Myocardial bridging is a potential risk factor of very late stent thrombosis of drug eluting stent

Summary

Drug eluting stents have been implanted worldwide and used in nearly 90% of percutaneous coronary interventions in China. Although many randomized trials have confirmed the efficacy and safety profile of drug eluting stents, they were not powered to detect or exclude the effect of drug eluting stents on rare events such as stent thrombosis. Several mechanisms of very late stent thrombosis have been postulated, but are not widely accepted. Virchow’s triad describes the 3 main factors of thrombus formation – stasis of blood flow, endothelial injury and hypercoagulability. Myocardial bridging is a common congenital anomaly. Modern anatomy and angiography regard myocardial bridging as widespread, but its pathophysiological response is always ignored. According to Virchow’s triad, myocardial bridging negatively affect endothelial function, and the turbulent shear stress and intimal trauma predispose the vessel toward thrombus formation. Therefore, we question whether a relationship between myocardial bridging and very late stent thrombosis of drug eluting stents exists. Also, we propose that myocardial bridging might be a potential risk factor of very late stent thrombosis of drug eluting stents; coronary artery bypass grafting might be a promising and novel choice in the treatment of myocardial bridging with severe stenosis in the coronary artery.

Background

Myocardial infarction from atherosclerotic coronary artery disease is a leading cause of mortality and morbidity worldwide. Emergent removal of the obstructive lesions and prevention of coronary artery disease is an imperative, ongoing challenge for scientists and cardiologists.

Percutaneous coronary intervention (PCI) was first introduced in 1977 by Andreas Gruentzig and by the mid-1980s it was promoted as an alternative to coronary artery bypass grafting (CABG). It has been used for over 3 decades and has been subjected to more randomized clinical trials than any other interventional procedure. In early 21^st century, sirolimus- and paclitaxel-coated drug eluting stents (DES) were developed. Its role in the treatment of patients presenting with stable CAD is challenged by advances in medical treatment, referred to as optimal medical therapy, which include intensive lifestyle and pharmacological management. Although DES have mostly replaced bare metal stents (BMS) due to their decreased rates of restenosis and re-intervention rates [1], higher rates of very late stent thrombosis is the significant disadvantages of DES [2,3]. To prevent stent thrombosis in DES, current guidelines recommend up to 1 year of dual anti-platelet therapy [4]. Nevertheless, DESs still have been criticized for events of stent thrombosis occurring anywhere from 1 to 5 years after implantation [5–9]. Especially, many results have been reported on an increased risk of very late stent thrombosis with DES [10,11].

Then, how is stent thrombosis exactly classified? The Academic Research Consortium classifies stent thrombosis into 4 types: acute (within 24 h of stent placement), sub-acute (24 h to 30 days), late (after 30 days), and very late (12 months after stent placement).

Known risk factors for stent thrombosis include premature discontinuation of oral antiplatelet agents, long stents, renal failure, bifurcation lesions, diabetes mellitus, and low ejection fraction [12]. The most important histological risk factor for stent thrombosis is considered as lack of endothelial coverage or delayed arterial healing, and the risk decreases after a year due to nearly complete endothelialization [13]. Increased risk of acute, sub-acute and late stent thrombosis can be explained based on the presence of unhealed endothelium causing activation of platelets and thrombosis [14].

Several mechanisms of very late stent thrombosis have been postulated. Gaddam et al. [15] proposed the cause of very late stent thrombosis to be formation of a de novo atherosclerotic lesion in the proximal segment of a stented artery. Farb et al. [16] reported pathological descriptions and showed that stenting across branch ostia, disruption of adjacent vulnerable plaques, and extensive plaque prolapse could precipitate late stent thrombosis. Cook et al. [17] showed that very late stent thrombosis resulted from delayed hypersensitivity to components of the drug polymer device combination that caused necrotizing vasculitis and late malposition.

All of the above statements are not widely accepted. Is there any other explanation for late stent thrombosis of DES? Virchow’s triad proposes the 3 main causes of thrombosis to be stasis of blood flow, endothelial injury and hypercoagulability [18]. Based on Virchow’s triad, question whether a relationship between myocardial bridging (MB) and very late stent thrombosis of DES exists.

MB is a congenital coronary anomaly defined as the tunneling of a segment of a major epicardial artery that travels intramurally through the myocardium beneath a muscle bridge. The current gold standard for diagnosing MB is coronary angiography with characteristic features of the “milking effect” and a “step down, step up” phenomenon induced by systolic compression of the epicardial coronary vessel. Modern imaging techniques, such as intracoronary ultrasound and Doppler and intracoronary pressure-wires, have contributed significantly to the diagnosis of MB [19].

Why do we question that a relationship between MB and very late stent thrombosis of DES exists? Firstly, it is because modern anatomy and angiography consider MB as widespread. MB’s prevalence has been reported to range between 5.4% and 85% in autopsy series and 0.5–29.4% on coronary angiography [20]. Although it is clinically silent in the majority of cases, approximately 20–30% of patients with cardiac chest pain have a normal coronary angiogram, and in about 5% of these patients an MB can be identified [21]. In other words, MB is common, but its pathophysiological response is always ignored. Secondly, we know that the mechanisms by which MB causes myocardial ischemia include compromised coronary blood flow, endothelial dysfunction, thrombus formation and a strong association with coronary vasospasm [22]. Based on the above 2 points and Virchow’s triad, we propose MB is a potential risk factor of very late stent thrombosis of DES.

Hypothesis

We propose the following hemodynamic and pathological mechanisms by which MB is a potential risk factor of very late stent thrombosis of DES. Firstly, MB can cause compromised coronary blood flow, which leads to acceleration of distal blood flow and stasis of proximal blood flow. The stasis of blood flow can be considered as potential risk factor for stent thrombus formation. Secondly, we propose that the “milking effect” of MB segments causes increased shear stress [23] and the increased shear stress and high intravascular pressure in MB may appear to negatively affect endothelial function [24,25]. Furthermore, thrombus formation in MB segments has been reported in patients with myocardial bridging-related cardiac events. These reports suggest that turbulent shear stress and intimal trauma predispose the vessel toward thrombus formation [26]. Increased shear stress associated with MB also appears to reduce the production of vasoactive agents such as endothelial nitric oxide synthase, endothelin-1 and angiotensin-converting enzyme within the bridging segment. According to Virchow’s triad, MB negatively affects endothelial function, and the turbulent shear stress and intimal trauma predispose the vessel toward thrombus formation. In summarize, the presence of MB distal to coronary lesions should be seriously considered in preprocedural evaluation of the lesions as a potential risk factor for intracoronary thrombus formation.

Which kind of treatment is most suitable for coronary heart disease patients with MB? Generally, medication, especially with beta-blockers or calcium channel blockers, is recommended as a first-line strategy for symptomatic patients with MB [27]. Although some patients are responsive to medical therapy, the changes from aging, weight and internal environment and increase of cardiac load, may still upset the balance between myocardial oxygen supply and oxygen consumption, resulting in myocardial ischemia. When medical management fails to yield results in severely symptomatic patients, intracoronary stenting and surgical interventions such as myotomy and CABG will be adopted.

However, stenting is not recommended in myocardial bridging (MB) due to the high rate of thrombosis and restenosis [28–30]. If the patient with severe stenosis in coronary artery and long segment muscle bridge receives stenting therapy, the risk of very late stent thrombosis of DES will significantly increase. Taken together, we propose that CABG or myotomy maybe a better choice to target the lesion with MB than DES implanting.

Pratt et al. [31] reported 2 cases of symptomatic MB refractory to medical management that were treated by minimally invasive CABG without cardiopulmonary bypass, and concluded that minimally invasive coronary artery bypass techniques are appropriate alternatives to muscle bridge division, or aortocoronary grafting with cardiopulmonary bypass for the management of symptomatic MB. WU Qing-yu et al. [32] reported on 31 consecutive patients with MB who underwent surgical treatment, all patients survived and recovered uneventfully. Postoperative exercise testing in all patients failed to reveal any persistent ischemia. After 3–115 months (mean 31 months) follow-up time, angiographic studies in 21 patients (68%) demonstrated restoration of coronary blood flow and myocardial perfusion without significant residual compression of the artery, and all patients were symptom-free and currently in NYHA class I–II. They concluded that patients who were refractory to medication would actively undergo surgical procedures such as myotomy and CABG.

Overall, we propose that MB of DES is a cause of very late stent thrombosis. CABG might be a promising and novel choice in the treatment of MB with severe stenosis in the coronary artery. MB can cause unstable blood flow and increase the shear stress, which is considered as a potential risk factor for very late stent thrombus formation. More epidemiological investigation is needed to determine the incidence of MB in coronary heart disease patients with very late stent thrombosis. More laboratory and clinical studies are critically needed to determine dynamics changes in patients with MB, such as blood flow resistance and shear stress in the coronary. The question of how to choose the optimal treatment for coronary heart disease patients with MB needs further investigation.

Conclusions

Since MB of DES is a cause of very late stent thrombosis, CABG maybe a better choice than DES implanting to target the lesion with MB.