Reversible Dilated Cardiomyopathy in a Patient With Cushing’s Syndrome

Cushing's syndrome (CS) develops when excess glucocorticoids are secreted. The etiology of this syndrome is adrenal hyperplasia due to adrenocorticotropic hormone-producing tumors of either the pituitary gland (Cushing's disease) or of non-endocrine tissue, adrenal adenomas, and adrenal carcinomas. It is characterized by truncal obesity, moon face, weakness, amenorrhea, hirsutism, and hypertension. The cardiovascular complications are usually attributed to hypertension and subsequent end-organ damage including left ventricular hypertrophy (LVH), diastolic heart failure, and myocardial ischemia. CS associated with dilated cardiomyopathy without LVH is rare but important to recognize. In this setting, treatment of CS can lead to total recovery of heart function. A 28-year-old woman presented with a 3-week history of progressive dyspnea, orthopnea, coughing frothy blood-stained sputum, and swelling of the lower limbs. Prior to this presentation, she had gained 12 kg over a period of 12 months and was amenorrheic for 18 months. Her medical history was unremarkable except for a smoking history of about 10 pack-years. She was not taking any regular medications including any over-the-counter or complementary therapy. She did not drink alcohol and had no family history of cardiomyopathy. Physical examination revealed a breathless woman with rounded facies, truncal obesity, buffalo hump, and abdominal striae. Her blood pressure was 140/80 mm Hg, and pulse was 100 beats per minute and regular. Her weight was 74 kg (body mass index, 26.5 kg/m2). There were signs of decompensated biventricular heart failure, which included rales in the lower lung fields bilaterally, raised jugular venous pressure, laterally displaced cardiac apex, and peripheral edema. She had proximal muscle weakness of both upper and lower limbs but no clinical evidence of muscle wasting. Relevant serum biochemistry findings on presentation are shown in Table I. Twenty-four–hour urinary-free cortisol and creatinine values were 964 nmol (50–350 nmol) and 5.3 mmol (6.0–16.0 mmol), respectively. There was loss of diurnal variation in serum cortisol levels, and adrenocorticotropin (ACTH) levels were consistently suppressed (<10 mIU/L; reference range, 10–60 mIU/L). Chest radiography revealed interstitial pulmonary edema and cardiomegaly. Electrocardiography showed sinus tachycardia. Transthoracic echocardiography revealed a markedly dilated left ventricle, normal left ventricle myocardial thickness, left ventricular ejection fraction (LVEF) of 34% (Table II), and mild mitral regurgitation, in keeping with dilated cardiomyopathy. Thallium myocardial perfusion scanning revealed no evidence of ischemic cardiomyopathy. No autoimmune, infective, or infiltrate cause was found to explain the cardiomyopathy. Computed tomography of the abdomen showed a 3.8×2.3-cm right homogenous adrenal mass with low attenuation (pre-contrast) and mild enhancement post-contrast (Figure ). The findings were consistent with ACTH-independent CS due to a unilateral adrenal adenoma. A unilateral 3.8×2.3-cm homogenous right adrenal mass with low attenuation on computed tomography abdomen prior to administration of contrast. Due to the patient's poor cardiac function, adrenalectomy was delayed. She was treated conservatively with ketoconazole to inhibit steroidogenesis, and anticardiac failure medications included ramipril, carvedilol, spironolactone, and furosemide. Six months after treatment, her symptoms improved; repeat echocardiography showed reduction in the left ventricular size and improvement of LVEF (50%). The urinary-free cortisol level was lower (Table I). The patient then underwent right adrenalectomy. Pathology confirmed a benign adrenal adenoma. Postoperative tertiary adrenal insufficiency developed, and the patient required hydrocortisone therapy for 5 months. Six months after surgery, features of CS had resolved. Repeat echocardiography showed normal left ventricular size and LVEF (Table II). All medications for cardiac failure were discontinued without any recurrence of symptoms. Reversible dilated cardiomyopathy has been associated rarely with CS and reported in 3 previous cases. The first case involved a 51-year-old man with refractory CS r who also had severe biventricular failure (LVEF, 19%).1 His heart failure improved dramatically (LVEF, 40%) following successful treatment of the Cushing's disease, which included incomplete surgical resection of the pituitary lesion, irradiation, and 18 months of mifepristone therapy. The other case was of a 48-year-old woman who presented with heart failure (LVEF, 27%) and was concurrently found to have CS, due to a 6-cm unilateral adrenal adenoma.2 Prior to surgery, she was treated with ketoconazole for an unspecified duration. Her cardiac function also improved (LVEF, 69%) following successful adrenalectomy. Another patient, a 28-year-old woman, also had biventricular failure as the first manifestation of CS caused by an adrenal adenoma with complete reversal of cardiac abnormalities after adrenalectomy.3 The case we describe also demonstrates the challenges arising in relation to the definitive treatment of CS in a patient with severe congestive heart failure. Medical therapy with ketoconazole prior to surgery was used for short-term control of cortisol excess. Following reduction in her cortisol level and improvement of her cardiac function, adrenalectomy was performed successfully. Although skeletal myopathy is a well-recognized complication of CS, our knowledge of cardiomyopathy in CS is comparatively limited. Several previous studies have evaluated cardiac changes in patients with CS.4-6 These studies revealed changes in the left ventricular structural characteristics, in particular asymmetric wall thickening, suggesting cardiac remodeling in these patients. These changes correlated significantly with duration of disease but not with blood pressure and urinary cortisol levels.3, 4 These studies indicate that cardiac remodeling occurs in CS independent of hypertension. Despite findings of cardiac remodeling, dilated cardiomyopathy or decompensated congestive heart failure was not reported in these studies. The remarkable improvement in cardiac function after amelioration of glucocorticoid excess implied that the cardiomyopathy is related to hypercortisolism, but the mechanism is uncertain. The pathophysiology of cardiac remodeling and decompensated congestive heart failure involves complex mechanisms including the effects of hypertension and activation of neurohormonal factors—α-adrenergic and renin-angiotensin-aldosterone systems.7, 8 Experimental models have found that the effects of noradrenaline, angiotensin II, and aldosterone can be heightened with hypercortisolism.9-11 As a result, excess cortisol itself may potentially explain the association between cardiomyopathy, cardiac failure, and CS. The saturation of 11-beta-hydroxysteroid dehydrogenase type 2 enzyme (11β-HSD2) resulting in mineralocorticoid receptor activation by cortisol has also been suggested as a possible reason for cardiomyopathy in CS.1 Observation of hypokalemia and metabolic alkalosis in the present patient and one previous report supports this hypothesis. In conclusion, dilated cardiomyopathy is a rare associated feature of CS that should be recognized. In all the cases reported to date, cardiomyopathy has been reversible after successful treatment of CS. The mechanism in the development of dilated cardiomyopathy associated with CS has not been defined precisely. Present findings suggest that excess cortisol is contributory to cardiac remodeling and dilated cardiomyopathy.