Introduction

Primary hypoadrenocorticism occurs in canine patients secondary to adrenal cortex atrophy, and becomes clinically significant after approximately 90% loss of adrenocortical tissue.¹ It is an uncommon illness in dogs, with a reported incidence of approximately 0.5%.¹ The pathophysiology and systemic consequences of hypoadrenocorticism are well documented.^1,2 Dogs can present with a wide variety of clinical signs, from mild chronic illness to hypovolemic shock, seizures secondary to hypoglycemia, or other severe clinical signs secondary to the systemic effects of decreased cortisol and aldosterone. Outside of hypovolemic shock, cardiac sequelae of hypoadrenocorticism have not been extensively described in dogs. Bradyarrhythmias have been described in as many as 34% of dogs with hypoadrenocorticism,² but there is little known in veterinary medicine about the consequences of untreated hypoadrenocorticism on the cardiac muscle.

In human patients diagnosed with typical hypoadrenocorticism, there is a rarely described, reversible cardiomyopathy that causes systolic dysfunction and left ventricular dilation consistent with an acquired dilated cardiomyopathy (DCM).^3–8 Ante-mortem diagnosis of DCM made via echocardiogram is characterized by left ventricular systolic dysfunction (reduced fractional shortening [<25%], reduced ejection fraction [<50%], increased sphericity index, and/or increased end-systolic volume) and chamber dilation predominantly affecting the left-sided heart chambers.⁹ Echocardiogram diagnosis of DCM was found to have a sensitivity of 93% in one veterinary study.⁹ DCM in dogs is generally suspected to be an inherited disease and is less likely associated with extracardiac factors like taurine deficiency or hypothyroidism.¹⁰ More recently, dietary associations have come to light as a possible cause of systolic dysfunction.¹¹

There are no instances in the veterinary literature of an acquired DCM in dogs secondary to hypoadrenocorticism. A recent case report describes reversible left ventricular systolic dysfunction and subsequent congestive heart failure in a dog with polyendocrinopathy,¹² but the presence of multiple endocrine diseases leaves room for interpretation in regard to the effect hypoadrenocorticism had on myocardial dysfunction, particularly because systolic dysfunction secondary to hypothyroidism has been consistently documented in dogs.¹³

Two dogs were presented to the same tertiary referral center and were diagnosed with hypoadrenocorticism based on serum biochemistry analyses and adrenocorticotropic hormone (ACTH) stimulation tests. Both dogs developed congestive heart failure following treatment (glucocorticoids, desoxycorticosterone pivalate [DOCP], and IV fluid therapy) and were subsequently diagnosed with left ventricular systolic dysfunction. The purpose of this paper is to describe two cases of acquired systolic dysfunction as a suspected sequelae of hypoadrenocorticism and to discuss the pathophysiology of the cardiac effects of hypoadrenocorticism.

Case Summaries

Case 1

Dog 1, a 6 yr old castrated male whippet weighing 14.3 kg, was presented for evaluation of collapse episodes that started 1 wk before presentation. His owners reported a 30 min episode 1 wk before presentation in which he was stiff, urinated on himself, and seemed to be too weak to stand but was alert and responsive to his owner’s voices. He was evaluated by his primary veterinarian, and two-view thoracic radiographs were performed that were unremarkable; the vena cava was normal in diameter. His owners reported another collapse episode a few days later that lasted approximately 1 hr, and he subsequently presented to the referral center. He had no other significant medical history and was not fed a grain free diet (contained corn, soy, and barley).

On presentation, the dog’s physical examination and vital parameters were normal, and cardiothoracic auscultation was normal. A complete blood count and serum chemistry revealed electrolyte abnormalities and azotemia concerning for hypoadrenocorticism (Table 1). The dog was admitted to the hospital on continuous electrocardiogram monitoring, IV fluid therapy (lactated Ringer’s solution^a at 120 mL/kg/day), and supportive care. Because of the suspicion of hypoadrenocorticism, he was given Dexamethasone sodium phosphate^b (0.1 mg/kg IV q 24) upon admission to the hospital. An ACTH stim was submitted to a reference laboratory^c and was diagnostic for hypoadrenocorticism (precortisol <0.2 μg/dL, reference interval [RI] = 0.5–4 μg/dL; postcortisol <0.2 μg/dL, RI = 8–20 μg/dL). The dog was given a dose of DOCP^d (2.2 mg/kg intramuscularly) and discharged the following day with oral prednisone^e (0.5 mg/kg per os [PO] q 24). His telemetric monitoring was unremarkable. He did not have any collapse episodes while in the hospital or for 1 wk following discharge.

TABLE 1 Relevant Serum Biochemical Values of Both Dogs at the Time of Initial Presentation

View Fullscreen

One week later, the dog was re-presented to the emergency service for evaluation of acute respiratory distress. Thoracic radiographs performed at that time showed equivocal cardiomegaly, pulmonary venous congestion, and pulmonary edema (Figure 1) most suggestive of left-sided congestive heart failure. Blood work performed at that time showed resolution of the previously noted electrolyte abnormalities. He was evaluated by a board-certified veterinary cardiologist, and the echocardiographic results (Figures 2, 3) were consistent with DCM (Table 2). He was hospitalized for two subsequent days for oxygen therapy, IV diuretic therapy (furosemide^f 2 mg/kg IV q 8), and oral inotropic support with pimobendan^g (0.25 mg/kg PO q 12). His dyspnea improved, and recheck thoracic radiographs showed resolution of the pulmonary edema. He was discharged with furosemide^f (2 mg/kg PO q 12), pimobendan^g (0.25 mg/kg PO q 12), prednisone^e (0.4 mg/kg PO q 24), and spironolactone^h (1.75 mg/kg PO q 12).

View Figure

• Download as Powerpoint
• Download Figure

View Figure

• Download as Powerpoint
• Download Figure

View Figure

• Download as Powerpoint
• Download Figure

TABLE 2 Echocardiographic Measurements of Both Dogs

View Fullscreen

Twelve hours following discharge, the dog developed respiratory distress at home and re-presented to the emergency service. Recheck thoracic radiographs revealed severe cardiogenic pulmonary edema, and, despite IV furosemide boluses and a furosemide constant rate infusion (0.66 mg/kg/hr), his respiratory distress did not improve. Escalation of oxygen therapy (high-flow oxygen therapy or mechanical ventilation) was recommended but given concerns for prognosis, euthanasia was elected.

Discussion

At present, there are a number of reports in the human literature that describe an acquired cardiomyopathy characterized by systolic dysfunction in patients with recently diagnosed adrenal insufficiency.^3–8 After treatment of congestive heart failure and careful titration of hormone replacement therapy, all surviving patients had complete resolution of systolic dysfunction.^3–8 The pathophysiology of systolic dysfunction in hypoadrenocorticism is incompletely understood. Glucocorticoids are important for intrinsic myocardial contractility and regulation of the sympathetic nervous system. In the absence of glucocorticoids, adrenergic receptors are downregulated, and there is decreased epinephrine synthesis, decreased tissue sensitivity to catecholamines, and decreased epinephrine activation of glycogenolysis in the myocardium,¹⁴ all contributing to systolic dysfunction, which compromises cardiac output. Cardiac output is further compromised by hypovolemia associated with renal loss of sodium and clinical signs of vomiting and inappetence, as well as by vasodilation associated with the increased production of bradykinin and reduced vascular reactivity secondary to glucocorticoid deficiency.¹⁵ Finally, hyperkalemia secondary to lack of aldosterone causes bradycardia secondary to increase in the resting membrane potential, which directly decreases cardiac output.¹ A combination of impaired systolic function and chronic hypovolemia may contribute to the development of acquired cardiomyopathy associated with hypoadrenocorticism.

Both dogs described in this report were not diagnosed with systolic dysfunction until they developed pulmonary edema and left-sided congestive heart failure. Neither dog had pre-existing suspicion of cardiac disease, did not have an auscultable heart murmur, and did not eat a grain-free diet. Dog 1 had collapse episodes that were not characteristic of cardiogenic syncope given their long duration and were more suggestive of untreated hypoadrenocorticism, particularly because they resolved following treatment with glucocorticoids and DOCP. This patient also had pre-existing thoracic radiographs performed shortly before presentation that were unremarkable. The dogs reported here were both diagnosed with hypoadrenocorticism shortly after presentation but had historical suspicion of chronic, undiagnosed adrenal insufficiency. Dog 1 had collapse events 1 wk before presentation. Dog 2 had a history of chronic gastrointestinal signs and bilaterally small adrenal glands on an abdominal ultrasound performed 2 mo before presentation, indicating chronic adrenal insufficiency by the time of definitive diagnosis. Had the dogs been evaluated echocardiographically before treatment with gluco- and mineralocorticoids, it is unknown whether or not systolic dysfunction would have been evident. In theory, the decreased afterload in both dogs at initial presentation (evidenced by Dog 2’s persistent systemic hypotension) could have masked systolic dysfunction that may have only become apparent after volume and afterload resuscitation. Additionally, dose reduction of oral mineralocorticoids appears to be important in reducing afterload in people; however, this is not a viable option in dogs because DOCP is an injectable medication. Although the reversibility of cardiac dysfunction was unable to be determined in these patients because they were both euthanized, it raises the question of whether or not systolic dysfunction would be reversible in surviving dogs with hypoadrenocorticism.

Both dogs in this case report developed congestive heart failure following administration of mineralocorticoids, glucocorticoids, and IV fluid therapy, which has been documented in humans.^8,16,17 Although the complete pathophysiology of this phenomenon is unknown, it is suspected that a renal adaptation to compensate for chronic salt and water deprivation is a possible mechanism for the development of congestive heart failure in patients who receive fludrocortisone.¹⁶ Chronic glucocorticoid deficiency can lead to systolic dysfunction in a subset of patients, and the necessary therapeutic administration of glucocorticoids and DOCP can lead to a sudden increase in blood volume that causes cardiac decompensation in these patients. Neither of these dogs had echocardiographic evidence of chronically elevated left atrial pressures or left atrial dilation, suggesting that an acute insult—like rapid volume overload in combination with undiagnosed systolic dysfunction—contributed to cardiac decompensation. Although a recent case report suggested an association between administration of fludrocortisone and development of congestive heart failure in a dog with both hypoadrenocorticism and hypothyroidism,¹² this has never been described secondary to administration of DOCP, although the underlying mechanism is likely similar.

Dog 2 had a postmortem histopathologic evaluation of the heart that did not show any structural abnormalities to the myocytes to suggest a primary cardiac cause of his systolic dysfunction. Grossly, the left heart chambers of dogs with primary DCM are dilated, although all four chambers can be enlarged depending on the severity of the disease. Histologically, findings may vary from attenuated wavy myofibers or fibro-fatty infiltration to less specific findings like fibrosis, myocyte vacuolization, or necrosis.¹⁸ Given the lack of changes to the cardiomyocytes on dog 2’s histopathology, the systolic dysfunction was deemed to be secondary to an extracardiac cause.

Conclusion

The pathophysiology of myocardial systolic dysfunction and congestive heart failure in these dogs may have been multifactorial; however, cardiogenic pulmonary edema seemed to be a direct consequence of the effect of treatment with glucocorticoids, DOCP, and fluid therapy. It is possible that both dogs had underlying, subclinical cardiovascular disease that was exacerbated by chronic glucocorticoid deficiency. Given the lack of changes to the cardiac myocytes on the histopathology of dog 2, however, this seems less likely and could suggest that the myocardial dysfunction was secondary to untreated adrenal insufficiency, particularly given the similar pathophysiology seen in human patients with hypoadrenocorticism. These cases highlight the clinical importance of cardiovascular consequences in patients with hypoadrenocorticism and underscores the importance of monitoring perfusion parameters, respiratory rates, and blood pressures during the treatment of these dogs.