The current study reveals that exposure to endogenous GC excess induces a peculiar early remodeling of affected patients’ left and right ventricles, which can persist after CS remission and is independent of traditional cardiometabolic risk factors. Namely, the higher LV and RV ESVi and EDVi observed in patients exposed to GC excess is accompanied by higher LVMi. However, LV and RV ejection fractions are only mildly reduced, suggesting that a morphological impairment anticipates a performance dysfunction. The fact that such alterations occur rapidly in CS and are partially irreversible after remission advocates the use of CMR to improve the management of fatal cardiac complications in this rare endocrine disease.

Several echocardiographic studies have evaluated cardiac structure and function in patients with CS and found LV systolic and diastolic dysfunction [19, 21, 38,39,40,41]. Albeit cardiac echocardiography is more practical in everyday clinical practice, CMR allows an evaluation of ventricular mass and volumes free of cardiac geometric assumption, ensuring a higher accuracy and reproducibility [29, 42].

Few controlled studies evaluating small cohorts have analyzed patients with CS using CMR [18, 26,27,28]. Kamenicky and coworkers compared 18 patients with active CS with 18 controls matched for age, sex, and BMI and found that patients had lower LV, RV, and left atrium ejection fractions, along with increased left and right ESVi and end-diastolic LV segmental thickness. Of note, successful treatment of CS was associated with an improvement in ventricular and atrial systolic performance [18]. A later study from the same group evaluated 23 patients with active CS and compared them with 27 controls matched for age, sex, and BMI, reporting increased left ventricular wall thickness, and reduced ventricular stroke volumes in patients [28]. A CMR study comparing CS patients with age and sex-matched controls showed that patients with active disease had higher LVMi than controls, as opposed to those in disease remission [27]. In all the studies mentioned above, patients and controls significantly differed in cardiovascular risk factors, with a worse cardiovascular profile in patients than controls. Conversely, our cohorts were largely homogeneous, without any significant difference between patients with CS and NFAI in glycometabolic profile, except for a surprisingly marginally lower fasting glucose levels in CS than in NFAI. This is likely because CS patients were either cured or drug-treated, and NFAI were comparable in terms of BMI and known CV risk factors.

As a result, the two groups did not significantly differ either in systolic and diastolic blood pressure levels or in the overall prevalence of cardiometabolic complications or the drugs prescribed to treat them. Nevertheless, our results confirmed the CMR findings of previous studies regarding higher cardiac volumes and mass and lower ejection fractions in patients with CS than in NFAI, advocating a direct effect of GC excess exposure in cardiac impairment beyond the known cardiovascular risk factors. Moreover, the results of the current study highlight the importance of a biventricular evaluation in this context, as opposed to most 2D-echocardiographic studies. Ultrasound measurement of RV volumes is challenging; therefore, most CS echocardiographic studies have mainly focused on the LV [19, 21, 38,39,40,41], whereas CMR studies suggest an impairment in both left and right ventricles. The RV is anatomically and functionally different from the LV. In the absence of clear alterations in pulmonary resistance, our findings suggest RV involvement is a direct effect of GC excess on cardiomyocytes, whose receptors are equally expressed in left and right ventricles in donor hearts and dilated cardiomyopathy [43].

Cardiac morphological alterations in our cohort were not related to increased myocardial fibrosis, as we did not find any difference between patients and controls in T1 mapping evaluation, probably also due to the superimposable cardiometabolic profile of the two study groups. Albeit patients had non-significantly higher postcontrast T1 values, none had ECV values compatible with fibrosis. Similarly, Roux and coworkers evaluated 10 patients with active CD matched with 10 hypertensive and 10 healthy controls and performed a CMR study using the T1 mapping technique and found increased native myocardial T1 in CD, independently from hypertension, without differences in myocardial partition coefficient (λ) between groups. These results support the hypothesis of a potential role of T1 mapping in identifying early biomarkers of subclinical myocardial fibrosis in this disease [26].

Even though we didn’t find any significant correlation between indicators of hypercortisolism severity (UFC x ULN, disease duration) and CMR parameters, the independency of cardiac alterations from traditional cardiometabolic risk factors, claims a direct role of hypercortisolism on cardiac impairment, acting as a fingerprint of GC excess exposure. Our data point toward a persistent toxic effect on the heart, mediated directly through GC and/or mineralocorticoid receptors [2, 11, 44], that produces changes in cardiac structure that are clinically silent but long-lasting, as if the heart retained a memory of GC excess exposure. The mineralocorticoid pathway increases collagen secretion by activating fibroblasts [45]. In addition, stimulating mineralocorticoid receptors decreases myocyte contractility and stimulates mitosis, resulting in myocardial hypertrophy and dysfunction [46]. However, previous data on mineralocorticoid antagonism in GC-induced hypertension did not prove convincing [47], disclosing the need for direct control of GC receptors (for example, via selective GC receptor antagonists such as relacorilant). Indeed, there is evidence supporting the role of GCs in driving alterations in vasoactive substances, thus impacting the balance between vasoconstriction and vasodilation (including catecholamines, nitric oxide, and atrial natriuretic peptide), as well as the activation of the renin-angiotensin system, leading to cardiac hypercontractility [11, 48].

The present study has shown more structural rather than functional changes at CMR in CS patients without evidence of fibrosis, thus suggesting the latter probably as a late phenomenon.

Additive to the direct role of cortisol, almost 60% of our patients presented hypertension, which could have contributed to the development of cardiac impairment. Similarly, the impact of other CS-related cardiovascular risk factors, such as visceral obesity, glucose intolerance and dyslipidemia, cannot be entirely ruled out.

Finally, our study showed for the first time that sex might affect cardiac morphological changes induced by GC excess. Male CS patients exhibited higher IVS thickness compared to females after adjusting for population age and sex reference ranges, independently from the prevalence of hypertension, supporting sex-related differences as observed in other cardiovascular diseases [49, 50]. Recently, a study by Wolf et al. showed that male sex was an independent predictor of increased epicardial and pericardial fat [28], which may play a role in the pathogenesis of CS cardiomyopathy. However, among CS patients, we did not find any differences in the prevalence of male and female hypogonadism (50% vs 42%, p = 1.000). Still, we can not exclude that estrogen exposure could have protected GC-related cardiomyopathy [51].

Very few studies have evaluated cardiac structure and function in CS using CMR, and this is a strength of the current study. However, it does have some limitations. The cross-sectional design and the lack of sample size in such a small and heterogeneous study population with different etiologies of endogenous CS, including both cured and well-controlled patients, might have underestimated the cardiac impairment. Anyway, considering that CS is a rare disease, we opted for a study design closer to a CS clinic’s real-life setting; this aspect represents a strength of this study. Nevertheless, according to the published evidence, as well as to our results, it is likely that cardiac dysfunction might persist in CS even after disease remission. Indeed, although our CS patients had higher biventricular volumes, the subgroup comparison between surgically cured and drug-treated patients revealed no differences in cardiac morphology or biochemical or cardiometabolic complications prevalence, althoghut the lack of standardization of the evaluation period. A previous paper found a significantly higher LVMi in active patients than in remission [27]. Anyway, longitudinal studies (baseline versus post-treatment) with larger population are needed to better clarify the reversibility of cardiac changes after treatment.

We propose a novel approach to cardiac disease in CS, going beyond the traditional cardiometabolic risk factors and evaluating both ventricles, preferably with CMR. Moreover, the present study highlights the importance of a sex-oriented approach in the management of CS complications, taking into account the sex-related differences in cardiac damage of these patients, for whom cardiac complications still represent the major cause of death, very often occurring during remission [2].