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Does Underlying Plaque Morphology Play a Role in Vessel Healing After Drug-Eluting Stent Implantation?^_*

Aloke V. Finn, MD, Gaku Nakazawa, MD, Elena Ladich, MD, Frank D. Kolodgie, PhD, Renu Virmani, MD, FACC^,_*

Emory University School of Medicine, Atlanta, Georgia
CVPath Institute, Inc., Gaithersburg, Maryland.

Key Words: drug-eluting stent • plaque rupture • arterial healing

We know from pathologic studies that there are important differences in plaque morphology in patients presenting with stable versus unstable angina. Plaque rupture is the predominant lesion underlying all cases of acute coronary syndromes (Fig. 1) (5). Plaque rupture is characterized by a necrotic core with an overlying thin-ruptured cap infiltrated by macrophages. Smooth muscle cells within the cap are absent or few (Fig. 1). The thickness of the fibrous cap near the rupture site measures 23 ± 19 µm, with 95% of caps measuring <65 µm. It has been observed that other plaques at nearby sites or remote locations in the coronary tree resemble ruptured plaques but lack a luminal thrombus and have an intact cap. These plaques have been termed TCFA or vulnerable plaques (Fig. 1). These 2 types of lesions differ greatly from the stable plaques or fibroatheromas/fibrocalcific lesions found in patients with stable angina (Fig. 1). The major differences are that fibroatheromas have a thicker fibrous cap (i.e., >100 µm), smaller necrotic core, fewer inflammatory cells, greater percentage of collagen-rich matrix, and are usually calcified. These same characteristic differences were observed by Kubo et al. (4) in the 2 groups of patients studied. There was a significantly greater incidence of plaque rupture, thrombus, lipid-rich plaque, and TCFA in the unstable angina group. Moreover, fibrous cap thickness was significantly less. These findings lend credence to the use of OCT to distinguish plaque morphologies.

View larger version (106K): [in this window] [in a new window] [Download PPT slide]   Figure 1 Representative Histologic Sections From Various Types of Plaque In the left panels, stable lesions have a predominance of fibrous tissue (f) with calcium (Ca2+). In the center panels, thin cap fibroatheromas have a necrotic core (NC) with overlying thin fibrous cap (FC; arrow), whereas in the right panels, ruptured plaques, the fibrous cap (FC) is disrupted (arrow) with superimposed thrombus (Thr).

Strut penetration of the necrotic core with resultant malapposition has important implications for healing. Lipid-rich necrotic cores are more avascular compared with fibrous plaques and have fewer cells. Therefore, these lesions are less likely to be covered by migrating and proliferating cells from adjacent areas (Fig. 2). Thin fibrous caps are either devoid of or are thinly populated with smooth muscle cells and, therefore, areas of injury and stent struts may not be able to be covered. Recently, Cook et al. (6) compared the prevalence of incomplete stent apposition in a series of patients with and without late stent thrombosis after DES placement and found it to be significantly more frequent in the cases of late stent thrombosis (77% vs.12%, p < 0.001). In our own series of human pathologic specimens, late malapposition is associated with the presence of thrombus between stent struts and underlying plaque. We have also found a significantly greater prevalence of incomplete strut apposition to the vessel wall in cases with versus those without thrombus (29% vs. 6%, p = 0.02) (7).

View larger version (137K): [in this window] [in a new window] [Download PPT slide]   Figure 2 Histologic Sections of Stable and Unstable Lesions With DES Stable lesions demonstrate mild neointimal growth with complete stent strut (*) coverage (left panels). Complex lesions demonstrate a severe delay in arterial healing (right panels). Note that struts overlying the necrotic core area demonstrate a lack of endothelial coverage (arrows), whereas those on the opposite side overlying normal medial area are covered by neointima. DES = drug-eluting stent; NC = necrotic core; Thr = thrombus.

These data are concordant with our own pathologic studies in that we also find a greater percentage of uncovered struts at the culprit site in patients receiving DES (i.e., SES and paclitaxel-eluting stents) for complex coronary lesions (i.e., TCFA or rupture) versus those with underlying stable plaque morphologies (47% vs. 23%, p = 0.01) at a mean of 280 days after stent implantation (3). Neointimal thickness was also significantly less and inflammation greater in patients with TCFA/rupture versus those with stable plaques. Because sirolimus and paclitaxel are highly lipophilic, it is likely that these agents have greater affinity for lipid-rich plaques (i.e., necrotic core) and dwell within the necrotic core for longer periods of time because of greater strut penetration as compared with when struts are exposed to more fibrotic types of plaque (8). Greater drug concentrations in these areas might also heavily influence healing by retarding smooth muscle cell proliferation as well as endothelial regrowth. Thrombus burden may also play a role by either increasing or decreasing wall uptake of drug, as shown by Hwang et al. with paclitaxel-eluting stents (9). These data underscore the concept that stents require some degree of neointimal hyperplasia to become endothelialized and that although total abolition of neointima will result in a larger lumen, it is at the expense of increasing risk for late stent thrombosis.

Collectively, these data support the contention that a significantly increased risk of late thrombotic complications should be expected in patients treated with DES for complex lesion morphologies. The fact that none of the 55 patients in the study by Kubo et al. (4) developed stent thrombosis or adverse coronary events is not reassuring, given the extremely small sample size and short duration of the study, as well as coverage by dual-antiplatelet therapy. Although initial pivotal clinical trials demonstrated that SES were safe in patients with unstable angina, these patients still have a greater risk for stent thrombosis than those with stable angina (2). Although not specifically examined in this paper, one might expect that patients presenting with myocardial infarction would be at even greater risk because the underlying lesion morphologies in these patients are often more advanced with luminal thrombus as compared with patients with unstable angina. Although randomized long-term data from patients receiving DES versus bare-metal stents for acute myocardial infarction are lacking, data from retrospective studies and registries supports this conclusion. Sianos et al. (10) published a retrospective study of the effectiveness of DES for ST-segment elevation myocardial infarction demonstrating a 2-year angiographic rate of stent thrombosis of 3.2%, increasing to 8.2% in those with large thrombus burden. More recently, Steg et al. (11), reporting results from a registry of DES versus bare-metal stents for ST-segment elevation myocardial infarction, found a significantly greater rate of death between 180 and 730 days after stent placement for DES versus bare-metal stents (hazard ratio: 6.7, p = 0.002), whereas there was no increased risk in patients treated for nonacute myocardial infarction.

Ultimately, every technology has its limitations, and optimal indications for every technology become apparent only after understanding the limitations. The study by Kubo et al. (4) lends important insights into the role of plaque morphology in vascular healing and suggests significant improvement will have to be made in the existing generation of DES before they can be used safely in patients with complex coronary lesion morphologies.

	Footnotes

 
Dr. Virmani received company-sponsored research support from Medtronic AVE, Abbott Vascular, Conor Medsystems, OrbusNeich, Terumo Corporation, Cordis Corporation, BioSensors International, Prescient Medical, Biotronik, and Alchimedics and has consulted for Medtronic AVE, Abbott Vascular, Prescient Medical, Biotronik, Jerini AG; Vascular Biogenics Ltd., CardioMind, Atrium, Volcano Therapeutics, and nMemoscience GmbH.

^_* Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology.

^_* Reprint requests and correspondence: Dr. Renu Virmani, CVPath Institute, Inc., 19 Firstfield Road, Gaithersburg, Maryland 20878. (Email: rvirmani{at}cvpath.org).

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