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Postpercutaneous Interventions: Endothelial Repair
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40 Postpercutaneous Interventions: Endothelial Repair Julio Flavio Marchini, Vinicius Esteves, and Pedro A. Lemos INTRODUCTION Evolution of interventional cardiology over the years has brought unquestionable clinical benefits to patients undergoing invasive procedures. Rechanneling of occluded arteries and reestablishment or normal myocardial perfusion in vessels with severe atherosclerotic lesions brings, in addition to symptoms relief, improvement in survival. However, despite all these benefits, percutaneous coronary intervention is directly associated with mechanical endothelial injury. Vascular trauma can result in excessive neointimal hyperplasia (NIH) formation and intra-stent restenosis or even acute stent thrombosis, usually related to severe ischemic events. Therefore, correct understanding of endothelial dysfunction process, as well as its regeneration, caused by the devices used in interventional procedures, is of great relevance both for prevention and for the treatment of adverse cardiac events. Several histopathological studies showed the presence of monocytes and macrophages in atherosclerotic plaque in all stages of atherosclerotic process [1] (Fig. 40.1A). Atherosclerotic plaque may be composed of a varied amount of extracellular accumulation of lipids (lipid nucleus), calcified nuclei, hematoma and thrombosis areas, and necrotic nuclei. Permeating the plaque are macrophages and foam cells, smooth muscle cells (SMC), lymphocytes and mast cells. Capillaries develop on plaque margins. Plaque is delimited by a fibrous layer of smaller or larger thickness, composed mainly of collagen. As a consequence of insufflation at high balloons pressures and apposition of rigid stents structures
Endothelium and Cardiovascular Diseases https://doi.org/10.1016/B978-0-12-812348-5.00040-4
against the vessel wall, there is local vascular lesion with loss of endothelial layer, compression and rupture of atherosclerotic plaque, and lacerations that extend from the internal elastic membrane to the outer layer [2,3]. Platelets and fibrin deposit on nonendothelized surfaces (Fig. 40.1B). There is a local and systemic triggering of inflammatory reactions, leading to cellular response with recruitment of monocytes and macrophages, neutrophils and lymphocytes to arterial wall (Fig. 40.1C and D). The release of cytokines and growth factors stimulates migration and proliferation of muscle cells and fibroblasts, triggering NIH and intra-stent restenosis (Fig. 40.1E).
NEOINTIMA AND REESTENOSIS The granulation phase or cell proliferation phase is characterized by the release of platelet, leukocyte and smooth muscle cell growth factors. Activated platelets express P-selectin and glycoprotein (GP) Ibα. These factors act on SMC themselves, stimulating proliferation and migration of media to intima on days after the injury. Platelet P-selectin binds to P-selectin GP ligand receptors present in circulating leukocytes and a rolling process begins. During rolling, stimulated by cytokines, leukocytes progress to adhesion by binding of Mac-1 (CD11b/CD18) to GPIbα and fibrinogen-GPIIb/IIIa and other receptors. After adhesion, the leukocytes migrate into atheroma due to tropism from cytokines and growth factors mentioned above. Resulting neointima consists of SMC, macrophages and extracellular matrix
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40. POSTPERCUTANEOUS INTERVENTIONS: ENDOTHELIAL REPAIR
composed of hyaluronium, fibronectin, osteopontin, and vitronectin. In the medium to long term, there is a remodeling of extracellular matrix with degradation and new synthesis of matrix proteins and impoverishment of cells present in the neointima (Fig. 40.1F).
In addition to NIH growth that may lead to restenosis, the vascular lumen may also “re-narrow” due to a neoatherosclerosis process. Histologically, it is similar to the initial atheromatosis process, but occurs late after NIH [4]. It is characterized by a cluster of macrophages covered by a lipids layer.
Leukocytes infiltration SMC migration and infiltraon
Coronary atheromatosis Mac-1 (CD1-1b/CD18)
Media
Endothelium
CML
(A)
Fibrinogen
Growth factors—FGF, PDGF, IGF, TGF-β, and VEGF
Macrophages
(D) Neointima growth Macrophages recruitment and smooth muscle cells proliferation
Immediately atier stent Loss of endothelium, platelets, and fibrin deposition
Neointima
Platelets/fibrinogen
(B)
(E) Leukocytes recruitment Cytokines release
Reestenotic lesion With time, increase of extracellular matrix and cell impoverishment
PSGL-1
Repaired endothelium
P-Selectina
Macrophages
(C)
Cytokines Neutrophils (MCP-1, IL-6, and IL-8)
(F)
FIG. 40.1 Successive events in restenosis development. (A) Preintervention atherosclerotic coronary lesion. (B) Immediate result after stent implantation with loss of endothelium and platelets and fibrin deposition. (C) and (D) Leukocyte recruitment and infiltration, SMC proliferation and migration in the days following the lesion. (E) Neointimal thickening in weeks after lesion with continued proliferation of CML and monocyte recruitment. (F) In the long term, neointima converts from a cells-rich plaque to an extracellular matrix-rich plate and poor in cells. SMC, smooth muscle cells. Adapted from Welt FG, Rogers C. Inflammation and restenosis in the stent era. Arterioscler Thromb Vasc Biol 2002;22:1769–76.
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These may be covered by necrotic or calcified tissue. This accumulation of macrophages may progress to formation of fibroatheromas and may be observed in the lumen or in deeper neointima layers. Neoatherosclerotic plaque necrotic nucleus contains a cellular debris and occasionally presents hemorrhagic processes with fibrin deposit, in generally with origin of luminal face fissures and ruptures. Furthermore, additional infiltration of macrophages in neointima results in the formation of thin cap atheroma, which often causes breakage of plates located within the stent. Calcifications can also be observed in neointimal, especially in patients undergoing stent implantation with longer evolution. Below we describe the effects of devices intervention on coronary endothelium, from the use of balloons to application of the bioabsorbable housing.
EEL
Media EEL
Intima
Negative remodeling
(A) EEL
EEL
Media
Intima
REPAIR PROCESS Balloon Angioplasty After lesion process of vascular layers by percutaneous coronary intervention, repair process depends fundamentally on the device used. Balloon angioplasty provides modest acute light gain and still suffers from significant negative remodeling (Fig. 40.2A). However, NIH is relatively small, about 0.3–0.4 mm (Fig. 40.2B) [2,5]. The damage is not limited to the balloon contact area, it also extends a few millimeters in both directions. These coronary segments may also have negative remodeling and NIH. The restenosis mechanism involves the activation of endothelial cells, which begin to express cell adhesion molecules like E-selectin and VCAM-17 [6] (vascular cell adhesion molecule). Cytokines, such as MCP-1 (monocyte chemoattractant protein-1) and IL-8, begin to be expressed even hours after intervention. A neutrophilic infiltrate occurs, which starts 30 min later, with a peak at 6 h. The more important this infiltrate, the greater the proliferation of SMC [8]. Neutrophils concentrate mainly in adventitia, which promote collagen synthesis and tissue contraction [7]. The CCR2 receptor blockade (MCP-1) does not alter remodeling process in balloon angioplasty, but a blockade of β2 integrin of CD18 beta subunit, related to neutrophil recruitment, reduces NIH with balloon [9].
Neointimal hyperplasia
(B) FIG. 40.2 Processes that contribute to the reduction of luminal area following angioplasty. (A) Negative remodeling [6] with reduction of area bounded by external elastic lamina. (B) Neointimal hyperplasia, which is an increase of atherosclerotic plaque area added to medium area. Remodeling is defined by the ratio of the area delimited by external elastic lamina (EEL) on the lesion and by EEL area in adjacent healthy tissue. Neointimal hyperplasia is defined by transverse area of plaque plus medias delimited externally by EEL.
The endothelium is reestablished by contiguity and by implantation of progenitor endothelial cells. Local signals such as SDF-1 (stromal cell-derived factor-1) derived from activated platelets recruit endothelial progenitor cells from the bone marrow to vascular lesion sites [10,11]. In general, the endothelium reestablishes in less than 30 days. This repair process may not be completely benign and, depending on local conditions, SDF-1 may also contribute to local inflammation. SDF-1 may contribute to monocyte recruitment. In addition, it has also been observed that progenitor endothelial cells have the ability to differentiate into SMC in the neointima, contributing with exaggerated reparatory response and restenosis.
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ANGIOPLASTY WITH CONVENTIONAL STENT Through its metallic framework, a stent prevents elastic recoil observed with balloon use. Thus, it achieves a higher gain than that obtained after simple balloon angioplasty. In addition, less negative remodeling occurs. However, NIH is much more exuberant than that observed with balloon angioplasty. Consequently, late loss of stent is worse than with the balloon [12], reaching 0.9–1 mm [13]. However, the balance between initial acute gain and late loss is even favorable to use a stent, compared to balloon use. Several factors influence NIH:lesion extension, coronary diameter, presence of calcification and bifurcations, lesion expansion after intervention, presence of residual stenosis, and poor apposition of stent struts. There is an important recruitment of monocytes and macrophages in neointima [14], which can be detected at least within 14 days [15]. Typically, NIH takes place in 6–12 months from stent implantation [16]. Unlike intervention with a balloon, early blocking of CCR2 receptor interferes with monocytes recruitment and reduces NIH [9]. Inflammatory cells contribute directly with NIH by mass effect [17], generation of reactive oxygen species [18], secretion of growth and chemotactic factors [19], and production of enzymes such as metalloproteinases and cathepsin [20]. Enzymatic modulation nitrosilation is capable of reducing the NIH and increase endothelialization [21].
ANGIOPLASTY WITH DRUGELUTING STENT A drug-eluting stent can significantly reduce NIH. Two families of drugs were successful for this role:sirolimus-like agents and paclitaxel. The first binds to the 12 binding protein, FK506, and the formed heterodimer binds to mTOR (mechanistic target of rapamycin) preventing its activation. MTOR is from PI3K-related kinase family that participates in critical steps in cell cycle [22]. The result is the interruption of the cell cycle between G1 and S [23]. It affects SMC, monocytes, and macrophages, reducing inflammation, migration of SMC and collagen synthesis and also reducing MCP-1 and IL6 cytokines expression [24,25]. The other drug is paclitaxel, which binds to beta-tubulin, promoting
formation and stabilization of microtubules. Cell cycle stagnates between G2 and M phases. Like sirolimus, it interferes with migration and proliferation of CML, it also acts on leukocytes reducing inflammation [26]. The pharmacological stents were very successful in reducing the NIH, reaching 0.1 values to 0.3 mm luminal late loss [27]. In addition to inhibiting SMC and leukocytes, they also inhibit endothelial cells and endothelial progenitor cells [28]. Drug-eluting stents may not cover the endothelial layer by prolonged periods exceeding 40 months with stay exposed stems, and this is correlated with late and very late stent thrombosis [29,30]. NIH can take place even with drug-eluting stents. It is associated with suboptimal stent implantation, as underexpansion, fracture, plaque prolapse, or geographic miss [31]. It further increases the risk of restenosis and presence of diabetes, and treatment involves venous graft, restenotic lesions, and bifurcations [32]. Drug-eluting stents consist not only of medication, but also polymer, which allows controlled drug release. Polymer has been associated with hypersensitivity reactions, late and very late stent thrombosis, development of neoatherosclerosis, and reduction of endothelium-mediated vasodilation [33–37]. Again, atherosclerosis occurs late and is known as neoatherosclerosis. It is a process distinct from NIH with histology compatible with development of a new atherosclerotic plaque and, when associated with an acute event, has vulnerable plaque characteristics [4]. Several changes have been implemented in a new generation of stents to mitigate adverse effects seen in the first generation. Stent struts have become thinner, and the polymer layer is biodegradable in some cases. Another innovation is the application of polymer only on the abluminal side, i.e., the stent face in contact with vessel wall. To illustrate the evolution, one can compare first-generation stent cypher strut, which is 140 μm thick and 13.7 μm polymer layer, with a Xience V stent strut, which is 81 μm thick and 7.8 μm polymer layer. In fact, the new generation of drug-eluting stents, compared to first-generation stents, maintained the same performance in reducing the NIH and also showed reduction of noncoated struts [38], decrease in fibrin deposition, lowest score of inflammation, less eosinophilic infiltration and giant cells, and lower hypersensitivity reaction. Associated with a lower prevalence of uncoated struts, less
II. ENDOTHELIAL DYSFUNCTION AND CLINICAL SYNDROMES
REFERENCES
inflammation, and lower fibrin deposition, a lower frequency of late and very late thrombosis was observed [38–40]. However, there was no great difference in the incidence of neoatherosclerosis between different stents generations (cobalt chromium-everolimuseluting stent: 29%, sirolimuseluting stent: 35%, and paclitaxel eluting stent: 19%).
ANGIOPLASTY WITH BIOABSORBABLE SCAFFOLDS The most recent technology for percutaneous coronary intervention consists of bioabsorbable Scaffolds, formed by polymers of poly-L-lactic acid and polyglycolic acid, among others. Within a year, there is a loss of structural strength of the device and within 2 years dissolution of the stent itself takes place until complete resorption after 3 years. In the porcine model, within a month from implant, there is no difference with Xience V implant [41]. From 12 months, one begins to observe positive remodeling, i.e., an increase in the luminal area, which is most important until 18 months and then in a slower pace. Initially, luminal area with Xience V is higher, but with positive remodeling the group with bioabsorbable stent reaches and even surpasses luminal area of the group with drug-eluting stents. Lesion and fibrin deposition scores were similar in both groups, but there was a greater presence of inflammatory cells in the absorb group for up to 36 months. Peak inflammation occurs at 18 months with the intensity of the inflammatory response proportional to stent biodegradation [42]. Two years after implantation, restoration of endothelial function, vasomotion, and late light gain can be observed. Studies are under way to test whether bioabsorbables will reduce the presence of neoatherosclerosis [43].
CONCLUSIONS Interventional cardiology has undergone numerous changes in recent decades, and advances allowed a significant reduction in the incidence of unfavorable clinical outcomes to patients. For many years, in order to reduce complications resulting from percutaneous coronary interventions, it focused first on occlusion and acute vascular
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thrombosis, then on suppression of cell proliferation and NIH. Then, with progressive improvement of the implantable devices, gradual reduction of late and very late thrombosis was achieved. Intravascular image assessment methods, such as ultrasound and especially the optical coherence tomography, allow accurate assessment of lesion and detailed feedback from the interventional procedure. This advance can be of great importance for a better understanding of NIH and neoatherosclerosis development, and consequently in preventing stents failure mechanisms. New studies and strategies such as use of stents with bioresorbable vascular platforms are a reality and can envision treatments that will restore an artery to a healthy condition with its vasomotion preserved without device presence.
References [1] Stary HC, Chandler AB, Dinsmore RE, et al. A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation 1995;92:1355–74. [2] Welt FG, Rogers C. Inflammation and restenosis in the stent era. Arterioscler Thromb Vasc Biol 2002;22:1769–76. [3] Costa MA, Simon DI. Molecular basis of restenosis and drugeluting stents. Circulation 2005;111:2257–73. [4] Park SJ, Kang SJ, Virmani R, et al. In-stent neoatherosclerosis: a final common pathway of late stent failure. J Am Coll Cardiol 2012;59:2051–7. [5] Schwartz RS, Topol EJ, Serruys PW, et al. Artery size, neointima, and remodeling: time for some standards. J Am Coll Cardiol 1998;32:2087–94. [6] Mintz GS, Popma JJ, Pichard AD, et al. Arterial remodeling after coronary angioplasty: a serial intravascular ultrasound study. Circulation 1996;94:35–43. [7] Okamoto E, Couse T, De Leon H, et al. Perivascular inflammation after balloon angioplasty of porcine coronary arteries. Circulation 2001;104:2228–35. [8] Welt FG, Edelman ER, Simon DI, et al. Neutrophil, not macrophage, infiltration precedes neointimal thickening in ballooninjured arteries. Arterioscler Thromb Vasc Biol 2000;20:2553–8. [9] Horvath C, Welt FG, Nedelman M, et al. Targeting CCR2 or CD18 inhibits experimental in-stent restenosis in primates: inhibitory potential depends on type of injury and leukocytes targeted. Circ Res 2002;90:488–94. [10] Asahara T, Murohara T, Sullivan A, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997;275:964–7. [11] Chatterjee M, Gawaz M. Platelet-derived CXCL12 (SDF-1alpha): basic mechanisms and clinical implications. J Thromb Haemost 2013;11:1954–67. [12] Fischman DL, Leon MB, Baim DS, et al. A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. Stent Restenosis Study Investigators. N Engl J Med 1994;331:496–501. [13] Morice MC, Serruys PW, Sousa JE, et al. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med 2002;346:1773–80.
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[14] Rogers C, Welt FG, Karnovsky MJ, et al. Monocyte recruitment and neointimal hyperplasia in rabbits. Coupled inhibitory effects of heparin. Arterioscler Thromb Vasc Biol 1996;16:1312–8. [15] Paolini JF, Kjelsberg MA, Edelman ER, et al. Sustained expression of chemokines monocyte chemoattractant protein-1 and interleukin-8 after stent—but not balloon-induced arterial injury. J Am Coll Cardiol 2000;35:15. [16] Kimura T, Yokoi H, Nakagawa Y, et al. Three-year follow-up after implantation of metallic coronary-artery stents. N Engl J Med 1996;334:561–6. [17] Moreno PR, Bernardi VH, Lopez-Cuellar J, et al. Macrophage infiltration predicts restenosis after coronary intervention in patients with unstable angina. Circulation 1996;94:3098–102. [18] Chen Z, Keaney Jr. JF, Schulz E, et al. Decreased neointimal formation in Nox2-deficient mice reveals a direct role for NADPH oxidase in the response to arterial injury. Proc Natl Acad Sci USA 2004;101:13014–9. [19] Assoian RK, Fleurdelys BE, Stevenson HC, et al. Expression and secretion of type beta transforming growth factor by activated human macrophages. Proc Natl Acad Sci U S A 1987;84:6020–4. [20] Sukhova GK, Shi GP, Simon DI, et al. Expression of the elastolyticcathepsins S and K in human atheroma and regulation of their production in smooth muscle cells. J Clin Invest 1998;102:576–83. [21] Manica A, Marchini JF, Travers R, et al. S-nitrosoglutathione reductase (GSNOR) modulates reendothelialization and vascular repair. Circulation 2011;124:A15820. [22] Schmelzle T, Hall MN. TOR, a central controller of cell growth. Cell 2000;103:253–62. [23] Marx SO, Jayaraman T, Go LO, et al. Rapamycin-FKBP inhibits cell cycle regulators of proliferation in vascular smooth muscle cells. Circ Res 1995;76:412–7. [24] Suzuki T, Kopia G, Hayashi S, et al. Stent-based delivery of sirolimus reduces neointimal formation in a porcine coronary model. Circulation 2001;104:1188–93. [25] Poon M, Marx SO, Gallo R, et al. Rapamycin inhibits vascular smooth muscle cell migration. J Clin Invest 1996;98:2277–83. [26] Zhou X, Li J, Kucik DF. The microtubule cytoskeleton participates in control of beta2 integrin avidity. J Biol Chem 2001;276:44762–9. [27] Saito S, Nakamura S, Fujii K, et al. Mid-term results of everolimuseluting stent in a Japanese population compared with a US randomized cohort: SPIRIT III Japan Registry with harmonization by doing. J Invasive Cardiol 2012;24:444–50. [28] Liu HT, Li F, Wang WY, et al. Rapamycin inhibits re-endothelialization after percutaneous coronary intervention by impeding the proliferation and migration of endothelial cells and inducing apoptosis of endothelial progenitor cells. Tex Heart Inst J 2010;37:194–201. [29] Joner M, Finn AV, Farb A, et al. Pathology of drug-eluting stents in humans: delayed healing and late thrombotic risk. J Am Coll Cardiol 2006;48:193–202.
[30] Nakazawa G, Finn AV, Joner M, et al. Delayed arterial healing and increased late stent thrombosis at culprit sites after drug-eluting stent placement for acute myocardial infarction patients: an autopsy study. Circulation 2008;118:1138–45. [31] Castagna MT, Mintz GS, Leiboff BO, et al. The contribution of “mechanical” problems to in-stent restenosis: an intravascular ultrasonographic analysis of 1090 consecutive in-stent restenosis lesions. Am Heart J 2001;142:970–4. [32] Marchini JF, Manica A, Croce K. Stent thrombosis: understanding and managing a critical problem. Curr Treat Options Cardiovasc Med 2012;14:91–107. [33] Virmani R, Guagliumi G, Farb A, et al. Localized hypersensitivity and late coronary thrombosis secondary to a sirolimus-eluting stent: should we be cautious? Circulation 2004;109:701–5. [34] Maekawa K, Kawamoto K, Fuke S, et al. Images in cardiovascular medicine. Severe endothelial dysfunction after sirolimus-eluting stent implantation. Circulation 2006;113:e850–1. [35] Togni M, Windecker S, Cocchia R, et al. Sirolimus-eluting stents associated with paradoxic coronary vasoconstriction. J Am Coll Cardiol 2005;46:231–6. [36] Hofma SH, van der Giessen WJ, van Dalen BM, et al. Indication of long-term endothelial dysfunction after sirolimus-eluting stent implantation. Eur Heart J 2006;27:166–70. [37] Nakazawa G, Finn AV, Vorpahl M, et al. Coronary responses and differential mechanisms of late stent thrombosis attributed to firstgeneration sirolimus- and paclitaxel-eluting stents. J Am Coll Cardiol 2011;57:390–8. [38] Otsuka F, Vorpahl M, Nakano M, et al. Pathology of secondgeneration everolimus-eluting stents versus first-generation sirolimus-and paclitaxel-eluting stents in humans. Circulation 2014;129:211–23. [39] Palmerini T, Biondi-Zoccai G, Della Riva D, et al. Stent thrombosis with drug-eluting and bare-metal stents: evidence from a comprehensive network meta-analysis. Lancet 2012;379: 1393–402. [40] Raber L, Magro M, Stefanini GG, et al. Very late coronary stent thrombosis of a newer-generation everolimus-eluting stent compared with early-generation drug-eluting stents: a prospective cohort study. Circulation 2012;125:1110–21. [41] Otsuka F, Pacheco E, Perkins LE, et al. Long-term safety of an everolimus-eluting bioresorbable vascular scaffold and the cobalt-chromium XIENCE V stent in a porcine coronary artery model. Circ Cardiovasc Interv 2014;7:330–42. [42] Shive MS, Anderson JM. Biodegradation and biocompatibility of PLA and PLGA microspheres. Adv Drug Deliv Rev 1997;28:5–24. [43] Shibuya M, Cheng Y, Wang Q, et al. TCT-657 Effect of the absorb bioresorbable vascular scaffold (BVS) on features of neoatherosclerosis in familial hypercholesterolemic swine at 1-year followup as assessed by in vivo imaging. J Am Coll Cardiol 2014;64:.
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40 Postpercutaneous Interventions: Endothelial Repair Julio Flavio Marchini, Vinicius Esteves, and Pedro A. Lemos INTRODUCTION Evolution of interventional cardiology over the years has brought unquestionable clinical benefits to patients undergoing invasive procedures. Rechanneling of occluded arteries and reestablishment or normal myocardial perfusion in vessels with severe atherosclerotic lesions brings, in addition to symptoms relief, improvement in survival. However, despite all these benefits, percutaneous coronary intervention is directly associated with mechanical endothelial injury. Vascular trauma can result in excessive neointimal hyperplasia (NIH) formation and intra-stent restenosis or even acute stent thrombosis, usually related to severe ischemic events. Therefore, correct understanding of endothelial dysfunction process, as well as its regeneration, caused by the devices used in interventional procedures, is of great relevance both for prevention and for the treatment of adverse cardiac events. Several histopathological studies showed the presence of monocytes and macrophages in atherosclerotic plaque in all stages of atherosclerotic process [1] (Fig. 40.1A). Atherosclerotic plaque may be composed of a varied amount of extracellular accumulation of lipids (lipid nucleus), calcified nuclei, hematoma and thrombosis areas, and necrotic nuclei. Permeating the plaque are macrophages and foam cells, smooth muscle cells (SMC), lymphocytes and mast cells. Capillaries develop on plaque margins. Plaque is delimited by a fibrous layer of smaller or larger thickness, composed mainly of collagen. As a consequence of insufflation at high balloons pressures and apposition of rigid stents structures
Endothelium and Cardiovascular Diseases https://doi.org/10.1016/B978-0-12-812348-5.00040-4
against the vessel wall, there is local vascular lesion with loss of endothelial layer, compression and rupture of atherosclerotic plaque, and lacerations that extend from the internal elastic membrane to the outer layer [2,3]. Platelets and fibrin deposit on nonendothelized surfaces (Fig. 40.1B). There is a local and systemic triggering of inflammatory reactions, leading to cellular response with recruitment of monocytes and macrophages, neutrophils and lymphocytes to arterial wall (Fig. 40.1C and D). The release of cytokines and growth factors stimulates migration and proliferation of muscle cells and fibroblasts, triggering NIH and intra-stent restenosis (Fig. 40.1E).
NEOINTIMA AND REESTENOSIS The granulation phase or cell proliferation phase is characterized by the release of platelet, leukocyte and smooth muscle cell growth factors. Activated platelets express P-selectin and glycoprotein (GP) Ibα. These factors act on SMC themselves, stimulating proliferation and migration of media to intima on days after the injury. Platelet P-selectin binds to P-selectin GP ligand receptors present in circulating leukocytes and a rolling process begins. During rolling, stimulated by cytokines, leukocytes progress to adhesion by binding of Mac-1 (CD11b/CD18) to GPIbα and fibrinogen-GPIIb/IIIa and other receptors. After adhesion, the leukocytes migrate into atheroma due to tropism from cytokines and growth factors mentioned above. Resulting neointima consists of SMC, macrophages and extracellular matrix
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composed of hyaluronium, fibronectin, osteopontin, and vitronectin. In the medium to long term, there is a remodeling of extracellular matrix with degradation and new synthesis of matrix proteins and impoverishment of cells present in the neointima (Fig. 40.1F).
In addition to NIH growth that may lead to restenosis, the vascular lumen may also “re-narrow” due to a neoatherosclerosis process. Histologically, it is similar to the initial atheromatosis process, but occurs late after NIH [4]. It is characterized by a cluster of macrophages covered by a lipids layer.
Leukocytes infiltration SMC migration and infiltraon
Coronary atheromatosis Mac-1 (CD1-1b/CD18)
Media
Endothelium
CML
(A)
Fibrinogen
Growth factors—FGF, PDGF, IGF, TGF-β, and VEGF
Macrophages
(D) Neointima growth Macrophages recruitment and smooth muscle cells proliferation
Immediately atier stent Loss of endothelium, platelets, and fibrin deposition
Neointima
Platelets/fibrinogen
(B)
(E) Leukocytes recruitment Cytokines release
Reestenotic lesion With time, increase of extracellular matrix and cell impoverishment
PSGL-1
Repaired endothelium
P-Selectina
Macrophages
(C)
Cytokines Neutrophils (MCP-1, IL-6, and IL-8)
(F)
FIG. 40.1 Successive events in restenosis development. (A) Preintervention atherosclerotic coronary lesion. (B) Immediate result after stent implantation with loss of endothelium and platelets and fibrin deposition. (C) and (D) Leukocyte recruitment and infiltration, SMC proliferation and migration in the days following the lesion. (E) Neointimal thickening in weeks after lesion with continued proliferation of CML and monocyte recruitment. (F) In the long term, neointima converts from a cells-rich plaque to an extracellular matrix-rich plate and poor in cells. SMC, smooth muscle cells. Adapted from Welt FG, Rogers C. Inflammation and restenosis in the stent era. Arterioscler Thromb Vasc Biol 2002;22:1769–76.
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REPAIR PROCESS
These may be covered by necrotic or calcified tissue. This accumulation of macrophages may progress to formation of fibroatheromas and may be observed in the lumen or in deeper neointima layers. Neoatherosclerotic plaque necrotic nucleus contains a cellular debris and occasionally presents hemorrhagic processes with fibrin deposit, in generally with origin of luminal face fissures and ruptures. Furthermore, additional infiltration of macrophages in neointima results in the formation of thin cap atheroma, which often causes breakage of plates located within the stent. Calcifications can also be observed in neointimal, especially in patients undergoing stent implantation with longer evolution. Below we describe the effects of devices intervention on coronary endothelium, from the use of balloons to application of the bioabsorbable housing.
EEL
Media EEL
Intima
Negative remodeling
(A) EEL
EEL
Media
Intima
REPAIR PROCESS Balloon Angioplasty After lesion process of vascular layers by percutaneous coronary intervention, repair process depends fundamentally on the device used. Balloon angioplasty provides modest acute light gain and still suffers from significant negative remodeling (Fig. 40.2A). However, NIH is relatively small, about 0.3–0.4 mm (Fig. 40.2B) [2,5]. The damage is not limited to the balloon contact area, it also extends a few millimeters in both directions. These coronary segments may also have negative remodeling and NIH. The restenosis mechanism involves the activation of endothelial cells, which begin to express cell adhesion molecules like E-selectin and VCAM-17 [6] (vascular cell adhesion molecule). Cytokines, such as MCP-1 (monocyte chemoattractant protein-1) and IL-8, begin to be expressed even hours after intervention. A neutrophilic infiltrate occurs, which starts 30 min later, with a peak at 6 h. The more important this infiltrate, the greater the proliferation of SMC [8]. Neutrophils concentrate mainly in adventitia, which promote collagen synthesis and tissue contraction [7]. The CCR2 receptor blockade (MCP-1) does not alter remodeling process in balloon angioplasty, but a blockade of β2 integrin of CD18 beta subunit, related to neutrophil recruitment, reduces NIH with balloon [9].
Neointimal hyperplasia
(B) FIG. 40.2 Processes that contribute to the reduction of luminal area following angioplasty. (A) Negative remodeling [6] with reduction of area bounded by external elastic lamina. (B) Neointimal hyperplasia, which is an increase of atherosclerotic plaque area added to medium area. Remodeling is defined by the ratio of the area delimited by external elastic lamina (EEL) on the lesion and by EEL area in adjacent healthy tissue. Neointimal hyperplasia is defined by transverse area of plaque plus medias delimited externally by EEL.
The endothelium is reestablished by contiguity and by implantation of progenitor endothelial cells. Local signals such as SDF-1 (stromal cell-derived factor-1) derived from activated platelets recruit endothelial progenitor cells from the bone marrow to vascular lesion sites [10,11]. In general, the endothelium reestablishes in less than 30 days. This repair process may not be completely benign and, depending on local conditions, SDF-1 may also contribute to local inflammation. SDF-1 may contribute to monocyte recruitment. In addition, it has also been observed that progenitor endothelial cells have the ability to differentiate into SMC in the neointima, contributing with exaggerated reparatory response and restenosis.
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ANGIOPLASTY WITH CONVENTIONAL STENT Through its metallic framework, a stent prevents elastic recoil observed with balloon use. Thus, it achieves a higher gain than that obtained after simple balloon angioplasty. In addition, less negative remodeling occurs. However, NIH is much more exuberant than that observed with balloon angioplasty. Consequently, late loss of stent is worse than with the balloon [12], reaching 0.9–1 mm [13]. However, the balance between initial acute gain and late loss is even favorable to use a stent, compared to balloon use. Several factors influence NIH:lesion extension, coronary diameter, presence of calcification and bifurcations, lesion expansion after intervention, presence of residual stenosis, and poor apposition of stent struts. There is an important recruitment of monocytes and macrophages in neointima [14], which can be detected at least within 14 days [15]. Typically, NIH takes place in 6–12 months from stent implantation [16]. Unlike intervention with a balloon, early blocking of CCR2 receptor interferes with monocytes recruitment and reduces NIH [9]. Inflammatory cells contribute directly with NIH by mass effect [17], generation of reactive oxygen species [18], secretion of growth and chemotactic factors [19], and production of enzymes such as metalloproteinases and cathepsin [20]. Enzymatic modulation nitrosilation is capable of reducing the NIH and increase endothelialization [21].
ANGIOPLASTY WITH DRUGELUTING STENT A drug-eluting stent can significantly reduce NIH. Two families of drugs were successful for this role:sirolimus-like agents and paclitaxel. The first binds to the 12 binding protein, FK506, and the formed heterodimer binds to mTOR (mechanistic target of rapamycin) preventing its activation. MTOR is from PI3K-related kinase family that participates in critical steps in cell cycle [22]. The result is the interruption of the cell cycle between G1 and S [23]. It affects SMC, monocytes, and macrophages, reducing inflammation, migration of SMC and collagen synthesis and also reducing MCP-1 and IL6 cytokines expression [24,25]. The other drug is paclitaxel, which binds to beta-tubulin, promoting
formation and stabilization of microtubules. Cell cycle stagnates between G2 and M phases. Like sirolimus, it interferes with migration and proliferation of CML, it also acts on leukocytes reducing inflammation [26]. The pharmacological stents were very successful in reducing the NIH, reaching 0.1 values to 0.3 mm luminal late loss [27]. In addition to inhibiting SMC and leukocytes, they also inhibit endothelial cells and endothelial progenitor cells [28]. Drug-eluting stents may not cover the endothelial layer by prolonged periods exceeding 40 months with stay exposed stems, and this is correlated with late and very late stent thrombosis [29,30]. NIH can take place even with drug-eluting stents. It is associated with suboptimal stent implantation, as underexpansion, fracture, plaque prolapse, or geographic miss [31]. It further increases the risk of restenosis and presence of diabetes, and treatment involves venous graft, restenotic lesions, and bifurcations [32]. Drug-eluting stents consist not only of medication, but also polymer, which allows controlled drug release. Polymer has been associated with hypersensitivity reactions, late and very late stent thrombosis, development of neoatherosclerosis, and reduction of endothelium-mediated vasodilation [33–37]. Again, atherosclerosis occurs late and is known as neoatherosclerosis. It is a process distinct from NIH with histology compatible with development of a new atherosclerotic plaque and, when associated with an acute event, has vulnerable plaque characteristics [4]. Several changes have been implemented in a new generation of stents to mitigate adverse effects seen in the first generation. Stent struts have become thinner, and the polymer layer is biodegradable in some cases. Another innovation is the application of polymer only on the abluminal side, i.e., the stent face in contact with vessel wall. To illustrate the evolution, one can compare first-generation stent cypher strut, which is 140 μm thick and 13.7 μm polymer layer, with a Xience V stent strut, which is 81 μm thick and 7.8 μm polymer layer. In fact, the new generation of drug-eluting stents, compared to first-generation stents, maintained the same performance in reducing the NIH and also showed reduction of noncoated struts [38], decrease in fibrin deposition, lowest score of inflammation, less eosinophilic infiltration and giant cells, and lower hypersensitivity reaction. Associated with a lower prevalence of uncoated struts, less
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REFERENCES
inflammation, and lower fibrin deposition, a lower frequency of late and very late thrombosis was observed [38–40]. However, there was no great difference in the incidence of neoatherosclerosis between different stents generations (cobalt chromium-everolimuseluting stent: 29%, sirolimuseluting stent: 35%, and paclitaxel eluting stent: 19%).
ANGIOPLASTY WITH BIOABSORBABLE SCAFFOLDS The most recent technology for percutaneous coronary intervention consists of bioabsorbable Scaffolds, formed by polymers of poly-L-lactic acid and polyglycolic acid, among others. Within a year, there is a loss of structural strength of the device and within 2 years dissolution of the stent itself takes place until complete resorption after 3 years. In the porcine model, within a month from implant, there is no difference with Xience V implant [41]. From 12 months, one begins to observe positive remodeling, i.e., an increase in the luminal area, which is most important until 18 months and then in a slower pace. Initially, luminal area with Xience V is higher, but with positive remodeling the group with bioabsorbable stent reaches and even surpasses luminal area of the group with drug-eluting stents. Lesion and fibrin deposition scores were similar in both groups, but there was a greater presence of inflammatory cells in the absorb group for up to 36 months. Peak inflammation occurs at 18 months with the intensity of the inflammatory response proportional to stent biodegradation [42]. Two years after implantation, restoration of endothelial function, vasomotion, and late light gain can be observed. Studies are under way to test whether bioabsorbables will reduce the presence of neoatherosclerosis [43].
CONCLUSIONS Interventional cardiology has undergone numerous changes in recent decades, and advances allowed a significant reduction in the incidence of unfavorable clinical outcomes to patients. For many years, in order to reduce complications resulting from percutaneous coronary interventions, it focused first on occlusion and acute vascular
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thrombosis, then on suppression of cell proliferation and NIH. Then, with progressive improvement of the implantable devices, gradual reduction of late and very late thrombosis was achieved. Intravascular image assessment methods, such as ultrasound and especially the optical coherence tomography, allow accurate assessment of lesion and detailed feedback from the interventional procedure. This advance can be of great importance for a better understanding of NIH and neoatherosclerosis development, and consequently in preventing stents failure mechanisms. New studies and strategies such as use of stents with bioresorbable vascular platforms are a reality and can envision treatments that will restore an artery to a healthy condition with its vasomotion preserved without device presence.
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