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PART I
Pathology, Indications, and Review of Clinical Trials
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CHAPTER 1
The pathobiology of CTO
Sergey Yalonetsky, Azriel B. Osherov & Bradley H. Strauss
Schulich Heart Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada
Introduction
Chronic total occlusion (CTO) is defined as occlusion age of at least one month, with angiographic thrombolysis in myocardial infarction (TIMI) flow grade 0 or 1 [1]. CTOs are classified as âearly chronicâ and âlate chronicâ if their age is 1â3 months old and > 3 months old respectively. The current understanding of CTO development is based on animal CTO models as well as on autopsy and imaging studies in humans. Recent progress in elucidating CTO pathobiology has led our group to identify several novel biological Âtargets to facilitate guidewire crossing during percutaneous coronary intervention (PCI).
Current paradigm of CTO evolution
The development of CTOs includes several specific stages with unique histologic characteristics present at each stage. The initial acute event leading to the development of a CTO is in many cases a ruptured atherosclerotic plaque with bidirectional thrombus formation [2]. Clinically the arterial occlusion may develop insidiously with minimal symptoms or may present as an acute coronary syndrome. In patients with minimal or no symptoms, the timing of the occlusive event cannot be clearly identified. In fact, the age of approximately 60% of CTO cases cannot be reliably dated by symptoms [3]. In patients with ST segment elevation myocardial infarction (STEMI) not treated with reperfusion therapy, an occluded infarct related artery has been found in 87% of patients within 4 hours, in 65% within 12â24 hours, and in 45% at 1 month [4, 5]. Up to 30% of patients treated with thrombolytic therapy alone have a chronically occluded artery 3â6 months after MI [6]. In patients treated with percutaneous coronary intervention (PCI) during evolving acute myocardial infarction (AMI), approximately 6â11% will have chronic occlusion of an infarct related artery at 6 months, due to either initial treatment failure or late re-occlusion [7].
Characterization of CTO development in human studies is problematic since CTOs are often diagnosed at a very late stage, and data regarding initial stages in their evolution is lacking. Several animal models have been developed to systematically define the development stages of a CTO; however these models have Âcertain characteristics that could potentially limit their relevance to humans, such as the lack of underlying atherosclerotic substrate or significant calcification. In this chapter we shall review the current understanding of CTO pathobiology.
Development of CTOs
Acute arterial occlusion due to atherosclerotic plaque rupture with thrombus formation seems to be a Âcommon initiating event, which then triggers an inflammatory reaction. The freshly formed thrombus contains platelets and erythrocytes within a fibrin mesh, which is followed by an invasion of acute inflammatory cells. Jaffe et al. [8] have recently shown that an acute inflammatory response during the first 2 weeks after the initial event is accompanied by patchy formation of a proteolycan-enriched extracellular matrix and myofibroblast infiltration into the thrombotic occlusion. At the initial part of the intermediate stage (6 weeks), there is marked negative arterial remodeling and disruption of the internal elastic Âlamina accompanied by intense intraluminal neovascularization and increased CTO perfusion. Total microvessel cross-sectional area increases 2-fold along with a nearly 3-fold increase in the size of individual intraluminal vessels. However, the latter Âintermediate stage (12 weeks) is characterized by decreasing microvessel formation and CTO perfusion which further declines at the advanced stage (18â24 weeks). A progressive decrease in the CTO perfusion coincides with gradual replacement of proteoglycans by collagen in the extracellular matrix. Accumulation of collagen and calcium characterize the later stages of CTO maturation (Figures 1.1 and 1.2). The density of the fibrocalcific tissue is highest at the proximal and distal ends of the lesion compared to the body. Thus, the composition of the CTO evolves over time with remarkable spatial variability along the length of the CTO. From a pathobiology standpoint, three specific regions of the CTO have been identified:
(1) The proximal fibrous cap is a thickened structure at the entrance (the proximal end) of the CTO containing particularly densely packed collagen. It usually contains types I, III, V, and VI of collagen. Type IV collagen has also been observed in calcified tissues [9]. This region represents a distinct physical barrier to accessing the CTO.
(2) The distal fibrous cap also contains densely packed collagen, but is commonly regarded (although not proven in studies) as a thinner and softer structure compared to the proximal cap. This has been part of the rationale for developing the retrograde approach to cross the CTO.
(3) The main body of CTO.
Human coronary artery autopsy studies [10] have shown that the lumen of the CTO in some cases contains organized thrombus. Recanalization channels were observed in nearly 60% of lesions. Unlike the preclinical rabbit femoral artery model, the frequency of lumen recanalization and sizes of the channels were similar in different CTO ages. The intimal plaques within the CTO contained collagen, calcium, elastin, cholesterol clefts, foam cells, giant cell atherophagocytes, mononuclear cells (lymphocytes, monocytes), and red blood cells. âSoftâ or cholesterol-laden lesions were more prevalent in younger CTOs age (< 1 year); however the amount of cholesterol-laden and foam cells declined with advancing CTO age. Older age CTOs typically contained hard fibrocalcific lesions (âhard plaqueâ). Iron and hemosiderin depositions could be observed at sites of previous intimal plaque hemorrhage. Extensive recanalization of the intimal plaques by neovascular channels was frequently evident particularly within and adjacent to the sites infiltrated by inflammatory cells (lymphocytes and macrophages). In some cases, intimal neovascular channels directly communicate with adventitial vasa vasorum, while their communication with lumen recanalization channels was rarely observed. Neovascular channels were also observed in the vascular medial layer; the extent of medial neovascularization was proportional to the cellular inflammation in the intimal plaque. The adventitia of the vessel is usually extensively revascularized in CTOs of all ages. Again, the extent of adventitial neovascularization is correlated to adventitial cellular inflammation. Munce et al. have shown in a rabbit peripheral artery CTO model that a large rise in extravascular vessels surrounding the occluded artery occurred at early time points, which was followed by a significant increase in intravascular vessels within the central body of the occlusion. The temporal and geographic pattern of microvessel formation and the presence of connecting microvessels support the thesis that the extravascular vessels may indeed initiate formation of the intravascular channels within the center of the occlusion. However, as the CTO matures beyond 6 weeks, a reduction in the size and number of central intraÂvascular microchannels was demonstrated, suggesting that many of the vessels in this region become nonfunctional [11].
Neovascularization and angiogenesis
There are three types of microvessel formation in arteries with advanced atherosclerotic lesions. The first pattern occurs in the vasa vasorum, which is the fine network of microvessels in the adventitia and outer media. These vessels proliferate in atherosclerosis and in response to vascular injury such as angioplasty and stenting [10, 12, 13]. Hypoxia in the outer layers of the vessel wall appears to act as an important stimulus [13]. Occasionally in CTOs these adventitial blood vessels are well developed and can be recognized as âbridging collaterals.â Such microchannels, which can recanalize the distal lumen, may result from thrombus derived from angiogenic stimuli [14], and can be recognized on an angiogram by the appearance of a well defined stump leading into the CTO. Second, neovascularization can develop within occlusive atherosclerotic intimal plaques, predominantly in response to chronic inflammation [15]. The localization of plaque vessels in so-called âhot spotsâ in the shoulders of atheromas may predispose these plaques to rupture and acute coronary events [16, 17]. The third type is the pattern of intraluminal microvessel formation or ârecanalization channels.â These microvessels generally range in size from 100 to 200 Âľm, but can be as large as 500 Âľm [10]. In contrast to the vasa vasorum which run in radial direction, these intimal microvessels run within and parallel to the thrombosed parent vessel [16], and therefore have particular relevance for crossing of CTOs as a pathway for guidewire crossing.
Angiogenesis within the CTO is a complex process which starts with recanalization of the thrombus through a mechanism that is dependent on the proteolytic activity of circulating mononuclear cells and engraftment of endothelial progenitor cells [17]. Angiogenesis within the arterial thrombi is modulated by pro-angiogenic molecules in the extracellular matrix, including perlecan [18], hyaluronan [19], and anti-angiogenic agents such as collagen type I [20] and decorin [21]. The process of angiogenesis is initiated by vasodilation and increased permeability of the existing microvessels. This is followed by coordinated proteolysis, resulting in the destabilization of the Âvessel wall and endothelial cell migration and proÂliferation with subsequent formation of primitive endothelial tubes [22, 23]. Maturation of these tubes includes recruitment of pericytes or smooth muscle cells and deposition of extracellular matrix [24, 25]. Various aspects of angiogenesis are regulated by Âmultiple growth factors including vascular endothelial growth factor (VEGF) and its receptor VEGFR2; platelet derived growth factor (PDGF) and its receptor PDGFR-β [25, 26] , angiopoietin-1, angiopoetin -2, and TIE-2 receptor [21, 22, 24, 27 ], fibroblast growth factor-2 (FGF-2) [28], TGFβ [29], and endothelium derived nitric oxide [30].
Calcification
For non-CTO atherosclerotic plaques; calcification is correlated with chronic kidney disease, diabetes mellitus, and is a consequence of aging. Our understanding of the balance between promotion and inhibition of calcification in the CTO is much more limited.
Most CTOs contain calcification that ranges from minor to extensive, depending on several factors including the age of the occlusion [31]. Intimal plaque calcification is seen in 54% of CTOs aged 3 months or less, and reaches ...
