This study demonstrated a significant correlation between the E/eʹ ratio and cortisol, age, SBP, eGFR, and usage of SGLT2 inhibitors in patients with DM. It has been reported that the E/eʹ ratio is linearly associated with invasively measured LV filling pressures(11)(3). Therefore, the E/eʹ ratio may serve as a surrogate measure of diastolic function.
The key findings of this study were that cortisol concentrations were significantly higher in the DM group than in the non-DM group, and cortisol levels were independently and positively associated with the E/eʹ ratio in patients with DM. There was no significant correlation between E/eʹ and cortisol concentrations in patients without DM. A previous study reported that DM patients with microangiopathy and macroangiopathy had higher blood cortisol concentrations than DM patients without diabetic complications and non-DM patients.(12). It is conceivable that pathological excess of cortisol, such as that found in Cushing’s syndrome, and mild cortisol excess found in DM plays a critical role in the development of cardiomyopathy.
Glucocorticoid receptors are abundantly expressed in the heart(13)(14). Therefore, cortisol may have direct effects on myocardial tissue. Indeed, in an animal study using several rodent models, glucocorticoids played an important role in the development of cardiac hypertrophy and progression to heart failure(15). Additionally, the mineralocorticoid receptor (MR) is present in cardiac tissue and has high affinity for both mineralocorticoids and glucocorticoids(16). Since glucocorticoids typically circulate at levels 100-fold higher than mineralocorticoids, the MR is likely to be constitutively occupied by glucocorticoids(16). In mineralocorticoid target tissues, the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11 β-HSD2) inactivates cortisol, which protects the MR from binding to glucocorticoids. Unlike other MR target tissues, there is no appreciable dehydrogenase activity in the heart, and glucocorticoids are free to activate the MR(16). Animal studies have shown that activation of the MR induces ventricular remodeling, hypertrophy, and fibrotic changes in the heart(17)(18) Furthermore, high concentrations of glucose stimulate protein kinase C β signaling, which leads to MR stabilization and induction of its transcriptional activities(19). Taken together, cortisol may be involved in the development of diastolic dysfunction via activation of the MR in patients with DM. In this study, multivariate linear regression analysis showed that cortisol was positively correlated with HbA1c and age in the DM group. Patients with poor glycemic control and older patients with diabetes have higher cortisol concentrations, which may lead to the development of LVDD.
The data from this study are consistent with previous reports that the prevalence of LVDD is associated with age, blood pressure, eGFR(20)(21)(22)(23). Recent studies have shown that the SGLT2 inhibitors empagliflozin and canagliflozin significantly reduced cardiovascular-mediated death, overall mortality, and hospitalization for heart failure in patients with type 2 DM (T2DM)(23)(24)(25). Additionally, another study reported that canagliflozin improved LVDD(26), which is consistent with the association between LVDD and SGLT2 inhibitors found in this study. Taken together, these observations suggest that SGLT2 inhibitors may protect against the development of HFpEF, which is characterized by LVDD, in patients with T2DM.
This study had several limitations. First, our study design was cross-sectional, and, therefore, cause-and-effect relationships could not be determined. Second, we did not collect 24-hour urine samples to measure cortisol, and cortisol measurements in blood may have been affected by diurnal fluctuations. Third, the number of study participants was relatively small. Future studies with larger cohorts will be required to validate the correlations that were observed in our study.