The heart has its own vascular system, which includes a network of coronary arteries to enable blood circulation within the organ. At the base of the aorta, vessels branch off forming two main coronary arteries; the right and the left, further diverging to the left circumflex and the left anterior descending artery, for coronary circulation (Fig 1). A common cause of coronary artery disease is the obstruction of these vessels, resulting in angina, heart failure, heart attacks and heart disease.

Blocks usually arise from plaque deposition in the arterial wall, driven by high plasma concentrations of cholesterol, to create atherosclerotic lesions that restrict blood flow and oxygen to the heart muscle; called ischemia¹. The process of atherogenesis is beyond the mere accumulation of lipids, as it presents a series of responses characteristic to inflammatory disease (Fig 2)². Repeated episodes of ischemia are a potential source of the inflammatory stimulus¹, and the so-called inflammatory hypothesis is now a targeted, therapeutic area in clinical cardiology³. However, coronary artery disease (CAD) could become chronic (arteries narrowing over time) or acute (resulting from a sudden rupture of plaque), necessitating stent-based clinical intervention, to unblock arteries and regulate normal blood flow.      

Intravascular Stents

In September 1977, the first percutaneous coronary intervention (PCI) was performed using a balloon angioplasty catheter, mounted on a fixed wire, prior to the development of a stent. Occlusion (blocking) or re-stenosis (re-narrowing) of arteries post-procedure, led to further development of an intravascular, permanent mechanical support i.e. a stent, trialed in vivo in 1987⁵. A stent forms a tiny wire mesh tube designed to remain permanently implanted at the intended site. Briefly, a guide-wire (usually inserted via the femoral artery approach), positions a balloon catheter to first crush the plaque at arterial site, and then assist expansion of the stent against the wall of the artery, to provide permanent mechanical support (video 1).

Although bare metal stents (BMS) prevented abrupt occlusion/recoil for reproducible clinical outcomes, the challenge of in-stent restenosis (re-narrowing artery wall after stent implantation) remained⁶. Drug eluting stents (DES) introduced at the beginning of this century⁷, primarily addressed in-stent restenosis, allowing PCI to become one of the most frequently performed therapeutic interventions in medicine⁶. Technological advancements of coronary stents have progressively revolutionized the treatment of ischemic heart disease over the past 40 years⁶.

Drug Eluting Stent Mechanisms

The artery is expected to undergo a process similar to wound healing after stent implantation, characterized by inflammation, cell proliferation and remodeling⁸. Contradictory complications arise due to many reasons, for one, when the stent is perceived as foreign, an adverse physiological response is triggered instead⁹. The incompatibility is characterized by blood clotting and activation of smooth muscle cells (SMCs) that proliferate/migrate to the site to form neointimal hyperplasia (NIH), also known as restenosis (Fig 3). 

In the mechanism of action with drug eluting stents (DES) an antiproliferative drug is released post-stent implantation to prevent restenosis. Structurally, DES is composed of a metallic stent backbone, and a drug carrier in the form of stent polymer coating that releases antiproliferative drugs (blue dots, Video 2).

First-Generation Stent Concerns:

In 2006, the safety of first generation drug eluting stents (Gen1-DES) were a cause for concern, due to increased rates of very late stent thrombosis observed, compared with bare metal stents (BMS)¹⁰. Usually after stent implantation, a natural healing response is expected, characterized by endothelial cell formation, while patients are maintained on a regime of anticoagulation therapy for a prescribed period of time, to prevent adverse clotting¹⁰. But Gen1-DES, in its overall role, inhibited the physiological vessel healing process as well, leaving struts in direct contact with blood flow. A permanently unhealed vessel wall surface caused further complications over time due to coagulation. As a result, long-term (~12 months) dual antiplatelet therapy (DAPT) was implemented after DES implantation¹¹. 

First-generation BMS were mainly limited by restenosis, addressed by first-generation DES, although the latter were limited by late stent thrombosis due to a delayed healing response (Fig 4)^12,13. New generation DES developed since, have addressed this issue meaningfully to improve the safety and efficacy of DES therapy⁶.

New Generation Drug Eluting Metallic Stent Technology: 

New generation DES have backbones made of novel metallic alloys including cobalt-chromium and platinum chromium, with thinner struts that favor healing at the site of implantation^6,13. Additionally, new DES technologies consist of novel polymeric materials, for controlled release of antiproliferative drugs at the site⁶. Polymer coatings are redundant after drug release¹⁴. New generation DES technologies are therefore composed of biocompatible or biodegradable polymer coatings that dissolve after drug release completion⁶. Another approach eliminates the polymer coating entirely, forming polymer-free DES to release antiproliferative drugs directly from the stent surface (Fig 5)¹⁵.

New generation DES dispense the drug sirolimus or its analogues (biolimus, everolimus, zotarolimus, and novolimus) as stent-bound antiproliferative agents. The new-DES currently approved and investigated in large-scale clinical trials are listed (Table 1)⁶.

Table 1: New generation DES with improved polymer characteristics to function as drug carriers. Table from reference 6.

Clinical Efficacy:

Markers of clinical efficacy post-stent implantation are 1) the absence of in-stent restenosis and 2) the absence of repeated revascularization^6,16. The new DES were accordingly associated with lowest risk for revascularization and percent stent thrombosis¹⁶.  First generation DES problems were also resolved, as evidenced with large-scale clinical trials at 6-year follow-up in 2016¹⁷, alongside studies to re-optimize DAPT duration⁶.

The Future of DES

In the present timeline, metallic DES have an optimized profile of safety for patients undergoing PCI, with room for improvement⁶. The metallic stent backbone that remains after controlled drug elution, could be engineered to disappear fully over time, as it becomes obsolete when the artery repairs and result in a potential nidus for adverse events. First generation bioresorbable coronary stents have already been developed¹⁸, with ongoing improvements and alterations. An in-depth review of bioresorbable stents and scaffolds deserve a separate post¹⁹. The field of PCI is evolving to facilitate safe and optimized treatment for patients with coronary artery disease. 

Poster Image: Coronary arteries via the Interactive Cardiovascular Library.

References:

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