEerence between t patients with greater ventricular ectopic activity during wakefulness was the higher prevalence of neurologic disease in the former. Sleep is not a passive state but is cbaraLterized by dramatic changes in parasympathetic and sympathetic

242 MQISE ETAL. lNHERlTEDARRHYTHMIASANDSUDDENDEATHINDOGS

tone (45). The transitions from one sleep state to another, phasic changes within a sleep state (i.e., rapid eye movement sleep) and sudden awakening are associated with burst of autonomic activity (

tibility may exist to that may account for cardiac arrhythmias

ed or identified, the ty of i~he~tan~~ is still un- OtflQWlt.

It is our premise that y inherited sudden death

thesis is correct, this animal model of cou!d provide innovation with re

tu the involvement and development of the a~to~~rni~ Bet=

VOUS System 8s it pertains to cardiac a~thmias and sudden death.

we thank and SuPn for consul

L. Lewis. BS, Karen Zettnski. DVM. cal assistance; P. C. Ursell. MD. RD. ion system: and Sal Crooks. Barbara

GtifBth. DVM. and Laura DeLcllis. DVM. for referral of cases.

Castcllanos A. Cardiac arrest and sudden cardiac death. In: . editor. Heart Disease: A Textbook of Cardiovascular

w York: Saunders, 1987742-7.

BD. I EL. Hirschman JC. Nussenfeld SR. Blackbourne

Davis JH. PathoPhysiologic observations in prehospit; 1 ventricular fibrillation and sudden cardiac death. Circulation 1974;495%0-8.

3. Zipes DP. Sudden cardiac death: future approaches. Suppl I:J-160-6.

Circulation 1992:85:

4. Myerburg RI, Kessler KM, Castellanos A. Sudden cardiac death: struc-

5.

6.

7.

8.

9.

to.

II.

82.

13.

14.

15.

ture, function, and time-dependence of risk. Circulation 1 1:1-Z-10. Moss A.!. Davis HT, RCamiBa J, Bayer LW. Veot~cu~~ ectopic beats

cardiac death after myocar~~~

rhythmias, left vent~c~~ar dysfunction, and morality in the 2 years after

~~wa~z PJ. Cardiac syrn~t~c~c ~a~erva~io~ and the sudden infamt

first 6 months of life: a pr 16.

17.

I8

19.

21.

dlir detected by t&hour coo!inuous e~ectr~~~~~~bic ~cco~io~s in the Cardiac A~~ytbmia Su~p~ssio~ Triai. Am J Cardiol I :887-&i.

c~omyo~thy: mo~holo~c studies in a canine m I ;135:~7~-8.

23. Patterson DF. Diseases due to single mutant genes. 3 Am Anim Hos Assoc 197~~~1:327-41.

24. Schwartz PJ. The quest for the mecbauisms of the sudden infant death syndrome: doubts and progress. Circulation l~7:75:~77-83.

25. Ursell PC. Ren CL, Danilo P Jr. Anatomic distribution of autonomic neural tissue in the developing dog hcatt: 1. Sympathetic innervation. Anal Ret 199&226371-80.

26. Schwartz PJ. Priori SC. Sympathetic nervous system and cardiac arrhythmias. In: Zipes DP. Jalife J. editors. Cardiac Etectrophysiology From Cell to Bedside. Phil~elpbia: Saunders. 199tk312-30.

ki T. The anatomic nervous system and the heart: basis

Ref. 26:312-30. inte~cti~~s and effects on ~byt~rnia development. In:

28. Schwartz PJ. Sympathetic imbalance and cardiac arrhythmias. In: Ran- dall WC, editor. Nervous Control of Cardiovascular Function. New York: Oxford Univ Press, 19843225-52.

29. Nador F. Beria G. De Ferrari GM. et al. U~s~s~cte~ ~c~oc~d~o~~Rhic - . abnormality in the long QT syndrome: diagnostic, prognostic, and patho- genetic implications. Circulation 1991;84:1530-42.

30. S&vart.z PJ, Locati E. Priori SG. Zaza A. The long QT syndrome. In: Ref. 2658945.

Where ’ _

interval-w~lat is normal? Am 9

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terval: techniques asld

eneman RS. An improved

ep in German sbth~d dogs [abstract].

oaks P. Skep and venrriwhr

4,.

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44.

4s.

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4%.

48.

49.

so.

51

r RL. Neural activity and ventricuha fh-illation. N Engl I&i-70.

. Alterations in ~~~0~~~~~ hctioras during

Spyer KM, editors. Central ~e~~iat~~~ of Auto- nomic Functioas. New York: Oxford Univ Press, 1989:369-d%.

KE, Selwyn NAP. Waking and dial ischcmia. Am j ChrdioP

mperiano 0. Phosic rapid eye movement cats. Arch Ptal Biol

inon AA. Taylor WR. Choi K. &XX: ill1 ~l~ex~la~ned nocturnal

gcs and risk for Phe sudden

Mental activity, adrenergic modulation. and tients with heart disease. Circulation 1991;83:

inherited ventricular arrhythmias and sudden death …jaw vol. 24. no. i july 1994:233-43 23% common...

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