Abstract
Exposure to cortisol excess in Cushing’s disease (CD) results in increased cardiovascular morbidity and reduces survival, with cardiovascular disease being a leading cause of death. At diagnosis, a significant number of patients have adverse cardiovascular profiles (e.g., obesity, diabetes or impaired glucose tolerance, dyslipidemia, hypertension, cardiac abnormalities and vascular disease). Remission of hypercortisolemia reduces but does not completely eliminate the cardiovascular complications; hazard ratios for myocardial infarction and stroke are high during long-term monitoring, highlighting the long-lasting effects of hypercortisolism and the importance of the timely diagnosis and successful management of this condition. Data on mortality of patients in remission are not consistent but in a multicenter study, an increased all-cause and circulatory mortality in patients with CD in remission for at least 10 years has been demonstrated. Cardiovascular morbidity requires particular focus and effective management during the care of patients with CD, from their presentation until long-term follow up.
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Introduction
Glucocorticoid excess causes several abnormalities leading to increased cardiovascular morbidity and mortality, which often do not normalize, even after achievement of biochemical remission [1]. In this review, we will focus on the impact of Cushing’s disease (CD) on the cardiovascular health and on the mortality of patients with this condition.
Metabolic manifestations
Obesity
Weight gain is frequently reported at diagnosis of CD, with obesity affecting 43–68% of patients [2]. There is also central fat distribution, with higher total, visceral and trunk subcutaneous adipose tissue than in matched controls [3]. Following remission, a decline in total, visceral and subcutaneous fat, as well as in weight and waist circumference has been observed [4]. However, by 5 years post-remission, 73% of patients remain overweight or obese [5] (Table 1).
Impaired glucose metabolism
CD can lead to impaired glucose tolerance and diabetes mellitus [2, 6,7,8]. Protracted hypercortisolemia impairs β-cell function and reduces insulin sensitivity in the liver, skeletal muscle and adipose tissue, resulting in gluconeogenesis [1]. After disease remission, abnormalities in glucose metabolism improve but do not completely resolve [6, 7]. Ntali et al. showed a significant reduction in the frequency of impaired glucose tolerance/diabetes mellitus type 2 from diagnosis (67/311, 22%) to last assessment (53/311, 17%), in a cohort with remission achieved in 77% of patients [8] (Table 1).
Dyslipidemia
Dyslipidemia in CD is characterized by high triglycerides and total cholesterol levels with variable changes in HDL levels [9], and is frequently present in active disease [2, 6, 7]. Glucocorticoid excess leads to increased lipolysis and free fatty acid production and subsequent hepatic steatosis [9]. Dyslipidemia improves but does not normalize after remission [6, 7]; Faggiano et al. found a significant reduction in LDL cholesterol between active disease and at 1 year remission but not in total cholesterol [7] (Table 1).
Cardiovascular manifestations
Hypertension
In active CD, hypertension is highly prevalent (49–78%) and is associated with the duration and severity of glucocorticoid excess [2, 6, 8, 10] (Table 1). The pathogenesis is multifactorial; increased mineralocorticoid action, increased production of vasoconstrictors, such as endothelin-1 and enhanced reactivity of the cardiovascular system to vasoconstrictors, modulation of renin–angiotensin–aldosterone-system activity, inhibition of vasodilator release (e.g., nitric oxide, prostaglandins E2 and I2) and up-regulation of the sympathetic nervous system [10]. Despite remission, in two series, hypertension persisted in 50% (at diagnosis 64%) and 40% (at diagnosis 72%) of patients [6, 7], likely due to irreversible structural cardiovascular changes and vascular remodeling.
Cardiac
Patients with active CD have left ventricular (LV) hypertrophy and concentric remodeling [11]. Systolic and diastolic dysfunction result from significant reduction in LV, right ventricular (RV) and left atrial (LA) ejection fractions [12]. Patients can rarely present with dilated cardiomyopathy or overt cardiac failure [12]. Pathogenesis includes enhanced response to angiotensin II, mineralocorticoid receptor activation and increased myocardial fibrosis [1]. At six-months post-remission, LV, RV and LA ejection fractions improve with a reduction in LV mass [12]. However, cardiac remodeling and relative wall thickness are still higher in patients in remission compared to controls [11]. Of note, hypokalemia can be present due to stimulation of the mineralocorticoid receptor by high cortisol levels predisposing to fatal arrhythmias [1].
Vascular
Vascular aberrations complicate active CD with increased intimal media thickness (IMT) of major arteries [7]. There is also increase in the formation of atherosclerotic plaques [5] and arterial thrombosis [1]. Dekkers et al. found raised risk of ischemic heart disease (IHD) (HR 3.6, 95% CI 2.2–5.9) and stroke (HR 2.1, 1.2–3.6) in CD patients compared to controls [13]. Pathogenesis is multifactorial; low grade inflammation, microvascular endothelial dysfunction and hypercoagulability all contribute [1]. After remission, there is a relative resolution in vascular abnormalities (reduced IMT and increased diameter of the carotid artery) [7]. However, at 5 years post -remission, coronary artery plaques persisted in 27% of patients vs. 3% of controls [5]. The risk of stroke and IHD remains above that of the general population even in long-term remission [1].
Mortality
The all-cause and cardiovascular-related mortality in patients with CD have been widely studied [2, 8, 13,14,15]. Patients with persistent disease have an undoubtedly high standard mortality ratio (SMR) [15]. Mortality data on patients in remission are not consistent; attributed to differences between studies (variability in criteria defining remission, in duration of cortisol excess, in recurrence rates, follow-up periods and therapeutic approaches) [15]. Notably, Clayton et al. reported increased all-cause mortality in patients with CD who had been in remission for at least 10 years at the time of entering the study (SMR 1.61, 95% CI 1.23–2.12); this group had median follow-up of 11.8 years from study entry and had remained in remission during the observation period [14].
Cardiovascular disease is a leading cause of death in patients with CD [1, 8]. Ragnarsson et al. in a series of 502 patients with CD (83% in remission) over a median follow up of 13 years, reported that cardiovascular disease was the commonest cause of death (SMR 3.3, 95% CI 2.6–4.3); IHD SMR 3.6 (95% CI 2.5–5.1) and stroke SMR 3.0 (95% CI 1.4–5.7). SMR related to circulatory disease of patients with active CD was even higher (9.5, 95% CI 4.15–17), and remained elevated even after remission (2.5, 95% CI 1.8–3.4) [16]. In the Clayton et al. series, circulatory SMR was 2.72 (95% CI 1.88–3.95) [14].
Predictors of elevated mortality remain unclear, as data on the impact of age at CD diagnosis, gender or pituitary radiotherapy are discordant [15].
Conclusions
CD is associated with compromised cardiovascular health; this is attributed to several metabolic and cardiovascular morbidities, which may persist even after apparent biochemical remission, highlighting the long-lasting effects of hypercortisolism and the importance of timely diagnosis and successful management of this condition. Mortality in active CD is elevated and a number (but not all) studies suggest that it is also adversely affected in patients in remission. Cardiovascular disease is a leading etiology of death. A thorough assessment of CD-related cardio-metabolic changes, pre-existing co-morbidities, as well as family history and lifestyle factors must be undertaken at diagnosis of CD. Furthermore, recurrent screening of cardiovascular risk factors, even after biochemical remission, is mandatory [15], and modifiable risk factors and co-morbidities must be meticulously treated as per recent consensus [17].
References
Varlamov EV et al (2021) Management of endocrine disease: cardiovascular risk assessment, thromboembolism, and infection prevention in Cushing’s syndrome: a practical approach. Eur J Endocrinol 184(5):R207–R224
Hassan-Smith ZK et al (2012) Outcome of Cushing’s disease following transsphenoidal surgery in a single center over 20 years. J Clin Endocrinol Metab 97(4):1194–1201
Geer EB et al (2010) MRI assessment of lean and adipose tissue distribution in female patients with Cushing’s disease. Clin Endocrinol (Oxf) 73(4):469–475
Geer EB et al (2012) Body composition and cardiovascular risk markers after remission of Cushing’s disease: a prospective study using whole-body MRI. J Clin Endocrinol Metab 97(5):1702–1711
Colao A et al (1999) Persistence of increased cardiovascular risk in patients with Cushing’s disease after five years of successful cure. J Clin Endocrinol Metab 84(8):2664–2672
Giordano R et al (2011) Metabolic and cardiovascular outcomes in patients with Cushing’s syndrome of different aetiologies during active disease and 1 year after remission. Clin Endocrinol (Oxf) 75(3):354–360
Faggiano A et al (2003) Cardiovascular risk factors and common carotid artery caliber and stiffness in patients with Cushing’s disease during active disease and 1 year after disease remission. J Clin Endocrinol Metab 88(6):2527–2533
Ntali G et al (2013) Mortality in Cushing’s syndrome: systematic analysis of a large series with prolonged follow-up. Eur J Endocrinol 169(5):715–723
Arnaldi G et al (2010) Pathophysiology of dyslipidemia in Cushing’s syndrome. Neuroendocrinology 92(Suppl 1):86–90
Cicala MV, Mantero F (2010) Hypertension in Cushing’s syndrome: from pathogenesis to treatment. Neuroendocrinology 92(Suppl 1):44–49
Toja PM et al (2012) Clinical relevance of cardiac structure and function abnormalities in patients with Cushing’s syndrome before and after cure. Clin Endocrinol (Oxf) 76(3):332–338
Kamenicky P et al (2014) Cardiac structure and function in Cushing’s syndrome: a cardiac magnetic resonance imaging study. J Clin Endocrinol Metab 99(11):E2144–E2153
Dekkers OM et al (2013) Multisystem morbidity and mortality in Cushing’s syndrome: a cohort study. J Clin Endocrinol Metab 98(6):2277–2284
Clayton RN et al (2016) Mortality in patients with Cushing’s disease more than 10 years after remission: a multicentre, multinational, retrospective cohort study. Lancet Diabetes Endocrinol 4(7):569–576
Hakami OA, Ahmed S, Karavitaki N (2021) Epidemiology and mortality of Cushing’s syndrome. Best Pract Res Clin Endocrinol Metab 35(1):101521
Ragnarsson O et al (2019) Overall and disease-Specific mortality in patients with Cushing disease: a swedish nationwide study. J Clin Endocrinol Metab 104(6):2375–2384
Fleseriu M et al (2021) Consensus on diagnosis and management of Cushing’s disease: a guideline update. Lancet Diabetes Endocrinol 9(12):847–875
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AC, RH and NK wrote the review. All authors (AC, RH, JA, NK) reviewed the manuscript. NK supervised the work.
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RH has received a conference grant from Recordati Rare Diseases UK Ltd. NK has received honoraria from Pfizer, Ipsen, HRA Pharma and Recordati Rare Diseases for lectures, research funding from Pfizer, Ipsen and Shire and has served as a member in Scientific Advisory Boards for Pfizer, Ipsen, Recordati Rare Diseases.
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Coulden, A., Hamblin, R., Wass, J. et al. Cardiovascular health and mortality in Cushing’s disease. Pituitary 25, 750–753 (2022). https://doi.org/10.1007/s11102-022-01258-4
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DOI: https://doi.org/10.1007/s11102-022-01258-4