Comparison of Pathology of CTO With and Without CABG
Comparison of Pathology of CTO With and Without CABG
The present histopathological study of human CTOs demonstrated several important features to clarify the difference among three different types of CTOs. First, CTOs with CABG are characterized by severe calcification and moderate negative remodelling. Second, LD-CTOs without CABG are characterized by severe negative remodelling and moderate calcification. Third, SD-CTOs without CABG are characterized by abundant organizing thrombi and necrotic cores, and least negative remodelling. Furthermore, the prevalence of abrupt patterns in proximal and distal lumens is not different among the three types of CTOs; however, the prevalence of the abrupt pattern in the proximal lumen is more frequent than that in the distal lumen.
Although the presence of coronary CTOs is commonly recognized during angiography, there are few existing reports in the literature describing the histological findings of the different types of CTO, especially in the presence of CABG. In one of the earliest correlative histopathological studies in the late 1990s, Srivatsa et al. investigated 96 angiographically proven CTO lesions where they recognized that angiographic CTO lesions were not always totally occluded at post-mortem studies with 90–95% stenosis observed in 25% of CTOs, 96–98% in 24% of CTOs, 99% in 29% of CTOs, and complete occlusion in 22%. Because the present study demonstrates that microchannels of adequate size (>200 μm) are infrequent, angiographic CTOs <95% must not be treated as CTOs. The importance of lesion morphology in defining treatment strategies for revascularizing CTOs was highlighted by Katsuragawa et al. They classified 10 CTO lesions with reference to the proximal segment lumens to help explain why the tapering type of occlusion and short-occluded segments have a favourable successful outcome following PCI. The findings indicated that the above morphology was associated with small microvessel recanalization with surrounding 'loose fibrous tissue' in the occluded segment and, therefore, such lesions were more amenable to PCI due to the ease of the wire to penetrate the lesion. However, there is no published histological study available to our knowledge that compares CTO with prior CABG with CTO without prior CABG.
Our results demonstrated that CTOs with CABG have extensive calcification not only in the CTO segments but also in the adjacent proximal and distal segments. Since extensive calcification is associated with diffuse coronary atherosclerotic disease, CTO with CABG exhibited more advanced stable atherosclerosis than CTO without CABG. Although precise mechanism of atherosclerosis in CTO with CABG is unknown, several clinical studies reported that atherosclerotic progression occurs more rapidly in grafted arteries than in non-grafted arteries. Furthermore, the progression from severe atherosclerosis to total occlusion, which is usually located proximal to the anastomosis, is common in grafted arteries. It is possible that blood stasis and low shear stress resulting from competitive flow between native and bypass graft may be the underlying mechanism of greater calcification in the grafted native arteries. It is also known that calcification is closely associated with difficulty in obtaining success during PCI in CTO. Therefore, it is likely that extensive and larger areas of calcification may be the most important explanation for lower success rate of PCI for CTO with prior CABG (>2 years duration) compared with CTO without CABG.
Although we defined CTO including organizing thrombus as short-duration CTO, it does not necessarily imply recent total occlusion. The time of complete organization of the thrombus in CTO is dependent on the length of CTO. As we have shown in Figure 6, both edges of CTO, which come in contact with flowing blood, are more likely to organize early, whereas the centre of CTO without blood contact remains unorganized. Furthermore, our data are consistent with the above concept as the length of SD-CTO lesions was significantly longer than in the other groups. Shorter length thrombotic CTOs are more likely to mature in a short time, whereas longer length CTOs will take a longer time to mature.
Negative remodelling is another important characteristic of CTO and is one of the determinants of success or failure of CTO lesions by PCI. In the rabbit femoral artery CTO model, Jaffe et al. reported negative remodelling of CTO. In their study, the SD-CTOs contained abundant proteoglycan extracellular matrix and low collagen density, whereas the longer duration CTOs contained less proteoglycan extracellular matrix and increased collagen density. In the present study, we demonstrated that least negative remodelling is observed in an organizing thrombus which was seen in SD-CTO. Also, negative remodelling of a proteoglycan-rich thrombus was significantly less than that of non-calcified CTOs rich in collagen, which represents the late stage of CTOs without CABG. Our results suggest that negative remodelling of human CTOs occurs in two phases. In the early phase, a fibrin-rich organizing thrombus becomes a proteoglycan-rich thrombus. In the late phase, proteoglycan-rich thrombus becomes replaced by dense collagen within the CTO. Furthermore, negative remodelling in calcified CTOs was significantly less than negative remodelling in non-calcified collagen-rich CTOs. Severe calcification might play a role by providing a solid frame that prevents the CTO vessels from negative remodelling. Since CTO with CABG had highest calcification, severe calcification might be the explanation for the moderate negative remodelling in CTOs with CABG compared with the LD-CTOs without CABG that had the severest negative remodelling.
When we look at lumens of coronary segments proximal and distal to CTOs to determine the nature of the lumen (i.e. abrupt or tapering), the reported prevalence of the proximal abrupt lumen pattern by angiography varies from 39.1 to 66.1%, which is comparable with our results of 51.6%. The prevalence of the proximal abrupt pattern was highest in CTO with CABG (58.8%), whereas the difference between groups was not significant [LD- CTO (46.9%) and SD- CTO (50%) without CABG, P = 0.56]. On the other hand, there are no reports describing the prevalence of the abrupt or tapering lumen pattern in the distal segments, since blood flow by collateral is not sufficient to judge the distal lumen pattern angiographically. The present results demonstrated that the majority of distal segments of CTO exhibited a tapered pattern and this would explain why true lumen placement of wire and devices is greater with retrograde approach. Also, the tapered pattern of CTO lumen is a better predictor of successful PCI based on a more favourable accessibility of guidewires into true lumens.
In the present study, the results are representative of histologically proven CTO lesions, which may not reflect what it seen angiographically. Moreover, information about the precise age (i.e. duration) of the CTO was not available, as most of the CTO without CABG were from our sudden coronary death registry from individuals without prior history of CAD. Finally, although our study provides pathological insight supporting a retrograde approach for treating CTO, it is not our intention to recommend that only the retrograde strategy be used, since complications can be fatal and, therefore, CTO procedures should be performed by highly experienced interventional cardiologists.
A comparison between different types of CTOs with CABG, and LD-CTOs and SD-CTOs without CABG was performed in a large number of autopsy cases and showed that severe calcification is observed in CTOs with CABG, which may affect negatively on the success of PCI. Long-duration CTO without CABG demonstrated severe negative remodelling, whereas SD-CTO without CABG demonstrated abundant organized thrombus and larger necrotic core with least negative remodelling. These differences along with abrupt and tapering pattern of proximal and distal lumens likely affect the success rate of PCI in CTOs. Furthermore, the prevalence of the tapering pattern in the distal lumen was significantly higher than that in the proximal lumen, suggesting the advantage of retrograde approach.
Discussion
The present histopathological study of human CTOs demonstrated several important features to clarify the difference among three different types of CTOs. First, CTOs with CABG are characterized by severe calcification and moderate negative remodelling. Second, LD-CTOs without CABG are characterized by severe negative remodelling and moderate calcification. Third, SD-CTOs without CABG are characterized by abundant organizing thrombi and necrotic cores, and least negative remodelling. Furthermore, the prevalence of abrupt patterns in proximal and distal lumens is not different among the three types of CTOs; however, the prevalence of the abrupt pattern in the proximal lumen is more frequent than that in the distal lumen.
Although the presence of coronary CTOs is commonly recognized during angiography, there are few existing reports in the literature describing the histological findings of the different types of CTO, especially in the presence of CABG. In one of the earliest correlative histopathological studies in the late 1990s, Srivatsa et al. investigated 96 angiographically proven CTO lesions where they recognized that angiographic CTO lesions were not always totally occluded at post-mortem studies with 90–95% stenosis observed in 25% of CTOs, 96–98% in 24% of CTOs, 99% in 29% of CTOs, and complete occlusion in 22%. Because the present study demonstrates that microchannels of adequate size (>200 μm) are infrequent, angiographic CTOs <95% must not be treated as CTOs. The importance of lesion morphology in defining treatment strategies for revascularizing CTOs was highlighted by Katsuragawa et al. They classified 10 CTO lesions with reference to the proximal segment lumens to help explain why the tapering type of occlusion and short-occluded segments have a favourable successful outcome following PCI. The findings indicated that the above morphology was associated with small microvessel recanalization with surrounding 'loose fibrous tissue' in the occluded segment and, therefore, such lesions were more amenable to PCI due to the ease of the wire to penetrate the lesion. However, there is no published histological study available to our knowledge that compares CTO with prior CABG with CTO without prior CABG.
Chronic Total Occlusion With Coronary Artery Bypass Graft
Our results demonstrated that CTOs with CABG have extensive calcification not only in the CTO segments but also in the adjacent proximal and distal segments. Since extensive calcification is associated with diffuse coronary atherosclerotic disease, CTO with CABG exhibited more advanced stable atherosclerosis than CTO without CABG. Although precise mechanism of atherosclerosis in CTO with CABG is unknown, several clinical studies reported that atherosclerotic progression occurs more rapidly in grafted arteries than in non-grafted arteries. Furthermore, the progression from severe atherosclerosis to total occlusion, which is usually located proximal to the anastomosis, is common in grafted arteries. It is possible that blood stasis and low shear stress resulting from competitive flow between native and bypass graft may be the underlying mechanism of greater calcification in the grafted native arteries. It is also known that calcification is closely associated with difficulty in obtaining success during PCI in CTO. Therefore, it is likely that extensive and larger areas of calcification may be the most important explanation for lower success rate of PCI for CTO with prior CABG (>2 years duration) compared with CTO without CABG.
Short-duration Chronic Total Occlusion Without Bypass Graft
Although we defined CTO including organizing thrombus as short-duration CTO, it does not necessarily imply recent total occlusion. The time of complete organization of the thrombus in CTO is dependent on the length of CTO. As we have shown in Figure 6, both edges of CTO, which come in contact with flowing blood, are more likely to organize early, whereas the centre of CTO without blood contact remains unorganized. Furthermore, our data are consistent with the above concept as the length of SD-CTO lesions was significantly longer than in the other groups. Shorter length thrombotic CTOs are more likely to mature in a short time, whereas longer length CTOs will take a longer time to mature.
Negative Remodelling
Negative remodelling is another important characteristic of CTO and is one of the determinants of success or failure of CTO lesions by PCI. In the rabbit femoral artery CTO model, Jaffe et al. reported negative remodelling of CTO. In their study, the SD-CTOs contained abundant proteoglycan extracellular matrix and low collagen density, whereas the longer duration CTOs contained less proteoglycan extracellular matrix and increased collagen density. In the present study, we demonstrated that least negative remodelling is observed in an organizing thrombus which was seen in SD-CTO. Also, negative remodelling of a proteoglycan-rich thrombus was significantly less than that of non-calcified CTOs rich in collagen, which represents the late stage of CTOs without CABG. Our results suggest that negative remodelling of human CTOs occurs in two phases. In the early phase, a fibrin-rich organizing thrombus becomes a proteoglycan-rich thrombus. In the late phase, proteoglycan-rich thrombus becomes replaced by dense collagen within the CTO. Furthermore, negative remodelling in calcified CTOs was significantly less than negative remodelling in non-calcified collagen-rich CTOs. Severe calcification might play a role by providing a solid frame that prevents the CTO vessels from negative remodelling. Since CTO with CABG had highest calcification, severe calcification might be the explanation for the moderate negative remodelling in CTOs with CABG compared with the LD-CTOs without CABG that had the severest negative remodelling.
Proximal and Distal Lumen Patterns
When we look at lumens of coronary segments proximal and distal to CTOs to determine the nature of the lumen (i.e. abrupt or tapering), the reported prevalence of the proximal abrupt lumen pattern by angiography varies from 39.1 to 66.1%, which is comparable with our results of 51.6%. The prevalence of the proximal abrupt pattern was highest in CTO with CABG (58.8%), whereas the difference between groups was not significant [LD- CTO (46.9%) and SD- CTO (50%) without CABG, P = 0.56]. On the other hand, there are no reports describing the prevalence of the abrupt or tapering lumen pattern in the distal segments, since blood flow by collateral is not sufficient to judge the distal lumen pattern angiographically. The present results demonstrated that the majority of distal segments of CTO exhibited a tapered pattern and this would explain why true lumen placement of wire and devices is greater with retrograde approach. Also, the tapered pattern of CTO lumen is a better predictor of successful PCI based on a more favourable accessibility of guidewires into true lumens.
Study Limitations
In the present study, the results are representative of histologically proven CTO lesions, which may not reflect what it seen angiographically. Moreover, information about the precise age (i.e. duration) of the CTO was not available, as most of the CTO without CABG were from our sudden coronary death registry from individuals without prior history of CAD. Finally, although our study provides pathological insight supporting a retrograde approach for treating CTO, it is not our intention to recommend that only the retrograde strategy be used, since complications can be fatal and, therefore, CTO procedures should be performed by highly experienced interventional cardiologists.
Conclusions
A comparison between different types of CTOs with CABG, and LD-CTOs and SD-CTOs without CABG was performed in a large number of autopsy cases and showed that severe calcification is observed in CTOs with CABG, which may affect negatively on the success of PCI. Long-duration CTO without CABG demonstrated severe negative remodelling, whereas SD-CTO without CABG demonstrated abundant organized thrombus and larger necrotic core with least negative remodelling. These differences along with abrupt and tapering pattern of proximal and distal lumens likely affect the success rate of PCI in CTOs. Furthermore, the prevalence of the tapering pattern in the distal lumen was significantly higher than that in the proximal lumen, suggesting the advantage of retrograde approach.
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