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ABSTRACT: 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).
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.
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.
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.
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.
06/2012; 5(6):666-74. · 1.07 Impact Factor
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ABSTRACT: This study examined myocardial microvascular emboli and obstruction, and related these to plaque in the epicardial coronary arteries supplying the affected microvessels.
Epicardial coronary thrombosis often causes microemboli and microvascular obstruction. The consequences of myocardial microvessel obstruction and myocyte necrosis are substantial, yet histopathologic characterization of epicardial coronary artery plaque has been incompletely characterized. This study examined myocardial microvascular emboli, and related these to plaque in the coronary arteries supplying the microvessels.
Hearts from sudden coronary death patients underwent examination for coronary artery plaque type and cardiac microemboli.
Forty-four hearts were available for evaluation. Mean age at death was 51 +/- 15 years. Coronary artery analysis found 26 plaque ruptures and 21 erosions, and a mean of 4.5 microemboli per heart. Microemboli and microvascular obstruction occurred most often from eroded plaques. Microemboli and occluded intramyocardial vessels were most common in the left anterior descending coronary artery, and all vessels contained fibrin and platelets. Mean stenoses of the culprit lesion was 74% in those with emboli and 75% in those without (p = NS). Intramyocardial microemboli were more common in plaque erosion than in rupture. Microvessels <200 mum were most often those that were occluded.
Microemboli and microvascular obstruction are common in patients dying of acute coronary thrombosis. Plaque erosion is more likely to cause emboli in vessels <200 mum. These emboli and microvessel obstruction have a prominent clinical role since myonecrosis is often associated with these findings.
Journal of the American College of Cardiology 12/2009; 54(23):2167-73. · 14.16 Impact Factor
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ABSTRACT: Cardiac and vascular involvement by sarcoid is only rarely recognized clinically. Involvement of muscular arteries such as epicardial coronaries or the splenic artery has not been previously reported in these patients, and valvular disease has been reported only rarely.
We present herein clinical, imaging and pathologic documentation of three such patients, each displaying one of these unusual manifestations and enlarging the spectrum of cardiac sarcoid.
The presentations were life threatening, one with myocardial infarction caused by a coronary artery aneurysm, a second with splenic artery rupture and hemorrhage, and the third with severe mitral regurgitation. The clinical and histopathologic findings are described and a review of the literature is undertaken.
Cardiovascular pathology: the official journal of the Society for Cardiovascular Pathology 07/2009; 19(4):e119-23. · 1.63 Impact Factor
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10/2007: pages 37 - 59; , ISBN: 9780470987575
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10/2007: pages 60 - 76; , ISBN: 9780470987575
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10/2007: pages 77 - 94; , ISBN: 9780470987575
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Michael Joner, Andrew Farb,
Qi Cheng,
Aloke V Finn,
Eduardo Acampado,
Allen P Burke,
Kristi Skorija,
Wendy Creighton,
Frank D Kolodgie,
Herman K Gold,
Renu Virmani
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ABSTRACT: Although emerging data from preclinical and clinical studies suggests a reduction of in-stent restenosis with peroxisome proliferator-activated receptor (PPAR)-gamma agonists, the reduction of neointimal growth via anti-inflammatory mechanisms has not been explored.
Hypercholesterolemic New Zealand White rabbits (n=45) received bilateral balloon-expandable stents implanted into atherosclerotic iliac arteries. Animals were randomized to oral pioglitazone 3 (low dose) or 10 mg/kg per day (high dose) started on the day of stent implantation; control rabbits received placebo. Tissue harvest was performed 28 days after stenting, and stented segments underwent histology, morphometry, immunostaining for macrophages, and scanning electron microscopy. In selected animals, stented arterial segments were placed in organoid culture for 48 hours, and the conditioned media was assayed for 23 different cytokines. There was a 21% reduction in neointimal area for high-dose pioglitazone treated versus placebo rabbits (P<0.005), which was associated with a significant reduction of neointimal macrophages. Analysis of conditioned media revealed an 82% and 74% reduction in the release of monocyte chemoattractant protein-1 (MCP-1) (P<0.007) and transforming growth factor (TGF)-beta1 (P<0.01), respectively, in stented segments from animals treated with 10 mg/kg per day pioglitazone versus placebo.
Oral pioglitazone suppresses in-stent neointimal growth by limiting local inflammatory pathways and may be useful as an adjunctive therapy in patients undergoing percutaneous interventions.
Arteriosclerosis Thrombosis and Vascular Biology 02/2007; 27(1):182-9. · 6.37 Impact Factor
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ABSTRACT: To determine if magnetic resonance (MR) microscopy can yield images sufficient for discriminating early progressive atherosclerotic lesions from nonprogressive atherosclerotic lesions in human coronary arteries.
Institutional review board approval and informed consent were not required. Seventeen coronary artery segments (mean diameter, 2.8 mm +/- 1.0 [standard deviation]) were collected within 36 hours after death from 11 cadavers (six men, five women; age range at death, 33-65 years). Quantitative T1, T2, intensity-weighted (IW), and magnetization transfer (MT) maps were acquired with a 9.4-T vertical-bore magnet. Coronary artery lesions were classified as adaptive intimal thickening (AIT), pathologic intimal thickening (PIT), or intimal xanthoma (IXA). Internal anatomic fiducial landmarks and stains were applied to proximal and epicardial vessel surfaces and used to register histologic sections with MR images and thus enable comparison of MR images and Movat pentachrome-stained histologic specimens. Unique 0.0012-0.0287-cm(2) regions of interest were visually identified on quantitative T1, T2, MT, and IW maps of AIT, IXA, and PIT lesions. Distributions of T1, T2, MT, and IW values were compared with Student t and Wilcoxon two-sample tests.
MR microscopic images of nonprogressive AIT and IXA lesions revealed two intimal layers. The luminal intima had higher T1 and T2 values and lower MT values than did the medial intima; these findings were consistent with compositional differences observed in histologic sections. In the IXA lesion, T2 values of both intimal layers were markedly reduced when compared with T2 values of AIT lesions because of the accumulation of lipid-laden macrophages in both layers. Progressive PIT lesions had a typical multilayered appearance or foci with a short T2 relaxation time and low IW values; these features were not observed in AIT or IXA lesions.
MR microscopy enabled identification of morphologic arterial wall features that enable discrimination of progressive PIT lesions from nonprogressive AIT or IXA lesions.
Radiology 11/2006; 241(1):107-15. · 5.73 Impact Factor
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ABSTRACT: This study examined human drug-eluting stents (DES) to determine the long-term effects of these stents on coronary arterial healing and identified mechanisms underlying late stent thrombosis (LST).
Although DES reduce the need for repeat revascularization compared with bare-metal stents (BMS), data suggest the window of thrombotic risk for Cypher (Cordis Corp., Miami Lakes, Florida) and Taxus (Boston Scientific Corp., Natick, Massachusetts) DES extends far beyond that for BMS.
From a registry of 40 autopsies of DES (68 stents), 23 DES cases of >30 days duration were compared with 25 matched autopsies of BMS implantation. Late stent thrombosis was defined as an acute thrombus within a stent >30 days old.
Of 23 patients with DES >30 days old, 14 had evidence of LST. Cypher and Taxus DES showed greater delayed healing characterized by persistent fibrin deposition (fibrin score 2.3 +/- 1.1 vs. 0.9 +/- 0.8, p = 0.0001) and poorer endothelialization (55.8 +/- 26.5%) compared with BMS (89.8 +/- 20.9, p = 0.0001). Moreover, DES with LST showed more delayed healing compared with patent DES. In 5 of 14 patients suffering LST, antiplatelet therapy had been withdrawn. Additional procedural and pathologic risk factors for LST were: 1) local hypersensitivity reaction; 2) ostial and/or bifurcation stenting; 3) malapposition/incomplete apposition; 4) restenosis; and 5) strut penetration into a necrotic core.
The Cypher and Taxus DES result in delayed arterial healing when compared with BMS of similar implant duration. The cause of DES LST is multifactorial with delayed healing in combination with other clinical and procedural risk factors playing a role.
Journal of the American College of Cardiology 07/2006; 48(1):193-202. · 14.16 Impact Factor
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ABSTRACT: The majority of patients with acute coronary syndromes (ACS) present with unstable angina, acute myocardial infarction, and sudden coronary death. The most common cause of coronary thrombosis is plaque rupture followed by plaque erosion, whereas calcified nodule is infrequent. If advances in coronary disease are to occur, it is important to recognize the precursor lesion of ACS. Of the three types of coronary thrombosis, a precursor lesion for acute rupture has been postulated. The non-thrombosed lesion that most resembles the acute plaque rupture is the thin cap fibroatheroma (TCFA), which is characterized by a necrotic core with an overlying fibrous cap measuring <65 microm, containing rare smooth muscle cells but numerous macrophages. Thin cap fibroatheromas are most frequently observed in patients dying with acute myocardial infarction and least common in plaque erosion. They are most frequently observed in proximal coronary arteries, followed by mid and distal major coronary arteries. Vessels demonstrating TCFA do not usually show severe narrowing but show positive remodeling. In TCFAs the necrotic core length is approximately 2 to 17 mm (mean 8 mm) and the underlying cross-sectional area narrowing in over 75% of cases is <75% (diameter stenosis <50%). The area of the necrotic core in at least 75% of cases is < or =3 mm2. These lesions have lesser degree of calcification than plaque ruptures. Thin cap fibroatheromas are common in patients with high total cholesterol (TC) and high TC/high-density lipoprotein cholesterol ratio, in women >50 years, and in those patients with elevated high levels of high sensitivity C-reactive protein. It has only recently been recognized that their identification in living patients might help reduce the incidence of sudden coronary death.
Journal of the American College of Cardiology 04/2006; 47(8 Suppl):C13-8. · 14.16 Impact Factor
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ABSTRACT: The death rate from coronary artery disease has declined in the past few decades through greater understanding of risk factors
of coronary heart disease as well as through better treatment, including the creation of coronary care units. However, because
of the lack of an animal model of unstable plaque, our understanding of atherosclerotic plaque morphology comes only from
static histology of lesion morphology in patients dying of acute coronary syndromes (1). Although transgenic models of atherosclerosis have markedly enhanced our understanding of certain aspects of plaque progression
and regression, they have failed thus far to explain the relationship of the coagulation parameters and plaque morphology
that precipitate coronary thrombosis (1). Until we are able to create a better model or study plaque morphology prospectively and determine the mechanisms and the
anatomic markers of progression, we will make progress very slowly. This review is based on examination of human coronary
artery pathology in patients dying a sudden coronary death, in order to ascertain the pathologic lesion morphologies that
are linked to plaque progression and thrombosis, which will be necessary for us to be able to recognized by invasive or noninvasive
means the prospective lesions that are likely to produce symptoms.
12/2004: pages 351-364;
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ABSTRACT: Recent publications on drug-eluting stents (DES) report a significant reduction in restenosis rates as compared to bare metal stents in patients mostly with single vessel disease. We have recently observed however, late stent thrombosis following CYPHER DES implantation. The patient developed a hypersensitivity reaction around stent struts limited to the polymer with aneurysmal dilatation and extensive inflammation of the arterial wall in the absence of vascular healing. This incidence promotes a cautionary view and perhaps supports the use of DES only in high-risk patients.
Coronary Artery Disease 10/2004; 15(6):313-8. · 1.24 Impact Factor
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ABSTRACT: Restenosis after stenting occurs secondary to the accumulation of smooth muscle cells (SMCs) and extracellular matrix (ECM), with the ECM accounting for >50% of the neointimal volume. The composition of the in-stent ECM has not been well characterized in humans.
Postmortem human coronary arteries (n=45) containing stents underwent histological assessment of neointimal proteoglycans, hyaluronan, collagen (types I and III), SMCs, and CD44 (a cell surface receptor for hyaluronan). The mean duration of stent implantation was 18.7 months; stents in place > or =3 to <9 months (n=17) were assigned to group 1, stents > or =9 to <18 months old (n=19) to group 2, and stents > or =18 months old (n=9) to group 3. In groups 1 and 2, neointimal versican and hyaluronan staining was strongly positive, colocalized with alpha-actin-positive SMCs, and was greater in intensity compared with group 3. Conversely, decorin staining was greatest in group 3. The neointima of both group 1 and 2 stents was rich in type III collagen, with reduced staining in group 3. Type I collagen staining was weakest in group 1 stents, with progressively stronger staining in groups 2 and 3. SMC density and stent stenosis were significantly reduced in group 3 stents compared with groups 1 and 2. CD44 staining colocalized with macrophages and was associated with increased neointimal thickness.
The ECM within human coronary stents resembles a wound that is not fully healed until 18 months after deployment, followed by neointimal retraction. ECM contraction may be a target for therapies aimed at stent restenosis prevention.
Circulation 08/2004; 110(8):940-7. · 14.74 Impact Factor
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ABSTRACT: Coronary atherosclerotic plaque composition of diabetic subjects and localization of receptor for advanced glycation end products (RAGE) and its ligands have not been extensively studied.
Hearts from diabetic subjects and age, race, and sex-matched nondiabetic subjects dying suddenly were examined. Coronary arteries were dissected and lesions were evaluated for plaque burden, necrotic core size, and inflammatory infiltrate. The expression of RAGE, the RAGE-binding protein (S100-A12, EN-RAGE), and cell death (apoptosis) were also determined. Lesions from type II diabetic subjects had larger mean necrotic cores (P=0.01) and greater total and distal plaque load (P<0.001) than nondiabetic subjects. Necrotic core size correlated positively with diabetic status, independent of other risk factors. Intimal staining for macrophages, T-cells, and HLA-DR was also significantly greater in diabetic subjects (P=0.03, P=0.003, and P<0.0001), respectively. The association of increased macrophage infiltrate was independent of cholesterol levels and patient age. Expression of RAGE and EN-RAGE was significantly greater in diabetic subjects (P=0.004) and was associated with apoptotic smooth muscle cells and macrophages.
In sudden coronary death, inflammation and necrotic core size play a greater role in the progression of atherosclerosis in diabetic subjects. The expression of RAGE and EN-RAGE may further compromise cell survival and promote plaque destabilization.
Arteriosclerosis Thrombosis and Vascular Biology 08/2004; 24(7):1266-71. · 6.37 Impact Factor
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J Eduardo Sousa,
Marco A Costa, Andrew Farb,
Alexandre Abizaid,
Amanda Sousa,
Ana C Seixas,
Lilian M da Silva,
Fausto Feres,
Ibraim Pinto,
Luiz A Mattos,
Renu Virmani
Circulation 08/2004; 110(1):e5-6. · 14.74 Impact Factor
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ABSTRACT: The US Food and Drug Administration recently issued a warning of subacute thrombosis and hypersensitivity reactions to sirolimus-eluting stents (Cypher). The cause and incidence of these events have not been determined.
We present findings of a 58-year-old man who died of late stent thrombosis 18 months after receiving 2 Cypher stents for unstable angina. Although angiographic and intravascular ultrasound results at 8 months demonstrated the absence of neointimal formation, vessel enlargement was present. An autopsy showed aneurysmal dilation of the stented arterial segments with a severe localized hypersensitivity reaction consisting predominantly of T lymphocytes and eosinophils.
The known pharmacokinetic elution profile of Cypher stents and the presence of polymer fragments surrounded by giant cells and eosinophils suggest that a reaction to the polymer may have caused late stent thrombosis. Careful long-term follow-up of patients with vessel enlargement after Cypher stent placement is recommended.
Circulation 03/2004; 109(6):701-5. · 14.74 Impact Factor
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ABSTRACT: Drug-eluting stents have reduced the frequency of in-stent restenosis. However, most of the results have been derived from simple lesions in noncomplex patients. In preclinical normal pig and rabbit studies, bare-metal stents show complete healing at 28 days, whereas drug-eluting stents show incomplete healing with persistence of fibrin and incomplete coverage of the stent struts by endothelial cells. In human beings similar delayed healing has been observed at 6 and 12 months in atherectomy specimens or at autopsy. The US Food and Drug Administration posted adverse event information for physicians regarding subacute thrombosis and hypersensitivity reaction following deployment of sirolimus-eluting stents in human beings. The authors have seen, at autopsy, late (18 months) stent thrombosis, aneurysm formation, and extensive inflammatory reaction limited to the arterial wall surrounding the stent that they interpret as a hypersensitivity reaction to the polymer. The authors advocate caution and aggressive use of nontoxic systemic drugs to prevent the complications of atherosclerosis along with better postmarket surveillance of patients and histologic examination of tissue from patients with drug-eluting stents.
The American Heart Hospital Journal 02/2004; 2(2):85-8.
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Frank D Kolodgie,
Herman K Gold,
Allen P Burke,
David R Fowler,
Howard S Kruth,
Deena K Weber, Andrew Farb,
L J Guerrero,
Motoya Hayase,
Robert Kutys,
Jagat Narula,
Aloke V Finn,
Renu Virmani
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ABSTRACT: Intraplaque hemorrhage is common in advanced coronary atherosclerotic lesions. The relation between hemorrhage and the vulnerability of plaque to disruption may involve the accumulation of free cholesterol from erythrocyte membranes.
We stained multiple coronary lesions from 24 randomly selected patients who had died suddenly of coronary causes with an antibody against glycophorin A (a protein specific to erythrocytes that facilitates anion exchange) and Mallory's stain for iron (hemosiderin), markers of previous intraplaque hemorrhage. Coronary lesions were classified as lesions with pathologic intimal thickening, fibrous-cap atheromas with cores in an early or late stage of necrosis, or thin-cap fibrous atheromas (vulnerable plaques). The arterial response to plaque hemorrhage was further defined in a rabbit model of atherosclerosis.
Only traces of glycophorin A and iron were found in lesions with pathologic intimal thickening or fibrous-cap atheromas with cores in an early stage of necrosis. In contrast, fibroatheromas with cores in a late stage of necrosis or thin caps had a marked increase in glycophorin A in regions of cholesterol clefts surrounded by iron deposits. Larger amounts of both glycophorin A and iron were associated with larger necrotic cores and greater macrophage infiltration. Rabbit lesions with induced intramural hemorrhage consistently showed cholesterol crystals with erythrocyte fragments, foam cells, and iron deposits. In contrast, control lesions from the same animals had a marked reduction in macrophages and lipid content.
By contributing to the deposition of free cholesterol, macrophage infiltration, and enlargement of the necrotic core, the accumulation of erythrocyte membranes within an atherosclerotic plaque may represent a potent atherogenic stimulus. These factors may increase the risk of plaque destabilization.
New England Journal of Medicine 01/2004; 349(24):2316-25. · 53.30 Impact Factor
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ABSTRACT: A 71-year-old woman underwent right coronary artery (RCA) bare metal stenting during an acute myocardial infarction. Seven months later the patient received a sirolimus-eluting stent as treatment for an 80% left anterior descending coronary artery (LAD) stenosis. She remained asymptomatic until she presented with unstable angina 16 months later. Angiography demonstrated subtotal occlusion of the left obtuse marginal branch. The LAD sirolimus-eluting stent showed 0% stenosis. The RCA stent showed 30% restenosis. The left obtuse marginal branch lesion was successfully stented, but the patient suffered a fatal stroke 24 hours after the coronary intervention. At autopsy the 16-month-old LAD sirolimus-eluting stent was widely patent with a minute thrombus near the ostium of a small side branch. The stent surface appeared free of any other irregularities. Scanning light microscopy showed mild neointimal thickening. Scanning electron microscopy showed > 80% endothelialization of the stent. The 24-month-old RCA bare metal stent showed mild to moderate neointimal growth with > 90% endothelialization.
Italian heart journal: official journal of the Italian Federation of Cardiology 11/2003; 4(10):713-20.
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ABSTRACT: Coronary stent deployment is associated with a low incidence of acute thrombosis. However, late stent thrombosis (LST) has likely been underrecognized clinically, and pathological descriptions are lacking.
LST was defined as an acute thrombus within a stent that had been in place > or =30 days. Cases of LST were selected from a registry of human coronary stents submitted for analysis. Thirteen cases of LST (9 men, 4 women) were identified. The mean duration from implantation to thrombosis was 3.6+/-3.5 months (range, 1 to 11.9 months). The causes of death were sudden cardiac death (n=10), acute myocardial infarction (n=2), and heart failure (n=1). The pathological mechanisms of LST were as follows: (1) stenting across ostia of major arterial branches (5 cases); (2) exposure to radiation therapy (3 cases); (3) plaque disruption in the nonstented arterial segment within 2 mm of the stent margin (2 cases); (4) stenting of markedly necrotic, lipid-rich plaques with extensive plaque prolapse (2 cases); and (5) diffuse in-stent restenosis (1 case). Twelve cases demonstrated a failure to form a completely healed neointimal layer overlying stent struts. Underlying in-stent restenosis was present in only 4 (31%) of 13 cases.
LST is a potentially fatal complication of coronary stenting. Stenting across branch ostia, disruption of adjacent vulnerable plaques, radiation therapy, and extensive plaque prolapse can precipitate LST. Impaired intimal healing (ie, the failure to form a complete neointimal layer over stent struts) extends the window during which stents are prone to thrombosis.
Circulation 10/2003; 108(14):1701-6. · 14.74 Impact Factor
