To the best of our knowledge, this is the first study systematically evaluating the impact of long-term steroid use on cardiac fat deposition in patients with different rheumatic disorders.
The main findings of the study are as follows: (1) Long-term steroid use is associated with increased epicardial and pericardial fat deposition compared to steroid-naïve controls. (2) High-dose steroid therapy (>7.5 mg prednisone equivalent daily) leads to higher amounts of epicardial and pericardial adipose tissue compared to low-dose steroid therapy. (3) Cardiac fat distribution correlates with BMI in steroid treated patients, but not in steroid-naïve controls.
Thus, in awareness that cardiac fat may represent a new risk factor for CAD, patients with rheumatic disorders and long-term steroid therapy should be closely monitored for early prevention of cardiovascular diseases.
Patient population
The mean patient age (54 years) and gender distribution (71 % female) are in line with previously published studies dealing with patients on long-term steroid treatment [18]. As to expect, the steroid group demonstrated more epicardial and pericardial fat than the steroid-naïve control group. Diabetes was present in 10 patients of the steroid group, compared to only one patient in the control (p = 0.01), underscoring the need for glucose-lowering medication in a cumulative dose-dependent manner in those patients [19, 20]. Moreover, the prevalence of arterial hypertension was increased in patients on steroid therapy vs. steroid-naïve controls (33 patients on steroids vs. 23 steroid-naïve controls, p = 0.10). These findings are in line with results from other groups, demonstrating that steroid treatment contributes to development of arterial hypertension [21, 22].
In total 9 patients, all treated with steroids, showed evidence of CAD, which might have several reasons: First, it is known that a high level of cortisol can lead to adverse events including cardiovascular disease mediated by effects which favors arterial hypertension, obesity, diabetes, hypercholesterolemia [23]. Second, it is known that some rheumatic disorders (e.g. rheumatoid arthritis, systemic lupus erythematosus (SLE), ANCA-associated vasculitis) [9], implicate an increased cardiovascular risk profile.
Low-dose steroid group vs. high-dose steroid group
Several studies suggested a dose-dependent interaction between steroids and the prevalence of adverse effects [13, 24]. Our steroid population was divided in a low-dose (<7.5 mg prednisone equivalent daily) and high-dose steroid group (>7.5 mg prednisone equivalent daily), taking steroids for at least 6 months, which is in line with other reports [13, 24]. Consequently, BMI was higher in the high-dose steroid group (28 ± 6 kg/m2) than in the low-dose steroid group (25 ± 5 kg/m2, p = 0.05). Interestingly, patients in the high-dose steroid group showed increased prevalence of arterial hypertension and diabetes compared to the steroid-naïve control group. However, this difference was not statistically significant.
Previous studies demonstrated that cardiac fat volumes gradually increased with the number of metabolic syndrome components [25]. Of note, in our population CAD was more prevalent in the high-dose steroid group (n = 7) compared to the low-dose steroid group (n = 2; p = 0.29). This trend supports the hypothesis that high levels of steroids lead to cardiovascular disease mediated by steroid side effects such as arterial hypertension, obesity, diabetes, or hypercholesterolemia [23, 26–28].
Epicardial and pericardial fat
Steroids are known to cause obesity [23], which is an important component of the metabolic syndrome. Moreover, previous studies could demonstrate that high-dose steroids yield an increase of visceral adipose tissues [29–31].
Epicardial fat surrounds the coronary arteries, and shares embryological origin with abdominal visceral fat, which is known to be an independent cardiovascular risk factor [32]. A frequent discussed mechanism for coronary atherosclerosis are paracrine effects by the close proximity to the coronary arteries and the high content of secreted inflammatory factors in epicardial adipose tissue [33–35].
Patients with high-dose steroid therapy showed significantly more epicardial fat compared to matched steroid-naïve controls. Furthermore, patients on high-dose steroid therapy had significantly increased amounts of epicardial fat compared to patients on low-dose steroid therapy, pointing towards a cumulative dose-dependent effect of steroids on cardiac adipose tissue accumulation. As described above, use of steroids might result in adverse effects, which are similar to the components of the metabolic syndrome. A recent study could show that patients with metabolic syndrome had significantly larger areas of epicardial and pericardial fat in comparison to subjects without metabolic syndrome [3]. In line with these results, our study revealed significantly elevated amounts of epicardial and pericardial adipose tissue in the steroid-treated group compared to steroid-naïve controls. Of note, the results for epicardial fat in our high-dose steroid group 7.2 [4.2–11.1] cm2 are in line with the amounts of epicardial fat in this latter study [3]: 8.4 [3.9–17.5] cm2. Moreover, the amounts of pericardial fat in our high-dose steroid group 18.6 [8.9–38.2] cm2 nicely matches the results of pericardial fat in patients with metabolic syndrome 19.1 [6.2–61.3] cm2, strongly suggesting similar effects of a (high-dose) long-term steroid therapy and the metabolic syndrome on cardiac adipose tissue deposition [3, 12].
Cardiac fat and BMI
In the steroid treated group epicardial and pericardial fat correlated with patients BMI, also see Fig. 3. Looking at patients with high-dose steroid therapy, this holds also true for the correlation of epicardial fat with BMI (p < 0.0001). Moreover, there was a trend for correlation of pericardial fat with BMI in the high-dose steroid group (p = 0.06). In the low-dose steroid group there was also a trend for correlation of epicardial fat and BMI (p = 0.1), whereas pericardial fat correlated with BMI (p < 0.05), suggesting that even in low-dose steroid treated patients weight gain is yielding increased cardiac adipose tissue accumulation.
Dividing steroid treated patients and matched controls in an obese (BMI > 25 kg/m2) and a non-obese group (BMI < 25 kg/m2) [36] revealed, that patients within the steroid group and a BMI > 25 kg/m2 showed significantly more epicardial fat than patients in the steroid group with BMI < 25 kg/m2 (p < 0.0001). Similar results could be found for pericardial fat in the steroid group (p = 0.001). However, no correlation of epicardial or pericardial fat deposition with BMI could be detected in the steroid-naïve control group. These findings confirm another large study measuring epicardial fat thickness by computed tomography in 970 patients. In this study epicardial fat was associated with presence of CAD, as well as CAD severity, but not with BMI, supporting our results [37].
Clinical implications
On the basis of the data presented, it may be safe to assume that patients with rheumatic disorders on long-term steroid therapy suffer from increased cardiac fat deposition compared to steroid-naïve controls. Furthermore, this effect seems to be dose-dependent, resulting in higher amounts of cardiac fat in patients with long-term use of >7.5 mg prednisone equivalent/day. Adding this new additional cardiovascular risk factor to our per se high-risk population for CAD, careful cardiovascular monitoring is mandatory.
Moreover, as stated by the European League Against Rheumatism (EULAR) recommendations on systemic steroid use [38], there should be effort to achieve a maximum of effectiveness with a minimum of toxicity.
Further large, randomized, multi-center studies are needed to clarify if quantification of cardiac fat distribution in long-term steroid treated patients with rheumatic disorders has the potential to serve as a powerful diagnostic tool in detecting patients of additional cardiovascular risk in this per se high-risk population for CAD.
Limitations
The quantification of epicardial and pericardial volumes in a single CMR four-chamber view instead of covering the whole ventricle by volume quantification in every short-axis slice might be susceptible to bias. However, recent reports demonstrated that this approach shows good correlation to the time-consuming Simpson method. This holds true for CMR imaging as well as for CT imaging [3, 12, 16, 39]. Another limitation might be the lack of standardized reference values for epicardial and pericardial fat volumes, which presently restrict a more widespread use in clinical routine. However, our results in the high-dose steroid group are similar to the results reported in patients with metabolic syndrome [3], suggesting a common pathway between high-dose steroid effects (steroid induced fat distribution) and effects in patients with metabolic syndrome. Moreover, there are different confounders, which must be addressed. First, we cannot exclude confounding by indication, since higher doses of steroids might be prescribed to those patients with more severe course of the disease. Second, patients were not paired-matched for arterial hypertension and CAD. Third, it is ambiguous, whether rheumatic disorders themselves might have impact on the distribution of cardiac adipose tissue. Fourth, our control group was not matched for rheumatic disorders, since a potential deprivation of steroids would have been largely unethical. Thus, in some of the results, it might be difficult to differentiate if they are attributable to steroid use only, to disease severity, or a combination of both.