Neoatherosclerosis: overview of histopathologic findings and implications for intravascular imaging assessment.

Despite the reduction in late thrombotic events with newer-generation drug-eluting stents (DES), late stent failure remains a concern following stent placement. In-stent neoatherosclerosis has emerged as an important contributing factor to late vascular complications including very late stent thrombosis and late in-stent restenosis. Histologically, neoatherosclerosis is characterized by accumulation of lipid-laden foamy macrophages within the neointima with or without necrotic core formation and/or calcification. The development of neoatherosclerosis may occur in months to years following stent placement, whereas atherosclerosis in native coronary arteries develops over decades. Pathologic and clinical imaging studies have demonstrated that neoatherosclerosis occurs more frequently and at an earlier time point in DES when compared with bare metal stents, and increases with time in both types of implant. Early development of neoatherosclerosis has been identified not only in first-generation DES but also in second-generation DES. The mechanisms underlying the rapid development of neoatherosclerosis remain unknown; however, either absence or abnormal endothelial functional integrity following stent implantation may contribute to this process. In-stent plaque rupture likely accounts for most thrombotic events associated with neoatherosclerosis, while it may also be a substrate of in-stent restenosis as thrombosis may occur either symptomatically or asymptomatically. Intravascular optical coherence tomography is capable of detecting neoatherosclerosis; however, the shortcomings of this modality must be recognized. Future studies should assess the impact of iterations in stent technology and risk factor modification on disease progression. Similarly, refinements in imaging techniques are also warranted that will permit more reliable detection of neoatherosclerosis.

In stent restenosis and thrombosis assessment after EP224283 injection in a rat model.

OBJECTIVE: After stent implantation, platelet aggregation and thrombus formation are thought to play a key role in the early phase of in-stent restenosis (ISR). Drug-eluting stents have reduced ISR, but are associated with healing-related issues or hypersensitivity reactions, leading to an increased risk of late acute stent thrombosis. EP224283 is a new dual-action antithrombotic molecule combining a GPIIbIIIa antagonist and a factor Xa inhibitor. We investigated its efficacy on restenosis in a rat model of ISR and on platelet adhesion. METHODS AND RESULTS: Rat aortas were stented and the animals received either EP224283 or vehicle subcutaneously every 48 h. At day 7 and day 28 after surgery, the stented aortas were removed and processed for morphometric analysis or protein analysis. At day 28, EP224283 significantly reduced neointima growth (in the range of 20%). Protein analysis revealed that EP224283 reduced cell proliferation pathways: ERK1/2 and Akt were down-regulated and p38 up-regulated. Expression of Ki67 was also reduced. In vitro assessment depicted a reduction of platelet activation and platelet adhesion among treated rats. CONCLUSION: These results show a beneficial effect of EP224283 on in-stent restenosis and on stent thrombogenicity that may improve results after stent implantation. Further investigations are required to assess the efficacy of a local delivery of EP224283 on both acute thrombosis and ISR.

Optical coherence tomography for the assessment of pericardium covered stents for the treatment of degenerated saphenous vein grafts.

AIMS: Pre- and post-interventional optical coherence tomography (OCT) assessment of degenerated saphenous vein grafts (SVG) treated with implantation of pericardium covered stents. Percutaneous treatment of SVG represents one of the major challenges of current percutaneous coronary interventions (PCI). Artificial membrane-covered stents have failed to show additional benefit over conventional stents. METHODS AND RESULTS: Six cases of PCI of de novo lesions in degenerated SVGs were successfully treated with a novel pericardium covered stent (PCS). Successful deployment was achieved in all cases. Large emboli were retrieved in a distal filter in one case with a long degenerated lesion. Pre- and postinterventional OCT was performed to assess the lesion characteristics and vessel diameter before stenting and the pericardium layer integrity, strut apposition and presence of plaque prolapse after stenting. In order to better understand the OCT images, three PCS of different diameters were deployed in silicone tubes of 700 microm thickness wall with inner tube diameter matching the stent diameter. OCT was repeated after spreading a thin layer of gel inside the tube, mimicking the toothpaste-like plaque observed in SVG. In vivo and in vitro OCT images excluded the presence of plaque prolapse in all but one case and detected a characteristic pattern with bulging of the pericardium between struts, possibly due to trapping of soft intraluminal plaque (or gel) behind the pericardial layer. CONCLUSIONS: These cases offer insight into the mechanism of protection against distal embolisation, elucidated by the appearance of these stents after deployment in vivo and in vitro.

Optical coherence tomography (OCT) in secondary revascularisation: stent and graft assessment.

Optical coherence tomography is a recently introduced intracoronary imaging modality with higher spatial resolution than intravascular ultrasound. For this reason, it is increasingly applied to investigate the characteristics of vulnerable atheromatous plaques and the result of stent implantation, struts coverage and restenosis, as well as in procedural decision-making. OCT is also useful in the field of secondary revascularisation, particularly in assessing implanted stents, evaluating relevant technologies like biodegradable stents, and in studying surgical grafts. In this article we perform a review of current developments and evidence in this area.

Peri-stent reference segment plaque burden is associated with disease progression in saphenous vein grafts (a serial intravascular ultrasound assessment).

We are aware of no studies of peri-stent disease progression or luminal compromise in saphenous vein graft (SVG) lesions. We used serial intravascular ultrasound (IVUS) to assess disease progression in peri-stent saphenous vein bypass graft reference segments. We studied 37 peri-stent SVG reference segments in 21 patients; 16 were proximal and 21 were distal to the stent. The same anatomic image slice was analyzed after the intervention and at follow-up; this site was 3.68 +/- 2.22 mm from the stent edge. Graft age was 10.1 +/- 5.4 years, and mean follow-up duration was 13 months (range 3 to 61). Overall, change in SVG area, change in lumen area, and change in plaque burden correlated with postintervention plaque burden (r = 0.448, p = 0.005; r = -0.584, p <0.001; and r = 0.507, p = 0.001, respectively). For the proximal edge, change in lumen area correlated with change in plaque area (r = -0.951, p <0.001), but not with change in SVG area (r = -0.337, p = 0.201). For the distal edge, change in lumen area correlated more strongly with change in plaque area (r = -0.982, p <0.001) than with change in SVG area (r = -0.624, p = 0.003). When peri-stent reference segments were divided into 2 groups according to postintervention plaque burden (>50% [n = 20] vs <50% [n = 17]), there was a greater decrease in lumen area (-1.12 +/- 0.81 vs -0.33 +/- 0.26 mm(2), p <0.001) and greater increases in SVG area (0.26 +/- 0.29 vs 0.09 +/- 0.09 mm(2), p = 0.027), plaque area (1.37 +/- 0.96 vs 0.42 +/- 0.30 mm(2), p <0.001), and plaque burden (8.2 +/- 5.6% vs. 2.8 +/- 1.6%, p <0.001) in segments with a plaque burden >50%. In conclusion, peri-stent reference segment SVG disease progression and lumen loss were more significant in segments with a greater postintervention plaque burden after implantation of a bare metal stent or drug-eluting stent.

Graft coronary artery disease in murine cardiac allografts: proposal to meet the need for standardized assessment.

BACKGROUND: Inconsistency exists in assessing the severity of graft coronary artery disease (GCAD) in studies that use mouse models. The central issue associated with this inconsistency is the lack of a standardized approach for assessing mouse GCAD. METHODS: We propose a new histologic definition of GCAD based on 3 successive stages (endotheliitis, premature lesion, and mature lesion) that mark the progression of this condition. In addition to these qualitative measures of GCAD, we propose including 2 additional morphometric parameters (percentage of luminal narrowing and intima-to-media ratio) and a measure of distribution (percentage of affected vessels) in the routine quantification of GCAD. RESULTS: We introduce 2 new mouse models of GCAD as examples that satisfy these criteria. CONCLUSION: The proposed assessment criteria may simplify data collection and interpretation of results in various models of GCAD.

Assessment of internal mammary artery and saphenous vein graft patency and flow reserve using transthoracic Doppler echocardiography.

OBJECTIVE: To investigate transthoracic Doppler echocardiography in the identification of coronary artery bypass graft (CABG) flow for assessing graft patency. DESIGN: The initial study group comprised 45 consecutive patients with previous CABG undergoing elective cardiac catheterisation for recurrent ischaemia. The Doppler variables best correlated with angiographic graft patency were then tested prospectively in a further 84 patients (test group). SETTING: Three tertiary referral centres. INTERVENTIONS: Flow velocities in grafts were recorded at rest and during hyperaemia induced by dipyridamole (0.56 mg/kg/4 min), under the guidance of transthoracic colour Doppler flow mapping. Findings on transthoracic Doppler were compared with angiography. MAIN OUTCOME MEASURES: Feasibility of identifying open grafts by Doppler and diagnostic accuracy for Doppler detection of significant (>/= 70%) graft stenosis. RESULTS: In the test group the identification rate for mammary artery grafts was 100%, for saphenous vein grafts to left anterior descending coronary artery 91%, for vein grafts to right coronary artery 96%, and for vein grafts to circumflex artery 90%. Coronary flow reserve (the ratio between peak diastolic velocity under hyperaemia and at baseline) of < 1.9 (95% confidence interval 1.83 to 2.08) had 100% sensitivity, 98% specificity, 87.5% positive predictive value, and 100% negative predictive value for mammary artery graft stenosis. Coronary flow reserve of < 1.6 (95% CI 1.51 to 1.73) had 91% sensitivity, 87% specificity, 85.4% positive predictive value, and 92.3% negative predictive value for significant vein graft stenosis. CONCLUSIONS: Transthoracic Doppler can provide non-invasive assessment of CABG patency.

Vein quality in infrainguinal revascularisation: assessment by angioscopy and histology.

The concept of vein quality has been slow to gain widespread acceptance, but an increasing body of evidence suggests that vein quality is relevant to the success of bypass grafting for peripheral vascular disease. The angioscope represents an additional tool for monitoring and preparing vein grafts during infrainguinal revascularisation. Within the overall theme of vein quality, this paper presents the cumulative experience with vascular endoscopy at Bristol Royal Infirmary. In clinical studies, the diagnostic role of angioscopy in quality control was evaluated by grafting preexisting, angioscopically detected, intraluminal abnormalities and correlating them with histological appearances. There were significant associations between angioscopy/histology grades and graft patency. To enable quantification of images, an innovative computerised video image processing method has been developed and validated against simultaneous ultrasound measurements of segments of saphenous vein. The therapeutic applications of angioscopy in vein graft preparation were studied prospectively in patients undergoing in situ femoropopliteal/distal bypasses by randomisation to full angioscopic or conventional preparation. There was a significant reduction in wound morbidity. Completion angioscopy and arteriography were complementary in the detection of technical defects. Harvested vein was maintained in organ culture to assess further the influence of pre-existing pathology and the potentially traumatic effects of angioscopy on development of neointimal hyperplasia. There was a significant correlation between the extent of pre-existing abnormality and smooth muscle cell proliferative activity in culture and although angioscopy caused endothelial cell loss, this did not stimulate neointimal hyperplasia in vitro. This work confirms that vein quality can be evaluated prospectively by angioscopy and that substandard vein is associated with inferior patency rates. Angioscopic and histological evaluation, together with vein organ culture studies, have definite application in helping to elucidate the mechanisms underlying graft failure.

Intimal fibromuscular hyperplasia at the venous anastomosis of PTFE grafts in hemodialysis patients. Clinical, immunocytochemical, light and electron microscopic assessment.

Failure of arteriovenous communications used for chronic hemodialysis was studied during sequential 5-year periods after placement of either endogenous Brescia-Cimino (B-C) fistulas (50 patients) or polytetrafluoroethylene (PTFE, Gore-Tex) grafts (66 patients). Venous stenosis near the anastomosis was the reason for failure in 45% of PTFE grafts compared with 16% of B-C fistulas (p less than 0.001). Failure occurred, on average, 16 months after PTFE graft placement compared with 22 for B-C fistulas (p = NS). Proximal vein segments removed from five failed and two functioning PTFE graft communications were studied using light and electron microscopy and immunocytochemical techniques. All venous segments removed during surgical shunt repair exhibited a marked intimal hyperplasia. The intimal cellular component was almost exclusively smooth muscle. Accumulation of intracellular lipid droplets was not seen. Foam cells as well as extracellular lipid deposits were absent; macrophages and lymphocytes were absent from the zone of proliferation. Ultrastructural examination revealed a large proportion of extracellular matrix surrounding smooth muscle cells in the neointima. Collagen and elastin were present in the extracellular matrix, in greatest concentration deeper in the intima. Closer to the lumen, most of the extracellular volume consisted of proteoglycan. Hemosiderin was absent from the lesions as were consistent signs of luminal and intimal fibrin. Uniform intimal gradients of actin, collagen, and proteoglycan suggest that this is a steadily progressive, rather than episodic, proliferative response. These clinical and histologic observations and an analysis of hemodynamic stresses support the postulate that upstream release of platelet-derived growth factor, and possibly, shear-induced intimal injury stimulate this response. This myointimal proliferative process provides a readily accessible model of fibromuscular hyperplasia in humans; its understanding may lead to effective methods for its prevention and may provide clues to the pathogenesis of arteriosclerosis.

A laboratory model for the evaluation of thromboembolic complications of small diameter vascular prostheses.

Seventeen 2 mm and twenty-five 3 mm internal diameter petrafluoroethylene (PTFE) vascular prostheses were inserted as aortic interposition grafts in 42 rabbits. The 3 month patency with 2 mm grafts was disappointingly low at 24% whereas patency with 3 mm grafts was 82%, comparable to other studies of small diameter prostheses. Hind limb paralysis occurred in 18 animals and proved a reliable indicator of graft thrombosis. Unexpected and previously unreported lower limb ulceration occurred in nine of the 23 long term survivors. Angiographic studies indicated that these ulcers were due to distal embolization of loosely attached mural thrombi. These were found in four of eight patent grafts removed from animals with leg ulcers. Aortic grafting in the rabbit is an economic model for the study of thromboembolic phenomena in small diameter vascular prostheses and their modification by pharmacological agents.