Causes and Prevention of Intimal Hyperplasia
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The document discusses intimal hyperplasia, which is the abnormal proliferation of smooth muscle cells within the innermost layer of arteries. It describes the pathophysiology, stages, and response to different types of arterial injury. Intimal hyperplasia is a major contributor to restenosis and graft failure. The document outlines the key stages following arterial injury, including platelet activation, thrombosis, leukocyte migration, and smooth muscle cell proliferation. It also discusses the response of veins, prosthetic grafts, and dialysis access sites to injury and techniques to reduce intimal hyperplasia.
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Causes and Prevention of Intimal Hyperplasia
- 1. Dr Venkatesh Bollineny DNB Resident Department of Vascular Surgery Narayana Hrudayalaya , Bengaluru INTIMAL HYPERPLASIA
- 2. Introduction Pathophysiology Fluid dynamics Stages of Intimal Hyperplasia Response of the artery to injury • Response of Vein bypass to injury • Response of the Prosthetic graft • Intimal hyperplasia in Dialysis access OUTLIN E
- 3. Introduction The abnormal migration and proliferation of vascular smooth muscle cells with the associated deposition of extracellular connective tissue matrix Remodelling of the tissue Firm, pale and homogenous Location: Endothelium/IEL , Endothelium/MSM
- 4. Key stimuli- Pathological Inflammation Injury Increased mean wall stress Physiological situations: closure of PDA, involution of uterus
- 5. Pathophysiology Arterial injury Platelet adhesion/activation Thrombosis Thrombus develops –endothelial layer Leucocyte demarginate from blood , migrate to subendothelial thrombus Smooth muscle cells proliferate and migrate into intima New matrix synthesized
- 6. Pathophysiology Arterial injury Platelet adhesion/activation Thrombosis Thrombus develops –endothelial layer Leucocyte demarginate from blood , migrate to subendothelial thrombus Smooth muscle cells proliferate and migrate into intima New matrix synthesized
- 7. Pathophysiology Arterial injury Platelet adhesion/activation Thrombosis Thrombus develops –endothelial layer Leucocyte demarginate from blood , migrate to subendothelial thrombus Smooth muscle cells proliferate and migrate into intima
- 8. Pathophysiology Arterial injury Platelet adhesion/activation Thrombosis Thrombus develops –endothelial layer Leucocyte demarginate from blood , migrate to subendothelial thrombus Smooth muscle cells proliferate and migrate into intima New matrix synthesized
- 9. Pathophysiology Arterial injury Platelet adhesion/activation Thrombosis Thrombus develops –endothelial layer Leucocyte demarginate , migrate to subendothelial thrombus Smooth muscle cells proliferate , migrate into intima New matrix synthesized
- 10. Intimal hyperplasia induced by vascular intervention causes lipoprotein retention and accelerated atherosclerosis Siavash Kijan et al., Physiol Rep. 2017 Jul; 5(14): e13334.
- 11. Stages of hyperpl a-sia Rutherford's Vascular Surgery and Endovascular Therapy 9th edition , Chapter 5
- 12. Molecular mechanisms in intimal hyperplasia Andrew C. Newby et al., Journal of Pathology-Review article : 2000
- 13. FLUID DYNAMICS The pulsatile flow in the straight part of the arterial tree is laminar with high shear stresses (10–70 dyn/cm2) 0.2 dyn/cm2 in the venous system . 3-6 dyn/cm2 in Vein graft
- 15. SMC - quiescent ,minimal turnover and contractile -Heparan sulphate proteoglycans, -cAMP- or cGMP-elevating vasodilator agents SMC- secretory phenotype -Injury, inflammation, stretch : heparanases and proteases Modified SMC secrete the growth factors, growth factor receptors, extracellular matrix, proteinases, and inflammatory mediators
- 16. HEMODYNAMICS Hehrlein : reduced vascular runoff after angioplasty results in the increased development of intimal hyperplasia Creation of AVF distal to the bypass –decreases IH in the bypass Jacobs MJ,. Prosthetic graft placement and creation of a distal arteriovenous fistula for secondary vascular reconstruction in patients with severe limb ischemia J Vasc Surg 1992; 15: 612–618.
- 17. Patient –Risk factors Exposure to cigarette smoke increases by two fold. Cholesterol reduction therapies with statins Diabetes is a predictor for restenosis. - Restenotic plaques in diabetic patients is composed of atherosclerotic plaque - This might suggest that recoil/remodeling may be predominant.
- 18. Rutherford's Vascular Surgery and Endovascular Therapy 9th edition
- 19. Response to arterial injury
- 20. Instent restenosis A stent is generally used if – the result of balloon angioplasty is technically unsatisfactory – if there is arterial occlusion, immediate elastic recoil, dissection, or restenosis • Four categories of in-stent restenosis have been defined: (1) focal (≤10-mm length) (2) diffuse (>10-mm length) (3) proliferative (>10-mm length and extending outside the stent)
- 21. Mechanism of In Stent stenosis
- 23. Response of Vein Graft to injury
- 24. Response of Prosthetic Graft
- 25. Anastomotic intimal hyperplasia: Mechanical injury or flow induced Hisham S. Bassiouny, JVS JUNE 2–5, 1991| VOLUME 15, ISSUE 4, P708-717, APRIL 01, 1992 Topography of Intimal thickening
- 26. Arterial floor and Heel- Low shear stress and oscillating shear forces Toe-High wall sheer stress (WSS) Suture line intimal thickening- PTFE anastomoses: Healing Arterial floor thickening-Vein and PTFE: Flow oscillations and low shear stress. Vein graft stenoses patterns: -Solitary/focal -80% -Multifocal -15-20% -Diffuse- 3-5%
- 27. Intimal Hyperplasia in Vascular Grafts , Susan Lemson et al., EJVES , 19(4):336-50 · May 2000
- 28. Intimal hyperplasia- Dialysis access AVG : The anastomoses appear to be the areas of maximal intimal hyperplasia The majority of stenoses occur at the venous anastomoses and within 1 cm of the anastomosis Five anatomic stenotic lesions in AV grafts have been categorized -stenosis in the draining vein proximal to the venous anastomosis (36%) -stenosis at the venous anastomosis (25%) -stenosis in the central vein (24%) -stenosis at the arterial anastomosis (11%) -intragraft hyperplasia (4%).
- 29. Nephrol Dial Transplant, Volume 28, Issue 5, May 2013, Pages 1085–1092, https://doi.org/10.1093/ndt/gft068 Different modalities of the vascular remodelling response after fistula creation. Whereas a healthy vein has ...
- 30. Nephrol Dial Transplant, Volume 28, Issue 5, May 2013, Pages 1085–1092, https://doi.org/10.1093/ndt/gft068 Potential mechanisms of the remodelling response upon fistula creation. Upon fistula creation, in response to ...
- 31. THIGH AV GRAFT: IH VENOUS END IH GSV- Femoral Vein confluence IH
- 32. BC AVF- Intimal Hyperplasia Juxta anastomotic Puncture site
- 33. The blood flow rate in AVGs is 5–10 times greater than that in ABGs. High flow causes turbulence that injures endothelial cells and eventually results in IH. The peak WSS in AVGs is about 6-10 N/m2, much higher than that in ABGs. Excessively high WSS may effect IH formation in AVGs. Several venous cuff or patch anastomotic designs have been used in attempts to regulate hemodynamic factors in grafts. In ABGs, these designs appear to help decrease IH formation. In AVGs, however, they generally have not improved patency rates. In a high-flow system such as an AVG, more drastic changes in anastomotic design may be required.
- 34. DEB/DES
- 35. DEB/DES
- 36. DEB
- 37. The chief benefit cited for DEBs is -Avoidance of additional metal and polymer barriers, which may disrupt or hinder vascular healing – DEB-treated vessels show - delayed vascular healing characterized by dose-dependent increases in fibrin deposition, - delayed re-endothelialization, - lower number of neointimal cells, - increased medial VSMC loss
- 38. Management of ISR POBA DCB / DES Heparin bonded endoprosthesis Atherectomy
- 39. Four established techniques of distal end-to-side anastomosis 1-Direct anastomosis 2-Linton patch 3-Taylor patch 4- Miller cuff were compared to investigate the local distribution of anastomotic intimal hyperplasia. These reduced anastomotic intimal hyperplasia and distribution patterns of hyperplasia Addition of vein improved patency (29% to 52% at 2 years)
- 40. Therapeutic strategies to combat neointimal hyperplasia in vascular grafts Michael J Collins Anastomotic techniques that resulted in the least intimal hyperplasia are end to end , and with length 4 or 4.5 times the internal diameter of the artery. Graft : Native vessel diameter – 1.6:2.1 Grafts >50 cm and vein diameter <3.5 mm associated with reduced patency Compliance match Angle of anastomoses - No correlation between the native vein/prosthetic graft at the proximal anastomoses - 45 degrees angle is superior (15,30,45,60)
- 41. THANK YOU
Editor's Notes
- Proliferation and migration of vascular smooth muscle cells into the tunica intima layer, resulting in vascular wall thickening and the gradual loss of luminal patency
- SMC and fibroblast accumulation in the tunica intima layer with extracellular matrix (ECM) or collagen deposition. On immunohistochemistry studies, vascular samples with neointimal hyperplasia show multi-layered SMCs, which stain positive for alpha-smooth muscle actin, endothelial cells staining positive for anti-von Willebrand factor antibodies, fibroblasts which secrete ECM, lymphocytes, and macrophages. The excessive cellular deposition results in the expansion of the intimal layer and loss of the luminal area. [10] Tunica media layer in arterial neointimal hyperplasia tends to remain thin despite the increased thickness of the intimal layer. This is in contrast to vein graft adaptation, where there is also a concurrent expansion of the tunica media layer.
- Cellular mechanisms of intimal hyperplasia. (A) Normal vessel structure. The diagram highlights the three compartments of the vessel wall, intima, media and adventitia, and the different kinds of extracellular matrix, basement membranes, interstitial matrix, and elastic laminae. SMC=smooth muscle cell. (B) Response to injury. Platelet‐derived growth factor (PDGF) produced from platelets (•) acts as a chemoattractant encouraging phenotypically modified smooth muscle cells (arrows) to migrate from the media into the neointima and proliferate there. PDGF also stimulates collagen and proteoglycan synthesis. Metalloproteinases (MMPs) facilitate the migration and proliferation of SMC by remodelling the extracellular matrix. (C) Response to inflammation. Platelet‐derived growth factor (PDGF) produced from platelets (•), activated endothelial cells, smooth muscle cells (SMC) and macrophage foam cells (FC) encourages smooth muscle cell (SMC) migration and proliferation. The production of metalloproteinases (MMPs) is stimulated by inflammatory mediators and cell to cell contact through the CD40/CD40 ligand system
- Laminar flow refers to streamline movement of blood. In laminar flow, blood flows in layers which move parallel to the long axis of the blood vessel (straight arrows parallel with the vessel long axis). Close to the vessel wall, an infinitely thin layer of blood in contact with the wall is stationary (i.e., does not flow). The next layer in contact with this layer has a low velocity. As the layers extend toward the vessel interior, their velocity increases. Velocity is highest for the layer at the center of the vessel lumen. Therefore, blood flow velocity is zero for the layer in contact with the vessel wall and highest at the center of the vessel lumen. Blood flow in most vessels of the body is laminar. Despite the pulsatile nature of flow in arteries, laminar blood flow is silent. Thus, no sound is normally heard via a stethoscope placed over arteries. Constriction of the vessel, or obstruction of the vessel lumen, disrupts laminar flow and leads to turbulent blood flow. This is shown in the illustration by curved arrows and short straight arrows showing flow in directions other than along the long axis of the blood vessel. At the point of constriction, blood flow velocity increases, but small eddies lead to flow in directions other than parallel to the long axis of the vessel. Such current eddies lead to turbulence. Turbulent blood flow is noisy and can be heard by using a stethoscope placed over the artery at or distal to the point of constriction or obstruction. Laminar and turbulent flow provide the physical basis for the auscultation method of blood pressure measurement using a pressure cuff placed over the upper arm (to cause vessel constriction) and a stethoscope placed over the brachial artery (to listen for the noise of turbulent flow when the vessel is constricted). The sounds heard by this method are referred to as the Korotkoff's sounds.
- (A)Undisturbed laminar flow is a smooth streamlined flow chacterized by concentric layers of blood moving in parallel along the course of the artery; (B)disturbed laminar flow is characterized by reversed flow (i.e., flow separation, recirculation, and reattachment to forward flow); (C)in turbulent flow the blood velocity at any given point varies continuously over time, even though the overall flow is steady. Adapted from Munson et al. (28). Re = Reynolds number.
- ED leads to endothelial activation and decreases the production of nitrous oxide (NO) due to the dysregulation of endothelial nitric oxide synthase (ENOS). When platelets come in contact with activated endothelial cells, it forms a platelet-rich thrombus. An inflammatory cascade begins at the vascular injury site, and leukocytes demarginate from the bloodstream and reach sub-endothelial thrombus. Oxidative stress promotes the expression of endothelial adhesion molecules, such as vascular cell adhesion molecules, that help recruitment and migration of monocytes into the subendothelial area.Matrix metalloproteinases are key enzymes that cause the breakdown of extracellular matrix proteins, such as collagen and elastin, and facilitate the migration of vascular SMCs across internal elastic lamina in neointimal hyperplasia formation. It is also noted in arteriovenous grafts studies that SMCs can alternately originate from fibroblasts from vascular adventitia or bone marrow progenitor cells. Once SMCs migrate at the vascular injury site intimal layer, they go through a phenotypic transition from predominantly contractile to secretory type SMCs.
- NO ADVENTITIAL CELL RECRUITMENT, NO PROGENITOR CELL RECRUITMENT
- COAGULAM AT SURFACE- INFILTRATED WITH MACROPHAGES- ADVENTITIAL INGROWTH- NEOINTIMA
- FIGURE 1: Different modalities of the vascular remodelling response after fistula creation. Whereas a healthy vein has the potential for successful outward remodelling (top left), adequate maturation may be partially hindered by CKD-induced pre-existing vasculopathy such as IH (top right). As shown below, we postulate that the net resultant of IH and outward remodelling may determine ultimate luminal calibre. In the case of IH formation, adequate outward remodelling could, to a certain extent, leave the lumen calibre intact, thus providing a patent fistula. However, if IH outbalances outward remodelling, this could result in stenosis and fistula failure. Unless provided in the caption above, the following copyright applies to the content of this slide: © The Author 2013. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
- FIGURE 2: Potential mechanisms of the remodelling response upon fistula creation. Upon fistula creation, in response to the altered haemodynamic environment a plethora of structural changes may occur in the vessel wall; among others, surgery induced endothelial denudation, matrix reorganization to accommodate outward expansion but possibly also VSMC proliferation and migration contributing to IH formation. Physiological outward remodelling may, to a certain extent, compensate for detrimental intimal lesions. Unless provided in the caption above, the following copyright applies to the content of this slide: © The Author 2013. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.