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Influence of Antiarrhythmia Therapy on Survival Times of 19 Clinically Healthy Doberman Pinschers With Dilated Cardiomyopathy That Experienced Syncope, Ventricular Tachycardia, and Sudden Death (1985–1998)

From the Department of Small Animal Medicine, College of Veterinary Medicine, University of Georgia, 501 DW Brooks Drive, Athens, Georgia 30602.

	Abstract

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Overtly healthy Doberman pinschers, having moderate to severe myocardial failure secondary to dilated cardiomyopathy, which experienced ventricular tachycardia, syncope or collapse, and sudden death were studied to determine the effect of antiarrhythmic medication on their clinical outcome. Antiarrhythmia drug therapy may have retarded sudden death in 13 treated dogs compared to the six dogs not administered antiarrhythmia drugs.

	Introduction

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Dilated cardiomyopathy (DCM) in Doberman pinschers is characterized by a protracted, slowly progressive occult phase during which ventricular and occasionally atrial premature contractions first appear, followed by development of progressive left ventricular dysfunction and usually progressively more severe ventricular tachyarrhythmias.^1–9 The incidence of sudden death, probably caused by ventricular tachycardia-fibrillation, prior to the onset of congestive heart failure (CHF) is at least 30%.^4,8–10 Subsequent to CHF, death is usually the result of CHF but can occur suddenly.^4,5,8,9

Cardiomyopathy in healthy appearing Doberman pinchers can be detected by Holter recording and echocardiography.^3,4,8–10 Furthermore, Holter recording and signal-averaged electrocardiography (EKG) may be useful in sudden-death risk stratification.^8–10 Heart-rate variability analysis has not yet been demonstrated to provide information relative to left ventricular function, arrhythmias, or sudden-death risk that cannot be ascertained from echocardiography and Holter recording.^11,12

The purpose of this study was to report the survival times of 19 Doberman pinschers with DCM that had experienced no overt abnormalities other than syncope or collapse, had ventricular tachycardia, were administered (n=13) or not administered (n=6) antiarrhythmia drugs, and subsequently died suddenly.

	Materials and Methods

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Animals Studied

The study population consisted of 19 client-owned Doberman pinschers that were evaluated from 1985 through 1998, that were clinically healthy, had recently experienced one (n=18) or two episodes of either syncope or collapse, had not been administered cardiac drugs, had abnormal echocardiograms, did not have atrial fibrillation, had EKG-documented ventricular tachycardia, and subsequently experienced sudden death. One additional dog, a 20th dog, had all of the above criteria including one episode of nonsustained ventricular tachycardia (six beats), but a subsequent syncopal episode was determined by event recording to be the result of neurocardiogenic bradycardia.¹³ This dog was not included in the study reported here. No other dogs with the above findings were excluded. Various echocardiographic, Holter recording, and survival data from these dogs has been included in prior studies.^4,5,8–11

Retrospective Analysis

Echocardiograms, EKGs, and 24-hour Holter recordings that had been obtained following the episode(s) were reviewed, and survival data was calculated.

Echocardiography

Echocardiography was performed in each dog. In the right parasternal sagittal plane, values that were considered normal for echocardiographic variables were as follows: left ventricular internal end-diastolic dimension (LVID_d), 47 mm; left ventricular internal end-systolic dimension (LVID_s), 38 mm; left ventricular fractional shortening (FS), 30%; and E-point to septal separation (EPSS) of the cranial mitral valve leaflet, <9 mm. Values that were considered abnormal and indicative of DCM were as follows: LVID_d, 50 mm; LVID_s, 40 mm; FS, 25%; and EPSS, 10 mm.^8,9

Initial EKG

Electrocardiograms were performed on each dog in right lateral recumbency. In addition, heart rhythms of 12 dogs were monitored on the EKG oscilloscope for approximately 5 to 30 minutes during the first examination.

Thoracic Radiography

Thoracic radiographs (lateral and ventrodorsal projections) were included in the initial database of nine dogs. Radiographs were not initially performed on the other 10 dogs.

Holter Recording

Twenty-four hour Holter recordings were performed initially on 11 dogs.^a,b Holter-tape data was transferred to a hard drive, and technician-supervised, chronological EKG analyses with online fine-tuning for accuracy verification were then performed. Retrospective technician validation and editing of each cardiac cycle were provided for each recording.

Follow-Up Evaluations

Fourteen dogs were evaluated at the University of Georgia at <1-week to 4-month intervals. One dog died before scheduled reevaluation, and four dogs were not returned for reevaluation. The reevaluation database variably included echocardiograms at each evaluation (n=14), Holter recordings (n=14), thoracic radiographs (n=7), and static EKGs (n=9). Holter recordings were repeated at the first reevaluation (3 to 15 days) on all 13 dogs administered antiarrhythmia drugs and on one of five untreated dogs. Subsequently, Holter recordings were performed on each surviving dog at variable intervals based on owner compliance, physical examination, and echocardiographic findings.

Treatment Summary

Sixteen dogs were initially treated with an angiotensin-converting enzyme (ACE) inhibitor at maintenance dosages of 1 mg/kg body weight, tid;^c 0.5 mg/kg body weight, bid;^d or 0.5 mg/kg body weight, once daily.^e As left ventricular dysfunction progressed, five dogs were eventually administered digoxin^f (0.005 mg/kg body weight, bid), and three were administered furosemide^g (1 to 2 mg/kg body weight, bid). Thirteen dogs initially were administered either tocainide^h (n=6; 15 to 20 mg/kg body weight, tid) or mexiletineⁱ (n=7; 5 to 8 mg/kg body weight, tid). Serum concentrations of tocainide (n=3) or mexiletine (n=2) were determined within the first 2 weeks of treating the 13 dogs. Six dogs were not administered antiarrhythmia drugs. Patients not receiving antiarrhythmia therapy were the result of owner choice (n=1, an author’s dog), due to lack of owner confidence in the diagnosis and treatment recommendations (n=2); second opinion (n=1); owner noncompliance retrospectively discovered; drug costs (n=1); and unknown factors (n=1).

When arrhythmias worsened, one or more of the following were administered sequentially or in combination: procainamide^j (15 to 20 mg/kg body weight, tid), quinidine gluconate^k (8 to 9 mg/kg body weight, tid), and amiodarone^l (5 to 10 mg/kg body weight, once daily following a 1- or 2-week loading schedule of 10 mg/kg body weight, bid). A beta-adrenergic blocking drug (propranolol^m [0.5 mg/kg body weight, tid], metoprololⁿ [0.5 mg/kg body weight, bid], or atenolol^o [0.5 mg/kg body weight, bid]) was added to the treatment regimen within 2 weeks in four dogs receiving tocainide (n=3) or mexiletine.

Statistical Analysis

A two-sample analysis of variance was used to determine if the survival times of the treated versus nontreated dogs were different (P<0.05).

	Results

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History of Syncope

All dogs were overtly healthy other than having a history of syncope or collapse. No dogs had exhibited coughing or dyspnea. In retrospect, some owners were aware of decreased exercise tolerance or decreased activity level for several days or longer before an episode. These dogs had the most severe echocardiographic abnormalities. Eighteen dogs had experienced one episode, and one dog experienced two episodes from 1 to 9 days before the authors’ examinations. Episodes occurred during or immediately following exercise in 13 dogs.

Signalment

There were 13 male and six female dogs with a mean (±standard deviation [SD]; range) age of 8 (±3.4; 6 to 11) years.

Echocardiography

At the approximate times of syncope or collapse, the approximate mean (±SD; range) LVID_d was 55 (±2.99; 51 to 59) mm; the approximate mean LVID_s was 44.4 (2.99; 39 to 56) mm; the approximate mean FS was 19.2% (2.04%; 15% to 23%); and the approximate mean EPSS was 13 (2.08; 10 to 16) mm [see Table].

Ventricular premature contractions (VPC) were detected initially in each dog, including at least one episode of non-sustained (five to approximately 100 consecutive VPC) ventricular tachycardia in 15 dogs. Singlets, couplets, triplets, and bigeminal VPC were variably observed in the remaining four dogs.

Thoracic Radiography

Initial radiographic interpretation indicated left atrial enlargement in two of nine dogs, but lobar pulmonary vein distention and pulmonary edema were absent.

Holter Recordings

Eleven of 11 dogs initially had multiple episodes of ventricular tachycardia at rates >200 beats per minute (bpm). Ventricular tachycardia (220 to 350 bpm) was nonsustained (<30 seconds) in eight and both nonsustained and sustained (>30 seconds) in three dogs. More than 100 couplets and >50 triplets of VPC occurred in all dogs. The approximate mean (±SD; range) number of VPC was 26,428 (±21,219; 8,228 to 89,547) per 24 hours.

First follow-up Holter recording analyses confirmed quantitative reduction of VPC frequency in all 13 treated dogs, including suppression of sustained ventricular tachycardia in three of three dogs. Subsequently, at variable intervals, arrhythmia frequency increased in each tested dog. Nonsustained ventricular tachycardia was detected in all 13 dogs, but sustained ventricular tachycardia was not detected.

Outcome

All (19) dogs experiencing an episode of syncope or collapse with documented ventricular tachycardia died suddenly prior to exhibiting overt signs (i.e., coughing and dyspnea) of CHF. The final thoracic radiographs taken in seven dogs from 3 to 11 weeks prior to death were interpreted to indicate left atrial enlargement (n=5), lobar pulmonary vein distention (n=4), and possible left ventricular enlargement (n=3). Pulmonary edema was absent. Echocardiographic data consistent with impending CHF (LVID_d, >60 mm; LVID_s, >50 mm; and FS, 13% to 15%) was obtained from five dogs within approximately 3 weeks of death. Signs of CHF may have been retarded in some dogs by the administration of furosemide, an ACE inhibitor, or both.

Survival times were not normally distributed. Among the six dogs not administered antiarrhythmia drugs, the mean, median, and range of survival times after the first episode were 15, 11, and 3 to 38 days, respectively. Among the 13 dogs administered antiarrhythmia drugs, the mean, median, and range of survival times after the first episode were 187, 198, and 78 to 345 days, respectively (P=0.0003). Sudden death occurred during or immediately following exercise in 13 dogs, during sleep in one dog, during quiet activity in three dogs, and two dogs were found dead in their yards within 30 minutes of being let outside.

	Discussion

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Sudden cardiac death in Doberman pinschers may be defined as abrupt loss of consciousness and death within minutes. Preexisting heart disease may or may not have been known to be present. The proximate cause of cardiac syncope is a disturbance of heart function that is incompatible with maintaining consciousness because of loss of cerebral blood flow. The incidence of sudden death in Doberman pinschers with DCM is similar to that of humans with idiopathic DCM and may approach 50%.^4,8,14,15 Sudden-death risk increases with deteriorating left ventricular function, and ventricular tachycardia-induced syncope is a powerful predictor of sudden cardiac death in human patients with DCM.^14,15

Cardiac syncope in Doberman pinschers is usually associated with atrial fibrillation, neurocardiogenic bradycardia, or, most often, ventricular tachycardia.^{1,4,5,8,10,13} Atrial fibrillation is associated with impending or overt CHF and complicated by ventricular tachyarrhythmias of variable severity.^1,4,5 Neurocardiogenic bradycardia-syncope is associated with mild to severe DCM, and ventricular tachy-arrhythmias may not be severe, especially when left ventricular dysfunction is mild.¹³ Exertion-associated syncope in the absence of both atrial fibrillation and Holter-recorded ventricular tachycardia suggests the likelihood of a neuro-cardiogenic origin, which, in Doberman pinschers, has not been proven to be a lethal syndrome.¹³ Holter recordings in Doberman pinschers that have experienced collapse-syncope caused by ventricular tachycardia are always characterized by many VPC (usually >10,000 per 24 hours) and episodes of at least nonsustained ventricular tachycardia.^4,8,10 Potentially lethal ventricular tachycardia in cardiomyopathic Doberman pinschers is associated with echocardiographic evidence of at least moderate left ventricular dysfunction.^4,8,10

Holter-recording documentation of ventricular tachycardia and signal-averaged EKG detection of ventricular late-potentials are useful in sudden-death risk stratification in Doberman pinschers.^4,10 Sustained, rapid ventricular tachycardia has been correlated to sudden-death risk in this breed.^4,8 However, DCM is a dynamic, progressive disease, and the absence of ventricular tachycardia and ventricular late-potentials does not exclude their latent emergence or sudden death, possibly within weeks of test results.^4,8,10

The small number of patients is a shortcoming of this study. The small number is due to the inclusion criteria of syncope or collapse, documented ventricular tachycardia, and sudden death prior to the onset of coughing and dyspnea. This small subset was chosen because it was known that all of the dogs had not only died suddenly but also died prior to the onset of coughing and dyspnea, thus limiting the variables and simplifying analysis. A study with less restricted inclusion criteria should be prospective and include a large number of patients.

The question of antiarrhythmia drug therapy is confounded by the progressive nature of cardiomyopathy, lack of proven efficacy of antiarrhythmia drugs, and drug toxicity. Drug-induced or drug-aggravated cardiac arrhythmias (i.e., proarrhythmia) are also a clinical concern.¹⁶ Moreover, the negative inotropic action of drugs such as beta blockers, procainamide, and quinidine must be considered. Because of similar efficacy, drugs are often selected empirically or based on potential adverse effects and cost.¹⁷ Drug combinations are chosen usually empirically.¹⁶ Although amiodarone may be a useful drug, adverse effects (probably dosage related) can limit its application.^18,19

The purpose of this study was not to suggest optimum treatment, but rather to suggest that the commonly used antiarrhythmia drugs may provide temporary reduction of sudden-death risk.

The authors’ experience is that the administration of a Class IA or IB drug, such as procainamide, quinidine, tocainide, or mexiletine, to Doberman pinschers with severe ventricular arrhythmias is usually followed within a few days by quantitative improvement. However, worsening arrhythmia that is progressively more refractory to treatment is common after 2 to 6 months and is associated with progressive myocardial failure.^4,8

	Conclusion

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Prospective studies that provide definitive evidence for favorable survival rates in dogs given antiarrhythmia drugs are lacking; however, it is appropriate to use such drugs in the treatment of some symptomatic patients,^15,20 including the subset described in this study. The study presented here suggested that sudden death in Doberman pinschers was retarded but not prevented. Syncope with subsequent documentation of many VPC, ventricular late-potentials, and rapid, sustained ventricular tachycardia are associated with a high sudden-death risk^{4,8,10,15,21,22} and are indications for drug intervention in this breed.

	Footnotes

 
^a Tracker; Reynolds Medical Ltd., Hertsford, England

^b Ambulatory Monitoring Service; LabCorp, Burlington, NC

^c Capoten; Bristol-Myers Squibb, Hillside, NJ

^d Vasotec; Merck and Co., Inc., West Point, PA

^e Lotensin; Novartis Pharmaceutical Corp., East Hanover, NJ

^f Lanoxin; Glaxo Wellcome, Inc., Research Triangle Park, NC

^g Lasix; Hoechst Marion Roussel, Kansas City, MO

^h Tonocard; Merck and Co., Inc., West Point, PA

ⁱ Mexitil; Boehringer Mannheim Therapeutics, Gaithersburg, MD

^j Procan SR; Parke-Davis, Morris Plains, NJ

^k Quinaglute; Berlex Laboratories, Wayne, NJ

^l Cordarone; Wyeth-Ayerst Laboratories, Philadelphia, PA

^m Inderal, Wyeth-Ayerst Laboratories, Philadelphia, PA

ⁿ Lopressor; Novartis Pharmaceutical Corp., East Hanover, NJ

^o Tenormin; Zeneca Pharmaceuticals, Wilmington, DE

	References

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