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Giovanni Romito Department of Veterinary Medical Sciences, Alma Mater Studiorum, University of Bologna, Ozzano dell’Emilia, Italy

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Nazzareno Giuseppe Pelle Clinica Veterinaria Porta Schiavonia, Forlì, Italy

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Mario Cipone Department of Veterinary Medical Sciences, Alma Mater Studiorum, University of Bologna, Ozzano dell’Emilia, Italy

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Introduction

A 15-year-old 15-kg male English Setter was evaluated because of polyuria, polydipsia, exercise intolerance, and intermittent panting for the preceding 3 weeks. The owners reported that episodes of panting were not related to either physical activity or emotional stress and that the dog had collapsed during a walk. The patient was an indoor dog that was up to date with vaccinations and parasite prevention and had no known exposure to toxic agents or human medications.

On initial examination, the dog was bright and alert. Cardiac auscultation revealed a grade 2/6 left apical systolic murmur; the heart rate was 140 beats/min with a regular rhythm. Femoral pulses were synchronous with the heartbeat and strong. Systolic arterial blood pressure was high (230 mm Hg), although the dog was quiet during measurement. The remainder of the examination was unremarkable.

Initial diagnostic evaluation included a CBC, serum biochemical analyses, urinalysis, thoracic radiography, abdominal ultrasonography, and transthoracic echocardiography. Laboratory abnormalities included increased alanine aminotransferase (373 U/L; hospital reference interval, 15 to 65 U/L), aspartate aminotransferase (85 U/L; hospital reference interval, 15 to 52 U/L), alkaline phosphatase (1238 U/L; hospital reference interval, 12 to 180 U/L) and gamma-glutamyl transferase (20.2 U/L; hospital reference interval, 0 to 5 U/L) activities, increased urea (131 mg/dL; hospital reference interval, 17 to 48 mg/dL) and proteinuria (protein-to-creatinine ratio, 1.6; upper reference limit, < 0.5). Thoracic radiographs were unremarkable. Abdominal ultrasonography revealed a rounded left adrenal mass without vascular involvement. Echocardiography showed thickened mitral valve leaflets associated with mild mitral valve regurgitation. No signs of cardiac dilatation were identified, but mild, symmetric left ventricular wall thickening was present. During the echocardiographic examination, simultaneous ECG monitoring showed bizarre-looking QRS complexes. Therefore, a 6-lead surface ECG tracing was obtained (Figure 1).

Figure 1
Figure 1

Six-lead ECG tracing obtained from a 15-year-old English Setter strongly suspected to have a pheochromocytoma. Note that the QRS complexes are wide (duration, 0.1 seconds) and tall (R-wave amplitude, 4 mV). Moreover, the QRS complexes are predominantly positive in leads I, II, III, and aVF and predominantly negative in the remaining leads. These findings are consistent with complete left bundle branch block. Paper speed = 50 mm/s; 1 cm = 2 mV.

Citation: Journal of the American Veterinary Medical Association 260, 15; 10.2460/javma.21.06.0305

ECG Interpretation

A regular rhythm with a mean heart rate of 120 beats/min was present. The P waves had normal duration (0.035 seconds; upper reference limit,1 < 0.04 seconds), amplitude (0.3 mV; upper reference limit,1 < 0.4 mV), and mean electrical axis (90°; reference interval,1 –18° to 90°). Normal PR intervals (0.09 seconds; reference interval,1 0.06 to 0.13 seconds) were followed by wide QRS complexes (0.1 seconds; upper reference limit,1 < 0.07 seconds) characterized by tall R waves (amplitude, 4 mV; upper reference limit,1 < 3 mV). The QRS complexes were positive in leads I, II, III, and aVF and negative in the remaining leads (mean electrical axis, 85°; reference interval,1 40° to 100°). These findings were consistent with sinus rhythm associated with complete left bundle branch block (cLBBB).

In light of the anamnestic, clinical, and diagnostic test findings, a pheochromocytoma was considered as a possible differential diagnosis. Various diagnostic approaches were offered to the owners, including the possibility of performing percutaneous fine-needle aspiration of the adrenal mass under ultrasound guidance. Because this diagnostic strategy was declined, urinary catecholamine concentrations were determined, revealing high urinary norepinephrine-, metanephrine-, and normetanephrine-to-creatinine ratios (151.4 [hospital reference interval, 8.4 to 117.9], 71.3 [hospital reference interval, 3.3 to 48.9], and 126.9 [hospital reference interval, 25.2 to 120.1], respectively).

Holter monitoring was performed with a 3-lead precordial system to exclude possible intermittent cardiac rhythm disturbances, especially in light of the collapse reported by the owners. The recording showed inappropriately sustained sinus tachycardia (ST), even during rest. Specifically, the heart rate ranged between 60 and 100 beats/min during sleep with a mean heart rate of 120 beats/min/24 h (rate in healthy dogs,2,3 approx 50 to 90 beats/min/24 h). The sinus rhythm was consistently associated with cLBBB. On a 24-hour tachogram (Figure 2), episodes of ST created multiple narrow bands of shorter R-R intervals and the occurrence of the physiological zone of avoidance was limited to a few hours.4,5 Moreover, the time-domain variables of heart rate variability were all decreased, including the SD of all the NN intervals (218 milliseconds; reference interval,6 387 to 452 milliseconds), the SD of the means of the NN intervals for all 5-minute segments (206 milliseconds; reference interval,6 218 to 255 milliseconds), the percentage of interval differences of successive NN intervals > 50 milliseconds (24%; reference interval,6 65% to 71%), and the square root of the mean squared difference of successive NN intervals (138 milliseconds; reference interval,6 391 to 484 milliseconds).

Figure 2
Figure 2

Holter monitor recordings obtained from the dog from Figure 1. A—A tachogram plotting time of day on the x-axis and R-R interval on the y-axis. Variations in the heart rate are depicted as increases and decreases in the band of RR intervals. Sinus complexes are depicted as green dots. Multiple downward conglomerations of green dots can be observed, both during the day and at night. These represent short R-R intervals (mainly < 600 milliseconds) induced by the high sympathetic tone. Interestingly, such episodes were infrequently associated with physical activity or excitement of the patient. Rare episodes of upward dispersion of green dots can also be identified. This pattern, identified only during sleep, represents longer R-R intervals (mainly 800 to 1,200 milliseconds) caused by transient increases in vagal tone. Note that the physiological zone of avoidance manifests exclusively during such phases and lasts only for a limited period. B—Selected portions of the Holter recording correspond to the red vertical line on the tachogram. At that time (4.34 am), the dog was sleeping (the owner documented all behaviors and activities in a diary). Note the inappropriately high heart rate (80 to 100 beats/min). Notice also that the bundle branch block pattern persists despite the variable coupling intervals, allowing the exclusion of a heart rate–dependent intraventricular conduction disorder. Channel = x-axis; paper speed = 29.5 mm/s; 1 cm = 2 mV.

Citation: Journal of the American Veterinary Medical Association 260, 15; 10.2460/javma.21.06.0305

Pheochromocytoma and stage B1 (American College of Veterinary Internal Medicine classification) myxomatous mitral valve disease were strongly hypothesized. The 2 diseases were judged to be concomitant but unrelated. The left ventricular wall thickening was thought to be secondary to pheochromocytoma-associated systemic arterial hypertension. Similarly, ST and reduced heart rate variability were suspected to be a consequence of catecholamine excess and the action of catecholamines on the conduction system.

Phenoxybenzamine was prescribed (approximately 0.25mg/kg, PO, q 12 h; then increased to approximately 0.5mg/kg, PO, q 12 h). Surgical treatment (ie, adrenalectomy) was also discussed with the owners; however, this was declined. Regular examinations were performed every 1 to 3 weeks over the following months. The owner reported an improvement in the dog’s quality of life and the gradual disappearance of clinical signs; moreover, progressive normalization of the systolic arterial blood pressure and heart rate was demonstrated on recheck examinations.

Discussion

Pheochromocytomas are uncommon catecholamine-producing tumors that arise from chromaffin cells in the adrenal medulla.79 Unilateral involvement occurs in most dogs, and approximately 50% of pheochromocytomas are considered malignant on the basis of their behavior.79 The tumor can be functionally active or inactive. Because adrenal chromaffin cells are capable of amine precursor uptake and decarboxylation, functionally active pheochromocytomas can cause a paraneoplastic syndrome associated with excess catecholamine production and secretion.79 This syndrome is often characterized by episodic weakness, panting, tachycardia, systemic arterial hypertension, polyuria, and polydipsia.79 However, the clinical picture may vary widely depending on the type and quantity of synthesized catecholamines, the unpredictable frequency of catecholamine release into the bloodstream, and the different effects that catecholamines have on receptors in various organs.79

Catecholamine receptors exist in 2 main categories, α and β, and these are further subdivided into α1- and α2-adrenergic receptors and β1-, β2-, and β3-adrenergic receptors.9,10 Even though adrenergic receptors are all activated by catecholamines, they mediate very different cellular responses on the basis of G-protein coupling and intracellular transduction pathways. The cardiovascular compromise caused by pheochromocytomas is mainly due to overstimulation of α1- and β1-adrenergic receptors, which are predominantly expressed in smooth muscle cells of blood vessels and the heart, respectively.9,10 α1-Adrenergic receptors are coupled to stimulatory Gq proteins that activate the enzyme phospholipase C, which in turn produces the second messengers inositol triphosphate and diacylglycerol, leading to the release of intracytosolic calcium from the endoplasmic reticulum. In vascular smooth muscle cells, this ultimately results in vasoconstriction.10 Stimulation of β1-adrenergic receptors results in activation of the Gs protein, which increases the activity of adenylyl cyclase, accelerating production of cyclic adenosine monophosphate. This, in turn, activates protein kinase A to phosphorylate multiple target proteins, including L-type calcium channel and cardiac troponin I, ultimately increasing cardiomyocyte contractility, enhancing the sinus node discharge rate, and facilitating conduction through the atrioventricular node.10 This explains why catecholamine excess can cause systemic arterial hypertension, concentric left ventricular hypertrophy, cardiomyocyte necrosis (especially through exaggerated coronary vasospasms leading to hypoxic damage), and arrhythmias.711

In human medicine, arrhythmias are a common complication of pheochromocytomas, with tachyarrhythmias being more common than bradyarrhythmias or conduction disturbances and ST being the most common tachyarrhythmia.12 Regrettably, data on pheochromocytoma-associated arrhythmias are currently sparse in dogs and mainly limited to premature ectopic complexes.79 Interestingly, although ST has frequently been mentioned in the list of cardiac complications of pheochromocytomas in dogs, no prior report provided detailed information on ST in dogs with this endocrine tumor.

In the case reported here, accurate analysis of qualitative and quantitative data obtained from the Holter recording was essential for an adequate understanding of the extent, duration, and clinical impact of pheochromocytoma-associated ST. Specifically, the tachogram provided graphic information on heart rate fluctuations recorded during long-term monitoring, acting as an easily interpretable fingerprint of the cardiac rhythm dynamics associated with the pheochromocytoma. Moreover, the analysis of time-domain variables allowed quantification of the effect of catecholamine excess on heart rate variability.

Awareness of this ECG entity may hold clinical relevance. Indeed, in humans, if not promptly recognized and properly treated, inappropriately sustained ST may lead to tachycardia-induced cardiomyopathy and congestive heart failure.1315 Whether the same complications occur in dogs remains to be established, primarily owing to the rarity of this cardiac rhythm disturbance in this species. In the present case, the effective medical management precluded us from studying the long-term effects of uncontrolled ST on myocardial function. Nevertheless, the similar effects of catecholamines on the human and canine cardiovascular systems makes it possible to hypothesize that the 2 species may share similar myocardial compromise due to inappropriately sustained ST.

In addition to ST, cLBBB was identified in the dog described in the present report. Because the cLBBB persisted despite coupling interval changes, a permanent (anatomic) intraventricular conduction disorder was diagnosed. Ischemia and fibrosis of the left ventricular myocardium and left bundle branch, likely secondary to pheochromocytoma-associated systemic arterial hypertension, were hypothesized to represent the main, presumptive predisposing factor for the development of cLBBB in the present case.16

In conclusion, ECG tracings in this case provided visual evidence of inappropriately sustained ST associated with cLBBB in a dog with a pheochromocytoma. In addition, this case illustrates how a tachogram and heart rate variability analysis through time-domain variables can be used in combination with standard ECG assessment to expand our understanding of the electrophysiological effects of catecholamine overstimulation in dogs.

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