Cardiovascular complications of Cushings syndrome: Impact on morbidity and mortality
Richard N. Clayton
Abstract
Patients with Cushing's syndrome have increased morbidity and mortality from cardiovascular causes, most commonly myocardial infarction and stroke, but also aneurysms and pulmonary emboli.1, 2 These are also common causes of death in the general population in developed countries and are age-dependent. It has been estimated that untreated Cushing's syndrome patients have a four- to five-fold higher mortality rate than the general population, with only 50% of patients surviving 5 years from diagnosis.3 The 5-year survival rate was improved to 86% after bilateral adrenalectomy.4 The major risk factors for this mortality in the general population are diabetes (DM2), hypertension, smoking, dyslipidaemia, abdominal obesity/metabolic syndrome, and male gender. These same risk factors pertain in all forms of glucocorticoid excess. Here, I focus on endogenous Cushing's syndrome and pertinent to this is that the majority of patients (70%–80%) have adrenocorticotrophic hormone (ACTH)-dependent pituitary Cushing's disease and are frequently women (75% of cases) of premenopausal age, typically between 30 and 55 years old at diagnosis. This sex and age-group has a low incidence of cardiovascular disease in the general population. Furthermore, Cushing's syndrome patients are exposed to excess glucocorticoid for approximately 3–4 years before diagnosis and effective treatment, thereby increasing the likelihood of early development of cardiovascular risk factors. Even more concerning is the fact that, even after ‘cure’ of the Cushing's syndrome, the risk factors may not fully normalise with adequate amelioration of glucocorticoid excess. The present review aims to briefly delineate the major cardiovascular complications of endogenous Cushing's syndrome as they relate to the heart, vasculature, and hypertension. I examine the evidence for the reversibility of these changes, particularly over the long-term (> 1 year), as well as how these factors relate to cardiovascular events and mortality. This is particularly important as long-term ‘cure’ of Cushing's disease may be associated with near-normal life-expectancy because younger patients may expect to live for 30–40 years after diagnosis and curative treatment.5 In this review, ‘cure’ is taken to mean ‘restoration of eucortisolaemia’ as defined by the authors of the publications, which use variable criteria, and those that were commonly accepted at the time of their publication. It does not necessarily equate to normalisation of metabolic risk factors. Treatments used were predominantly surgical but may have included other modalities (for details, see individual studies). Table 1 shows some of the literature regarding the main changes that have been observed in the heart over the last 20 years using various echocardiographic modalities. This is by no means exhaustive, but is representative. These changes are separate from the increased left ventricular mass index and the concentric left ventricular hypertrophy that accompanies hypertension. Although many studies have demonstrated left ventricular remodelling, fewer have examined the effect of this on left ventricular function. The study by Muiesan et al6 compared 42 patients with Cushing's syndrome with the same number of controls matched for age, gender, and blood pressure. In the patients, left ventricular relative wall thickness was greater and midwall fractional shortening was reduced compared to controls. Both of these factors led to reduced systolic performance and diastolic dysfunction and appear to be cortisol specific because the same changes were observed in normotensive patients versus normotensive controls. Although these features have been linked as risk factors for cardiovascular disease in the general population, there is no such link demonstrated for Cushing's syndrome. There are no post-treatment data in this report. Moreover, in the study,6 there is no mention of clinical cardiac symptoms in the cohort. In a later echocardiographic study, Toja et al9 found that parameters of left ventricular mass and relative wall thickness significantly improved 1 year after ‘cure’, although they were still greater than in controls. Subtle left ventricular systolic dysfunction reversed and diastolic function was normal. In a small group (n = 15) of Cushing's syndrome patients investigated by Periera et al7 using two-dimensional speckle strain imaging, left ventricular diastolic dysfunction remained significantly lower than in controls after multivariate analysis with body mass index and left ventricular mass index as covariates. At 12–18 months after resolution of hypercortisolaemia, these changes resolved. Speckle strain imaging allows left ventricular mechanical properties to be tracked in real time in three dimensions along the cardiac cycle, giving more detail of functional changes. No information on clinical features of heart disease was provided. A follow-up report on the same patients by Yiu et al,8 using calibrated integrated backscatter, demonstrated increased myocardial fibrosis that was significantly related to left ventricular systolic and diastolic dysfunction. This reversed after ‘cure’ but, again, there was no mention of clinical cardiac function resulting from these changes. Using cardiac magnetic resonance imaging, Kamenicky et al10 showed that left ventricular, right ventricular, and left atrial ejection fractions were lower and end-diastolic left ventricular segmental thickness increased compared to controls. All of these features improved 2–12 months after resolution of hypercortisolaemia. Dilated cardiomyopathy (DCM) with severe left ventricular failure is rare in Cushing's syndrome. However, a study by Frustaci et al11 found eight cases of Cushing's syndrome as a result of adrenal adenoma in 473 patients with DCM (1.7%). These patients all had left ventricular ejection fractions < 30% and symptoms of heart failure. Endomyocardial biopsies were performed pre-treatment and on three of eight patients 1 year after adrenalectomy. Biopsies showed increased myocyte diameter, myocardial fibrosis, and myofibrillolysis area compared to subjects with idiopathic DCM and controls with valvular heart disease without heart failure. These changes decreased dramatically after adrenalectomy. An interesting observation was marked increase in expression of atrogin-1 mRNA and protein compared to the idiopathic DCM and control groups, which reduced dramatically after adrenalectomy. Atrogin-1 is a L3 ligase enzyme expressed in skeletal, smooth, and cardiac muscle. It is overexpressed in sarcopenic muscle of aged individuals. Atrogin-1 functions in the ubitquitination of proteins, which is essential for directing intracellular proteins to proteasomes for degradation.12 This pathway could be a target for therapeutic intervention in severe cardiomyopathy of Cushing's syndrome where resolution of hypercortisolaemia is difficult, although this remains to be tested. What is the clinical relevance of these cortisol specific changes in the heart and their impact on cardiovascular events and mortality in Cushing's syndrome? Several observations are pertinent here. First, there is no systematic large scale study of the frequency of the aforementioned changes. Second, there are no long-term (> 18 months) follow-up studies in patients with the described changes. Third, with successful treatment of hypercortisolaemia the changes are largely, although not always, completely reversible. Fourth, for patients, apart from those with the rare dilated cardiomyopathy, the functional consequences are not clearly described and are likely ‘subclinical’. Fifth, it is unclear whether these changes impact on cardiovascular events and mortality because there are no studies that have examined specific cardiac changes particularly in the mortality studies. The conclusion is that, although interesting, these observations are likely relatively less important than atherosclerotic, blood pressure, and metabolic changes in determining mortality in Cushing's patients. The structural changes in large/medium-sized blood vessels that have been shown to have a direct relationship with myocardial infarction, stroke, aneurysms, and other vascular events in the general population are well-known and include: diffuse increased thickness of the intima media layer of carotid and other large vessels (IMT); increased number of carotid and coronary artery plaques; increased arterial stiffness and reduced distensibility; increased calcification in coronary arteries; and reduced flow-mediated dilatation of the brachial artery. These are all increased/decreased in patients with untreated Cushing's syndrome compared with age and body mass index (BMI)-matched controls. The pathogenesis of these changes is multifactorial and includes glucose intolerance/insulin resistance, abdominal obesity, dyslipidaemia, prothrombotic tendency, and probably chronic increases in inflammatory markers, as briefly reviewed by De Leo et al.1 This section examines to what extent changes in the vasculature are reversible after ‘cure’ of hypercortisolaemia. The first systematic study,13 from Naples, of 15 patients examined 5 years after ‘cure’ found carotid artery IMT to be significantly increased, and lumen diameter, peak flow velocity, and distensibility coefficient all significantly reduced, compared to age and sex-matched controls. However, compared with BMI-matched controls these changes were less marked, highlighting the use of appropriately matched controls. Some although not all features of metabolic syndrome remained higher in patients vs. BMI matched controls, the most significant of which was waist-hip ratio (WHR). Interestingly, in this early study, neither fasting insulin, nor WHR predicted carotid IMT or distensibility coefficient. The study emphasises the crucial fact that the control group should be matched for WHR because this has subsequently been shown to be a more reliable than BMI as a determinant of features of metabolic syndrome. A subsequent study from the same group by Faggiano et al14 examined the carotid arteries of 25 Cushings disease patients studied before and 1 year after cure compared to 32 age-, sex-, and BMI-matched controls. IMT was significantly increased and distensibility coefficient reduced vs. BMI-matched controls pre-treatment, and these variables improved after ‘cure’, although they remained higher than in the non-BMI-matched controls but were no different from BMI-matched controls. WHR was a significant determinant of IMT and distensibility coefficient both pre- and post-treatment. The only metabolic syndrome parameter that remained different from BMI-matched controls was 2 h post glucose insulin level. In the study, eight of 25 (32%) of patients vs. two of 32 (6%) of BMI–matched controls had carotid artery plaques and their diameters and IMT of their carotid arteries remained the same as before treatment, and so there was no improvement with ‘cure’. Lupoli et al15 published a meta-analysis of 14 studies examining IMT, carotid plaque prevalence, and flow-mediated dilatation of the brachial artery (FMD). Of 10 studies evaluable, IMT was significantly higher in active Cushing's syndrome patients than in controls (but it is unclear whether the latter were all BMI or WHR matched). Post ‘cure’, three out of studies reported that the difference in IMT between patients and controls persisted but, in one (vide infra), IMT was no different in ‘cured’ patients vs. controls.16 Overall, there was no statistically significant difference in IMT between ‘cured’ patients and controls. The prevalence of carotid plaques was significantly higher in active Cushing's syndrome (five studies) and remained so post-‘cure’ (three studies). FMD was lower in active Cushing's syndrome than controls (three studies), and no post-‘cure’ studies were available at that time (but vide infra). In their meta-regression analysis Lupoli et al15 showed that, of the factors contributing to IMT, the mean difference in IMT between active Cushing's syndrome and controls was negatively correlated with age, obesity, and diabetes, and positively correlated with ACTH dependence, urinary cortisol, and serum cortisol. This shows that the older, more obese, and diabetic the patient with Cushing's syndrome, the lower the impact of Cushing's syndrome on IMT, suggesting that ‘general population’ risk factors may be as important in this context. Nevertheless, there is a suggestion that the degree of hypercortisolaemia may have a role to play in determination of IMT, although this requires further clarification. Lupoli et al15 state that, by only analysing studies that used BMI-matched controls (six out of 14) the meta-regression analysis results were confirmed but the data were not shown. Although this meta-analysis is interesting and contains the greatest number of active Cushing's syndrome patients for IMT analysis, there are far fewer patients in the ‘cured’ Cushing's syndrome group, and especially for carotid plaques and FMD analysis. Moreover, there is considerable heterogeneity between studies. One study16 has examined FMD in a small number (n = 14) of Cushing's syndrome patients at least 4 years after ‘cure’ but, unfortunately, there is no pre-treatment data for comparison in the same patients. FMD and measures of arterial stiffness were no different in ‘cured’ patients and controls. IMT and number of carotid plaques were also no different in the ‘cured’ patients. It was stated that metabolic comorbidities at the time of study were ‘well controlled’ although 30% of patients were hypertensive, 20% had dyslipidaemia, and 7% had diabetes. Mean BMI was the same in both patients and controls but was only marginally in the overweight range and certainly not obese. The conclusion was that vascular health, at least 4 years after ‘cure’ of Cushing's syndrome, is similar to that of a healthy control population provided that co-morbidities are well-controlled and, moreover, the effects of previous hypercortisolaemia on the vasculature may be reversible. Although this latter suggestion may well be the case, it is certainly evident from the study16 and the meta-analysis of Lupoli et al15 that detailed attention to the comorbidities of is paramount importance. What of the coronary arteries? A study by Neary et al17 of 15 active Cushing's syndrome patients (14 of whom had ectopic Cushing's syndrome) revealed a greater number of both calcified and non-calcified coronary artery plaques in the Cushing's syndrome patients using multidetector computerised tomography (MDCT). There were no post-treatment data in the study. However, a study by Barahona et al18 using the same methods, in a sample of 29 patients ‘cured’ of Cushing's syndrome for a mean of 11 years (very wide range), showed that there was a tendency to greater prevalence of coronary calcifications and non-calcified plaques in the patients than the controls. In the whole patient cohort, this was not statistically significant but, in women (n = 24), 42% had an abnormal MDCT vs. 18% for controls (p ≤ 0.05), and, in 10 subjects (9 women) < 45 years old, 30% had non-calcified plaques vs. no plaques in controls (p ≤ 0.01). Of the ‘cured’ women, 29% had hypertension vs. 6% of controls and they also had a significantly higher BMI than controls. Thus, as with carotid atherosclerosis, similar conclusions appear to apply to the coronary arteries: persistence of vascular disease despite ‘cure’ and persistence of two other major risk factors namely hypertension and obesity. No review of atherosclerosis is complete without a brief mention of changes in metabolic risk factors for atherosclerosis after ‘cure’ of Cushing's syndrome. In the study from Naples conducted 5 years after ‘cure’,13 WHR, glucose stimulated glucose and insulin levels, and fibrinogen were all higher and high-density lipoprotein-cholesterol levels lower than in BMI-matched controls. Another study of 58 Cushing's syndrome patients after 5 years in remission revealed significantly higher waist circumference, WHR, and percentage of truncal fat as measured by dual-energy X-ray absorptiometry scanning than BMI-matched controls.19 There was no difference in insulin resistance (Homeostatic Model Assessment for Insulin Resistance) and the only lipid abnormality was a higher triglyceride level,19 although 7% and 12% were diabetic and hypercholesterolaemic,respectively, vs. 0% for controls.19 In the study by Barahona et al,20 total and truncal fat mass was significantly greater 11 years after ‘cure’ than for BMI-matched controls. The aforementioned studies were all cross-sectional studies. Study of the same patients before and 1 year after ‘cure’ (longitudinal study) showed a reduction in the prevalence of impaired glucose tolerance and diabetes, although these measures were still greater than in BMI-matched controls.21 Waist circumference and dyslipidaemia were also higher 1 year post-‘cure’.21 In our own multicentre study,5 10% of 320 patients 10 years after ‘cure’ were still taking antidiabetic medication, although we did not compare this with pre-treatment or with a control population. In a study from New Zealand, Bolland et al22 report that, a mean of 6 years after presumed ‘cure’, the percentage of patients with diabetes (approximately 6%) was the same as at presentation, and so there was no improvement in this cohort in this These studies are of the literature on this with a that, although the metabolic features of Cushing's syndrome not normalise and so to cardiovascular risk as as and diastolic hypertension is to in active Cushing's syndrome and is by as reviewed by et is this by et state that hypertension in approximately 30% of ‘cured’ patients. In the study by Faggiano et 1 year after ‘cure’, both systolic and diastolic blood were similar to that of BMI-matched controls and reduced compared to In the study by et the prevalence of hypertension, although reduced, was still higher than in controls 1 year after ‘cure’, at between of patients. surgical ‘cure’ of Cushing's syndrome, of patients remission or improvement in hypertension 10 of at 1 patients had data were not available for and so it is unclear what the real is at 1 In the study by et of 58 patients 5 years after ‘cure’ were still In our own study,5 10 years after ‘cure’, 50% of 320 patients were for hypertension. In the New the prevalence of hypertension was still 50% 6 years after ‘cure’, from at the time of an improvement but certainly still with atherosclerosis risk markers, although hypertension is improved and, in some the number and of be reduced, there is persistence of hypertension systematic and It is well in that mortality from cardiovascular causes is still that of the general population in ‘cured’ Cushing's syndrome patients. There is no systematic review or meta-analysis of relationship between cardiovascular risk factors and a reduction or in cardiovascular events in these patients. However, the New shows a significant of patients with heart disease and of disease a mean of 6 years after a presumed ‘cure’. the prevalence of these comorbidities despite normalisation of The is likely the persistence of the risk factors although further also There are two studies that have at and incidence of cardiovascular events in long-term follow-up of Cushing's syndrome patients. et reported a fully hypertension, of for myocardial for heart and for years after diagnosis and are not reported but, because the for heart failure and these are statistically et state what of these patients remained ‘cured’ the follow-up In a study from in patients in long-term remission were for for myocardial for heart and for heart failure. The study from that of et in that it is and not myocardial infarction that is Nevertheless, taken the studies increased cardiovascular morbidity despite long-term However, neither study the of hypertension or syndrome to this increased There is no direct evidence to link the changes in cardiac and function described in the first section of this review to cardiovascular morbidity or mortality in Cushing's syndrome. Several and large studies have the of hypertension and diabetes to mortality. be age at diagnosis was the most of excess mortality rate see individual studies). the three was to effect of hypertension or diabetes, despite the last by et later studies than the first two of the especially the early of the first two not report on prevalence of hypertension and diabetes and, even in the study by et there was data on these variables for analysis. the total number of was small and, with so many variables to the likelihood of a relationship be the only evidence to from large or multicentre studies. Some of the results are shown in Table 2 expressed as and the with to the multivariate The factors included in the used for the in these studies are variable and not the same in all (for details, see individual The New shows hypertension as a clearly significant variable and, in two of the three other this is 30 However, the shows no effect of hypertension despite the causes of death in patients with heart disease and infarction the of these despite these patients in The for the difference in the study compared to the other three are not especially of the of patients in were on treatment for hypertension at the time of analysis. diabetes, a similar with three of studies this to be associated with mortality the is an despite of patients in remission treatment for diabetes. It be interesting to the of the large study after a time has because the early study from et examined mortality of In this early post-treatment was the of death and of those had diabetes compared to of the whole patient cohort. prevalence was not increased in those It is well that there are significant long-term changes in the with cortisol excess by A is common in Cushing's syndrome pre-treatment and after ‘cure’ in a of patients. In the population, is a risk for myocardial infarction, although the extent to which is a in cardiovascular mortality in Cushing's syndrome has not been However, in the study by et pre-treatment was a significant risk in one of mortality. The study did not cardiovascular mortality was reported to be associated with increased mortality in a between 1 and years after diagnosis. However, there were only from three of whom were in remission at the time and one was The remission was not in two patients. Although these data are interesting, further study is before that and significantly cardiovascular morbidity and mortality in Cushings disease in the long-term in ‘cured’ patients. as the evidence from large individual it is to that diabetes and hypertension are likely risk factors for long-term cardiovascular morbidity and mortality in Cushing's syndrome. This conclusion has the of for from large studies with of events for analysis. dyslipidaemia and cardiac there are no it remains important to all these comorbidities as one for the general population. In this treatment should be by with in of Cushing's syndrome and, not this at least in with It to be to that the of Cushing's syndrome patients is a It is not to and that this is It is also important to that, although Cushing's syndrome is a chronic disease by an This is of an on the diagnosis and treatment of Cushing's data review and The that they have no of The review for this is available at is not to this as no data were or in this study.