Preclinical restenosis models and drug-eluting stents
Still important, still much to learn
Robert S. Schwartz, MD, FACC*, ,*,
Nicolas A. Chronos, MBBS and
Renu Virmani, MD
* Minneapolis Heart Institute
Minnesota Cardiovascular Research Institute, Minneapolis, Minnesota
American Cardiovascular Research Institute, Atlanta, Georgia
Armed Forces Institute of Pathology, Bethesda, Maryland
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Figure 1 Stent-induced arterial injury in patients generates a proportional neointimal response. Panels from left to right indicate that as the internal elastic lamina becomes more severely disrupted by the stent and as the proportion of medial fracture transitions from <30% to >30% (middle and right columns), neointimal growth becomes progressively more severe.
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Figure 2 Diagram illustrating the time course of events leading to neointimal hyperplasia in atherosclerotic human coronary arteries. In the first stage, the atherosclerotic artery is depicted before stent placement. NC = non-cellular region of the plaque. Within the first three days after stent placement, platelets/fibrin and neutrophils accumulate at the stent site. At 14 to 30 days, chronic inflammation develops (macrophages, lymphocytes) and persistent fibrin is visible. Smooth muscle cells also are beginning to appear within the stent. At three months, chronic inflammation remains, and fibrin frequently persists. Proteoglycan and matrix deposition occurs. At 6 to 12 months, there often is persistent, chronic inflammation close to the struts, and endothelialization generally is complete. A neointima rich in smooth muscle cells, with a proteoglycan and collagen matrix, has developed. Adapted from Virmani et al. (136).
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Figure 3 Microscopic computed tomography examination of normal (left) and stented (middle and right) porcine coronary arteries. Massive angiogenesis results in a highly vascular but disorganized array of vessels after the stenting of a normal porcine coronary artery. (Image courtesy Dr. Hyuck Moon Kwon.)
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Figure 4 Actinomycin-D studies in rabbit iliac arteries. These images show excellent neointimal inhibition at 8 µg and 25 µg doses (middle and right columns), respectively, compared with control (left column). Lower rows are higher power views, showing that the 25-µg dose appears cytotoxic with poor healing present.
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Figure 5 Porcinecoronary arteries at 28 days (top) and 90 days (bottom) after actinomycin-D eluting stent placement. The 28-day data show substantial residual fibrin, inadequate vascular healing, but little mature neointima. At 90 days, there is a marked increase in neointimal thickening, greater than control, which occurred over time. The graph at lower right shows neointimal thickness measures for 90-day control and 10-µg datasets. The ACTION trial of actinomycin-D elution was stopped prematurely because of elevated major adverse clinical event rates due in part to abnormally high late loss.
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Figure 6 Photomicrographs of porcine coronary arteries at 28 days after the implantation of Quannum-DS (Quanam Medical Corp., Santa Clara, California) stents. These images show neointimal stimulation by high-dose taxane in these stents. Similar results occurred in the SCORE clinical trial. Low power histomorphometry of mid-stent cross-section shows marked vessel lumen narrowing from neointimal hyperplasia. (B, C, and D) Rampant inflammation at sites of the polymer-drug combination in these vessels is shown. Several areas of granuloma and hemorrhage (B) are present. The inflammation was likely a major cause of the neointimal thickening. (E) Cine-film frame of Quannum stent showing marked in-stent restenosis.
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