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We investigated whether local hemodynamics were associated with sites of plaque erosion and hypothesized that patients with plaque erosion have locally elevated WSS magnitude in regions where erosion has occurred.We generated 3D, patient-specific models of coronary arteries from biplane angiographic images in 3 human patients with plaque erosion diagnosed by optical coherence tomography (OCT). Using computational fluid dynamics, we simulated pulsatile blood flow and calculated both wall shear stress (WSS) and oscillatory shear index (OSI). We also investigated anatomic features of plaque erosion sites by examining branching and local curvature in x-ray angiograms of barium-perfused autopsy hearts.Neither high nor low magnitudes of mean WSS were associated with sites of plaque erosion. OSI and local curvature were also not associated with erosion. Anatomically, 8 of 13 hearts had a nearby bifurcation upstream of the site of plaque erosion.This study provides preliminary evidence that neither hemodynamics nor anatomy are predictors of plaque erosion, based upon a very unique dataset. Our sample sizes are small, but this dataset suggests that high magnitudes of wall shear stress, one potential mechanism for inducing plaque erosion, are not necessary for erosion to occur.

Coronary angiographic studies conducted over 20 years ago helped confirm thrombosis as the cause of acute myocardial infarction (AMI) ([1][1]). However, with the emerging newer technologies, the limitations of conventional angiography for furthering our understanding of the pathophysiology of AMI

Background and aims It is well known that the interaction between platelets (PLTs), endothelial cells, and leukocytes contributes to thrombosis in patients with acute coronary syndrome. The aim of this study was to investigate the significance of PLTs and eosinophils (EOS) in coronary arterial thrombi. Methods PLT count, mean PLT volume, PLT mass, EOS count, EOS percentage, and troponin I level in peripheral blood were determined in 81 patients with angina pectoris (AP) and 49 patients with acute myocardial infarction (AMI). A total of 12 thrombus specimens from AMI patients were submitted for histopathological analysis. EOS presence in thrombectomy specimens were checked by hematoxylin–eosin staining and confirmed by Luna staining. Results Results showed that EOS were present in all 12 samples (100%). Cell count and percentage of EOS in peripheral blood of patients with AMI were lower than those in patients with AP (both P

Objectives To investigate the safety and efficacy of durable polymer drug eluting stents (DES) and biodegradable polymer biolimus eluting stents (biolimus-ES). Design: Network meta-analysis of randomised controlled trials. Data sources and study selection: Medline, Google Scholar, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) database search for randomised controlled trials comparing at least two of durable polymer sirolimus eluting stents (sirolimus-ES) and paclitaxel eluting stents (paclitaxel-ES), newer durable polymer everolimus eluting stents (everolimus-ES), Endeavor and Resolute zotarolimus eluting stents (zotarolimus-ES), and biodegradable polymer biolimus-ES. Primary outcomes: Safety (death, myocardial infarction, definite or probable stent thrombosis) and efficacy (target lesion and target vessel revascularisation) assessed at up to one year and beyond. Results: 60 randomised controlled trials were compared involving 63 242 patients with stable coronary artery disease or acute coronary syndrome treated with a DES. At one year, there were no differences in mortality among devices. Resolute and Endeavor zotarolimus-ES, everolimus-ES, and sirolimus-ES, but not biodegradable polymer biolimus-ES, were associated with significantly reduced odds of myocardial infarction (by 29-34%) compared with paclitaxel-ES. Compared with everolimus-ES, biodegradable polymer biolimus-ES were associated with significantly increased odds of myocardial infarction (by 29%), while Endeavor zotarolimus-ES and paclitaxel-ES were associated with significantly increased odds of stent thrombosis. All investigated DES were similar with regards to efficacy endpoints, except for Endeavor zotarolimus-ES and paclitaxel-ES, which were associated with significantly increased the odds of target lesion and target vessel revascularisations compared with other devices. Direction of results beyond one year did not diverge from the findings for up to one year follow-up. Bayesian probability curves showed a gradient in the magnitude of effect, with everolimus-ES and Resolute zotarolimus-ES offering the highest safety profiles. Conclusions: The newer durable polymer everolimus-ES and Resolute zotarolimus-ES and the biodegradable polymer biolimus-ES maintain the efficacy of sirolimus-ES; however, for safety endpoints, differences become apparent, with everolimus-ES and Resolute zotarolimus-ES emerging as the safest stents to date

Background— Clinical trials have demonstrated that the second-generation cobalt-chromium everolimus-eluting stent (CoCr-EES) is superior to the first-generation paclitaxel-eluting stent (PES) and is noninferior or superior to the sirolimus-eluting stent (SES) in terms of safety and efficacy. It remains unclear whether vascular responses to CoCr-EES are different from those to SES and PES because the pathology of CoCr-EES has not been described in humans. Methods and Results— A total of 204 lesions (SES=73; PES=85; CoCr-EES=46) from 149 autopsy cases with duration of implantation >30 days and ≤3 years were pathologically analyzed, and comparison of vascular responses was corrected for duration of implantation. The observed frequency of late and very late stent thrombosis was less in CoCr-EES (4%) versus SES (21%; P =0.029) and PES (26%; P =0.008). Neointimal thickness was comparable among the groups, whereas the percentage of uncovered struts was strikingly lower in CoCr-EES (median=2.6%) versus SES (18.0%; P P P =0.007 for CoCr-EES versus SES), whereas fracture-related restenosis or thrombosis was comparable among the groups (CoCr-EES=6.5%; SES=5.5%; PES=1.2%). Conclusions— CoCr-EES demonstrated greater strut coverage with less inflammation, less fibrin deposition, and less late and very late stent thrombosis compared with SES and PES in human autopsy analysis. Nevertheless, the observed frequencies of neoatherosclerosis and fracture-related adverse pathological events were comparable in these devices, indicating that careful long-term follow-up remains important even after CoCr-EES placement.

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 (

Background With hybrid coronary revascularization (HCR), minimally invasive left internal mammary artery (LIMA) to left anterior descending coronary artery (LAD) grafting is combined with percutaneous coronary intervention (PCI) of non-LAD vessels. The purpose of this study was to examine the short-term clinical and angiographic results in one of the largest HCR series to date. Methods From 2003 to 2012, 300 consecutive patients (aged 64 ± 12 years, female 31.7%, predicted risk of mortality 1.6% ± 2.1%) underwent HCR on an intent-to-treat basis at a single institution. After robotic or thoracoscopic LIMA harvest, off-pump LIMA to LAD grafting was performed through a 3- to 4-cm sternal-sparing, non–rib-spreading thoracotomy. PCI was utilized to treat non-LAD lesions either before, after, or concomitant with the surgical procedure. Results Of the 300 patients undergoing HCR on an intent-to-treat basis, HCR was performed with surgery first in 192 patients (64.0%), PCI first in 56 (18.7%), and as a concomitant procedure in 21 (7.0%). Of the 31 patients (10.1%) who did not undergo HCR, 24 patients (8.0%) did not have PCI and thus were incompletely revascularized. For all patients, 30-day mortality, stroke, and nonfatal myocardial infarction occurred in 4 (1.3%), 3 (1.0%), and 4 (1.3%), respectively. Angiographic LIMA evaluation was performed in 248 patients and revealed a FitzGibbon A LIMA patency rate of 97.6% (242 of 248 patients). Repeat revascularization was required in 13 of 300 patients (4.3%). Conclusions Hybrid coronary revascularization represents an alternative approach for patients with multivessel coronary disease with excellent short-term outcomes. It provides a minimally invasive alternative to traditional coronary artery bypass graft surgery and may prove more durable than multivessel PCI.

Metformin impairs endothelialization of drug eluting stents (DES) due to convergent signaling at the mammalian target of rapamycin (mTOR) pathway. We assessed whether metformin will continue to adversely affect stent endothelialization despite design improvements in newer generation DES.Rabbit iliac artery stenting with newer generation DES was performed followed by 14 days of either normal chow diet or one with metformin (100 mg/kg/day) added. Scanning electron microscopy was used to assess stent endothelialization after sacrifice.In the metformin-treated group there was significantly less endothelialization compared to the placebo-treated group. Paclitaxel-eluting stents in placebo-treated group had the greatest degree of endothelialization with significantly less in its metformin-treated counterpart and all-limus eluting stent groups.Metformin inhibited stent endothelialization in newer generation DES despite improvements in stent design. By impairing stent endothelialization, metformin may increase the risk for thrombotic complications after newer generation DES placement.

Although mortality rates from coronary heart disease in the western countries have declined in the last few decades, morbidity caused by this disease is increasing and a substantial number of patients still suffer acute coronary syndrome (ACS) and sudden cardiac death. Acute coronary syndrome occurs as a result of myocardial ischaemia and its manifestations include acute myocardial infarction and unstable angina. Culprit plaque morphology in these patients varies from thrombosis with or without coronary occlusion to sudden narrowing of the lumen from intraplaque haemorrhage. The coronary artery plaque morphologies primarily responsible for thrombosis are plaque rupture, and plaque erosion, with plaque rupture being the most common cause of acute myocardial infarction, especially in men. Autopsy data demonstrate that women

Drug eluting stents have decreased the rate of ISR. Concurrently DES increase the rate of neoatherosclerosis (NA) which occurs more rapid and frequent compared to BMS. The mechanism of accelerated NA remains elusive. mTOR inhibitors released from the DES which prevent proliferation of smooth muscle

Clinical data indicates differences in acute thrombosis among different drug-eluting stents (DES), which may relate to properties of DES polymer coatings and stent design. We sought to investigate differences between a durable fluoropolymer coated DES (Xience Alpine, X-EES, Abbott Vascular), an

Alternative macrophages exist in human atherosclerosis but their role in atherogenesis remains uncertain. Intraplaque hemorrhage (IPH) is an important stimulus driving alternative macrophage polarization. Intake of hemoglobin (Hb) by the hemoglobin: haptoglobin receptor CD163 leads to a distinct non

Data linking intraplaque hemorrhage with atherosclerosis lesion progression have mainly been derived from pathological studies ([1][1]). In the individuals who had died of sudden cardiac death, the frequency of previous intraplaque hemorrhage (IPH) in the culprit coronary atherosclerotic lesions or

Background Extremes of wall shear stress ( WSS ) have been associated with plaque progression and transformation, which has raised interest in the clinical assessment of WSS . We hypothesized that calculated coronary WSS is predicted only partially by luminal geometry and that WSS is related to plaque composition. Methods and Results Twenty‐seven patients with coronary artery disease underwent virtual histology intravascular ultrasound and Doppler velocity measurement for computational fluid dynamics modeling for WSS calculation in each virtual histology intravascular ultrasound segment (N=3581 segments). We assessed the association of WSS with plaque burden and distribution and with plaque composition. WSS remained relatively constant across the lower 3 quartiles of plaque burden ( P =0.08) but increased in the highest quartile of plaque burden ( P< 0.001). Segments distal to lesions or within bifurcations were more likely to have low WSS ( P< 0.001). However, the majority of segments distal to lesions (80%) and within bifurcations (89%) did not exhibit low WSS . After adjustment for plaque burden, there was a negative association between WSS and percent necrotic core and calcium. For every 10 dynes/cm 2 increase in WSS , percent necrotic core decreased by 17% ( P =0.01), and percent dense calcium decreased by 17% ( P< 0.001). There was no significant association between WSS and percent of fibrous or fibrofatty plaque components ( P = NS ). Conclusions In patients with coronary artery disease: (1) Luminal geometry predicts calculated WSS only partially, which suggests that detailed computational techniques must be used to calculate WSS . (2) Low WSS is associated with plaque necrotic core and calcium, independent of plaque burden, which suggests a link between WSS and coronary plaque phenotype. ( J Am Heart Assoc. 2012;1:e002543 doi: 10.1161/ JAHA .112.002543.)

To the Editor: Macrophages are the major inflammatory cells involved in the progression of atherosclerosis. Microenvironment directs these cells into morphologically and functionally distinct phenotypes. It has been classically thought that macrophages exist in two distinct subtypes: (1) “classically” activated (M1) macrophages, which are induced by Th1 cytokines such as interferon-γ and lipopolysaccharide and produce proinflammatory cytokines and (2) alternative M2 cells, which are stimulated by Th2 cytokines such as IL-4 or IL-13 and produce anti-inflammatory cytokines such as IL-10. Evidence for the existence of M2 macrophages in human atherosclerosis recently was shown by Chinetti-Gbaguidi et al1 using histological analysis of human atherosclerotic plaques to characterize a subpopulation of CD68+ cells that were positive for the mannose receptor (MR), a surface marker for M2 macrophages. These cells contained minimal amounts of lipid by oil red O stain. To support their contention that these cells are IL-4–induced M2 macrophages, the authors show higher …

The diagnosis of acute coronary syndrome (ACS) is primarily based on the mode of clinical presentation and is a term used for any conditions suggesting the acute induction of myocardial ischemia. The precise molecular and cellular triggers that lead to ACS remain poorly understood; however, histopathologic studies have illustrated several mechanisms that may explain the sudden onset of symptoms in ACS patients. The most common substrate underlying ACS is thought to be rupture of a vulnerable plaque that contains a necrotic core covered by a fibrous cap. The term, thin-cap fibroatheroma (TCFA) is used to describe vulnerable plaque because histomorphometric analysis of ruptured plaques revealed fibrous cap thickness to be 120 degree of circumferential arc; whereas thick cap fibroatheromas have the smallest necrotic core (1.2±2.2 mm2).2,3 The highest positive remodeling index is seen in plaque ruptures, followed by plaque hemorrhage, TCFA, healed plaque rupture, and fibroatheroma.4 Also, plaque rupture and TCFA are located predominantly in the proximal portions of the coronary tree.5 Following the rupture of plaque, the exposure of necrotic core material to blood flow leads to thrombotic luminal obstruction with or without distal embolization of platelet-rich thrombus, or less commonly, atherosclerotic debris. Article see p 620 The main causes of coronary thrombosis include plaque erosion as well as rupture, with erosion accounting for 25% to 35%, and rupture …

Objectives The purpose of this study was to examine selective macrophage differentiation occurring in areas of intraplaque hemorrhage in human atherosclerosis. Background Macrophage subsets are recognized in atherosclerosis, but the stimulus for and importance of differentiation programs remain unknown. Methods We used freshly isolated human monocytes, a rabbit model, and human atherosclerotic plaques to analyze macrophage differentiation in response to hemorrhage. Results Macrophages characterized by high expression of both mannose and CD163 receptors preferentially exist in atherosclerotic lesions at sites of intraplaque hemorrhage. These hemoglobin (Hb)-stimulated macrophages, M(Hb), are devoid of neutral lipids typical of foam cells. In vivo modeling of hemorrhage in the rabbit model demonstrated that sponges exposed to red cells showed an increase in mannose receptor–positive macrophages only when these cells contained Hb. Cultured human monocytes exposed to Hb:haptoglobin complexes, but not interleukin-4, expressed the M(Hb) phenotype and were characterized by their resistance to cholesterol loading and up-regulation of ATP-binding cassette (ABC) transporters. M(Hb) demonstrated increased ferroportin expression, reduced intracellular iron, and reactive oxygen species (ROS). Degradation of ferroportin using hepcidin increased ROS and inhibited ABCA1 expression and cholesterol efflux to apolipoprotein A-I, suggesting reduced ROS triggers these effects. Knockdown of liver X receptor alpha (LXRα) inhibited ABC transporter expression in M(Hb) and macrophages differentiated in the antioxidant superoxide dismutase. Last, LXRα luciferase reporter activity was increased in M(Hb) and significantly reduced by overnight treatment with hepcidin. Collectively, these data suggest that reduced ROS triggers LXRα activation and macrophage reverse cholesterol transport. Conclusions Hb is a stimulus for macrophage differentiation in human atherosclerotic plaques. A decrease in macrophage intracellular iron plays an important role in this nonfoam cell phenotype by reducing ROS, which drives transcription of ABC transporters through activation of LXRα. Reduction of macrophage intracellular iron may be a promising avenue to increase macrophage reverse cholesterol transport.

Objectives The purpose of this study was to assess the pathological responses of atherosclerotic saphenous vein bypass grafts (SVBGs) to drug-eluting stents (DES) versus bare-metal stents (BMS). Background Repeat bypass surgery is typically associated with a high rate of morbidity and mortality. Percutaneous coronary interventions have emerged as the preferred treatment; however, only limited data are available on SVBGs pathological responses to DES and BMS. Methods Formalin-fixed SVBG of >2 years duration (n = 31) were collected to histologically characterize advanced atherosclerotic lesions in native SVBG. In a separate group, SVBGs treated with DES (n = 9) and BMS (n = 9) for >30 days duration were assessed for morphological and morphometric changes. Results Necrotic core lesions were identified in 25% of SVBG sections, and plaque rupture with luminal thrombosis was observed in 6.3% of histological sections (32% [10 of 31] vein grafts examined). Morphometry of DES demonstrated reduction in neointimal thickening versus BMS (0.13 mm [interquartile range: 0.06 to 0.16 mm] vs. 0.30 mm [interquartile range: 0.20 to 0.48 mm], p = 0.004). DES lesions also showed greater delayed healing characterized by increased peristrut fibrin deposition, higher percentage of uncovered struts, and less endothelialization compared with BMS. Stent fractures (DES 56% vs. BMS 11%, p = 0.045) and late stent thrombosis (DES 44% vs. BMS 0%, p = 0.023) were more common in DES versus BMS. Conclusions Advanced SVBG atherosclerotic lesions are characterized by large hemorrhagic necrotic cores. Stenting of such lesions is associated with delayed vascular healing and late thrombosis particularly following DES implantation, which may help explain the higher rates of cardiovascular events observed in SVBG stenting as compared with native coronary arteries.

ObjectivesHuman coronary bare-metal stents (BMS) and drug-eluting stents (DES) from autopsy cases with implant duration >30 days were examined for the presence of neointimal atherosclerotic disease.BackgroundNeointimal atherosclerotic change (neoatherosclerosis) after BMS implantation is rarely reported and usually occurs beyond 5 years. The incidence of neoatherosclerosis after DES implantation has not been reported.MethodsAll available cases from the CVPath stent registry (n = 299 autopsies), which includes a total of 406 lesions—197 BMS, 209 DES (103 sirolimus-eluting stents [SES] and 106 paclitaxel-eluting stents [PES])—with implant duration >30 days were examined. Neoatherosclerosis was recognized as clusters of lipid-laden foamy macrophages within the neointima with or without necrotic core formation.ResultsThe incidence of neoatherosclerosis was significantly greater in DES lesions (31%) than BMS lesions (16%; p < 0.001). The median stent duration with neoatherosclerosis was shorter in DES than BMS (DES, 420 days [interquartile range [IQR]: 361 to 683 days]; BMS, 2,160 days [IQR: 1,800 to 2,880 days], p < 0.001). Unstable lesions characterized as thin-cap fibroatheromas or plaque rupture were more frequent in BMS (n = 7, 4%) than in DES (n = 3, 1%; p = 0.17), with relatively shorter implant durations for DES (1.5 ± 0.4 years) compared to BMS (6.1 ± 1.5 years). Independent determinants of neoatherosclerosis identified by multiple logistic regression included younger age (p < 0.001), longer implant durations (p < 0.001), SES usage (p < 0.001), PES usage (p = 0.001), and underlying unstable plaques (p = 0.004).ConclusionsNeoatherosclerosis is a frequent finding in DES and occurs earlier than in BMS. Unstable features of neoatherosclerosis are identified for both BMS and DES with shorter implant durations for the latter. The development of neoatherosclerosis may be yet another rare contributing factor to late thrombotic events.

Today’s concept of vulnerable plaque has evolved primarily from the early pioneering work uncovering the pivotal role of plaque rupture and coronary thrombosis as the major cause of acute myocardial infarction and sudden cardiac death. Since the first historical description of plaque rupture in 1844, several key studies by leading researchers and clinicians have lead to the current accepted views on lesion instability. Important to the complex paradigm of plaque destabilization and thrombosis are many discoveries beginning with the earliest descriptions of advanced plaques, reminiscent of abscesses encapsulated by fibrous tissue capable of rupture. It was not until the late 1980s that studies of remodeling provided keen insight into the growth of advanced plaques, beyond the simple accumulation of lipid. The emphasis in the next decade, however, was on a focused shift toward the mechanisms of lesion vulnerability based on the contribution of tissue proteolysis by matrix metalloproteinases as an essential factor responsible for thinning and rupture of the fibrous cap. In an attempt to unify the understanding of what constitutes a vulnerable plaque, morphological studies, mostly from autopsy, suggest the importance of necrotic core size, inflammation, and fibrous cap thickness. Definitive proof of the vulnerable plaque, however, remains elusive because animal or human data supporting a cause-and-effect relationship are lacking. Although emerging imagining technologies involving optical coherence tomography, high-resolution MRI, molecular biomarkers, and other techniques have far surpassed the limits of the early days of angiography, advancing the field will require establishing relevant translational animal models that produce vulnerable plaques at risk for rupture and further testing of these modalities in large prospective clinical trials.

Drug delivery polymers play a role in late in-stent thrombosis of first generation drug-eluting coronary stents (DES) via an inflammatory reaction, which contributes to delayed endothelialization seen in patients with late stent thrombosis. Subsequent generation DES have non-polymer based DES whose surface pores serves as a drug reservoir. While drug elution for pores in the nanometer range have been shown to be comparable to polymer-based DES in terms of luminal renarrowing (i.e restenosis), how different pore sizes effect drug elution has not been fully characterized. We hypothesized that drug elution can be characterized with a mathematical model that takes into account the pore size of the stents and molecular characteristics of the eluted drug. Structural data from porous, non-polymer based stents were examined with pore radius ranging from the nanoporous to macroporous range (5 nm to > 10 mm). All stents eluted tacrolimus, sirolimus or paclitaxel. A mathematical model based on Stefan-Maxwell equations describing the mass transport of molecules through a porous media was constructed. A dimensionless number was derived characterizing molecular flux of the drugs through a porous membrane. It was observed that there was exponential rise in molecular flux of the eluted drug with pore sizes greater than 5 micrometers. The molecular characteristics of the eluted drug did not affect the molecular flux. In conclusions, stents in the nano- and microporous range will have similar drug elution profiles while macroporous stents will vary greatly. Careful attention to pore size may significantly enhance the design and efficacy of porous polymer free stents.

To the Editor: We read with interest Dr Drachman’s editorial1 on “Comparison of Inflammatory Response After Implantation of Sirolimus- and Paclitaxel-Eluting Stents in Porcine Coronary Arteries” by Wilson et al.2 We are concerned that Dr Drachmann gives the impression that animal models for preclinical testing before conducting human clinical trials provide relatively little information about the safety of drug-eluting stents and that human data thus far show no “additional risk of death or myocardial infarction, even in the most complex cases.” Wilson et al cautiously suggest that excessive inflammation, especially the extensive, granulomatous, eosinophil-rich reaction after deployment of Cypher stents (Cypher™, Cordis Corp., Miami Lakes, Fla), is a …

A number of patients with coronary artery disease present with chronic total occlusion (CTO), in which the extent of distal reperfusion and myocardial salvage is dependent on collateral circulation. These patients represent a real challenge to the interventionalist, because there is no proven

Patients with diabetes mellitus are at increased risk of death resulting from cardiovascular disease, but the best strategy to control excess cardiovascular risk is not yet clear. Although the use of statins and angiotensin antagonists has been successful, treatment of diabetes mellitus itself, especially from the standpoint of degree of glycemic control and type of antidiabetic agents, remains an area of ongoing investigation. Once touted as having the potential for atheroprotection because of their favorable effects on inflammatory biomarkers, endothelial function, carotid intimal-medial thickness, and even macrophage and lipid deposition, the thiazolidinediones (TZD) have become substantially controversial after a meta-analysis suggested an increase in the risk of myocardial infarction in patients treated with rosiglitazone.1 Although this notion was not confirmed in an interim analysis of the prospective study Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD), owing to several serious limitations of this report and several unanswered questions,2 studies such as Assessment on the Prevention of Progression by Rosiglitazone on Atherosclerosis in Type 2 Diabetes Patients with Cardiovascular History (APPROACH)3 become important. Taking a leaf from the statin playbook, the APPROACH was to see whether imaging the atheroma in the coronary vasculature could explain some of the outcome data with rosiglitazone. This prospective, multicenter, double-blind, randomized study compared potentially glucose-independent effects of rosiglitazone with those of a sulfonylurea (glipizide) on progression of coronary atherosclerotic disease in 672 patients with type 2 diabetes mellitus. Patients underwent baseline intravascular ultrasound (IVUS) of the longest and least angulated nonintervened epicardial artery with noncritical plaque at baseline and 18 months later. Atheroma, as measured by IVUS, did not progress significantly in either arm over time; the primary end point of the trial—change in percent atheroma volume (ΔPAV)—in individuals treated with rosiglitazone (−0.21%) was not significantly different from …

From a clinical perspective, the contribution of pathologic angiogenesis to the development of high-risk plaques is substantial, since the immature ‘leaky’ vasa vasorum (Vv) are considered a primary source of intraplaque hemorrhage. The occurrence of hemorrhagic events is beginning to emerge as a leading factor contributing to necrotic core expansion in late plaques based on accumulated erythrocyte-derived cholesterol and complications of secondary inflammation. Therefore, a further understanding of neovascularization of coronary atheroma may impact new treatment strategies targeted at plaque stabilization. While the Vv of normal arteries represents a quiescent, but functional microvascular network localized to the adventitia, atherosclerotic plaques express a latent proangiogenic phenotype represented by invading adventitial vasa vasorum (Vv). The development of intraplaque Vv represents a complex process supported by a multitude of factors involving endothelial proliferation and migration and a microenvironment enriched in growth factors, inflammatory cells, and extracellular matrix proteases. Initiating factors of angiogenesis constitute a physiologic response strongly driven by molecular signals triggered by hypoxia along with a positive association with hypercholesterolemia. The development of necrosis however, in complicated plaques, further provides a chronic inflammatory milieu consisting of a wide array of infiltrating immune cells and their secretory cytokines, chemokines, and growth factors in addition to bioactive lipid oxidation products. Moreover, immune activators also produce many proteases, ranging from urokinase Plasminogen Activator (uPA) to a variety of matrix metalloproteinases, to help degrade the basement membrane thereby facilitating the directional invasion of microvessels from the adventitia. Finally, restoring the balance of pro- and anti-angiogenic factors in plaques to that of a ‘normalized’ physiologic setting may provide a therapeutic strategy thereby reducing or eliminating intraplaque hemorrhage. The mechanisms of how a lipid rich inflammatory microenvironment contributes to the development of plaque angiogenesis will be a crucial step for furthering an understanding of plaque biology as well as for developing innovative approaches for treating atherosclerosis ahead of current lipid lowering therapies and stents.

Using human pathologic specimens from the CVPath registry, we aimed to investigate the location of the atherosclerotic plaque at bifurcation in native coronary atherosclerotic lesions and to determine the responses at bifurcation after implantation of bare-metal stents (BMS) and drug-eluting stents (DES).Greater atherosclerotic plaque burden has been reported to occur at low-shear regions of bifurcation.Twenty-six randomly selected human atherosclerotic nonstented coronary bifurcation lesions were examined longitudinally for plaque distribution in patients dying of severe coronary artery disease. Forty stented bifurcation lesions (21 BMS and 19 DES) were reviewed and analyzed by morphometry.In nonstented coronary bifurcations, the lateral wall showed significantly greater intima as well as necrotic core thickness than the flow divider. In the stented lesion, the frequency of late stent thrombosis was greater in the DES group (75%) than in the BMS group (36%), whereas restenosis was more frequent in the BMS group (33%) than in the DES group (5%). Neointimal formation was significantly less at the flow divider compared with the lateral wall in the DES group (0.07 mm [interquartile range (IQR) 0.03 to 0.15 mm] vs. 0.17 mm [IQR 0.09 to 0.23 mm]; p = 0.001), whereas this difference was not significant in the BMS group. Similarly, uncovered struts and fibrin deposition was significantly greater at the flow divider compared with the lateral wall in the DES group (uncovered: 40% [IQR 16% to 76%] vs. 0% [IQR 0% to 15%]; p = 0.001; fibrin: 60% [IQR 21% to 67%] vs. 17% [IQR 0% to 55%]; p = 0.01), but not in the BMS group.Plaque formation in native coronary bifurcations and neointimal growth after DES implantation was significantly less at the flow divider versus the lateral wall. A higher prevalence of late stent thrombosis in DES compared with BMS was associated with greater uncovered struts at flow divider sites, which is likely due to flow disturbances.

Despite the widespread use of coronary artery stenting for the treatment of ST-elevation acute myocardial infarction (STEMI), little information exists about the long-term outcomes of drug eluting stents (DES) in this setting. Although DES result in a marked reduction in the rate of restenosis, concern still exists about the long-term safety of this technology, especially with respect to late stent thrombosis (LST), a catastrophic event associated with significant morbidity and mortality. Observational studies have shown that this risk continues at a constant rate up to at least 4 years after stenting.1 Our lab has demonstrated that delayed healing (i.e. lack of complete endothelialization) is the primary pathologic substrate underlying these events and that >50% of stent struts in humans are not covered by endothelium up to 24 months after DES placement.2 Given that myocardial infarction is one of the only clinical presentations in which percutaneous coronary intervention has been shown to decrease the risk of death compared with medical therapy alone, the long-term outcomes after DES for acute myocardial infarction (AMI) is of immense clinical importance.3,4 Recent data from our laboratory in patients dying after DES placement for the treatment of AMI vs. stable angina demonstrated vessel healing at culprit sites (CSs) of plaque rupture is substantially delayed compared with CSs of stable lesions, emphasizing the importance of plaque morphology in the arterial response to DES.5 While randomized trials and observational studies of patients receiving DES for AMI have yielded inconsistent results regarding the safety of this practice, our data offer a pathophysiologic underpinning for the possibility that the benefits of opening an infarct-related artery in this setting might be outweighed by long-term risks of death and myocardial infarction associated with DES-driven LST. Several randomized trials have compared clinical outcomes for patients with STEMI …

Polymer-based sirolimus (Cypher) and paclitaxel (Taxus) drug-eluting stents (DES) have become the treatment of choice for patients with symptomatic coronary artery disease. While these stents have reduced rates of restenosis and target lesion revascularization compared with bare metal stents (BMS), late thrombosis [i.e. stent thrombosis occurring30 days after percutaneous coronary intervention (PCI)], an often life-threatening complication, has emerged as a major safety concern.Using human pathological data, we have demonstrated that the current generation US Food and Drug Administration (FDA) Cypher and Taxus DES cause substantial impairment of arterial healing, defined as impaired re-endothelialization, persistent fibrin deposition, and absence or focal presence of smooth muscle cells covering the stent struts compared with BMS. This delay in healing constitutes the most important pathological substrate underlying cases of late DES thrombosis.This review will focus on the effects of these vascular implants in both animals and humans, especially as they relate to the process of late-stent thrombosis. We will use these data to make practical recommendations regarding anatomic and lesion considerations that may help the interventionalist to minimize the late thrombotic risk of these devices.

Drug-eluting stents (DES) have become the standard of care for the treatment of coronary artery disease. However, late stent thrombosis has emerged as a major concern, especially in 'off-label' use. Pathologic studies of patients dying from late DES thrombosis demonstrate delayed arterial healing, characterized by persistent fibrin deposition and poor endothelialization as the primary substrate. Therefore, next-generation DES are being developed to increase the safety and biocompatibility by optimizing the three major components of DES: the stent platform, the polymer and the drug. Stents with thinner struts are endothelialized rapidly and cause less vessel-wall injury. Non-erodable polymers applied thinly and without defect or cracking cause less inflammation and will result in better long-term safety. Furthermore, use of biodegradable polymers, which fully degrade and leave a bare metal stent, will result in less inflammation. The choice of drug, dose and release kinetics should also be optimized. In addition to the improvement of DES components, new approaches, such as polymer-free drug delivery, prohealing approach and fully biodegradable stents, are emerging. Importantly, these technologies focus not only on efficacy but also on safety. The next-generation DES will probably be safer, with goals of improving endothelialization and more rapid arterial healing compared with first- and second-generation DES.

The aim of this study was to perform pathologic assessment on stent fracture.Clinically, stent fracture has been reported in 1% to 2% of patients after drug-eluting stent (DES) implantation.High-contrast film-based radiographs of 177 consecutive lesions from the CVPath DES autopsy registry were reviewed. Stent fracture was graded as I (single-strut fracture), II (or =2 struts), III (or =2 struts with deformation), IV (with transection without gap), and V (with transection causing gap in stent segment). The incidence of adverse pathologic findings (thrombosis and restenosis) was assessed histologically.Stent fracture was documented in 51 lesions (29%; grade I = 10, II = 14, III = 12, IV = 6, and V = 9). Lesions with stent fracture had longer duration after implantation (172 days [interquartile range (IQR) 31 to 630 days] vs. 44 days [IQR 7 to 270 days], p = 0.004), a higher rate of Cypher (Cordis Corp., Miami Lakes, Florida) stent usage (63% vs. 36%, p = 0.001), longer stent length (30.0 mm [IQR 22.0 to 40.0 mm] vs. 20.0 mm [IQR 14.0 to 27.3 mm], p0.0001), and a higher rate of overlapping stents (45% vs. 22%, p = 0.003). Although fracture with grade I to IV did not have significant impact on the occurrence of adverse pathologic findings such as thrombosis and restenosis, 67% of the grade V fracture lesions were associated with adverse pathologic findings at fracture sites. Longer stent length, use of Cypher, and longer duration of implant were identified as independent risk factors of stent fracture by logistic regression analysis.The incidence of stent fracture was 29% lesions at autopsy, which is much higher than clinically reported. A high rate of adverse pathologic findings was observed in lesions with grade V stent fracture, whereas fracture with grade I to IV did not have a significant impact on the pathological outcome.

Objective— TRM-484 is a novel drug consisting of nanoparticles of prednisolone with high affinity to chondroitin sulfate proteoglycans (CSPGs). This may allow for neointimal suppression via directed targeting to areas of injury at systemic concentrations low enough to avoid adverse side effects known to occur with oral delivery of steroids. Methods and Results— Atherosclerotic New Zealand white Rabbits were implanted with bare metal stents and randomized to receive intravenous TRM-484 at doses of 1 mg/kg or 0.32 mg/kg starting at the day of stenting and continuing 3 times a week for the duration of the study. Control animals received empty liposomes (placebo) or saline infusion. Stented arterial segments were harvested at 42 days and processed for histomorphometry and immunohistochemistry. Tissue and plasma levels were determined along with confocal microscopic analysis to determine distribution of rhodamine-labeled TRM-484 at various time points. TRM-484 was exclusively observed at sites of stent-induced injury, with absence of drug in contralateral nonstented arteries. Tissue concentration of stented arteries exceeded that of contralateral nonstented arteries by 100-fold 24 hours after administration of 1 mg/kg TRM-484 and resulted in significant reduction of percent stenosis compared to saline and placebo treated rabbits (22.5±4.4 versus 31.0±8.4 and 29.5±8.1%, P Conclusion— TRM-484 at doses of 1 mg/kg resulted in significant suppression of in-stent neointimal growth in atherosclerotic rabbits. Site-specific targeting by this nanoparticle steroid in injured atherosclerotic areas might be a valuable and cost-effective approach for the prevention of in-stent restenosis.

Background Type 2 diabetics (DM2) are at increased risk for restenosis as well as nonculprit coronary artery lesion (NCCL) progression. Rosiglitazone (RSG) favorably modifies many of the altered biologic processes in DM2, although recent reports have questioned its safety. We conducted a double-blind randomized trial to assess the effects of RSG versus placebo on in-stent late lumen loss (LL) and angiographic progression of NCCL. Methods A total of 65 DM2 were randomized to RSG (4 mg/d) (n = 32) or placebo (n = 33) at the time of stenting and underwent clinical and laboratory analysis at 1 and 4 months and 8-month angiography (n = 46 patients). Rapid angiographic progression (RAP) was defined as ≥20% diameter reduction of preexisting NCCL by quantitative coronary angiography, or a new narrowing ≥30%. Results Mean LL in RSG (n = 33 lesions) was not different from that of placebo (0.62 ± 0.59 vs 0.70 ± 0.67, P = NS). Seven (13.5%) of 52 NCCLs have RAP in RSG versus 9 (16.1%) of 56 in placebo ( P = NS). High-sensitivity C-reactive protein (hs-CRP) was the only predictor of RAP. Patients with a 120-day hs-CRP ≥75th percentile had an OR of 7.35 (95% CI 2.35-23) for RAP versus those below. Although RSG treatment also lowered log (hs-CRP) at 4 months (RSG 0.10 ± 0.37 vs placebo 0.26 ± 0.49, P = .06), it did not decrease the likelihood of plaque progression while also raising LDL and N-terminal brain naturetic peptide. Conclusions Rosiglitazone appears not to lower LL or reduce angiographic progression of NCCL in DM2 and had complex effects on markers of cardiac risk.

We describe the case of a 43 year old man with a history of aortic stenosis, for which he had undergone aortic valve replacement in 1991 with a 25-mm Medtronic Hall prosthesis. He presented with several acute episodes of dyspnea and flash pulmonary edema. Transthoracic and transesophageal echocardiography performed to evaluate prosthetic valve function revealed evidence of "intermittent" episodes of AI, documented on color M-mode flow mapping to have a variable duration of diastolic flow (early vs. pandiastolic) across the left ventricular outflow tract and the pulse wave Doppler in the descending thoracic aorta showed similar variability in the duration of diastolic flow reversal.

We appreciate the interest shown by Dr Testa and colleagues regarding our article.1 First, we acknowledge the wide variation in duration of stent implantation in our samples. Unlike clinical trials, where large numbers of patients can be studied and followed up at regular intervals, the pathological samples presented in the article are referred to us and are both rare and impossible to obtain at regular intervals. To the best of our knowledge, ours is the largest registry of these samples. We chose the time point >30 days to coincide with the clinical definition of late stent thrombosis (LST) reported in registries and …

Background: We examined the effect of 4mg/day rosiglitazone (RSG) versus placebo (PLC) on rapid angiographic progression (RAP) of non-culprit coronary lesions (NCCL) in type 2 diabetes (DM 2). Methods: Using biomarkers and angiograms from 43 DM 2 enrolled in a randomized controlled double blind trial examining the effects of RSG or PLC on late loss after PCI, we investigated the effects of RSG on RAP of NCCL using logistic regression. All stenoses >=30% of vessel diameter were identified at baseline and quantified by QCA. Patients had 8 month angiography and biomarkers (HOMA (insulin resistance index), insulin, MMP-9, adiponectin (ADI), fibrinogen, hs-CRP, A1C, and LDL and HDL cholesterol) drawn at baseline and 4 months. RAP was defined as >=20% diameter reduction of pre-existing NCCL by QCA, or a new narrowing >=30% arising in a segment angiographically normal at baseline. Results: There were 52 NCCL in the RSG versus 56 in the PLC. 14.8 % (16/108) of lesions had RAP with 7/52 (13.5%) lesions progressing in RSG versus 9/56 (16.1%) in PLC, p=ns. RSG was not a predictor of RAP. Of the biomarkers and angiographic variables examined, hsCRP was the only predictor of RAP. Patients with a 120 day hsCRP above the 75th percent had an OR of 7.35 [2.35,23] for RAP versus those below. Interestingly, although RSG treatment lowered hsCRP at 4 months (RSG 2.03±2.8 mg/dl vs. Placebo 3.37±4.25, p=0.06), it did not decrease the likelihood of plaque progression in either the low or high hsCRP groups (see graph). LDL levels at this time were not different (RSG 74±23 mg/dl vs. PLC 89±32, p=ns). Conclusion: 120 day hsCRP is a predictor of RAP. Despite lowering 120d hsCRP, RSG did not lower the frequency of RAP.

Background Although early clinical results of DES implantation for acute myocardial infarction (AMI) show no significant differences in late thrombosis however, long-term safety is still unclear. We evaluated the pathologic responses following DES implantation in AMI patients and compared to stents implanted in non-AMI lesions. Methods From CVPath DES autopsy registry of 116 cases, we identified 22 who presented with AMI at the time of DES implantation and had underlying plaque rupture (PR) or thin-cap fibroatheroma (TCFA). Morphometric analysis was performed using calibrated software (IPLab, Scanalytics) in patients who died ≥30 days after DES implantation. The percentage of struts with fibrin deposition, inflammation (>10 cells/strut), and uncovered struts were also recorded. We assessed arterial healing, by comparing culprit to non-culprit sites within each stented section. Furthermore, age and stent duration matched non-AMI patients who had underlying fibroatheroma (FA) lesion were selected as controls. Results Of the 22 patients with AMI, 14 died ≥30 days (mean duration: 285±277 days) and stent thrombosis was documented in 7 (50%, mean duration: 333±396 days), whereas in non-AMI patients with underlying FA, thrombosis was significantly less frequent (8%). Morphometric analysis revealed neointimal thickness was significantly less in culprit sites as compared to non-culprit sites in AMI patients. The percentages of uncovered struts, and struts with inflammation were significantly greater in culprit sites as compared to non-culprit sites in AMI lesions. Lesions in non-AMI patients were significantly different from AMI patients with greater neointimal thickness, less fibrin around struts, inflammation and uncovered struts (Table ). Conclusions A higher prevalence of stent thrombosis was observed in patients with AMI than those without AMI and is associated with substantial delayed in arterial healing especially at culprit sites. Pathologic and Morphmetric Analysis, Culprit vs. Non-Culprit and AMI vs. Non-AMI

Objectives The purpose of this study was to assess trends in endothelial coverage and recovery among leading polymer-based drug-eluting stents (DES). Background Autopsy studies of human U.S. Food and Drug Administration (FDA)–approved DES implanted coronary arteries suggest that complications of late stent thrombosis are associated with incomplete endothelial coverage of struts. Methods Rabbits received sirolimus-eluting stents (SES), paclitaxel-eluting stents (PES), zotarolimus-eluting stents (ZES), and everolimus-eluting stents (EES) for 14 or 28 days along with MULTI-LINK (ML) Vision control stents. Endothelial coverage above and between struts was measured by morphometric analysis of images acquired through en face scanning electron microscopy. Dual fluorescent immunolabeling was performed for platelet-endothelial cell adhesion molecule (PECAM)-1 and thrombomodulin (TM), factors involved in cell-to-cell contact and thrombogenicity, respectively. In a separate analysis, the endothelial mitogen, vascular endothelial growth factor (VEGF), was also assessed. Results Varying rates of endothelialization among comparator DES were most notable at 14 days, where coverage above struts remained poor in SES, PES, and ZES (≤30%) relative to EES and ML Vision controls (≥70%), whereas no significant differences were observed at 28 days. Select DES with poor endothelialization showed a further reduced expression of PECAM-1. All DES showed an absence or weak expression of the antithrombotic cofactor TM. Incomplete endothelialization in select DES was further associated with increased VEGF secretion and messenger ribonucleic acid levels at 14 days, providing evidence of a transitional healing surface. Conclusions The present study marks the first comparator analysis of endothelial coverage in leading polymeric DES, supporting disparities in arterial healing based on endothelial regrowth and recovery, favoring newer designs over the current generation of FDA-approved stents.

Background— Late stent thrombosis (LST) after Cypher and Taxus drug-eluting stent placement has emerged as a major concern. Although the clinical predictors of LST have been reported, specific morphological and histological correlates of LST remain unknown. Methods and Results— From a registry totaling 81 human autopsies of drug-eluting stents, 46 (62 lesions) had a drug-eluting stent implanted >30 days. We identified 28 lesions with thrombus and compared those with 34 of similar duration without thrombosis using computer-guided morphometric and histological analyses. LST was defined as an acute thrombus within a coronary artery stent in place >30 days. Multiple logistic generalized estimating equations modeling demonstrated that endothelialization was the best predictor of thrombosis. The morphometric parameter that best correlated with endothelialization was the ratio of uncovered to total stent struts per section. A univariable logistic generalized estimating equations model of occurrence of thrombus in a stent section versus ratio of uncovered to total stent struts per section demonstrated a marked increase in risk for LST as the number of uncovered struts increased. The odds ratio for thrombus in a stent with a ratio of uncovered to total stent struts per section >30% is 9.0 (95% CI, 3.5 to 22). Conclusions— The most powerful histological predictor of stent thrombosis was endothelial coverage. The best morphometric predictor of LST was the ratio of uncovered to total stent struts. Heterogeneity of healing is a common finding in drug-eluting stents with evidence of LST and demonstrates the importance of incomplete healing of the stented segment in the pathophysiology of LST.