Kazuyuki Yahagi

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.

Has Our Understanding of Calcification in Human Coronary Atherosclerosis Progressed

Coronary artery calcification is a well-established predictor of future cardiac events; however, it is not a predictor of unstable plaque. The intimal calcification of the atherosclerotic plaques may begin with smooth muscle cell apoptosis and release of matrix vesicles and is almost always seen microscopically in pathological intimal thickening, which appears as microcalcification (≥0.5 &mgr;m, typically <15 &mgr;m in diameter). Calcification increases with macrophage infiltration into the lipid pool in early fibroatheroma where they undergo apoptosis and release matrix vesicles. The confluence of calcified areas involves extracellular matrix and the necrotic core, which can be identified by radiography as speckled (⩽2 mm) or fragmented (>2, <5 mm) calcification. The calcification in thin-cap fibroatheromas and plaque rupture is generally less than what is observed in stable plaques and is usually speckled or fragmented. Fragmented calcification spreads into the surrounding collagen-rich matrix forming calcified sheets, the hallmarks of fibrocalcific plaques. The calcified sheets may break into nodules with fibrin deposition, and when accompanied by luminal protrusion, it is associated with thrombosis. Calcification is highest in fibrocalcific plaques followed by healed plaque rupture and is the least in erosion and pathological intimal thickening. The extent of calcification is greater in men than in women especially in the premenopausal period and is also greater in whites compared with blacks. The mechanisms of intimal calcification remain poorly understood in humans. Calcification often occurs in the presence of apoptosis of smooth muscle cells and macrophages with matrix vesicles accompanied by expression of osteogenic markers within the vessel wall.

Long-Term Safety of an Everolimus-Eluting Bioresorbable Vascular Scaffold and the Cobalt-Chromium XIENCE V Stent in a Porcine Coronary Artery Model

Background—The Absorb everolimus-eluting bioresorbable vascular scaffold (Absorb) has shown promising clinical results; however, only limited preclinical data have been published. We sought to investigate detailed pathological responses to the Absorb versus XIENCE V (XV) in a porcine coronary model with duration of implant extending from 1 to 42 months. Methods and Results—A total of 335 devices (263 Absorb and 72 XV) were implanted in 2 or 3 main coronary arteries of 136 nonatherosclerotic swine and examined by light microscopy, scanning electron microscopy, pharmacokinetics, and gel permeation chromatography analyses at various time points. Vascular responses to Absorb and XV were largely comparable at all time points, with struts being sequestered within the neointima. Inflammation was mild to moderate (with absence of inflammation at 1 month) for both devices, although the scores were greater in Absorb at 6 to 36 months. Percent area stenosis was significantly greater in Absorb than XV at all time points except at 3 months. The extent of fibrin deposition was similar between Absorb and XV, which peaked at 1 month and decreased rapidly thereafter. Histomorphometry showed expansile remodeling of Absorb-implanted arteries starting after 12 months, and lumen area was significantly greater in Absorb than XV at 36 and 42 months. These changes correlated with dismantling of Absorb seen after 12 months. Gel permeation chromatography analysis confirmed that degradation of Absorb was complete by 36 months. Conclusions—Absorb demonstrates comparable long-term safety to XV in porcine coronary arteries with mild to moderate inflammation. Although Absorb was associated with greater percent stenosis relative to XV, expansile remodeling was observed after 12 months in Absorb with significantly greater lumen area at ≥36 months. Resorption is considered complete at 36 months.

Thrombus formation following transcatheter aortic valve replacement.

OBJECTIVES This paper reviews the published data and reports 3 cases of thrombosis involving CoreValve (Medtronic, Minneapolis, Minnesota) and 1 involving Edward Sapien (Edwards Lifesciences, Irvine, California) devices. Three of these cases had pathological findings at autopsy. BACKGROUND Only a limited number of cases of valve dysfunction with rapid increase of transvalvular aortic gradients or aortic insufficiency post-transcatheter aortic valve replacement (TAVR) have been described. This nonstructural valvular dysfunction has been presumed to be because of early pannus formation or thrombosis. METHODS Through reviews of the published reports and 4 clinical cases, pathological and clinical findings of early valve thrombosis are examined to elucidate methods for recognition and identifying potential causes and treatments. RESULTS This paper presents 4 cases, 2 of which had increasing gradients post-TAVR. All 3 pathology cases showed presence of a valve thrombosis in at least 2 TAV leaflets on autopsy, but were not visualized by transthoracic echocardiogram or transesophageal echocardiogram. One case was medically treated with oral anti coagulation with normalization of gradients. The consequence of valve thrombosis in all 3 pathology patients either directly or indirectly played a role in their early demise. At least 18 case reports of early valve thrombosis have been published. In 12 of these cases, the early treatment with anticoagulation therapy resolved the thrombus formation and normalized aortic pressures gradients successfully. CONCLUSIONS These 4 cases elucidate the occurrence of valve thrombosis post-TAVR. Consideration should be given to treatment with dual antiplatelet therapy and oral anticoagulation in patients post-TAVR with increasing mean pressure gradients and maximum aortic valve velocity. Further research should be conducted to create guidelines for antithrombotic therapy following TAVR procedure.

Sex differences in coronary artery disease: Pathological observations

Cardiovascular disease (CVD) remains the most frequent cause of death in both men and women. Many studies on CVD have included mostly men, and the knowledge about coronary artery disease (CAD) in women has largely been extrapolated from studies primarily focused on men. The influence of various risk factors is different between men and women; untoward effects of smoking of CAD are greater in women than men. Furthermore, the effect of the menopause is important in women, with higher incidence of plaque erosion in young women versus greater incidence of plaque rupture in older women. This review focuses on differences in plaque morphology in men and women presenting with sudden coronary death and acute myocardial infarction.

Why is the mammary artery so special and what protects it from atherosclerosis

The internal mammary artery (IMA) grafts have been associated with long-term patency and improved survival as compared to saphenous vein grafts (SVGs). Early failure of IMA is attributed to poor surgical technique and less with thrombosis. Similarly, bypass surgery especially with the use of IMA has also been shown to be superior at 1-year as well as over five years compared to percutaneous procedures, including the use of drug-eluting stents for the treatment of coronary artery disease. The superiority of IMAs over SVGs can be attributed to its striking resistance to the development of atherosclerosis. Structurally its endothelial layer shows fewer fenestrations, lower intercellular junction permeability, greater anti-thrombotic molecules such as heparin sulfate and tissue plasminogen activator, and higher endothelial nitric oxide production, which are some of the unique ways that make the IMA impervious to the transfer of lipoproteins, which are responsible for the development of atherosclerosis. A better comprehension of the molecular resistance to the generation of adhesion molecules that are involved in the transfer of inflammatory cells into the arterial wall that also induce smooth muscle cell proliferation is needed. This basic understanding is crucial to championing the use of IMA as the first line of defense for the treatment of coronary artery disease.

Comparison of pathology of chronic total occlusion with and without coronary artery bypass graft

AIMS The aim of our study was to investigate chronic total occlusion (CTO) in human coronary arteries to clarify the difference between CTO with prior coronary artery bypass graft (CABG) and those without prior CABG. METHODS AND RESULTS A total of 95 CTO lesions from 82 patients (61.6 ± 14.0 years, male 87.8%) were divided into the following three groups: CTO with CABG (n = 34) (CTO+CABG), CTO without CABG--of long-duration (n = 49) (LD-CTO) and short-duration (n = 12) (SD-CTO). A histopathological comparison of the plaque characteristics of CTO, proximal and distal lumen morphology, and negative remodelling between groups was performed. A total of 1127 sections were evaluated. Differences in plaque characteristics were observed between groups as follows: necrotic core area was highest in SD-CTO (18.6%) (LD-CTO: 7.8%; CTO+CABG: 4.5%; P = 0.02); calcified area was greatest in CTO+CABG (29.2%) (LD-CTO: 16.8%; SD-CTO: 12.1%; P = 0.009); and negative remodelling was least in SD-CTO [remodelling index (RI) 0.86] [CTO+CABG (RI): 0.72 and LD-CTO (RI): 0.68; P < 0.001]. Approximately 50% of proximal lumens showed characteristics of abrupt closure, whereas the majority of distal lumen patterns were tapered (79%) (P < 0.0001). CONCLUSION These pathological differences in calcification, negative remodelling, and presence of necrotic core along with proximal and distal tapering, which has been associated with greater success, help explain the differences in success rates of percutaneous coronary intervention in CTO patients with and without CABG.

Pathology of Human Coronary and Carotid Artery Atherosclerosis and Vascular Calcification in Diabetes Mellitus

The continuing increase in the prevalence of diabetes mellitus in the general population is predicted to result in a higher incidence of cardiovascular disease. Although the mechanisms of diabetes mellitus-associated progression of atherosclerosis are not fully understood, at clinical and pathological levels, there is an appreciation of increased disease burden and higher levels of arterial calcification in these subjects. Plaques within the coronary arteries of patients with diabetes mellitus generally exhibit larger necrotic cores and significantly greater inflammation consisting mainly of macrophages and T lymphocytes relative to patients without diabetes mellitus. Moreover, there is a higher incidence of healed plaque ruptures and positive remodeling in hearts from subjects with type 1 diabetes mellitus and type 2 diabetes mellitus, suggesting a more active atherogenic process. Lesion calcification in the coronary, carotid, and other arterial beds is also more extensive. Although the role of coronary artery calcification in identifying cardiovascular disease and predicting its outcome is undeniable, our understanding of how key hormonal and physiological alterations associated with diabetes mellitus such as insulin resistance and hyperglycemia influence the process of vascular calcification continues to grow. Important drivers of atherosclerotic calcification in diabetes mellitus include oxidative stress, endothelial dysfunction, alterations in mineral metabolism, increased inflammatory cytokine production, and release of osteoprogenitor cells from the marrow into the circulation. Our review will focus on the pathophysiology of type 1 diabetes mellitus- and type 2 diabetes mellitus-associated vascular disease with particular focus on coronary and carotid atherosclerotic calcification.

Human autopsy study of drug-eluting stents restenosis: histomorphological predictors and neointimal characteristics

AIMS Restenosis in drug-eluting stents (DESs) occurs infrequently, however, it remains a pervasive clinical problem. We interrogated our autopsy registry to determine the underlying mechanisms of DES restenosis, and further we investigated the neointimal characteristics of DESs and compared with bare metal stents (BMSs). METHODS AND RESULTS Coronary lesions from patients with DES implants (n = 82) were categorized into four groups based on cross-sectional area narrowing: patent (<50%), intermediate (50-74%), restenotic (≥ 75% with residual lumen), and total occlusion (organized thrombus within the stent). Restenosis and occlusion were significantly dependent on the total stented length: restenosis (26.7 mm) and occlusion (25.7 mm) compared with patent DESs (17.3 mm). Further, restenotic and occluded lesions were located more distally in the coronary arteries and had greater vessel injury and uneven strut distribution suggesting local drug gradient. Multivariate analysis revealed that normalized maximum inter-strut distance was associated with DES restenosis (OR: 17.4, P = 0.04) while medial tear length was a predictor of DES occlusion (OR: 5.1, P = 0.03). No differences were observed between different DESs (sirolimus-, paclitaxel-, and everolimus-eluting stents) for restenosis and occlusion. Further, neointimal compositions of restenotic DESs demonstrated greater proteoglycan deposition and less smooth muscle cellularity over time, when compared with BMS with greater cell density and collagen deposition. CONCLUSIONS Our study indicates the impacts of inadequate drug concentration due to wider inter-strut distance and vessel injury as primary mechanisms of DES restenosis and occlusion, respectively. Moreover, the differences in neointimal compositions between DESs and BMSs might serve as a potential target for the suppression of late neointima growth via inhibition of proteoglycans in DESs.

Thrombogenicity and Early Vascular Healing Response in Metallic Biodegradable Polymer-Based and Fully Bioabsorbable Drug-Eluting Stents

Background—Acute thrombogenicity and re-endothelialization represent clinically relevant end points pertaining to the safety of coronary stents, which have not been compared among biodegradable polymer-based drug-eluting metallic stents and fully bioabsorbable scaffolds to date. Methods and Results—We investigated comparative outcomes with respect to acute thrombogenicity and re-endothelialization among thin-strut biodegradable polymer metallic everolimus eluting stents (EES), thick-strut fully bioabsorbable EES, thick-strut biodegradable polymer metallic biolimus-eluting stents and control bare metal stents. An ex-vivo porcine arterio-venous shunt model was used to assess platelet aggregation, whereas a healthy rabbit model of iliofemoral stent implantation was used to assess re-endothelialization and inflammation. Confocal microscopy was used to detect fluorescently labeled antibody staining directed against CD61/CD42b for the identification of aggregated thrombocytes, CD14/PM-1, and RAM-11 for identification of neutrophils and monocytes/macrophages. Endothelial recovery was assessed by scanning electron microscopy, whereas CD31/PECAM-1 was used to confirm endothelial maturity. EES demonstrated significantly less acute thrombogenicity compared with bioabsorbable EES and biolimus-eluting stents. EES showed greater re-endothelialization at 28 days and reduced inflammatory cell adhesion of monocytes/macrophages at 14 days compared with bioabsorbable EES. Only bare metal stents showed complete re-endothelialization at 28 days. Conclusions—These outcomes indicate differential trends in thrombogenicity and vascular healing among contemporary stents used in clinical practice and suggest a need for long-term adjunct antithrombotic pharmacotherapy for bioabsorbable EES.