Materials and Methods

Dogs—From November 2001 through July 2004, all dogs at Kansas State University Veterinary Medical Teaching Hospital in which dysautonomia was diagnosed (n = 20) were echocardiographically evaluated by 1 of 2 authors (BJB or DSB). Informed consent was obtained for all diagnostic and therapeutic procedures.

Diagnosis of dysautonomia—An antemortem diagnosis of dysautonomia was suspected if dogs had clinical signs and physical examination findings consistent with the disease. The diagnosis was confirmed in 13 dogs during necropsy and in 7 dogs when results of 3 of 4 antemortem screening tests were consistent with dysautonomia. The 4 screening tests performed were the Schirmer tear test, pilocarpine response test, atropine response test, and ID histamine test.² The Schirmer tear test was performed with commercial test strips and was considered supportive of dysautonomia when tear production was ≤ 5 mm/min in both eyes. The pilocarpine response test was performed by placing 1 drop of 0.1% pilocarpine hydrochloride in the right eye and 1 drop of 0.01% pilocarpine in the left eye. If the pupil constricted in the right eye within 45 minutes after treatment or if the pupil constricted in the left eye within 120 minutes after treatment, the results were deemed consistent with dysautonomia. The atropine response test was not performed until the pilocarpine test was completed. The atropine response test was performed by recording a baseline heart rate; administering an injection of 0.06 mg of atropine sulfate/kg (0.027 mg/lb), SC; and monitoring heart rate every 15 minutes for 1 hour. Test results were supportive of dysautonomia when the heart rate remained < 140 beats/min or the increase in heart rate was < 40 beats/min.^2,16 The ID histamine test was performed by administering an injection of 0.05 mL of histamine (diluted 1:10,000), ID, adjacent to the injection site of an equivalent volume of sterile saline (0.9% NaCl) solution and comparing the responses for each injection. The anticipated response in a dog with dysautonomia was lack of a flare response. The ID histamine test was not performed when results of the first 3 tests were supportive of dysautonomia.

Patient evaluation—Information recorded for the dogs included breed, age, sex, month of admission, duration of clinical signs, clinical signs, and results of physical examination (including heart rate). Additional tests performed at the discretion of the attending clinician included a CBC, serum biochemical analysis, measurement of blood pressure (via Doppler ultrasonography in 2 dogs and via oscillometric evaluation^a in 2 dogs), and abdominal and thoracic radiography.

Echocardiographic evaluation—Routine echocardiographic evaluations with M-mode examinations were performed by use of commercially available equipment.^b,c Left ventricular and left atrial dimensions were measured in triplicate on the right parasternal shortaxis view; a mean value was then calculated. Because of the wide distribution in body weight of the dogs, M-mode echocardiographic ratio indices were calculated and compared with published reference values.^17,d Similarly, the reference interval for FS was obtained from published values.¹⁷

Dobutamine response test—Permission was obtained from the owner of 1 dog to perform a dobutamine response test. This dog had the lowest FS value, and the dobutamine response test was performed in hopes of effecting a clinical response. Dobutamine was initially infused at a rate of 1 μg/kg/min (0.45 μg/lb/min), and the rate was doubled every 15 minutes until the FS was > 2 times the baseline value. Echocardiography was performed immediately before each increase in the dobutamine infusion rate.

Postmortem examination—Permission was obtained from the owners of 13 dogs to perform necropsy. A thorough gross examination was performed on all 13 dogs, and histologic examination was performed on tissue specimens obtained from all organs, including the heart and the cranial mesenteric, celiac, paradrenal, cervicothoracic, and cranial cervical autonomic ganglia.

Statistical analysis—The FS of dogs with or without bronchopneumonia was compared to determine if a secondary disease process affected systolic function. The data were analyzed by use of a Mann-Whitney U test, and a value of P < 0.05 was considered significant.^e

Results

The 20 dogs comprised 4 Labrador Retrievers, 2 Golden Retrievers, 2 German Shorthaired Pointers, 1 English Shepherd, 1 Chihuahua, 1 Great Pyrenees, 1 Australian Cattle Dog, 1 Brittany, 1 pit bull–type terrier, 1 Doberman Pinscher, 1 English Setter, 1 Rat Terrier, and 3 mixed-breed dogs. Dogs ranged from 4 months to 14 years of age (median, 17 months). Seventeen dogs were ≤ 3 years old. There were 8 sexually intact males, 4 neutered males, 3 sexually intact females, and 5 neutered females. Body weight ranged from 2.6 to 37.0 kg (5.7 to 81.4 lb), with a median of 20.3 kg (44.7 lb).

Dogs were admitted during 11 months. Four dogs were admitted in March; 3 dogs were admitted in September; 2 dogs were admitted in February, August, November, and December; and 1 dog was admitted in each of the remaining months, except June. Duration of clinical signs ranged from 1 to 21 days (median, 5 days). Duration of clinical signs ranged from 3 to 7 days in 11 dogs and from 14 to 21 days in 5 dogs. Clinical signs included vomiting (n = 15 dogs), anorexia (9), dysuria (7), nasal congestion (7), diarrhea (4), severe weakness or recumbency (4), tenesmus (3), severe weight loss (3), photophobia (2), gagging (2), coughing (1), mucoid nasal discharge (1), drooling (1), prolapsed third eyelid (1), and tetraparalysis (1). Most dogs had 2 or more clinical signs, but one had only 1 clinical sign (dysuria).

All dogs were considered to have signs of depression during physical examination. Heart rate ranged from 70 to 180 beats/min (median, 120 beats/min). Heart rate ranged from 100 to 130 beats/min in 14 dogs, and heart rate exceeded 130 beats/min in only 2 dogs (both had a heart rate of 180 beats/min). Physical examination findings included mydriasis with a total lack of or a diminished papillary light response (n = 16 dogs), lack of anal tone (14), crusted nasal discharge (9), a distended and easily expressed urinary bladder (6), prolapsed third eyelid (5), marked weakness (4), weak pulses (3), xerostomia (1), dyspnea (1), blepharospasm (1), and diffuse lower motor neuron paralysis (1). Most dogs had 2 or more clinical signs, but one had only 1 clinical sign (distended and easily expressed bladder).

A CBC and serum biochemical analysis were performed for 14 dogs, and results were within respective reference ranges, except for leukopenia (3.3 × 10³ WBCs/μL; reference interval, 6.0 × 10³ WBCs/μL to 17.0 × 10³ WBCs/μL) with a left shift (860 band cells/μL; reference interval, < 300 band cells/μL) in 1 dog and an inflammatory leukogram (16.8 × 10³ WBCs/μL; 13.0 × 10³ neutrophils/μL [reference interval, 3 × 10³ neutrophils/μL to 11.5 × 10³ neutrophils/μL]; and 1,200 band cells/μL) in another dog.

Systolic blood pressure, as determined by Doppler measurement, was 100 and 95 mm Hg, respectively, in 2 dogs. Systolic and diastolic blood pressure, as determined by oscillometric measurement, in 2 other dogs was 113 and 97 mm Hg and 116 and 72 mm Hg, respectively.

Thoracic radiography was performed for 10 dogs, and abdominal radiography was performed for 9 dogs. Thoracic radiography revealed evidence of aspiration pneumonia and megaesophagus in 5 dogs, aspiration pneumonia alone in 2 dogs, and no abnormalities in 3 dogs. The cardiac silhouette and pulmonary vasculature were unremarkable in these 10 dogs. Abdominal radiography revealed ileus and a distended urinary bladder in 2 dogs, ileus alone in 5 dogs, and 2 dogs with no abnormalities.

Tear production was evaluated in 15 dogs; values were < 5 mm/min in both eyes in 7 dogs, 6 to 10 mm/min in 4 dogs, and > 10 mm/min in 4 dogs. The pilocarpine response test was performed in 14 dogs; results were consistent with dysautonomia in 13 dogs. The atropine response test was performed in 12 dogs; results were consistent with dysautonomia in all 12 dogs. The median resting heart rate for all 12 of those dogs was 120 beats/min (range, 80 to 130 beats/min), and the median heart rate after atropine administration was 120 beats/min (range, 80 to 132 beats/min). Median change in heart rate in response to atropine administration was 0 beats/min (range, −2 to 24 beats/min). The ID histamine test was performed in 10 dogs; 8 had no wheal or flare, 1 had a wheal but no flare, and 1 had both a wheal and flare.

Echocardiographic measurements and weight-based echocardiographic ratio indices were determined (Tables 1 and 2). Reduced thickness of the interventricular septal wall was detected in 3 of 19 dogs during diastole and 6 of 19 dogs during systole, whereas reduced thickness of the free wall of the left ventricle was detected in 4 of 20 dogs during diastole and 9 of 20 dogs during systole. Increases in LVIDd and LVIDs were measured in 4 of 20 and 14 of 20 dogs, respectively. The FS was reduced in 17 of 20 dogs (median, 17.9%; range, 4.0% to 31.1%). Paradoxical septal motion was not detected in any dog. Left atrial enlargement was detected in 3 of 15 dogs in which the variable was measured, and 1 of these 3 dogs had concurrent aortic enlargement. Left atrial size was just slightly less than the reference range for 1 dog.

A dobutamine response test was performed on a 7-year-old 24-kg (52.8-lb) male mixed-breed dog (Rottweiler crossbred with an unknown breed). The dog had a 3-week duration of weight loss (approx 4 kg [8.8 lb]), regurgitation, hyporexia, and lethargy. The dog had results consistent with dysautonomia for the pilocarpine response test (miosis of the right eye within 30 minutes after administration) and atropine response test (heart rate remained at 120 beats/min for the entire test period), but the dog had negative results for the Shirmer tear test (> 20 mm/min in both eyes) and ID histamine test (wheal and flare both evident). The dobutamine response test was performed 3 days after admission and the initial echocardiographic examination. During the 3-day interval, the dog was treated by IV administration of fluids. Immediately before administration of dobutamine, the heart rate was 120 beats/min, dorsal pedal arterial pulses were not palpable in either pelvic limb, and FS (4%), LVIDd (4.52 cm), and LVIDs (4.34 cm) were unchanged from those of the initial echocardiographic examination. At a dobutamine administration rate of 2 μg/kg/min (0.9 μg/lb/min), the FS was 8%, with an LVIDd of 4.4 cm and LVIDs of 4.0 cm. At a dobutamine administration rate of 4 μg/kg/min (1.8 μg/lb/min), the FS was 17%, with an LVIDd of 4.2 cm and LVIDs of 3.5 cm. At that time, the heart rate was 111 beats/min and dorsal pedal arterial pulses were readily palpable. There was no improvement in the dog's lethargy, so the dog was euthanatized at completion of the test; necropsy confirmed dysautonomia and megaesophagus. The heart was grossly and histologically normal, and there was no gross or histologic evidence of bronchopneumonia or other abnormalities.

Nineteen of 20 dogs were euthanatized from 1 to 14 days (median, 2 days) after admission to the veterinary medical teaching hospital. The remaining dog was lost to follow-up monitoring following discharge.

Results of necropsy were consistent with dysautonomia in all 13 dogs examined, with evidence of chromatolytic degeneration in the autonomic ganglia of all 13 dogs. There were no gross or histologic abnormalities detected in the heart of any of the dogs. Severe, suppurative bronchopneumonia consistent with aspiration was identified in 8 dogs (2 of which also had megaesophagus), megaesophagus alone was identified in 1 dog, and an adrenocortical adenoma of the right adrenal gland was found in 1 dog.

Bronchopneumonia was detected during radiography or necropsy in 10 of 20 dogs. The FS in those 10 dogs ranged from 6.8% to 26.1% (median, 19.3%), whereas the FS in the dogs without evidence of bronchopneumonia ranged from 4.0% to 31.1% (median, 15.1%). These values did not differ significantly (P = 0.52).

Discussion

The most important finding in the study reported here was evidence of systolic dysfunction, as defined by a reduced FS, in 17 of 20 dogs. Fourteen of 20 dogs also had a larger than predicted end-systolic left ventricular diameter. There were no other remarkable findings in this study because signalment, clinical signs, physical examination findings, results of a CBC and serum biochemical analysis, radiographic findings, and necropsy findings were consistent with those in other studies.^2,3,11 Additionally, results of screening tests for dysautonomia were consistent with those reported elsewhere.^2,11 To our knowledge, echocardiographic findings have not been reported, and this is the first study to detect systolic dysfunction in dogs with dysautonomia.

Cause of systolic dysfunction in the dogs of this study is not known. Ventricular underfilling is an unlikely explanation for the reduced FS in that none of the dogs had an LVIDd less than the reference range. Four dogs had an enlarged LVIDd, and dilated cardiomyopathy cannot be excluded from the antemortem echocardiographic findings; however, necropsy was performed on 3 of these dogs, and none of them had gross or histologic evidence supportive of dilated cardiomyopathy. Additionally, the hearts were grossly and histologically normal in this study for the other 10 dogs in which necropsy was performed.

Lack of chronotropic response to atropine has been suggested as evidence of sympathetic denervation to the heart or failure of atropine to disinhibit the parasympathetic nervous system, although failure of both branches of the autonomic nervous system is likely to result in the heart rate commonly being in the range of 100 to 130 beats/min in dogs with dysautonomia.² Two dogs in the study reported here had heart rates of 180 beats/min at the time of admission, although the heart rate had decreased to 100 to 110 beats/min in both dogs within 48 hours. This finding may be suggestive of loss of parasympathetic innervation before loss of sympathetic innervation.

The authors are unaware of any long-term studies on the effects of denervation on systolic function of the heart in dogs, but denervation of the heart in other species does not typically result in substantial evidence of inotropic failure. Investigators in 1 study¹⁸ evaluated left ventricular ejection fractions in human patients 0.5 to 8.2 years after orthotopic heart transplantation and found that the values were similar in denervated hearts (mean ± SD, 61 ± 6%), reinvervated hearts (62 ± 6%), and clinically normal subjects (64 ± 7%). Twenty-four hours after orthotopic heart transplantation in pigs, left ventricular and right ventricular ejection fractions were reduced by half, although impedance catheter variables revealed that contractility was unchanged from values for the preoperative period.¹⁹ The reduced ejection fraction was attributed to a 200% increase in pulmonary vascular resistance and not to sympathetic denervation.

In humans, familial dysautonomia and dysautonomias secondary to diabetes mellitus, Parkinson's disease, tick-borne encephalitis, and multiple-system atrophy manifest autonomic failure through a lack of heart rate variability and orthostatic intolerance, but evidence of myocardial dysfunction has not been detected.^13,20–23 In 1 study,²⁰ investigators reported that 6 human patients with motor neuron disease (of 300 examined) had concurrent cardiomyopathy manifesting as global hypokinesis and diminished ejection fractions. The diagnosis was ALS in 4 of those patients and hereditary spastic paraplegia in the other 2 patients, and the authors speculated that sympathetic dysfunction influenced cardiac function. However, a separate study²⁴ of ALS revealed mild sympathetic hyperactivity, which suggests that the myocardial dysfunction in those 6 patients may have been unassociated with ALS. Additionally, a study²⁵ in which investigators evaluated the effects of selective sympathetic denervation in the heart of dogs revealed no change in myocardial blood flow and no change in β-adrenoceptor density 3 weeks after sympathetic denervation. The lack of evidence for systolic dysfunction in sympathetic denervation of the heart suggests the need to consider other possible causes for the depressed systolic function in the dogs reported here.

Myocardial hibernation (ie, reversible myocardial depression) has been associated with hypoxia, ischemia, and sepsis and is characterized by ventricular dysfunction.^26–29 The mechanism responsible for this decrease in ventricular function is not known, but it has been speculated that it is caused by true or functional cellular hypoxia or the negative inotropic actions of tumor necrosis factor-α via the sphingomyelin pathway.^27,28 Decreased cardiac output and stroke volume are a result of the hypocontractile state that develops with this phenomenon. In humans, reduced coronary blood flow has been suggested as the primary cause; however, myocardial hibernation has been detected in the face of normal coronary perfusion.²⁷ Responsiveness to adrenergic stimulation with dobutamine is preserved in myocardial hibernation,³⁰ a feature evident in the 1 dog in the study reported here that was tested by administration of dobutamine.

Results for 16 dogs with critical illness and echocardiographic, but not clinical, evidence of myocardial depression were reported in 1 study.²⁹ In that study, bacterial sepsis in 5 dogs and cancer in 5 dogs were the most common causes, followed by coccidiomycoses in 3 dogs. Only 2 dogs in that study had an FS < 20% (13% and 19%, respectively), compared with results for the dogs in the present study, in which 14 of 20 had an FS < 20%. Similar to the dogs in this study, the dogs in that other study²⁹ did not have gross or histologic abnormalities of the heart during necropsy. Sepsis-induced myocardial depression in a 5-month-old female Rhodesian Ridgeback has been reported.²⁶ The dog in that report had an FS of 27% and an end-systolic volume index of 41 cm³/m², both of which were reportedly abnormal. These values were 44% and 16.5 cm³/m² 3 months later, after resolution of bacterial polyarthritis.

In the present report, 10 of 20 dogs had bronchopneumonia. In the dogs with bronchopneumonia, 8 had diminished FS. Diminished FS was detected in 9 of the dogs without bronchopneumonia. The median FS value was 19.3% in dogs with bronchopneumonia and 15.1% in dogs without evidence of bronchopneumonia. Although sepsis from bronchopneumonia may have contributed to myocardial depression in 8 of the dogs, it does not explain the myocardial depression in the remaining 9 dogs with diminished FS but without bronchopneumonia. Lesions of dysautonomia typically do not have histologic evidence of substantial inflammation, but there have been no reports on the measurement of concentrations of tumor necrosis factor-α or any other inflammatory cytokines in dogs with dysautonomia.^1,2

The role reduced FS played in the clinical signs of dysautonomia is unclear. In 1 study,¹¹ orthostatic hypotension was reported in 4 dogs with dysautonomia and was attributed to failure of the sympathetic nervous system to rapidly adapt to changes in posture with vasoconstriction; however, echocardiographic evaluations were not performed in any of those dogs. Lethargy is also a common finding in dogs with dysautonomia, and poor cardiac output may also play a role in this clinical sign. Whether short-term or long-term inotropic support would benefit dogs with dysautonomia is not known; however, the primary reasons for euthanasia or death are typically related to complications resulting from esophageal and gastrointestinal tract dysfunction.

To our knowledge, this is the first study in which systolic impairment in dogs with dysautonomia or, for that matter, any domestic animal with dysautonomia has been reported. Myocardial hibernation seems a more likely explanation than sympathetic denervation. Whether myocardial hibernation is a consequence of dysautonomia in dogs or a result of secondary complications, such as aspiration pneumonia, is not known. However, the fact that an equivalent number of dogs with depressed systolic function did not have evidence of aspiration pneumonia suggests the possibility of a direct relationship. Additional studies are warranted to identify the cause of systolic dysfunction in dogs with dysautonomia.