The Evolution of Plaque Composition in CTOs

Lloyd W. Klein, MD;  Divya Korpu, MD;  Ibett Colina, MD

Lloyd W. Klein, MD;  Divya Korpu, MD;  Ibett Colina, MD

Chronic total occlusion (CTO) is defined as a complete obstruction of a coronary artery (TIMI 0 flow) that is more than 3 months old. CTOs are found in 10%-20% of patients undergoing coronary angiography. When they subtend segments of viable myocardium, often associated with distal filling via collaterals, they may be targets for complex PCI revascularization. These lesions are usually described as being composed of fibroatheroma, predominantly collagen and calcium, with no patent lumen.1,2 Numerous intravascular ultrasound (IVUS) studies have confirmed these findings in the vast majority of CTO plaques.3-5 

The traditional view has been that CTOs represent the end stage of plaque evolution.1,2 A more descriptive view6 is that coronary plaque continues to evolve after acute occlusion, and its composition depends on its age.7 Acute occlusions result from plaque rupture followed by intraluminal thrombosis and subsequent organization. Thrombus propagates retrogradely, then undergoes organization. Collagen deposition and fibrous tissue form predominantly at the proximal and distal ends of the occlusion, referred to as the proximal and distal fibrous caps. The occluded intramural segment remains active, with recanalization, neovascularization, and inflammation within the occlusion. After occlusion, plaque composition continues to evolve,7 ranging from cholesterol laden to fibrocalcific. Older CTOs have fewer foam cells and macrophages and greater calcification and fibrosis. Nishida et al8 showed that older CTOs undergo negative remodeling. Suzuki et al9 identified only moderate correlations between lesion age and indices of calcification by IVUS. They identified some very recent CTOs that were heavily calcified, signifying that the CTO had arisen in vessels with diffuse atheroma, suggesting a considerably complex pathophysiology. 

In this issue of the Journal of Invasive Cardiology, Christakopolous et al10 evaluate the composition of plaque in CTOs being treated with PCI and determine, departing from the classical depiction, that many are high in lipid content. The authors employed NIRS imaging in 15 patients undergoing PCI after the guidewire had already been passed through the stenosis. The lipid was located in the body of the CTO in 6/15 cases, suggesting that coronary inflammation and the occurrence of acute plaque rupture likely was the precursor of the CTO development. In this regard, it is of interest that the authors report that only 47% of these cases had a prior myocardial infarction (MI) clinically. 

The observations of Christakopolous et al indicate that the classic fibrocalcific histology is seen in a final stage, whereas earlier in the evolutionary process, a high lipid core content may be present. The frequency of this finding in CTOs that are clinical targets for revascularization implies that age might not be the sole determinant of composition, which may also be modulated by vascular mediators and viability. This poses a new view of CTO plaque as an active environment, and not merely the end stage.

The potential anatomic conveyance for mediators of metabolism within the plaque is clear. Neovascular channels are frequent in CTOs, sometimes communicating with the central lumen vestige, even though no distal flow is visualized angiographically. These vessels originate in adventitial vasa vasorum, a mesh-like capillary plexus within the media extending into the intima, associated with cellular inflammation and age. Vasa vasorum participate in atheroscelerosis progression, proliferating in response to arterial injury. They are significant participants in the pathogenesis of acute plaque rupture leading to MI, as a consequence of high intravascular pressure tearing the wall. Post occlusion, the vasa vasorum continue to exist and play a role in distributing vascular mediators. Patients with CTO have higher coronary sinus vascular endothelial growth factor (VEGF) concentration than those with non-total occlusion, emphasizing the local paracrine role of VEGF in angiogenesis.11 In CTO, two different type of microvessels are observed: (1) circumferential extravascular vessels, maximal at 2 weeks and thereafter gradually decrease over time, with minimal vessels evident beyond 12 weeks; and (2) longitudinally oriented intravascular microvessels, which sprout from extravascular microvessels under hypoxic conditions in response to HIF-1 expressed by the macrophages, peaking at 6 weeks. Intraplaque vasa vasorum are tortuous, branching at right angles from main vessels within the adventitia, generally through a disrupted medial wall, and generally are neither straight nor continuous. These microvessels associated with CTO develop at the proximal end of the occlusion and rarely have communication with the distal open artery.12,13 Intraplaque microvessels have endothelial cell abnormalities and disrupted cell-to-cell contacts and basement membrane defects. In early CTOs (6-12 weeks), the presence of microvessels is thought to be associated with greater local tissue compliance. As the CTO ages, there is a reduction in the size and number of intravascular microvessels, which accompanies changes in composition to more fibrous content. Thus, the pattern of microvascular vessel formation depends on the time after occlusion12 and is associated with alterations in plaque composition. 

The presence of viable myocardium beyond the CTO depends on collateralization. Collateral development is central to the survival and function of the myocardium, since their purpose is to maintain oxygenation to a region where there is no epicardial blood flow. In contrast to plaque neovascularization, collaterals form by arteriogenesis as a physiological response to occlusion.14-17 Their mechanism of development is structural enlargement of preexisting arterioles. Collaterals are not new vessels, and their proliferation is not a process of passive dilation, but rather are the result of active proliferation and remodeling of channels that were present in the fetal circulation when the myocardium was spongiform. The mural structures enlarge and become better defined with maturation. Pulsatile shear stress caused by a large pressure gradient between the high preocclusive and the very low postocclusive pressure regions are the driving forces for arteriogenesis, by activating the endothelium.18 Upregulation of cell adhesion molecules (ICAM-1) and increased endothelial production of cytokines (MCP-1, GM-CSF, TNFa) and growth factors (VEGF, FGF) result.19 ICAM-1/Mac-1 mediated monocyte adhesion to the endothelium is an essential step for arteriogenesis. 

These observations indicate that it is time to revisit the classic portrayal of CTOs as a “dead-end” and recognize there are transitional stages in plaque evolution and the vascular supply to viable myocardium. Compositional change may not be exclusively age dependent, but might be modifiable by inflammatory mediators signaling the presence of viable myocardium, or the occurrence of periods of ischemia. Another significant inference is that negative remodeling is not necessarily the only path to CTO. Linking vascular supply and structure with plaque composition in occluded vessels, in particular collateral flow, neovascularization, chronic inflammation, and endothelial dysfunction, is speculative, but it’s evident how their interplay could impact plaque evolution.20

These considerations could have several potentially meaningful clinical implications. High plaque lipid content likely correlates with viable myocardium; when the distal segment is not alive, plaque fibrosis ultimately results. It may be that if we could detect the distribution and the density of the vasa vasorum in CTOs, we might be able to determine which plaques maintain high mural lipid content, and hence, signify viable myocardium. Furthermore, the finding of high plaque lipid content suggests that such CTOs could be targets for regression therapies; if the lipids could be transported (by the vasa vasorum) and the plaque passivated, the vessel might recanalize medically. Also, these plaques are probably more amenable to guidewire placement than fibrotic and calcified occlusions, since the presence of vessel recanalization is associated with looser fibrous tissue, it likely provides less resistance to wire passage.7,21 Finally, the presence of high plaque lipid content was predictive of restenosis in this very small series, a provocative observation of immense consequence, if confirmed. Therefore, plaque composition and vascularity may predict which stenoses are appropriate targets of intervention, which are most likely to be successful, and also which are most likely to require repeat procedures.

One limitation of this study is the inclusion of lipid analysis within the vessel rather than just in the CTO plaque. The authors imply that the observed lipid core was close to the CTO, but do not provide details. The finding of lipid core plaque in 11/15 (73%) and large lipid content in 4/15 (27%) is therefore open to interpretation. Another question is how well IVUS and NIRS correlate, and whether the observational discrepancies between studies are technical in origin. Possibly, NIRS findings may overestimate the frequency of lipid content in CTOs. Further, the cases included were symptomatic requiring revascularization, and thus more likely related to a recent acute event and viable myocardium. Moreover, a guidewire was successfully passed beyond the obstruction to obtain the images, so they may be “selected” cases in that sense. 


1.    Stary HC, Chandler AB, Dinsmore R, et al. A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Arterioscler Thromb Vasc Biol. 1995;15:1512-1531. 

2.    Libby P. Current concepts of the pathogenesis of the acute coronary syndromes. Circulation. 2001;104:365-372. 

3.    Guo J, Maehara A, Mintz GS, et al. A virtual histology intravascular ultrasound analysis of coronary chronic total occlusions. Catheter Cardiovasc Interv. 2013;81:464-470.

4.    Fujii K, Ochiai M, Mintz GS, et al. Procedural implications of intravascular ultrasound morphologic features of chronic total coronary occlusions. Am J Cardiol. 2006;97:1455-1462. 

5.    Park YH, Kim YK, Seo DJ, et al. Analysis of plaque composition in coronary chronic total occlusion lesion using virtual histology-intravascular ultrasound. Korean Circ J. 2016;46:33-40. 

6.    Irving J. CTO pathophysiology: how does this affect management? Curr Cardiol Rev. 2014;10:99-107.

7.    Srivatsa SS, Edwards WD, Boos CM, et al. Histologic correlates of angiographic chronic total coronary artery occlusions. Influence of occlusion duration on neovascular channel patterns and intimal plaque composition. J Am Coll Cardiol. 1997;29:955-963. 

8.    Nishida T, Di Mario C, Briguuori C, Albiero R, Columbo A. Characterization of total occlusions with intracoronary ultrasound: the importance of the duration of occlusion. J Invasive Cardiol. 2001;13:1-8. 

9.    Suzuki T, Hosokawa H, Yokoya K, et al. Time-dependent morphologic characteristics in angiographic chronic total coronary occlusions. Am J Cardiol. 2001;88:167.

10.    Christakopolous GE, Karacsonyi J, Danek BA, et al. Near-infrared spectroscopy analysis of coronary chronic total occlusions. J Invasive Cardiol. 2016;28:485-488.

11.    Lin TH, Yeh HW, Su HM, et al. Effects of total coronary artery occlusion on vascular endothelial growth factor and transforming growth factor beta. Kaohsiung J Med Sci. 2005;21:460-465.

12.    Munce NR, Strauss BH, Qi X, et al. Intravascular and extravascular microvessel formation in chronic total occlusions. A micro-CT imaging study. JACC Cardiovasc Imag. 2010;3:797-805.

13.    Finn AV, Kolodgie FD, Nakano M, Virmani V. The differences between neovascularization of chronic total occlusion and intraplaque angiogenesis. JACC Cardiovasc Imag. 2010;3:806-810. 

14.    Werner GS, Jandt E, Krack A, et al. Growth factors in the collateral circulation of chronic total coronary occlusions: relation to duration of occlusion and collateral function. Circulation. 2004;110:1940-1945.

15.    Heil M, Schaper W. Influence of mechanical, cellular, and molecular factors on collateral artery growth (arteriogenesis). Circ Res. 2004;95:449-458.

16.    Chen CH, Walterscheid JP. Plaque angiogenesis versus compensatory arteriogenesis in atherosclerosis. Circ Res. 2006;99:787-789.

17.    Royen NV, Piek JJ, Buschmann I, Voskul M, Schaper W. Stimulation of arteriogenesis; a new concept for the treatment of arterial occlusive disease. Cardiovasc Res. 2001;49:543-553.

18.    Schierling W, Troidl K, Troidl C, Schmitz-Rixen T, Schaper W, Eitenmuller IK. The role of angiogenic growth factors in arteriogenesis. J Vasc Res. 2009;46:365-374. 

19.    van Royen N, Piek JJ, Buschmann I, Hoefer I, Voskuil M, Schaper W. Stimulation of arteriogenesis; a new concept for the treatment of arterial occlusive disease. Cardiovasc Res. 2001;49:543-553.

20.    Sakakura K, Yahagi K, Virmani V, Joner M. Pathology of coronary chronic total occlusion. Int Cardiovasc Res J. 2016;10:55-60.

21.    Siegrist PT, Sumitsuji S. Chronic total occlusion: current methods of revascularization. Cardiovasc Med. 2014;17:347-356.

From Advocate Illinois Masonic Medical Center, Chicago, Illinois.

Address for correspondence: Lloyd W. Klein, MD, FSCAI, 3000 North Halsted, Suite 625, Chicago, IL 60614. Email: