Syphilis is a chronic and systemic sexually transmitted disease caused by Treponema pallidum. Clinically, syphilis can be divided into four stages based on disease progression: primary, secondary, latent, and tertiary. As the disease progresses, syphilis not only affects the skin and mucous membranes, but also involves almost all tissues and organs of the body. In particular, at the late stage, syphilis affects the cardiovascular system, that is, cardiovascular syphilis, which can eventually lead to death. Syphilitic coronary artery ostial lesions (SCAOL) are cardiovascular syphilis lesions associated with a high rate of disability and mortality. Therefore, how to improve the long-term survival rate and quality of life in SCAOL patients has been an active area of research in the field.
Currently, there are two major treatments for SCAOL: coronary bypass grafting (CABG), which includes the left internal mammary artery (LIMA) and saphenous vein graft (SVG), and percutaneous coronary intervention (PCI). However, which treatment is more efficient in the treatment of SCAOL has not been clear. The purpose of this study was to compare the efficacy of CABG and PCI in the treatment of SCAOL patients. We also compared LIMA and SVG in terms of efficacy, and compared the efficacy of anti-syphilis vs non-anti-syphilis therapies in the treatment of SCAOL.
2 Materials and methods
2.1 Subject selection
This retrospective study included a total of 60 patients who were admitted to our hospital between October 2015 and October 2019 with SCAOL, including 32 males and 28 females with an average age of 50.2 ± 7.5 years. Patients who met the following criteria were included in this study:
- 1. clinical manifestation as angina pectoris, often with emotional agitation, fatigue, excessive exercise, and mental tension;
- 2. on electrocardiography, a decreased ST segment, inverted T-wave, and ST segment elevation in an aVR lead. Myocardial infarction occurred occasionally;
- 3. hematological examination of syphilis was strongly positive;
- 4. coronary angiography (CAG) revealed severe stenosis of left main artery ostial lesions, and/or severe stenosis of right coronary artery ostial lesions.
Severe stenosis was defined as having a lumen area stenosis rate >50 and/or minimum lumen area of the left main artery <6 mm2, as revealed by intravascular ultrasonography (IVUS) and quantitatively determined by CAG three-dimensional (3D) reconstruction quantitative analysis (Figs. 1 and 2).
All patients were given standard treatment for coronary heart disease: aspirin 0.1 g once a day, tegrilol 90 mg twice a day, and atorvastatin 20 mg before bed. Drugs for underlying diseases such as diabetes and hypertension were continuously administered.
Patients who had one of the following were excluded from this study: history of autoimmune disease, history of other infectious diseases, history of recent acute infectious disease, other cardiovascular disease, or tumor. This report was approved by the Ethics Committee of The First Affiliated Hospital of Xiamen University. Written informed consent was obtained from the patient.
2.2 Data collection
Demographic characteristics including age, gender, and body mass index (BMI) were collected through the hospital's database. Smoking was defined as having more than 10 years of smoking, at least 20 cigarettes/day. Diabetes was defined as having a: fasting blood glucose level ≥7.0 mmol/L or having a blood glucose level ≥11.1 mmol/L 2 h after a meal.
Hyperlipidemia was defined as having a total cholesterol concentration >5.7 mmol/L and/or a low-density cholesterol concentration >3.3 mmol/L.
Syphilis was diagnosed when the results of the toluidine red unheated serological test (TRUST) and the treponema pallidum particle agglutination (TPPA) test were positive.
2.3 Clinical examination
All patients underwent the following examinations: blood tests for hematologic evidence of syphilis, BNP, electrocardiography, and echocardiography before surgery. CAG was performed to identify coronary artery ostial lesions without contraindications. A diagnosis of SCAOL required positive results on a syphilis test (TPPA and TRUST), stenosis of coronary artery ostial lesions (QCA determination of lumen area stenosis rate and/or minimum lumen area of the left main by IVUS). Patients were divided into two treatment groups: the CABG group (n = 32) and the PCI group (n = 28), according to the different treatments. One week after surgery, BNP, left ventricular end-diastolic diameter (LVDd), and ejection fraction (EF) were measured. After 6 months, the coronary stent restenosis rate was determined by QCA and/or IVUS with PCI. Patients with CABG were evaluated with coronary computed tomography angiography (CCTA; QCA determination of lumen area stenosis rate >50% and/or degree of vascular stenosis >50% is defined as restenosis; Fig. 3). We also measured BNP, EF, LVDd, and the incidence of major adverse cardiovascular events (MACEs). The MACES included the recurrence of angina pectoris, heart failure, myocardial infarction, and cardiac death. CABG was performed with two different methods: the left internal mammary artery (LIMA) approach and saphenous vein graft (SVG) approach. After surgery, patients were assigned to one of two groups based on whether they had received anti-syphilis treatment: an anti-syphilis treatment group and a non-anti-syphilis treatment group. The anti-syphilis treatment was standard: an intramuscular injection of benzathine penicillin G (2.4 million units, 3 times/week).
2.4 Statistical analysis
All data were analyzed and processed with SPSS 23.0 statistical software. Statistical significance was determined by chi-square test and t test. P < .05 was considered statistically significant.
3.1 Comparison of demographic and preoperative clinical characteristics between the CABG and PCI groups
There were no significant differences between the CABG and PCI groups in terms of age, gender, history of smoking, diabetes, BMI, hyperlipidemia, mean systolic blood pressure, mean diastolic blood pressure, degree of coronary stenosis (as determined by intravascular ultrasound), BNP, LVDd, and EF (P > .05, Table 1).
3.2 Comparison of clinical characteristics between CABG and PCI groups 1 week after surgery
Measurements of serum BNP levels, LVDd, and EF of all patients obtained 1 week after the operation revealed no significant difference between groups (P > .05, Table 2).
3.3 Comparison of clinical characteristics between CABG and PCI groups 6 months after surgery
The incidence of stent restenosis and bridging restenosis, serum BNP levels, LVDd, EF, and MACEs were determined in all patients at 6 months after surgery. As shown in Table 3, the CABG group had significantly greater improvement in all aforementioned indexes, compared with the PCI group (∗P < .05, Table 3).
We also compared the restenosis rates after LIMA vs SVG in the CABG group. The results showed that the LIMA group had a significantly lower restenosis rate than the SVG group (∗P < .05, Table 4).
3.4 Comparison of restenosis rate between anti-syphilis treatment and non-anti-syphilis treatment at 6 months
The anti-syphilis treatment group had a significantly lower restenosis rate than the non-anti-syphilis treatment group (∗P < .05, Table 5).
4 Discussion and conclusions
There are no reports on the incidence of SCAOL. However, some epidemiological data show that the incidence of syphilis is ∼45 out of 100,000 cases, and that 25% to 35% of cases have lesions extending to the mouth of the coronary artery, resulting in narrowing of the coronary artery mouth. The incidence also varies across geographic areas, with higher incidence observed in areas with more developed economies.[1,2]
The major findings from this study were that:
- 1. CABG-treated SCAOL patients had better short-term outcomes than PCI-treated patients;
- 2. LIMA-treated SCAOL patients had a lower restenosis rate than SVG-treated patients;
- 3. SCAOL patients who received anti-syphilis therapy had better outcomes than patients who did not receive anti-syphilis therapy.
It has been well documented that syphilis spirochetes can enter lymph nodes and other organs through the lymphatic system, causing damage to various systems throughout the body.[6–8] For the cardiovascular system, at the beginning, syphilis spirochetes enter the nutrient vessels of the aortic root from the lymphatic tissue of the mediastinum hilum. Because the ascending aorta is rich in lymphatics and nutrient vessels, syphilis easily causes aortitis, which may affect bilateral coronary artery openings, but is limited to the area 1.5 to 2.0 cm from the openings. These pathological changes result in endarteritis, stenosis, and/or the occlusion of coronary arteries, and lead to severe clinical manifestations,[11,12] which are different from the manifestations of coronary heart disease caused by atherosclerosis. In patients with cardiovascular syphilis, coronary artery stenosis may occur. When syphilis is accompanied by coronary artery opening stenosis, patients are diagnosed with SCAOL, while patients with concurrent coronary artery ostial stenosis are more likely to be diagnosed with coronary atherosclerotic heart disease.[13,14] In this study, all patients were diagnosed with SCAOL rather than traditional coronary artery atherosclerotic heart disease by coronary angiography. This approach was elected because:
- 1. these patients were syphilis-test positive and
- 2. did not have increased stenosis below the coronary artery ostial lesions, which is characteristic of SCAOL.[15,16]
In our study, we compared the efficacy of two therapies, CABG and PCI, in the treatment of SCAOL patients. We found that there were no significant differences in outcomes between these two groups at 1 week after surgery. However, at the 6-month follow-up, patients in the CABG group were found to have better cardiac function, a lower restenosis rate, and fewer MACEs than those in the PCI group.
As mentioned above, SCAOL should be considered distinct from atherosclerotic coronary artery disease, which is a lesion of the aorta rather than a problem of the coronary artery itself. Endarteritis of the aorta leads to endovascular necrosis and the destruction of elastic tissue. Therefore, coronary stent implantation is often ineffective, and the smooth muscle of the aorta is often unable to fully expand after stenting, which increases the risk for restenosis. The aorta has substantial muscle mass, which facilitates stent restenosis. We concluded that CABG-treated SCOAL patients had better prognoses than PCI-treated patients, at least within the 6-month period post-surgery, as reported previously.
CABG may be performed via the LIMA or SVG approach. Because persistent infection of the ascending aorta can lead to proximal anastomotic restenosis, syphilis-induced arteritis does not usually involve the main branch of the aortic arch. Therefore, restenosis often occurs at the proximal anastomosis of the great saphenous vein transplantation, and LIMA is superior to SVG in the treatment of this condition.[20,21] In accordance with the above findings, in the present study, we also compared the efficacy of two CABG treatments, LIMA and SVG, in managing SCAOL. The results showed that LIMA was better than SVG, as evidenced by the significantly lower restenosis rate in the LIMA group, compared with the SVG group. Thus, our observations support the notion that LIMA is more effective than SVG in the treatment of SCAOL patients.
In our study, we also compared outcomes between SCAOL patients who received anti-syphilis treatment and those who did not. We showed that patients in the anti-syphilis treatment group had a significantly lower restenosis rate than those in the non-anti-syphilis treatment group. These findings suggest that anti-syphilis treatment for SCAOL patients is important and can benefit SCAOL patients, at least with respect to the restenosis rate. These findings also confirmed that the diagnosis of SCAOL was correct.
Some limitations of this study should be acknowledged. For example, this study was a single-center retrospective study with a small sample size. Therefore, our findings need to be further corroborated by multi-center randomized double-blind controlled studies that include large cohorts. Also, the follow-up period of this study was short, and thus a long term follow-up will be needed in future studies.
In conclusion, the short-term outcomes observed in our study population demonstrate that CABG is more efficient than PCI in the treatment of SCAOL. LIMA can also significantly reduce the incidence of restenosis, compared with SVG. Finally, anti-syphilis treatment is important for improving prognosis in SCAOL patients.
Data curation: Weihua Li, Qiang Xie.
Formal analysis: Junyu Han, Zhengrong Huang.
Investigation: Wuyang Zheng, Weihua Li.
Supervision: Shuyu Yang.
Writing – original draft: Junyu Han, Wuyang Zheng
Writing – review & editing: Shuyu Yang.
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