Relationship of vascular thrombosis and inflammatory leukocyte infiltration to neointimal growth following porcine coronary artery stent placement

D. Douglas Miller, M. Asad Karim, William D. Edwards, Robert S. Schwartz

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

Background: Superficial and intramural thrombosis are reproducible histopathological features of the porcine coronary oversized stent injury model. Fibrin and its degradation products are chemotactic for mononuclear leukocytes, and promote the proliferation and migration of vascular smooth muscle cells (VSMC) in vitro. The goal of this study was to quantitate the serial histomorphologic evolution of thrombosis, leukocyte infiltration, VSMC proliferation and collagen accumulation following porcine coronary artery stent placement in a porcine model. Methods: Twenty-four normocholesterolemic swine underwent oversized balloon (3.5-4.0 mm) coronary angioplasty and tantalum metal stent placement. Twenty-six different arterial sites were injured, followed by serial sacrifice at day 4 (n = 6), 8 (n = 6), 14 (n = 6), and 28 (n = 6). Quantitative analysis of the neointima was performed using a high resolution video-microscopy interface and a validated histomorphometric software program. Alpha actin-positive VSMC density (per 104 μ2 neointimal area) and collagen-specific picro-sirius red fluorescence (percent of neointima) were quantitated at sites adjacent to and distant from coronary artery stent placement. Results: The percent of total neointimal area occupied by resolving thrombus material was greater at days 4-8 compared to 14-28 days (59-63% vs. 1-2%; P = 0.001). Mononuclear leukocytes were also significantly increased at days 4 and 8 (92 ± 1 and 70 ± 8%) compared to days 14-28 (both 3 ± 3%; P = 0.001), as a percentage of the total neointimal cellularity. Total neointimal cell density did not change (20 ± 10, 12 ± 6.23 ± 7 and 20 ± 3 cells/104 μ2; P-value, NS), despite progressive cross-sectional vascular area stenosis reduction from 7 ± 3% at day 4 to 72 ± 14% at day 28 (P = 0.001). Percent neointimal fibrinoid thrombus content and mononuclear leukocyte cellularity were correlated in this model (R = 0.81; P < 0.001). Peri-stent neointimal collagen staining exceeded that at vascular sites distant from porcine coronary stent placement by 14 days (29 ± 6 vs. 15 ± 3%), and remained greater at 28 days (35 ± 11 vs. 16 ± 12%) (both P < 0.05). Conclusions: Quantitative serial histomorphometry of porcine coronary vascular stent delivery sites demonstrates early (4-8 day) neointimal mononuclear leukocyte infiltration which is histomorphologically and temporally related to intramural fibrinoid thrombosis. Significant vascular stenosis and collagen deposition occurs by 14-28 bays at these vascular injury sites. These data suggest a local interaction between thrombotic and inflammatory elements in porcine coronary neointima following oversized stent injury.

Original languageEnglish (US)
Pages (from-to)145-155
Number of pages11
JournalAtherosclerosis
Volume124
Issue number2
DOIs
StatePublished - Aug 2 1996

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Stents
Blood Vessels
Coronary Vessels
Thrombosis
Leukocytes
Swine
Mononuclear Leukocytes
Growth
Neointima
Collagen
Vascular Smooth Muscle
Smooth Muscle Myocytes
Pathologic Constriction
Cell Count
Tantalum
Fibrin Fibrinogen Degradation Products
Video Microscopy
Vascular System Injuries
Wounds and Injuries
Angioplasty

Keywords

  • Angioplasty
  • Coronary artery disease
  • Fibrin
  • Leukocytes
  • Restenosis
  • Vascular stent

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Relationship of vascular thrombosis and inflammatory leukocyte infiltration to neointimal growth following porcine coronary artery stent placement. / Miller, D. Douglas; Karim, M. Asad; Edwards, William D.; Schwartz, Robert S.

In: Atherosclerosis, Vol. 124, No. 2, 02.08.1996, p. 145-155.

Research output: Contribution to journalArticle

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title = "Relationship of vascular thrombosis and inflammatory leukocyte infiltration to neointimal growth following porcine coronary artery stent placement",
abstract = "Background: Superficial and intramural thrombosis are reproducible histopathological features of the porcine coronary oversized stent injury model. Fibrin and its degradation products are chemotactic for mononuclear leukocytes, and promote the proliferation and migration of vascular smooth muscle cells (VSMC) in vitro. The goal of this study was to quantitate the serial histomorphologic evolution of thrombosis, leukocyte infiltration, VSMC proliferation and collagen accumulation following porcine coronary artery stent placement in a porcine model. Methods: Twenty-four normocholesterolemic swine underwent oversized balloon (3.5-4.0 mm) coronary angioplasty and tantalum metal stent placement. Twenty-six different arterial sites were injured, followed by serial sacrifice at day 4 (n = 6), 8 (n = 6), 14 (n = 6), and 28 (n = 6). Quantitative analysis of the neointima was performed using a high resolution video-microscopy interface and a validated histomorphometric software program. Alpha actin-positive VSMC density (per 104 μ2 neointimal area) and collagen-specific picro-sirius red fluorescence (percent of neointima) were quantitated at sites adjacent to and distant from coronary artery stent placement. Results: The percent of total neointimal area occupied by resolving thrombus material was greater at days 4-8 compared to 14-28 days (59-63{\%} vs. 1-2{\%}; P = 0.001). Mononuclear leukocytes were also significantly increased at days 4 and 8 (92 ± 1 and 70 ± 8{\%}) compared to days 14-28 (both 3 ± 3{\%}; P = 0.001), as a percentage of the total neointimal cellularity. Total neointimal cell density did not change (20 ± 10, 12 ± 6.23 ± 7 and 20 ± 3 cells/104 μ2; P-value, NS), despite progressive cross-sectional vascular area stenosis reduction from 7 ± 3{\%} at day 4 to 72 ± 14{\%} at day 28 (P = 0.001). Percent neointimal fibrinoid thrombus content and mononuclear leukocyte cellularity were correlated in this model (R = 0.81; P < 0.001). Peri-stent neointimal collagen staining exceeded that at vascular sites distant from porcine coronary stent placement by 14 days (29 ± 6 vs. 15 ± 3{\%}), and remained greater at 28 days (35 ± 11 vs. 16 ± 12{\%}) (both P < 0.05). Conclusions: Quantitative serial histomorphometry of porcine coronary vascular stent delivery sites demonstrates early (4-8 day) neointimal mononuclear leukocyte infiltration which is histomorphologically and temporally related to intramural fibrinoid thrombosis. Significant vascular stenosis and collagen deposition occurs by 14-28 bays at these vascular injury sites. These data suggest a local interaction between thrombotic and inflammatory elements in porcine coronary neointima following oversized stent injury.",
keywords = "Angioplasty, Coronary artery disease, Fibrin, Leukocytes, Restenosis, Vascular stent",
author = "Miller, {D. Douglas} and Karim, {M. Asad} and Edwards, {William D.} and Schwartz, {Robert S.}",
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AU - Miller, D. Douglas

AU - Karim, M. Asad

AU - Edwards, William D.

AU - Schwartz, Robert S.

PY - 1996/8/2

Y1 - 1996/8/2

N2 - Background: Superficial and intramural thrombosis are reproducible histopathological features of the porcine coronary oversized stent injury model. Fibrin and its degradation products are chemotactic for mononuclear leukocytes, and promote the proliferation and migration of vascular smooth muscle cells (VSMC) in vitro. The goal of this study was to quantitate the serial histomorphologic evolution of thrombosis, leukocyte infiltration, VSMC proliferation and collagen accumulation following porcine coronary artery stent placement in a porcine model. Methods: Twenty-four normocholesterolemic swine underwent oversized balloon (3.5-4.0 mm) coronary angioplasty and tantalum metal stent placement. Twenty-six different arterial sites were injured, followed by serial sacrifice at day 4 (n = 6), 8 (n = 6), 14 (n = 6), and 28 (n = 6). Quantitative analysis of the neointima was performed using a high resolution video-microscopy interface and a validated histomorphometric software program. Alpha actin-positive VSMC density (per 104 μ2 neointimal area) and collagen-specific picro-sirius red fluorescence (percent of neointima) were quantitated at sites adjacent to and distant from coronary artery stent placement. Results: The percent of total neointimal area occupied by resolving thrombus material was greater at days 4-8 compared to 14-28 days (59-63% vs. 1-2%; P = 0.001). Mononuclear leukocytes were also significantly increased at days 4 and 8 (92 ± 1 and 70 ± 8%) compared to days 14-28 (both 3 ± 3%; P = 0.001), as a percentage of the total neointimal cellularity. Total neointimal cell density did not change (20 ± 10, 12 ± 6.23 ± 7 and 20 ± 3 cells/104 μ2; P-value, NS), despite progressive cross-sectional vascular area stenosis reduction from 7 ± 3% at day 4 to 72 ± 14% at day 28 (P = 0.001). Percent neointimal fibrinoid thrombus content and mononuclear leukocyte cellularity were correlated in this model (R = 0.81; P < 0.001). Peri-stent neointimal collagen staining exceeded that at vascular sites distant from porcine coronary stent placement by 14 days (29 ± 6 vs. 15 ± 3%), and remained greater at 28 days (35 ± 11 vs. 16 ± 12%) (both P < 0.05). Conclusions: Quantitative serial histomorphometry of porcine coronary vascular stent delivery sites demonstrates early (4-8 day) neointimal mononuclear leukocyte infiltration which is histomorphologically and temporally related to intramural fibrinoid thrombosis. Significant vascular stenosis and collagen deposition occurs by 14-28 bays at these vascular injury sites. These data suggest a local interaction between thrombotic and inflammatory elements in porcine coronary neointima following oversized stent injury.

AB - Background: Superficial and intramural thrombosis are reproducible histopathological features of the porcine coronary oversized stent injury model. Fibrin and its degradation products are chemotactic for mononuclear leukocytes, and promote the proliferation and migration of vascular smooth muscle cells (VSMC) in vitro. The goal of this study was to quantitate the serial histomorphologic evolution of thrombosis, leukocyte infiltration, VSMC proliferation and collagen accumulation following porcine coronary artery stent placement in a porcine model. Methods: Twenty-four normocholesterolemic swine underwent oversized balloon (3.5-4.0 mm) coronary angioplasty and tantalum metal stent placement. Twenty-six different arterial sites were injured, followed by serial sacrifice at day 4 (n = 6), 8 (n = 6), 14 (n = 6), and 28 (n = 6). Quantitative analysis of the neointima was performed using a high resolution video-microscopy interface and a validated histomorphometric software program. Alpha actin-positive VSMC density (per 104 μ2 neointimal area) and collagen-specific picro-sirius red fluorescence (percent of neointima) were quantitated at sites adjacent to and distant from coronary artery stent placement. Results: The percent of total neointimal area occupied by resolving thrombus material was greater at days 4-8 compared to 14-28 days (59-63% vs. 1-2%; P = 0.001). Mononuclear leukocytes were also significantly increased at days 4 and 8 (92 ± 1 and 70 ± 8%) compared to days 14-28 (both 3 ± 3%; P = 0.001), as a percentage of the total neointimal cellularity. Total neointimal cell density did not change (20 ± 10, 12 ± 6.23 ± 7 and 20 ± 3 cells/104 μ2; P-value, NS), despite progressive cross-sectional vascular area stenosis reduction from 7 ± 3% at day 4 to 72 ± 14% at day 28 (P = 0.001). Percent neointimal fibrinoid thrombus content and mononuclear leukocyte cellularity were correlated in this model (R = 0.81; P < 0.001). Peri-stent neointimal collagen staining exceeded that at vascular sites distant from porcine coronary stent placement by 14 days (29 ± 6 vs. 15 ± 3%), and remained greater at 28 days (35 ± 11 vs. 16 ± 12%) (both P < 0.05). Conclusions: Quantitative serial histomorphometry of porcine coronary vascular stent delivery sites demonstrates early (4-8 day) neointimal mononuclear leukocyte infiltration which is histomorphologically and temporally related to intramural fibrinoid thrombosis. Significant vascular stenosis and collagen deposition occurs by 14-28 bays at these vascular injury sites. These data suggest a local interaction between thrombotic and inflammatory elements in porcine coronary neointima following oversized stent injury.

KW - Angioplasty

KW - Coronary artery disease

KW - Fibrin

KW - Leukocytes

KW - Restenosis

KW - Vascular stent

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