Introduction

A 10-year-old spayed female Japanese Spitz was presented to the Konkuk University Veterinary Medicine Teaching Hospital for a routine medical check-up of systemic lupus erythematosus. Physical examination revealed an overall good body condition (weight, 7.8 kg; body condition score, 6/9), pink mucous membranes, and normal capillary refill time (< 1 second). The dog was bright, alert, and responsive. Respiratory rate was 30 breaths/min, and rectal temperature was 38.5 °C. Cardiac auscultation revealed no heart murmur, but a slower heart rate (78 beats/min) than that recorded during the previous examination (124 beats/min) and an irregular heart rhythm was detected. Femoral pulses were associated with the heart beats.

The dog had been prescribed prednisolone (0.5 mg/kg, PO, q 12 h) and cyclosporine (10 mg/kg, PO, q 12 h) as immunosuppressive drugs for treatment of systemic lupus erythematosus 3 years earlier as well as theophylline (10 mg/kg, PO, q 12 h) because of bronchial collapse detected radiographically. However, new cutaneous lesions, including crusts and scaling, developed despite this immunosuppressive therapy. Cyclosporine was therefore changed to tacrolimus (0.1 mg/kg, PO, q 12 h), and the cutaneous lesions resolved within a month. The clinical signs associated with systemic lupus erythematosus, including erythema of the skin, alopecia, crusts, scaling, swollen joints, and hyperthermia, were subsequently well controlled with tacrolimus and prednisolone over 2 years.

At the time of the present visit, no abnormalities were detected on a CBC. Serum biochemical analysis showed high alanine aminotransferase (881 U/L; reference range, 10 to 100 U/L), aspartate aminotransferase (132 U/L; reference range, 0 to 50 U/L), alkaline phosphatase (1669 U/L; reference range, 23 to 212 U/L), and γ-glutamyl transpeptidase (76 U/L; reference range, 0 to 7 U/L) activities. The serum trough concentration of tacrolimus was high (1.9 ng/mL; therapeutic range, 0.1 to 0.4 ng/mL) and close to the toxic trough concentration (> 2 ng/mL).¹ Thoracic radiographic findings were unremarkable except for a mild broncho-interstitial pattern observed overall in the lung field. Abdominal ultrasonography revealed gravity-dependent sludge in the gallbladder and reactive features of abdominal lymph nodes without any masses. Results of a neurologic examination were unremarkable.

Electrocardiography (Figure 1) and echocardiography were performed. On echocardiography, left ventricular end-diastolic and end-systolic diameters, measured with allometric time-motion scaling, were 2.49 cm (reference range,² 2.4 to 3.4 cm) and 1.64 cm (reference range,² 1.4 to 2.5 cm), respectively. Fractional shortening was 34%, and ejection fraction was 65%. The left atrial-to-aortic root ratio was 1.02. Degeneration of the anterior mitral valve and trivial mitral valve regurgitation (maximum velocity, 2.21 m/s) was detected. The transmitral flow velocity pattern was abnormal, with a reduced ratio of early and late ventricular filling velocities (E wave-to-A wave ratio, 0.86). Therefore, the dog was classified as having myxomatous mitral valve disease stage B1 on the basis of consensus statements of the American College of Veterinary Internal Medicine.³ An evident mass or thrombus was not detected. Systolic blood pressure determined by means of an oscillometric method was within the normal range (132 mm Hg).

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Six-lead ECG recording obtained from a 10-year-old dog that was presented for regular medical evaluation of systemic lupus erythematosus. The dog had no clinical signs associated with cardiac abnormalities. Sinus arrhythmia, a wandering pacemaker, and intermittent periods of sinus arrest were evident. Pauses exceeded 2 P-P intervals combined. Paper speed = 50 mm/s; 5 mm = 1 mV.

Citation: Journal of the American Veterinary Medical Association 260, 15; 10.2460/javma.20.08.0480

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ECG Interpretation

The 6-lead ECG recording revealed that the rhythm was regularly irregular (Figure 1). Intermittent periods of sinus arrest, which exceeded 2 P-P intervals combined, and sinus arrhythmia were identified, and a slower heart rate (83 beats/min) than that recorded previously (124 beats/min) was evident. P waves were consistently present without alteration of the PR interval (0.1 seconds; reference range, 0.06 to 0.13 seconds). P-wave amplitude varied from 0.2 to 0.4 mV, with taller complexes occurring during periods of faster heart rate and smaller complexes during periods of slower heart rate, which corresponded with a wandering sinus pacemaker. There were no atrial premature complexes. The QRS complexes appeared normal (duration, 0.02 seconds [reference range, < 0.05 seconds]; amplitude, 1.8 mV [reference range, < 2.5 mV]). The ST segments and T waves showed no alterations.

To discriminate the potential causes of sinus arrest, an atropine test was performed. Atropine sulfate (0.04 mg/kg, SC) was administered, and after 30 minutes, an increase in heart rate to 185 beats/min was detected via ECG (Figure 2).

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ECG recording obtained from the dog 30 minutes after SC administration of atropine (0.04 mg/kg). A heart rate of 185 beats/min with restoration of normal sinus rhythm was observed. A wandering pacemaker was no longer detected as well. Paper speed = 50 mm/s; 5 mm = 1 mV.

Citation: Journal of the American Veterinary Medical Association 260, 15; 10.2460/javma.20.08.0480

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Given the results of all examinations and laboratory findings, tacrolimus was discontinued because the serum trough concentration of tacrolimus approached the toxic concentration. However, sinus arrest still persisted 4 months later, although the serum concentration of tacrolimus had decreased closer to the therapeutic concentration (0.5 ng/mL). Because clinical signs related to sinus arrest, such as syncope, weakness, and congestive heart failure, had not developed, more invasive treatments, such as pacemaker implantation, were not warranted. Instead, with the owner’s consent, the dog was closely and regularly monitored.

Eventually, the dog attained a regular heart rhythm, with a heart rate similar to that recorded before developing sinus arrest (120 beats/min). A 6-lead ECG recording revealed a regular rhythm with a return of normal sinus rhythm (Figure 3). The intermittent periods of sinus arrest had resolved, and serum concentration of tacrolimus was undetectable (< 0.5 ng/mL).

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Six-lead ECG recording obtained from the dog 4 months after cessation of tacrolimus administration. Sinus rhythm has been restored, with a heart rate similar to that recorded before sinus arrest occurred (120 beats/min). Paper speed = 50 mm/s; 5 mm = 1 mV.

Citation: Journal of the American Veterinary Medical Association 260, 15; 10.2460/javma.20.08.0480

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Discussion

Sinus arrest is defined as an absence of sinus activity lasting for a period that exceeds 2 P-P intervals combined and indicates inactivity within the sinus node.⁴ A high vagal tone or dysfunction of the sinus node can induce sinus arrest.⁴ The pathological causes associated with sinus arrest are degenerative dilated heart disease; acute or chronic myocarditis; sick sinus syndrome; electrolyte imbalance; any increase in vagal tone such as associated with respiratory, gastrointestinal, or ocular disease; and thoracic, cervical, or cardiac neoplasia.⁵ Certain drugs, such as β-adrenoreceptor antagonists, acepromazine, and digitalis, can also induce sinus arrest.⁵

For the dog described in the present report, an atropine response test was performed to differentiate between vagal and nonvagal causes of sinus arrest. Because the results of the atropine response test were positive, radiography and ultrasonography were conducted to detect any potential underlying disease that could increase vagal tone; however, no obvious dysfunction in the respiratory, gastrointestinal, and ocular systems were found.

In general, electrolyte imbalances can cause ECG changes, but the dog described in this report did not have any electrolyte imbalances, including hyperkalemia. While sinus node dysfunction could be considered a potential cause of sinus arrest, it commonly develops in specific canine breeds, such as Miniature Schnauzer, Cocker Spaniel, West Highland White Terrier, Dachshund, and Pug,^6,7 and the dog described in this report did not belong to a breed that is predisposed to sinus node dysfunction. Moreover, a normal atropine response test excluded sinus node dysfunction as a cause of sinus arrest. On echocardiography, degeneration of the anterior mitral valve leaflet was detected, but the size of the heart was normal. Further, the grade of the heart disease was unchanged from that observed in the previous month when the dog had a regular cardiac rhythm and normal heart rate (145 beats/min). Therefore, myxomatous mitral valve disease was also an unlikely cause of the sinus arrest.

Tacrolimus is an immunosuppressive drug that is commonly used for organ transplantation, with documented cardiotoxicity reported in human medicine.⁸ Both sinus arrest and syncope were observed in a bone marrow transplant recipient who received tacrolimus and digitalis.⁸ Although the underlying mechanisms of sinus arrest associated with tacrolimus are unclear, some authors have suggested that tacrolimus enhances outflux of potassium, which results in prolongation of action potentials and the consequent development of sinus arrest.⁹ Moreover, tacrolimus can activate the transient receptor potential channel M8 (TRPM8) in mice, rats, and humans.¹⁰ TRPM8 is a nonselective cation channel that belongs to the transient receptor potential superfamily.^10,11 TRPM8 is activated by cooling agents and cold temperature, and it is widely distributed on the afferent nerves innervating the visceral organs, including the bronchopulmonary system.¹¹ Since the main afferent nerves of the bronchopulmonary system originate from the vagus nerve, factors activating TRPM8 can stimulate the vagus nerve, thereby inducing autonomic responses.¹¹ Therefore, it is plausible that long-term administration of tacrolimus can activate TRPM8, resulting in stimulation of the vagus nerve such as that observed in our patient.

The only abnormality in the dog when sinus arrest was first detected on ECG recordings was the high serum concentration of tacrolimus. When the dog achieved a normal sinus rhythm, the serum concentration of tacrolimus was lower than the measurable laboratory range (< 0.5 ng/mL). Therefore, the ECG patterns of the dog appeared to correlate with serum concentrations of tacrolimus, indicating that it could have been the cause of sinus arrest.

In summary, the dog in this case report demonstrated sinus arrest that could be attributed to tacrolimus, which stimulates vagal tone and could therefore lead to sinus arrest. This case indicates that dogs treated with tacrolimus should be carefully monitored via ECG.