Revascularization Versus Medical Therapy in Takayasu's Arteritis Patients with Coronary Artery Involvement

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Takayasu's arteritis (TA) is a rare chronic nonspecific vasculitis that predominantly affects the aorta and its main branches, including pulmonary and coronary arteries [1]. The majority of cases are female, with a relatively young age, usually between 20 and 40 years. The exact mechanism of this disease is still unknown. Due to the lack of specific symptoms, early diagnosis of TA remains a huge challenge for most clinicians. Coronary arterial involvement is not rare in TA and is observed in approximately 10–20% in angiographic imaging [2]. Actually, the incidence of coronary artery disease (CAD) associated with TA is likely to be underestimated, as many patients with TA do not undergo coronary angiography assessment. Among these involved coronary lesions, ostial stenosis of the left main coronary artery and/or right coronary artery are the most common lesions, with a proportion of 87.5% [2]. The optimal therapeutic strategy is a difficult task in TA, especially the monitoring of disease activity. The best treatment option for coronary lesions induced by TA has not been established. The treatment regime to improve the prognosis of CAD patients with TA includes medications (steroid and/or immunosuppressive agents), coronary balloon dilation and stents, as well as coronary artery bypass grafting. It should be emphasized, however, that there is currently no consensus or guidelines regarding the treatment of CAD related to TA. Some case studies have indicated that inflammatory coronary stenosis could be reversible by medical treatment, and we may avoid early intervention revascularization for CAD in TA [3, 4]. For a long time, coronary artery bypass surgery (CABG) has been considered to be the only option available to treat such subjects with TA after failure of medicine. However, with the advances of percutaneous interventional therapy, in addition to coronary balloon angioplasty, percutaneous coronary stenting may be used as an alternative to CABG, however in-stent restenosis is still a major concern in terms of long-term outcomes [5, 6]. Of note, a high restenosis rate does not mean a poor long-term prognosis. There is no unequivocal therapy for coronary arterial lesions for favorable long-term prognosis in CAD patients with TA. In addition, the choice of a patient’s treatment depends not only on the location and severity of the coronary lesions but also on the clinical situation such as the patient’s willingness or economic conditions. There are currently scarce data on the comparison of medical treatment and revascularization in TA patients with coronary involvement. Our hospital is a national center focused on cardiovascular disease, so many patients with severe and unusual cardiovascular diseases are admitted to our center, including TA patients with CAD. Therefore, we believe that analyzing the data of these patients enables providing some valuable clinical treatment recommendations for patients with TA involving coronary lesions. The aims of the present study were to (1) compare the long term outcomes in TA patients involved coronary lesions who received revascularization or medical Therapy, (2) evaluate the results of TA patients involving coronary lesions with open surgery or endovascular intervention.

In the present study, we investigated the long-term results of TA patients with coronary artery involvement with medical treatment or revascularization. We found that there is no significant difference in cardiovascular death between medical treatment and revascularization. Besides, the analysis of subgroup indicated that the mortality caused by cardiovascular disease was also similar in the CABG group and PCI group. But the proportion of restenosis is much higher in the PCI group compared with that of CABG group.

The probable mechanism of coronary artery stenosis caused by TA is the progress of chronic inflammation of the ascending aorta, which causes endothelial cell hyperplasia, contraction of the fibrotic media and adventitia. In the advanced stage, destruction of the elastic fibers in the medial wall can cause dilatation or aneurismal.

Changes [11]. According to previous studies, the prevalence was estimated that 10-20% of all TA patients have coronary artery involvement [2, 8, 12], based on autopsy and clinical diagnosis. In our study, the prevalence of coronary lesions in TA patients was 11.2%. However, not all patients with TA underwent coronary imaging evaluation. Therefore, the incidence of TA with coronary involvement is likely to be underestimated. Kang et al. have recently reported a higher incidence of coronary lesions diagnosed with CT. It is up to 53.2% [13]. It is suggested that more attention should be paid to the TA patients with CAD. Because these patients are at risk of serious complications such as death from myocardial infarction. However, seen from the criteria of the ACR for diagnosing TA, the role of coronary lesions of TA had been ignored.

According to previous reports [2, 8], coronary lesions are divided into three types based on the results of coronary angiography. Type 1 is stenosis or occlusion of the coronary ostia and the proximal segment of the coronary arteries. Type 2 is diffuse or focal coronary arteritis, which can extend to all epicardial branches or may involve focal segments (skip lesions). Type 3 is the presence of coronary artery aneurysms. Type 1 is believed to be the most common lesion, while types 2 and 3 are considered uncommon. In our study, similar to previous studies, type 1 lesions are the most common. The ostial and proximal segments of coronary lesions were involved in 77 patients (85.6%). Of note, type 2 lesions were not uncommon, and 15 subjects (16.7%) had distal segments. This result reminds us that diffuse lesions may also be caused by the TA. Only one patient had coronary aneurysms. The ostia and proximal segments of RCA, LAD, and LMCA were the most common lesions involved (65.6, 57.8, and 47.8%, respectively). Additionally, previous studies had shown that the SYNTAX score was an independent predictor of the prognosis of patients with CAD [14, 15]. However, our results did not support the previous findings. A reasonable explanation for this is that the coronary lesions involved in TA are different from CAD caused by atherosclerotic plaque. Coronary lesions could be inhibited or reversed by controlling the activity of disease with glucocorticoids and (or) immunosuppressants. On the other hand, TA patients with coronary artery involvement may have developed abundant collateral coronary circulation during the long-term chronic ischemia period.

Therapeutic strategies for TA patients with coronary involvement include medications with glucocorticoid and immunosuppressive agents, endovascular intervention, or surgical vascular reconstruction. It must be stressed, however, that there is no consensus on how coronary lesions linked to TA should be treated. Some case studies indicated that inflammatory coronary stenosis could be reversible by medical treatment, and we may avoid early intervention revascularization for coronary lesions in TA [3, 4]. These cases demonstrated that inflammatory coronary stenosis might be reversible or controlled, and we could avoid early invasive revascularization for CAD in patients with TA. There are currently scarce data on the comparison of medical treatment and revascularization in TA patients with coronary involvement, even in a small group of subjects. Our outcomes suggested that the survival was similar between the medical treatment and revascularization groups. Although mortality had no significance, the symptoms related to ischemia were more common in the conservative treatment group, especially in patients without steroids and immunosuppressive agents. Cipriano and colleagues reported that the prognosis of patients with coronary involvement who have received conservative treatment is often poor with a high risk of death caused by cardiac events [16]. However, there were no records on the medications in these patients. Additionally, there was no intervention of revascularization arms. It is hard to evaluate the outcomes of conservative treatments. With the progression of medical treatment of TA patients with coronary lesions, the prognosis of patients has been improved. Univariate analysis suggested that disease activity and heart failure were associated with mortality, but multivariate Cox proportional regression hazard models indicated that heart failure was independently associated with mortality after adjustment for other risk factors. This finding was supported by previous studies [17, 18].

In theory, fixed, irreversible coronary lesions may be amenable by revascularization procedures, with the result of low morbidity and mortality. In terms of outcomes of treatment, the traditional view is that CABG has better long-term results than PCI. Several previous studies have shown that percutaneous transluminal angioplasty with or without stenting has led to unsatisfactory results [19‐21]. With the emergence of a new generation of drug-eluting stents, it is believed that the incidence of restenosis may be significantly reduced. Recently, Wang et al. [6] and Yang et al. [22] reported long-term results regarding the comparison of CABG and PCI. In the first study, a high rate of restenosis was observed following PCI (63.2%), despite the use of new drug-eluting stents (rapamycin in seven cases, zotarolimus in three cases, and paclitaxel in two cases) when compared with CABG (25.0%) at a median follow-up time of 101 months [6]. The second study found that the incidence of MACE was higher in the PCI group than CABG group during the median follow-up of 48 months, especially in those who underwent intervention during disease activity. However, for patients with stable arteritis, the long-term efficacy of PCI is similar to that of CABG [22]. Our subgroup analysis indicated that the survival rate had no significant difference between PCI and CABG, but the MACE (composite events) in the CABG group was significantly lower than that of the PCI group. The difference is mainly due to restenosis after revascularization. The rate of restenosis was 39.3% in the PCI group and 8.7% in the CABG group (P = 0.022), but sometimes we often encounter severe calcification in the aorta in patients with TA. For such patients, PCI could be an alternative treatment strategy for CABG. It was worth noting that there were five patients with uncontrolled disease activity in those with restenosis. This suggests that it is necessary to control the disease activity for prevention of in-stent restenosis, which is in line with previous research [23]. Interestingly, two patients in the PCI group had normal levels of ESR and CRP with prednisone and cyclophosphamide, but in-stent restenosis still occurred repeatedly. This implies that the pathophysiological mechanism of TA involving coronary arteries is more complicated than we thought. We need to explore new biomarkers for monitoring disease activity, and more sensitive, specific, and targeted medical drugs in the future study. Several candidates have been investigated, including serum autoantibodies, interleukins (ILs), vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMPs), pentraxin 3 (PTX3), as well as adipokines [24]. What is more, FDG-PET examination may play an important role in early diagnosis and for monitoring disease activity. The SUV ratio cutoff for determining TA activity was 1.27 with a sensitivity and specificity of 79.3 and 100.0%, respectively [25].

The present study data indicate that there is no significant difference in cardiovascular death between medical treatment and revascularization. Besides, the analysis of subgroup indicated that the mortality caused by cardiovascular disease was also similar in the CABG group and PCI group, but the proportion of restenosis is much higher in the PCI group compared with that of CABG group. Heart failure is an independent predictor of death in these patients. The current challenges we face in treating this condition mainly include a lack of awareness of early diagnosis, delays in diagnosis due to various clinical manifestations, and limited disease activity assessment methods.