Thrombin promotes arteriogenesis and hemodynamic recovery in a rabbit hindlimb ischemia model Konstantinos Katsanos, MD, Dimitrios Karnabatidis, MD,

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Presentation transcript:

Thrombin promotes arteriogenesis and hemodynamic recovery in a rabbit hindlimb ischemia model Konstantinos Katsanos, MD, Dimitrios Karnabatidis, MD, PhD, Athanasios Diamantopoulos, MD, George C. Kagadis, PhD, Panagiota Ravazoula, MD, PhD, George C. Nikiforidis, PhD, Dimitrios Siablis, MD, PhD, Nikos E. Tsopanoglou, PhD Journal of Vascular Surgery Volume 49, Issue 4, Pages 1000-1012 (April 2009) DOI: 10.1016/j.jvs.2008.11.004 Copyright © 2009 The Society for Vascular Surgery Terms and Conditions

Fig 1 Flowchart of experimental protocol. Seventy-four (n = 74) New Zealand White rabbits underwent bilateral femoral artery surgical excision. On the 20th postsurgical day increasing doses of thrombin or VEGF or bFGF were injected in one ischemic limb per rabbit and an equal volume of normal saline to the contralateral control limbs; ie, groups of ischemic controls. A group of nonoperated subjects (n = 6) was included in the study as an external control group of normal rabbit hindlimbs; ie, group of normal controls. On the 40th postsurgical day imaging and histology was performed as indicated. Journal of Vascular Surgery 2009 49, 1000-1012DOI: (10.1016/j.jvs.2008.11.004) Copyright © 2009 The Society for Vascular Surgery Terms and Conditions

Fig 2 Thrombin promotes arteriogenesis in the rabbit ischemia model. A, Representative quantitative angiography in normal rabbits. (a) DSA of the rabbit hindlimbs. The normal vascular anatomy of the abdominal aorta (1), the internal iliac artery (2), the femoral artery (3), the profunda femoris (4), and the saphenous artery below the knee (5) are shown. Surgical ischemia is invoked bilaterally by excising the femoral artery (3) and ligating all its branches (vessels within the circles). Hemodynamic functional analysis was performed in the indicated region of tissue (area within the rectangular box). (b) Image analysis and vessel enhancement after sequential filtering and computerized postprocessing. (c) Final image after isolation of the large vessels (d > 500 μm), which permits quantitative measurements of the area and the length of the segmented vessels. (d) Skeletonization of segmented large vessels, which is superimposed on the original DSA image. B, Representative quantitative angiography in thrombin-treated ischemic rabbits. (a) Final DSA angiogram 20 days after intramuscular injection of 5000 IU of thrombin in the right hindlimb of the rabbit. Left (L) foot served as the control foot. (b) Corresponding enhanced image after postprocessing. (c) Segmentation of the large vessels. Red circles include the newly developed collateral vessels. (d) Skeletonization of large vessels to permit calculation of total area and length. C, Quantitation of developed collaterals. Total length and area of large collateral vessels were analyzed in the areas of femoral artery excision 20 days after single intramuscular administration of the indicated doses of VEGF or bFGF or thrombin. Results are expressed as mean percentage change of internal control hindlimbs of each study group ± standard error (SE). Each study group included 7-8 rabbits (*P < .05). Journal of Vascular Surgery 2009 49, 1000-1012DOI: (10.1016/j.jvs.2008.11.004) Copyright © 2009 The Society for Vascular Surgery Terms and Conditions

Fig 3 Effects of 15,000 IU-thrombin administration in rabbit ischemia arteriogenic response. A and B, Total length (A) and area (B) of large collateral vessels were quantified within the regions of interest (the femoral artery excision area) in normal nonoperated rabbits (normal, n = 6) or control ischemic hindlimbs of all treatment groups (control limbs, n = 66) or hindlimbs treated with 5000 IU-thrombin (Thr 5000 IU, n = 7) or hindlimbs treated with 15,000 IU-thrombin (Thr 15,000 IU, n = 8) or contralateral control hindlimbs of the 15,000 IU-thrombin treated limbs (15,000 IU controls, n = 8). Results are expressed as mean pixel counts (each pixel is equal to approximately 200 μm) ± SE. *P < .05, ***P < .001. C, Estimation of collateral diameter (the ratio of vessel area to length) in the regions-of-interest (the femoral artery excision area) in normal nonoperated rabbits (normal, n = 6) or hindlimbs treated with 15,000 IU-thrombin (Thr 15,000 IU, n = 8) or contralateral control hindlimbs of the 15,000 IU-thrombin treated limbs (15,000 IU controls, n = 8). Results are expressed as mean pixel counts ± SE. *P < .05. D, Three-dimensional reconstruction of CT angiogram of bilateral hindlimbs on the 40th postsurgical day (posterior view). White asterisks denote the internal iliac arteries from where helical branching collaterals originate (double white arrow). Saphenous arteries reconstitute through collateral blood flow at the level of the knee (dotted white lines). Journal of Vascular Surgery 2009 49, 1000-1012DOI: (10.1016/j.jvs.2008.11.004) Copyright © 2009 The Society for Vascular Surgery Terms and Conditions

Fig 4 Histopathologic analysis. A, Immunolocalization of arterioles. Anti-CD31 staining of histologic sections of ischemic hindlimbs adductor muscle tissue 20 days after treatment with saline (control ischemic hindlimbs) or the indicated doses of VEGF or bFGF or thrombin (Thr). Representative photos are shown (Original magnification ×20; black arrows point to arterioles). B, Count of arterioles per optical field. Stained vessels were counted in the histologic sections of control ischemic hindlimbs (control limbs) or of hindlimbs treated with indicated doses of VEGF, bFGF, and thrombin (Thr) or the contralateral control hindlimbs of the 15,000 IU-thrombin treated limbs (15,000 IU controls). Results are expressed as mean arteriolar count ± SE. *P < .05. C, Hematoxylin-eosin (left image) and positive PGM1 immunostaining (right image) of adductor muscle specimens treated with 15,000 IU thrombin. Note the abundant proliferation and infiltration of nonspecific cells (magnification ×40). Immunoreactions of these cells were positive for PGM1 and PK1 (fibroblast-specific immunomarkers) and also positive for Sm-Actin, Vimentin, and S100 (relating to differentiating monocyte cells of mesenchymal origin, data not shown). Journal of Vascular Surgery 2009 49, 1000-1012DOI: (10.1016/j.jvs.2008.11.004) Copyright © 2009 The Society for Vascular Surgery Terms and Conditions

Fig 5 Cross-sectional CT and MR of 15,000 IU-thrombin treated rabbits. A, Representative axial (left panel) and parasagittal (right panel) maximum intensity projection (MIP) contrast-enhanced CT images of rabbit limbs 20 days after single intramuscular injection of 15,000 IU of thrombin. B, Representative axial MR images pre- (left panel) and postgadolinium injection (right panel) of rabbits 20 days after single intramuscular administration with 15,000 IU of thrombin. Note the higher enhancement and signal intensity of the muscle injected with 15,000 IU thrombin (white arrows). Journal of Vascular Surgery 2009 49, 1000-1012DOI: (10.1016/j.jvs.2008.11.004) Copyright © 2009 The Society for Vascular Surgery Terms and Conditions

Fig 6 Thrombin improves hemodynamic recovery in the rabbit ischemia model. A, Representative dynamic computed tomography of rabbit saphenous arteries 20 days after administration of 5000 IU-thrombin (right limb). Top baseline cross-sectional image at a distal level below-the-knee before infusion of iodinated contrast from a marginal auricular vein. A region-of-interest was set within the intravascular space of the saphenous artery (bright vessels within the red and yellow circles). Intermediate image after contrast infusion and arrival of contrast shows peak enhancement of the arteries. The bright enhancement within the arteries corresponds to the circulating blood volume. Bottom final image after digital subtraction of the above. B, Perfusion analysis of dynamic-CT study. Peak vessel enhancement (left panel) and the corresponding time-to-peak intervals (right panel) were calculated in the regions of saphenous arteries 20 days after single intramuscular administration of the indicated doses of VEGF or bFGF or thrombin. Results expressed as mean percentage change in comparison to internal control hindlimbs of each study group ± SE. Each study group included seven to eight rabbits. *P < .05. C, Average time-resolved curves of saphenous artery enhancement were calculated in normal nonoperated hindlimbs (normal, n = 6) or total control ischemic hindlimbs (control limbs, n = 66) or hindlimbs treated with indicated doses of thrombin (n = 7) or VEGF (n = 8) or bFGF (n = 8) or contralateral control hindlimbs of the 15,000 IU-thrombin treated limbs (15,000 IU controls, n = 8). Results expressed as mean Hounsfield Units ± SE. D and E, Dynamic CT perfusion analysis of 15,000 IU-thrombin treated rabbits. Peak vessel enhancement (D) and the corresponding time-to-peak enhancement (E) were calculated in the regions of saphenous arteries 20 days after single intramuscular administration of 15,000 IU thrombin. Results expressed as mean Hounsfield Units ± SE (left panel) or as mean seconds ± SE (right panel). ***P < .001. F, Semiquantitative perfusion score calculated with the slope method.24 *P < .05. Journal of Vascular Surgery 2009 49, 1000-1012DOI: (10.1016/j.jvs.2008.11.004) Copyright © 2009 The Society for Vascular Surgery Terms and Conditions