Effects of rosuvastatin treatment on coronary artery ectasia in different patient age groups

Background: This study investigated the relationship between coronary artery ectasia (CAE) and serum levels of high-sensitivity C-reactive protein (Hs-CRP) to test our hypothesis that patient age is associated with the efficacy of anti-inflammatory therapy in CAE. Method: We conducted a prospective analysis of 217 patients with CAE treated at the Department of Cardiology, Shanghai East Hospital, Shanghai East Hospital (Ji'an Campus), Cardiovascular Medicine of Baoshan People’s Hospital of Yunnan Province, from January 1, 2015, to July 30, 2019. Baseline data of patients, including sex, age, hypertension, hyperlipidemia, and diabetes, were collected from patient medical records. Study participants were grouped by age: CAE-A (age ≤50 years); CAE-B (50 years 70). Results: All CAE patients received oral rosuvastatin therapy (10 mg, QN quaque night) and maintained good follow-up, with a loss rate of 0.0% at the 6-month follow-up. The control group (NC Group, n = 73, with normal coronary arteries) received regular symptom-relieving treatments. Among these four groups, the inflammatory markers were significantly higher in patients with CAE than in the NC Group. The inflammatory markers in the CAE-A group were higher than in the CAE-B group, which were higher than the CAE-C group. Follow-up after 6 months of rosuvastatin therapy showed a significantly greater reduction in Hs-CRP and interleukin-6 levels in the CAE-A group than the CAE-B group, which, again, were higher than the CAE-C group. Conclusions: Anti-inflammatory therapy using rosuvastatin was more effective in younger CAE patients, indicating the need for early statin therapy in CAE patients.

Conventionally, CAE has been considered a variant of coronary atherosclerosis [10]. Recent studies have found that inflammation plays a key role in active defense against various insults. Current consensus indicates that atherosclerosis is an inflammatory disease, although the triggering factors and atherosclerotic processes, including plaque rupture, coronary artery spasm, coronary slow flow, coronary microvascular dysfunction, asymptomatic myocardial ischemia, and restenosis, may be variable. Furthermore, CAE is closely related to myocardial infarction; however, there are currently no standard treatment guidelines specified for CAE. The anti-inflammatory and endothelium-protective effects of rosuvastatin have been proven to improve symptoms in patients with coronary artery disease [11]. However, there is no conclusive evidence of the therapeutic efficacy and optimal timepoint for rosuvastatin therapy in CAE patients from different age groups. We conducted the present study to compare the inflammatory status and therapeutic effects of rosuvastatin in CAE patients of different age groups.

Methods Subjects
We prospectively enrolled 6542 patients who were first diagnosed using coronary angiography at our centers from January 1, 2015 to July 30, 2019. Exclusion criteria included various malignant tumors, and intolerance to statin treatment, patients with dilated segments appearing within or directly associated with coronary bypass grafts, patients who developed a coronary dilation after coronary interventions, patients with a diagnosis of Kawasaki disease, patients with fistulas or coronary artery anomalies, patients with acute or chronic coronary total occlusion [12], or inability to complete a 6month follow-up. Finally, 302 patients were diagnosed with CAE and 85 patients were excluded blood lipids, blood routine, high-sensitivity C-reactive protein (Hs-CRP), and other biochemical indicators ( Table 1). The primary outcome included changes in inflammatory markers. The secondary outcome included levels of inflammation. This study was approved by the medical ethics committee of Shanghai East Hospital, Shanghai East Hospital (Ji'an Campus), and Baoshan People's Hospital of Yunnan Province. According to the results of coronary angiography and patient age, participants were divided into four groups: CAE-A (age ≤ 50 years), CAE-B (50 years < age ≤ 70 years), CAE-C (age > 70 years), and a normal control group (NC Group; age matched) with normal coronary arteries.

Measurement of related indicators
Hypertension is defined as a systolic blood pressure (SBP) ≥ 140 mmHg and/or diastolic blood pressure (DBP) ≥ 90 mmHg; BP was measured three times on the same day without the use of any

Coronary angiography
The Siemens Artis zeego III was used to conduct coronary angiography with a routine radial artery approach. X-ray photography was performed with the injection of a contrast agent. Blood-vessel diameter measurements were performed by skilled coronary intervention doctors. CAE was defined as local or diffuse dilated coronary arteries with a diameter exceeding 1.5-fold of the adjacent normal coronary lumen. The coronary artery images considered indicative of CAE after qualitative comparative analysis by two independent operators were included in this study (Fig. 2).
Pharmacological therapy was withheld at least 24 h before angiography.

Statistical analysis
Statistical analysis was conducted using SPSS19.0 software. Data from continuous variables are presented as means ± standard deviations; non-normally distributed data are presented as medians.
A comparison between two groups was conducted with an independent samples t-test, and qualitative data were evaluated by Fisher's exact test. A comparison of continuous variables between the three groups was performed by one-way ANOVA with post hoc Dunnett's correction. A p-value < 0.05 was considered statistically significant. Logistic regression analysis and stepwise methods were applied to screen the factors showing correlations with CAE, with the entry criteria set at p < 0.05 and rejection criterion at p > 0.1.

Results
The baseline characteristics of the risk factors associated with CAE, including sex (male), hypertension, diabetes, hyperlipidemia, and smoking history, were similar between the total CAE group and normal controls. Laboratory findings such as total cholesterol, LDL-C, Hs-CRP, WBC, and IL-6 were elevated in the total CAE group compared to that in the NC Group (p < 0.05). The levels of total cholesterol, LDL-C, Hs-CRP, and IL-6 were significantly higher in the CAE-A group than in the CAE-B, CAE-C, or NC group (p < 0.05), furthermore the levels of TC, LDL-C, Hs-CRP, and IL-6 in the CAE-B group were higher than in the CAE-C or NC group. Under similar circumstances, the levels of TC, LDL-C, Hs-CRP, and IL-6 in the CAE-C group were higher than in the NC group. There were no statistical differences in sex, hypertension, diabetes, waist circumference, smoking index, triglyceride, glycosylated hemoglobin red blood cell distribution width (RBW), and mean platelet volume among the three different age groups of CAE patients (p > 0.05; Table 1).
Logistic regression analysis was performed to identify the independent risk factors associated with CAE. In stepwise method analysis, covariant factors included hypertension, diabetes mellitus, Hs-CRP, LDL-C, smoking, triglycerides, WBC, and IL-6. Multivariate analysis showed that increased levels of Hs-CRP and IL-6 were independent predictors of CAE (p < 0.05; Table 2).  After the 6-month treatment with rosuvastatin, serum levels of Hs-CRP and IL-6 were differentially reduced in the three CAE age groups (Table 4), supporting the efficacy of rosuvastatin as an antiinflammatory agent. Among the three CAE age groups, the CAE-A (age ≤ 50 years) group showed the highest compliance to rosuvastatin treatment, as evidenced by the most significant reduction in serum levels of Hs-CRP and IL-6. The CAE-A group showed the greatest reduction in serum levels of Hs-CRP and IL-6 followed by the CAE-B group and then the CAE-C group.

Discussion
Dyslipidemia is a well-recognized, major risk factor for atherosclerosis [13,14]. The increased serum lipids, especially LDL-C, will deposit in the arterial wall, and gradually form atherosclerotic plaques, which can consequently block the native artery and cause cardiovascular diseases such as coronary heart disease [15]. Increased inflammation is the core process in all stages of atherosclerosis. With the application and development of many techniques such as anti-inflammatory therapy, antithrombotics, thrombolysis drugs, and catheter treatment in recent decades, the incidence and mortality of atherosclerosis or obstructive vascular diseases have been significantly reduced [16,17].
CAE is a multifactorial disease and the pathogenic mechanism has not yet been fully elucidated. CAE was considered a variation of atherosclerosis, mainly resulting from the thinning and/or destruction of the myocardial membrane. However, the dilatation process may be independent from the atherosclerotic process because it can be found as an isolated lesion in coronary arteries and other vascular systems [18]. It has been found that elevated inflammatory markers, such as plasma IL-6, and plasma soluble adhesion molecules are closely linked to the presence of coronary artery dilation [19][20][21]. Long-term exposure to nitrites, herbicide sprays, acetylcholine inhibitors, cocaine, and smoking can also lead to degeneration of the endometrium of the coronary arteries through oxidative stress-induced inflammation, which can eventually cause CAE [10]. Research on inflammation and CAE has characterized CAE-related inflammation, which includes elevated Hs-CRP and IL-6 levels [22].
Accumulation of excess circulating LDL-C was associated with an overproduction of reactive oxygen species and an increase in pro-inflammatory cytokines in the coronary endothelium, linking elevated cholesterol with cardiovascular inflammation [23].
Rosuvastatin is a selective hydroxy methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor widely used in the field of coronary atherosclerotic heart disease [24]. The liver is the main target organ of rosuvastatin, where it can lower cholesterol levels and increase the number of LDL receptors on the surface of liver cells, thereby improving lipid metabolism by promoting LDL absorption and inhibiting hepatic synthesis of very-low-density lipoprotein (VLDL) [25]. Statin therapy can exert pleiotropic effects in atherosclerotic processes such as regulating inflammatory responses, endothelial function, and thrombus formation based on the reduction in LDL-C levels [26]. Rosuvastatin can also stabilize or reverse atherosclerotic plaque through suppressing MMP expression and protect the vascular endothelium against inflammation [27,28].
There are limited studies focused on the inflammatory status of different age groups of CAE patients.
In this study, the cholesterol, LDL-C, Hs-CRP, and IL-6 levels were significantly higher in the total CAE groups than in the NC Group (Table 1). The total cholesterol and LDL-C levels are important for the risk evaluation of coronary heart disease, which benefits from statin therapy through the reduction of LDL-C, Hs-CRP, and IL-6 [29]. Moreover, comparisons between CAE groups of different ages revealed that the highest serum levels of Hs-CRP and IL-6 were found in younger CAE patients (CAE-A), suggesting that cardiovascular inflammation related to CAE may occur at a comparatively younger age (Table 4). There are some potential explanations for this result. First, younger patients are more likely to be stressed resulting in a more primed or activated inflammatory status [30]. In addition, younger patients responded more strongly to physical and emotional stimulation [31] which can lead to increased levels of inflammatory markers. There are other life factors that can also lead to inflammation, such as cocaine abuse and trauma [8].
Previous retrospective studies have also found that statins could efficiently slow down the growth rate of an abdominal aortic aneurysm compared with controls [32]. In the present study, the efficacy of rosuvastatin in CAE patients among different age groups was investigated and compared. The results of follow-up found that younger patients had a greater reduction in the serum levels of Hs-CRP and IL-6, suggesting that rosuvastatin had a greater anti-inflammatory effect in younger patients (Table 4, Fig. 3, Fig. 4). This may be explained by higher levels of inflammatory markers in younger patients compared to older patients, thus the same dose of rosuvastatin could be more likely to produce a greater anti-inflammatory effect.

Conflict of interest:
Not applicable. The patient screening flow chart.  Comparison of serum IL-6 levels in CAE patients treated with rosuvastatin