Restenosis: Difference between revisions
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==Histopathology== | ==Histopathology== | ||
Restenosis can considered a local vascular manifestation of the general biological response to arterial wall injury. Following vessel wall injury, there is endothelium damage with the exposure of media to the blood, which results in platelet adhesion to the media's collagen via the Von Williebrand factor. This results in platelet activation, which is followed by aggregation and soon evolving into a vicious cycle, which feeds and nurtures itself till a clot is formed from the coagulation cascade (which is activated from the tissue thromboplastin released from the media following vessel wall injury) and fibrin. Basically, this phenomenon can be considered synonymous to hemostasis. Activated platelets express adhesion molecules, to which circulating leukocytes attach and begin the process of leukocyte migration. Also during this process, several chemotactic factors are released and multiple adhesion molecules are expressed by various activated inflammatory cells in the vicinity of the inflammation, which cause chemotaxis of leukocytes to the core of the inflammation. Growth factors, cytokines and adhesion molecules released and expressed by platelets, leukocytes and other inflammatory cells, result in the migration of vascular smooth muscle cells from the media and proliferation with resultant neo-intima formation. Hence, neo-intima consists of vascular smooth muscle cells, macrophages and extracellular matrix, which has formed over several weeks. | |||
When reading through the above process, we realize that plaque rupture and stent thrombosis follows the same final common pathway as mentioned above. However, depending on how extensive the plaque rupture or how strong the inciting stimulus for stent thrombosis is, the process of clot organization and neo-intima formation may not occur, if sufficient time is not allowed. This happens when the pathology materializes to significant clinical symptomatology in shorter period of time resulting in an intervention or serious fatality. If the patient survives the ordeal in the absence of any intervention, then this clot progresses through the natural course and results in clot organization and finally evolves into a scar, which consists of components similar to the neo-intima. This may eventually result in lumen stenosis or recanalization of the organized thrombus. In the scenario, where an intervention is formed such as a balloon angioplasty or stent placement, then the disease process is modulated. | |||
In balloon angioplasty, the lumen size is increased from its baseline diseased state, but it results in elastic recoil, negative remodeling and contraction and finally neo-intima formation, which has a strong propensity to cause clinical restenosis. Also, to be noted is the fact that there is a 30% risk of abrupt closure of the vessel from acute thrombosis from plain balloon angioplasty as it is a form of vascular injury too (iatrogenic controlled injury). As the lumen size is increased (same amount of neo-intima formation with a relatively larger lumen size) and in the presence of antiplatelet/anticoagulants, clinical restenosis and thrombosis is not a 100% phenomenon. However, there are several other factors which interplay with each other in determining, which patients are at risk for restenosis (as discussed below) and thrombosis. | |||
In stent implantation, the lumen size is increased from its baseline diseased state and has a better patency than plain balloon angioplasty, as the stent scaffold holds the vessel open and therefore elastic recoil and negative remodeling is reduced significantly. As seen in incidence, the restenosis rates are lower in BMS when compared to plain balloon angioplasty, as the elastic recoil and negative remodeling is virtually eliminated. Hence, the final lumen size is greater and neo-intima formation does not materialize into clinical restenosis in a rate as successful as seen in balloon angioplasty. Similarly, it is well known that DES has a lower re-stenosis rate than BMS as the DES have the added advantage of releasing anti-stenotic drug which can retard the neo-intima formation. Once again, there are several other factors involved in re-stenosis of BMS and DES (as discussed below). The occurrence of stent thrombosis is similar between the DES and BMS and its detailed discussion is beyond the scope of this chapter. | |||
Re-stenosis can be considered in two different settings of a percutaneous coronary intervention: | |||
1. In pure angioplasty in the absence of stenting | |||
Following balloon angioplasty, there is injury to the vessel wall, which triggers the expected inflammatory response from the vessel wall. Hence, there is elastic recoil, negative remodelling (reduction in lumen size due to the healing process) or contraction, thrombus at the site of injury (i.e., release of prothrombotic thromboplastin like material from the vessel wall, exposure of the collagen of the media), smooth muscle proliferation and migration and excessive extracellular matrix production. Neointima is composed principally smooth muscle cells and extracellular matrix. | |||
2. With stenting | |||
Stenting prevents elastic recoil and negative remodelling. However, neointimal formation progresses and causes re-stenosis, which is reduced with antistenotic drugs. | |||
The porcine model of ISR has demonstrated the formation of a thick neointima in 28 days-which may be the reason as to why the earlier DES released their antistenotic drug by the end of 30 days. However, it is well known that the peak period of ISR development in humans is approximately 3 to 6 months-hence the newer DES are aiming to release the drug for an extended period. Interestingly, in these porcine models they found a positive correlation between the inflammatory infiltrate, degree of arterial injury and extent of stent strut penetration into the vessel wall with the neointimal thickness. | |||
The above mentioned responses and time periods were in porcine models with near normal coronaries and this may not be the case in humans who have had balloon angioplasty, BMS and DES for atherosclerotic lesions. The inflammatory response in DES is very different in terms of cell composition and timing, when compared to balloon angioplasty and BMS and also among the different DES. These differences could be explained by the presence of various forms of polymer among DES. For example, the inflammatory response (predominantly giant cell infiltrates) to Sirolimus DES has been shown to persist beyond 180 days and up to 2 years. In contrast, the inflammatory response to BMS and the second generation Everolimus DES (which has a more biocompatible polymer) has been limited to 90 days and 12 months, respectively. Evidence of such persistence of inflammatory response has been found in autopsy cases and from thrombus aspirates taken from patients during percutaneous coronary intervention for late stent thrombosis. | |||
==Clinical Presentation== | ==Clinical Presentation== | ||
Revision as of 23:31, 13 February 2012
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Restenosis On the Web |
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American Roentgen Ray Society Images of Restenosis |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1], Associate Editor(s)-In-Chief:: Bhaskar Purushottam, M.D. [2]
Overview
Restenosis literally means the reoccurrence of stenosis. This is usually restenosis of an artery, or other blood vessel, but possibly any hollow organ that has been "unblocked". This term is common in vascular surgery, cardiac surgery, interventional radiology, or interventional cardiology following angioplasty, all branches of medicine that frequently treat stenotic lesions. In simple words, coronary re-stenosis can be considered as the reduction in the lumen diameter after a percutaneous coronary intervention (PCI), which induces iatrogenic arterial injury and results in neointimal tissue proliferation.[1] It can be defined based on angiography or as clinical restenosis. By angiography, the term 'Binary Angiographic Re-stenosis' is defined as > 50% luminal narrowing at follow-up angiography.[2] However, the most widely accepted and relevant definition would be a 'Clinical Re-stenosis', which is defined as need for a repeat target lesion revascularization (TLR) due to symptomatic coronary ischemia from the previously intervened vessel (proposed by the Academic Research Consortium). Therefore, this definition needs angiographic narrowing as well as clinical correlation. If the lesion does not meet angiographic criteria, but meets the criteria for a physiologically significant lesion by fractional flow reserve (FFR) or anatomically by intravascular ultrasound (IVUS) with the appropriate clinical context, it is still considered 'Clinical Re-stenosis'. PCI has evolved significantly from plain balloon angioplasty to the development of biodegradable stents in the last few decades. Currently, almost all coronary interventions use a bare metal stent (BMS) or more so a drug eluting stent (DES). Hence, the discussion in the following paragraphs will focus on in-stent re-stenosis of drug eluting and bare metal stents.
Coronary Restenosis
There are probably several mechanisms that lead to restenosis. An important one is the inflammatory response, which induces tissue proliferation around an angioplasty site.
Cardiologists have tried a number of approaches to decrease the risk of restenosis. Stenting is becoming more commonplace; replacing balloon angioplasty. During the stenting procedure, a metal mesh (stent) is deployed against the wall of the artery revascularizing the artery. Other approaches include local radiotherapy and the use of immunosuppressive drugs, coated onto the stenting mesh. Analogues of rapamycin, such as tacrolimus (FK-506), sirolimus and more so everolimus, normally used as immunosuppressants but recently discovered to also inhibit the proliferation of vascular smooth muscle cells, have appeared to be quite effective in preventing restenosis in clinical trials. Antisense knockdown of c-myc, a protein critical for progression of cell replication, is another approach to inhibit cell proliferation in the artery wall and has been through preliminary clinical trials using Morpholino oligos.
Histopathology
Restenosis can considered a local vascular manifestation of the general biological response to arterial wall injury. Following vessel wall injury, there is endothelium damage with the exposure of media to the blood, which results in platelet adhesion to the media's collagen via the Von Williebrand factor. This results in platelet activation, which is followed by aggregation and soon evolving into a vicious cycle, which feeds and nurtures itself till a clot is formed from the coagulation cascade (which is activated from the tissue thromboplastin released from the media following vessel wall injury) and fibrin. Basically, this phenomenon can be considered synonymous to hemostasis. Activated platelets express adhesion molecules, to which circulating leukocytes attach and begin the process of leukocyte migration. Also during this process, several chemotactic factors are released and multiple adhesion molecules are expressed by various activated inflammatory cells in the vicinity of the inflammation, which cause chemotaxis of leukocytes to the core of the inflammation. Growth factors, cytokines and adhesion molecules released and expressed by platelets, leukocytes and other inflammatory cells, result in the migration of vascular smooth muscle cells from the media and proliferation with resultant neo-intima formation. Hence, neo-intima consists of vascular smooth muscle cells, macrophages and extracellular matrix, which has formed over several weeks.
When reading through the above process, we realize that plaque rupture and stent thrombosis follows the same final common pathway as mentioned above. However, depending on how extensive the plaque rupture or how strong the inciting stimulus for stent thrombosis is, the process of clot organization and neo-intima formation may not occur, if sufficient time is not allowed. This happens when the pathology materializes to significant clinical symptomatology in shorter period of time resulting in an intervention or serious fatality. If the patient survives the ordeal in the absence of any intervention, then this clot progresses through the natural course and results in clot organization and finally evolves into a scar, which consists of components similar to the neo-intima. This may eventually result in lumen stenosis or recanalization of the organized thrombus. In the scenario, where an intervention is formed such as a balloon angioplasty or stent placement, then the disease process is modulated.
In balloon angioplasty, the lumen size is increased from its baseline diseased state, but it results in elastic recoil, negative remodeling and contraction and finally neo-intima formation, which has a strong propensity to cause clinical restenosis. Also, to be noted is the fact that there is a 30% risk of abrupt closure of the vessel from acute thrombosis from plain balloon angioplasty as it is a form of vascular injury too (iatrogenic controlled injury). As the lumen size is increased (same amount of neo-intima formation with a relatively larger lumen size) and in the presence of antiplatelet/anticoagulants, clinical restenosis and thrombosis is not a 100% phenomenon. However, there are several other factors which interplay with each other in determining, which patients are at risk for restenosis (as discussed below) and thrombosis.
In stent implantation, the lumen size is increased from its baseline diseased state and has a better patency than plain balloon angioplasty, as the stent scaffold holds the vessel open and therefore elastic recoil and negative remodeling is reduced significantly. As seen in incidence, the restenosis rates are lower in BMS when compared to plain balloon angioplasty, as the elastic recoil and negative remodeling is virtually eliminated. Hence, the final lumen size is greater and neo-intima formation does not materialize into clinical restenosis in a rate as successful as seen in balloon angioplasty. Similarly, it is well known that DES has a lower re-stenosis rate than BMS as the DES have the added advantage of releasing anti-stenotic drug which can retard the neo-intima formation. Once again, there are several other factors involved in re-stenosis of BMS and DES (as discussed below). The occurrence of stent thrombosis is similar between the DES and BMS and its detailed discussion is beyond the scope of this chapter.
Re-stenosis can be considered in two different settings of a percutaneous coronary intervention:
1. In pure angioplasty in the absence of stenting Following balloon angioplasty, there is injury to the vessel wall, which triggers the expected inflammatory response from the vessel wall. Hence, there is elastic recoil, negative remodelling (reduction in lumen size due to the healing process) or contraction, thrombus at the site of injury (i.e., release of prothrombotic thromboplastin like material from the vessel wall, exposure of the collagen of the media), smooth muscle proliferation and migration and excessive extracellular matrix production. Neointima is composed principally smooth muscle cells and extracellular matrix.
2. With stenting Stenting prevents elastic recoil and negative remodelling. However, neointimal formation progresses and causes re-stenosis, which is reduced with antistenotic drugs.
The porcine model of ISR has demonstrated the formation of a thick neointima in 28 days-which may be the reason as to why the earlier DES released their antistenotic drug by the end of 30 days. However, it is well known that the peak period of ISR development in humans is approximately 3 to 6 months-hence the newer DES are aiming to release the drug for an extended period. Interestingly, in these porcine models they found a positive correlation between the inflammatory infiltrate, degree of arterial injury and extent of stent strut penetration into the vessel wall with the neointimal thickness.
The above mentioned responses and time periods were in porcine models with near normal coronaries and this may not be the case in humans who have had balloon angioplasty, BMS and DES for atherosclerotic lesions. The inflammatory response in DES is very different in terms of cell composition and timing, when compared to balloon angioplasty and BMS and also among the different DES. These differences could be explained by the presence of various forms of polymer among DES. For example, the inflammatory response (predominantly giant cell infiltrates) to Sirolimus DES has been shown to persist beyond 180 days and up to 2 years. In contrast, the inflammatory response to BMS and the second generation Everolimus DES (which has a more biocompatible polymer) has been limited to 90 days and 12 months, respectively. Evidence of such persistence of inflammatory response has been found in autopsy cases and from thrombus aspirates taken from patients during percutaneous coronary intervention for late stent thrombosis.
Clinical Presentation
In-stent restenosis (ISR) can be clinically silent, but majority of them present with recurrent symptoms of angina. The incidence of recurrent angina pectoris after a percutaneous coronary intervention (PCI) was reported in the past to be around 50% with a wide range. This number may have reduced as most the PCIs end up in a DES as opposed to a BMS. The positive predictive value of symptoms indicating a significant stenosis is as low as 60%. ISR is often thought to be a benign phenomenon since the process of neointimal formation and proliferation is of gradual onset and progressive in nature. Given the pathophysiology of coronary re-stenosis, it is thought that re-stenosis is a rare cause of acute myocardial infarction or death. However, there are several reports which have shown that ISR can present as an acute coronary syndrome. 26% to 53% and 3.5% to 20% of BMS ISR can present as unstable angina and myocardial infarction, respectively. Similarly, 16% to 66% and 1% to 20% of DES ISR can present as unstable angina and myocardial infarction, respectively. A highly stenotic ISR lesion can lead to an non-occlusive thrombus, which can result in an acute coronary syndrome. Also, patients with clinically silent re-stenosis can be identified on coronary cineangiograms when neighbouring plaques undergo rupture or intimal tear and present as an acute coronary syndrome. Sometimes, local plaque rupture or intimal tear can initiate an inflammatory process which can promote thrombosis of neighbouring stenotic lesions. Thus, it is important to thoroughly evaluate the patient as coronary re-stenosis can present as an acute coronary syndrome.
BMS ISR has been reported to occur usually after five and half months after stent implantation. The time frame for DES ISR presentation is not well-known with one study reporting a mean time duration of 12 months. Delayed restenosis is known to occur especially with DES. There have been reports, using intravascular ultrasound that have shown neointimal proliferation to occur even at 4 years after stent implantation. The exact reasons as to why this delayed neointimal proliferation occurs is not well known. Some of the suspected pathophysiological mechanisms are delayed healing response, persistent biological reaction caused by the drug present in the polymer, or a hypersensitivity reaction to the polymer and a possible a genetic predisposition. This eludes to the fact that the clinician should entertain the possibility of coronary re-stenosis in patients who present with recurrent angina about 2 years after the stent implantation.
Among the clinical predictors of coronary re-stenosis, diabetes mellitus continues to be a strong clinical predictor. In a study conducted by Singh et al., they found that patients with treated diabetes mellitus had a 45% higher risk of restenosis compared with nondiabetics. Interestingly, in their study they found that current smokers have less restenosis. This smoker's paradox has been described in the past. Some of the other predictors are increasing age, female sex and chronic renal disease and patients on hemodialysis. Angiographic and other predictors are listed under the other sections.
Related Chapters
References
- ↑ Dangas GD, Claessen BE, Caixeta A, Sanidas EA, Mintz GS, Mehran R (2010). "In-stent restenosis in the drug-eluting stent era". J Am Coll Cardiol. 56 (23): 1897–907. doi:10.1016/j.jacc.2010.07.028. PMID 21109112.
- ↑ Mehran R, Dangas G, Abizaid AS, Mintz GS, Lansky AJ, Satler LF; et al. (1999). "Angiographic patterns of in-stent restenosis: classification and implications for long-term outcome". Circulation. 100 (18): 1872–8. PMID 10545431.