Endogenous Cushing's syndrome may be caused by overproduction of adrenocorticotropic hormone (ACTH) (Cushing's disease in most cases) or by an independent high cortisol secretion from the adrenal cortex.1 Cardiovascular impairments are frequent, due to hypertension, hyperglycemia, hypercholesterolemia, weight gain, and a prothrombotic state. Hypercortisolism can also cause cardiac structural and functional changes2–5: hypertrophy, concentric remodeling, fibrosis, biventricular and left atrial systolic dysfunction, and diastolic dysfunction, leading in rare cases to dilated cardiomyopathy (DCM).
We present here the case of a man with DCM related to Cushing's disease (CD).
A 43-year-old man with a medical history of hypertension for 8 years and history of smoking, presented to the emergency department with dyspnea. He was under treatment with amlodipine at a dose of 5 mg/day. Physical examination, blood tests, and chest imaging revealed global heart failure. Coronary angiography revealed an isolated significant stenosis in the marginal branch of the circumflex artery. Transthoracic echography showed a globally dilated heart (left ventricular end-diastolic diameter: 64 mm), a mild left ventricular hypertrophy, and a global hypokinesia with a more prominent posterolateral wall hypokinesis (probably explained by the stenosis of the marginal branch). Left ventricular ejection fraction (LVEF) was calculated as 28% to 30%. No significant valvular heart disease, no sign of pulmonary hypertension, and no pericardial effusion were noted. Cardiac magnetic resonance imaging (MRI) also showed a DCM, with no sign of necrosis. The patient reported no excessive alcohol consumption and investigations for usual infective, autoimmune and infiltrative causes of cardiomyopathy were negative.
The clinical picture suggested a Cushing's syndrome: easy bruising, reddish purple striae (Fig. 1), proximal myopathy, facial fullness, as well as facial and truncal fat distribution. This was confirmed by blood tests showing severe hypokalemia (2.4 mmol/L), urinary-free cortisol (UFC) 14 times higher than the normal range (2016 nmol/L, N < 138), 8am ACTH level 7 times higher than the normal range (178 ng/L, N < 26), and by a failure of low-dose dexamethasone to suppress serum cortisol in a suppression test. Pituitary gadolinium-enhanced MRI revealed a macroadenoma measuring 15 mm in diameter (Fig. 2). Thus a final diagnosis was DCM complicating CD.
Pituitary surgery had to be postponed due to the severe heart failure.
Optimal pharmacological treatment of systolic heart failure was administered (beta-blocker, ACE inhibitor, diuretics including anti-aldosterone agent) and, as described in such severe conditions,6,7 2 adrenolytic drugs (metyrapone and ketoconazole) were initiated: UFC was normalized within 2 months (Table 1).
Unfortunately, a new episode of acute heart failure occurred two months after initial presentation. Transthoracic cardiac echography showed mitral insufficiency related to rupture of the mitral valve pillar. Percutaneous transluminal angioplasty and stenting (bare metal) was performed in the obtuse marginal artery. Another cardiac MRI then revealed an impaired lateral contractility (territory of the marginal branch) related this time to necrosis (Fig. 3). Infective endocarditis was ruled out (hemocultures were negative and no vegetation was visualized at transesophageal echocardiography).
In spite of optimal treatment and normalization of cortisol levels, no improvement was found in the LVEF 6 months after discovery of the Cushing's disease (Table 1).
Thus a single-chamber defibrillator was implanted for primary prevention, and percutaneous mitral valve repair (Mitraclip) was performed to treat the mitral regurgitation.
After 1 year, since LVEF remained at 30%, cardiac transplantation was discussed.
In view of the patient's heart failure, anesthesia for transphenoidal surgery was considered too dangerous; therefore, stereotaxic radiotherapy was performed to treat the CD 14 months after initial presentation. While awaiting the therapeutic effects of the pituitary irradiation, tolerance and efficacy of the 2 adrenolytic agents proved acceptable.
Cardiovascular complications, including myocardial ischemia, left ventricular hypertrophy and cardiomegaly account in part for the higher mortality rate among patients with Cushing's syndrome.8 Some studies having examined the relationship between cardiac dysfunction and hypercortisolism, found that cardiac remodeling is independent of hypertension, and is probably due to a direct action of cortisol on myocardial tissue via glucocorticoid receptors.2–4
A recent cardiac MRI study showed that patients with Cushing's syndrome have lower left ventricular, right ventricular, and left atrial ejection fractions and increased left ventricular mass.5 Repetition of imaging after treatment revealed that these systolic dysfunctions and structural changes are reversible upon correction of hypercortisolism. None of the patients in this study had DCM.
Several cases with DCM related to hypercortisolism have been published9–18 (Table 2).
Interestingly, all these cases showed an improvement in LVEF after several months of cortisol normalization (median LVEF improvement of 30% [min: 15%; max: 42%]; in a median time of 9 months [min: 4; max: 18]). Cushing's syndrome was due to unilateral adrenal adenoma in 5 cases,11,12,14,15,17 ACTH-secreting adenoma in 4 cases,9,10,13,18 and of unknown cause in 1 case.16 LVEF improvement was noted whatever the initial etiology, with a median improvement of 30% (min: 15%; max: 42%) for adrenal adenomas, 25% (min: 15%; max: 33%) for pituitary adenomas, and 38% after bilateral adrenectomy in the subject for whom the cause was undetermined. In view of these observations, DCM related to hypercortisolism could be considered as “reversible.”
Here we have reported the first case showing no improvement of DCM in a context of Cushing's syndrome. At presentation the cardiomyopathy could only be attributed to hypercortisolism (usual other causes of DCM were eliminated, MRI initially showed no ischemic signs; however, unfortunately, several weeks later the patient suffered an acute coronary syndrome with rupture of the mitral pillar and objective signs of necrosis in the lateral territory (MRI). This combination of different causes of DCM (hypercortisolism, ischemia, and valvular defect) could explain the absence of improvement of LVEF in response to a eucortisolemic state.
Another possible explanation can be a publication bias due to the selective reporting of cases in which DCM had been reversed.
The standard treatment of CD is transphenoidal surgery with up to 65% remission rate for macroadenomas.19 For recurrent or residual disease, therapeutic possibilities are second transphenoidal surgery, radiotherapy, medical adrenolytic therapy (mainly comprising mitotane, metyrapone, and ketoconazole, and more rarely etomidate and mifepristone) or bilateral adrenalectomy in cases of uncontrolled cortisol levels.
Unfortunately for our patient, anesthesia for pituitary surgery was contraindicated due to very low LVEF. Combination of 2 adrenolytic agents (metyrapone, blocking the 11-beta-hydroxylase enzyme; and ketoconazole, blocking several steps in cortisol synthesis) normalized cortisol levels and tolerance was good. The observed efficacy is consistent with results from 2 studies in which this combination provided rapid control of severe hypercortisolism elicited by ACTH-dependent Cushing's syndrome6 (a combination of mitotane, metyrapone, and ketoconazole in this study) and by ectopic ACTH syndrome or adrenal carcinoma.7
Our patient was treated by external pituitary radiation, the therapeutic effects of which will be delayed.
In conclusion, we report here the case of a DCM as a presenting feature of CD, without improvement of LVEF after normalization of cortisol level (probably explained by subsequent associated ischemic lesions).
We would like to thank Pr Didier Revel for his interpretation of the cardiac MRI, and Dr Thibault Perret for his kind advices.
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