Pasterkamp, G.

Collagenase matrix metalloproteinase-8 expressed in atherosclerotic carotid plaques is associated with systemic cardiovascular outcome (Article)

2011-09-01T00:00:00Z

Aims Atherosclerotic plaque rupture and subsequent thrombus formation are the major cause of acute cardiovascular events. Local plaque markers may facilitate detection of the vulnerable plaque and help identify the patient at risk for cardiovascular events. Matrix metalloproteinases (MMPs) are prevalent in the arterial wall throughout the arterial system and are associated with local plaque destabilization. We hypothesized that local MMP plaque levels are predictive for atherosclerotic cardiovascular events in other vascular territories. Methods and resultsAtherosclerotic plaques were obtained from 543 patients undergoing carotid endarterectomy (CEA). Plaques were analysed for the presence of macrophages, lipid-core, smooth muscle cells, collagen, calcification, and presence of plaque haemorrhage. MMP-2, MMP-8, and MMP-9 levels were assessed within the plaque. Following CEA, all patients underwent follow-up during 3 years. The primary outcome was defined as the composite of vascular death, non-fatal vascular event, and surgical or percutaneous vascular intervention. In contrast with MMP-2 plaque levels, MMP-8 and MMP-9 levels in the plaque were associated with an unstable carotid plaque composition and clinical presentation at baseline. Increased plaque MMP-8 level (>4.58) was associated with an increased risk for the occurrence of secondary manifestations of atherosclerotic disease during follow-up [hazard ratio 1.76, 95 CI (1.252.48)] (P 0.001), whereas plaque MMP-2 and MMP-9 levels were not predictive for systemic cardiovascular events. ConclusionIn contrast with MMP-2, increased carotid MMP-8 and MMP-9 plaque levels are associated with an unstable plaque phenotype. High collagenase MMP-8 levels in the carotid plaque are associated with the occurrence of systemic cardiovascular outcome during follow-up.

Ets2 determines the inflammatory state of endothelial cells in advanced atherosclerotic lesions (Article)

2011-08-05T00:00:00Z

Rationale: Neovascularization is required for embryonic development and plays a central role in diseases in adults. In atherosclerosis, the role of neovascularization remains to be elucidated. In a genome-wide microarray-screen of Flk1+ angioblasts during murine embryogenesis, the v-ets erythroblastosis virus E26 oncogene homolog 2 (Ets2) transcription factor was identified as a potential angiogenic factor. Objectives: We assessed the role of Ets2 in endothelial cells during atherosclerotic lesion progression toward plaque instability. Methods and Results: In 91 patients treated for carotid artery disease, Ets2 levels showed modest correlations with capillary growth, thrombogenicity, and rising levels of tumor necrosis factor-α (TNFα), monocyte chemoattractant protein 1, and interleukin-6 in the atherosclerotic lesions. Experiments in ApoE mice, using a vulnerable plaque model, showed that Ets2 expression was increased under atherogenic conditions and was augmented specifically in the vulnerable versus stable lesions. In endothelial cell cultures, Ets2 expression and activation was responsive to the atherogenic cytokine TNFα. In the murine vulnerable plaque model, overexpression of Ets2 promoted lesion growth with neovessel formation, hemorrhaging, and plaque destabilization. In contrast, Ets2 silencing, using a lentiviral shRNA construct, promoted lesion stabilization. In vitro studies showed that Ets2 was crucial for TNFα-induced expression of monocyte chemoattractant protein 1, interleukin-6, and vascular cell adhesion molecule 1 in endothelial cells. In addition, Ets2 promoted tube formation and amplified TNFα-induced loss of vascular endothelial integrity. Evaluation in a murine retina model further validated the role of Ets2 in regulating vessel inflammation and endothelial leakage. Conclusions: We provide the first evidence for the plaque-destabilizing role of Ets2 in atherosclerosis development by induction of an intraplaque proinflammatory phenotype in endothelial cells.

Stabilisation of atherosclerotic plaques position paper of the european society of cardiology (ESC) working group on atherosclerosis and vascular biology (Article)

2011-07-01T00:00:00Z

Plaque rupture and subsequent thrombotic occlusion of the coronary arteryaccount for as many as three quarters of myocardial infarctions. Theconcept of plaque stabilisation emerged about 20 years ago to explainthe discrepancy between the reduction of cardiovascular events in patientsreceiving lipid lowering therapy and the small decrease seen in angiographicevaluation of atherosclerosis. Since then, the concept of a vulnerableplaque has received a lot of attention in basic and clinical researchleading to a better understanding of the pathophysiology of thevulnerable plaque and acute coronary syndromes. From pathological andclinical observations, plaques that have recently ruptured have thin fibrouscaps, large lipid cores, exhibit outward remodelling and invasion byvasa vasorum. Ruptured plaques are also focally inflamed and this maybe a common denominator of the other pathological features. Plaqueswith similar characteristics, but which have not yet ruptured, are believ ed to be vulnerable to rupture. Experimental studies strongly support thevalidity of anti-inflammatory approaches to promote plaque stability. Unfortunately,reliable non-invasive methods for imaging and detection ofsuch plaques are not yet readily available. There is a strong biologicalbasis and supportive clinical evidence that low-density lipoprotein loweringwith statins is useful for the stabilisation of vulnerable plaques. Thereis also some clinical evidence for the usefulness of antiplatelet agents,beta blockers and renin-angiotensin-aldosterone system inhibitors forplaque stabilisation. Determining the causes of plaque rupture and designingdiagnostics and interventions to prevent them are urgent prioritiesfor current basic and clinical research in cardiovascular area.

Adipocyte fatty acid binding protein in atherosclerotic plaques is associated with local vulnerability and is predictive for the occurrence of adverse cardiovascular events (Article)

2011-07-01T00:00:00Z

Aims There is an increasing need for translational studies identifying molecular targets contributing to atherosclerotic plaque destabilization. Local molecular plaque markers that are related to plaque vulnerability may hold predictive value to identify patients who are at increased risk to suffer from cardiovascular events. Animal studies revealed that adipocyte fatty acid binding protein (FABP4) is associated with the progression of atherosclerosis; however, FABP4 expression studies in human atherosclerotic plaques are lacking. We investigated FABP4 expression in carotid atherosclerotic lesions in relation to plaque composition and future cardiovascular events. Methods and results therosclerotic plaques were obtained from 561 patients undergoing carotid endarterectomy (CEA). Plaques were analysed for the presence of macrophages, lipid core, smooth-muscle cells, collagen, calcification, and intraplaque haemorrhage. Patients were followed for 3 years after CEA. The primary outcome was defined as the composite of vascular death, vascular event, and surgical or percutaneous vascular intervention. Fatty acid binding protein levels correlated with unstable plaque characteristics and symptomatic lesions. Patients with increased FABP4 plaque levels showed a two-fold increased risk [HR 1.99, 95 confidence interval (95% CI) (1.30-3.04)] (P=0.005) to reach the primary outcome during follow-up. Increased FABP4 levels related to primary outcome, independent from general cardiovascular risk factors [HR 1.33, 95 CI (1.081.65)] (P = 0.008). Conclusion FABP4 levels in atherosclerotic lesions are associated with an unstable plaque phenotype and an increased risk for cardiovascular events during follow-up. Besides risk stratification for adverse future cardiovascular events, the outcome of the present study supports the relevance of exploring FABP4 antagonists as a potential pharmaceutical intervention to treat atherosclerotic disease progression. Published on behalf of the European Society of Cardiology.

Composition of carotid atherosclerotic plaque is associated with cardiovascular outcome: A prognostic study (Article)

2010-05-01T00:00:00Z

BACKGROUND-: Identification of patients at risk for primary and secondary manifestations of atherosclerotic disease progression is based mainly on established risk factors. The atherosclerotic plaque composition is thought to be an important determinant of acute cardiovascular events, but no prospective studies have been performed. The objective of the present study was to investigate whether atherosclerotic plaque composition is associated with the occurrence of future vascular events. METHODS AND RESULTS-: Atherosclerotic carotid lesions were collected from patients who underwent carotid endarterectomy and were subjected to histological examination. Patients underwent clinical follow-up yearly, up to 3 years after carotid endarterectomy. The primary outcome was defined as the composite of a vascular event (vascular death, nonfatal stroke, nonfatal myocardial infarction) and vascular intervention. The cumulative event rate at 1-, 2-, and 3-year follow-up was expressed by Kaplan-Meier estimates, and Cox proportional hazards regression analyses were performed to assess the independence of histological characteristics from general cardiovascular risk factors. During a mean follow-up of 2.3 years, 196 of 818 patients (24%) reached the primary outcome. Patients whose excised carotid plaque revealed plaque hemorrhage or marked intraplaque vessel formation demonstrated an increased risk of primary outcome (risk difference=30.6% versus 17.2%; hazard ratio [HR] with [95% confidence interval]=1.7 [1.2 to 2.5]; and risk difference=30.0% versus 23.8%; HR=1.4 [1.1 to 1.9], respectively). Macrophage infiltration (HR=1.1 [0.8 to 1.5]), large lipid core (HR=1.1 [0.7 to 1.6]), calcifications (HR=1.1 [0.8 to 1.5]), collagen (HR=0.9 [0.7 to 1.3]), and smooth muscle cell infiltration (HR=1.3 [0.9 to 1.8]) were not associated with clinical outcome. Local plaque hemorrhage and increased intraplaque vessel formation were independently related to clinical outcome and were independent of clinical risk factors and medication use. CONCLUSIONS-: The local atherosclerotic plaque composition in patients undergoing carotid endarterectomy is an independent predictor of future cardiovascular events.

Cryoplasty of the Venous Anastomosis for Prevention of Intimal Hyperplasia in a Validated Porcine Arteriovenous Graft Model (Article)

2010-05-01T00:00:00Z

Objectives: Cryoplasty combines conventional angioplasty - percutaneous transluminal angioplasty (PTA) - with cold thermal energy. In this animal study, we investigated if preventive cryoplasty could reduce intimal hyperplasia (IH) at the venous anastomosis. Design: We investigated cryoplasty versus PTA of the venous anastomosis in a validated porcine, bilateral, arteriovenous graft model. Animals and methods: In 12 pigs, 24 expanded polytetrafluoroethylene (ePTFE) grafts were bilaterally inserted between the common carotid artery and internal jugular vein. Directly after surgery, one venous anastomosis was treated with cryoplasty at -10 °C, the contralateral anastomosis with conventional PTA. At 4 weeks, graft flow was measured, quantitative angiography was performed and grafts with adjacent vessels were excised for histological analysis. Results: Due to a number of thromboses, data for paired analysis were available from eight pigs. Angiographic outflow vein diameter and graft blood flow were not different between treatment groups. Compared with the control group, IH at the venous anastomosis was reduced by 47% (P = 0.21) and intima/media ratio was reduced by 45% (P = 0.07) by cryoplasty. Effects were most profound in those animals that tended to develop most IH. Conclusion: Our results suggest that preventive cryoplasty of the venous anastomosis might help to reduce IH in those cases that develop most profound IH.

Toll like receptor 4 in atherosclerosis and plaque destabilization (Article)

2010-04-01T00:00:00Z

The immune system plays a pivotal role in initiation and progression of atherosclerosis. Monocytes and T-lymphocytes are the first cells to enter the damaged endothelium. Differentiation of monocytes into macrophages and ingestion of lipids by these macrophages turning them into foam cells is a crucial step in the development of a fatty streak, the first sign of atherosclerosis. In recent years there has been accumulating evidence for the involvement of Toll like receptor 4, a pattern recognition receptor of the innate immune system, in the pathogenesis of atherosclerosis. Different cell types present in the atherosclerotic plaque express TLR4 and several pro-atherogenic ligands have been shown to activate TLR4.The innate immune system and the TLR signaling cascade may play an important role not only in the pathogenesis of atherosclerosis, but also in plaque destabilization. In this review, we discuss the role of TLR4 in the pathogenesis of atherosclerosis and vulnerable plaque development.

Local atherosclerotic plaques are a source of prognostic biomarkers for adverse cardiovascular events (Article)

2010-03-01T00:00:00Z

Objective-Atherosclerotic cardiovascular disease is a major burden to health care. Because atherosclerosis is considered a systemic disease, we hypothesized that one single atherosclerotic plaque contains ample molecular information that predicts future cardiovascular events in all vascular territories. Methods and Results-AtheroExpress is a biobank collecting atherosclerotic lesions during surgery, with a 3-year follow-up. The composite primary outcome encompasses all cardiovascular events and interventions, eg, cardiovascular death, myocardial infarction, stroke, and endovascular interventions. A proteomics search identified osteopontin as a potential plaque biomarker. Patients undergoing carotid surgery (n=574) served as the cohort in which plaque osteopontin levels were examined in relation to their outcome during follow-up and was validated in a cohort of patients undergoing femoral endarterectomy (n=151). Comparing the highest quartile of carotid plaque osteopontin levels with quartile 1 showed a hazard ratio for the primary outcome of 3.8 (95% confidence interval, 2.6-5.9). The outcome did not change after adjustment for plaque characteristics and traditional risk factors (hazard ratio, 3.5; 95% confidence interval, 2.0-5.9). The femoral validation cohort showed a hazard ratio of 3.8 (95% confidence interval 2.0 to 7.4) comparing osteopontin levels in quartile 4 with quartile 1. Conclusion-Plaque osteopontin levels in single lesions are predictive for cardiovascular events in other vascular territories. Local atherosclerotic plaques are a source of prognostic biomarkers with a high predictive value for secondary manifestations of atherosclerotic disease.

Maternal TLR4 and NOD2 gene variants, pro-inflammatory phenotype and susceptibility to early-onset preeclampsia and HELLP syndrome (Article)

2008-04-02T00:00:00Z

Background: Altered maternal inflammatory responses play a role in the development of preeclampsia and the hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome. We examined whether allelic variants of the innate immune receptors toli-like receptor 4 (TLR4) and nucleotide-binding oligomerization domain (NOD2), that impair the inflammatory response to endotexin are related to preeclampsia and HELLP syndrome. Methods and Finding: We determined five common mutations in TLR4 (D299G and T399I and NOD2 (R70W, G908R and L1007fs) in 340 primiparous women with a history of early-onset preeclampsia, of whom 177 women developed HELLP syndrome and in 113 women with a history of only uneventful pregnancies as controls. In addition, we assessed plasma levels of pro-inflammatory biomarkers C-reactive protein, interleukin-6 soluble intercellular adhesion molecule-1, fibrinogen and von Willebrand factor in a subset of 214 women included at least six months after delivery. After adjustment for maternal age and chronic hypertension, attenuating allelic variants of TLR4 were more common in women with a history of early onset preeclampsia than in controls (OR 2.9 [95% CI 1.2-6.7]). Highest frequencies for TLR4 variants were observed in women who developed HELLP syndrome (adjusted OR 4.1 [9.5% CI 1.7-9.8]). In addition, high levels of interleukin-6 and fibrinogen were associated with a history of early-onset preeclampsia. Combined positivity for any of the TLR4 and NOD2 allelic variants and high levels of interleukin-6 was 6.9-fold more common in women with a history of early-onset preeclampsia (95% CI 2.1-23.2) compared to controls. Conclusions: We observed an association of common TLR4 and NOD2 gene variants, and pro-inflammatory phenotype with a history of early-onset preeclampsia and HELLP syndrome. These suggest involvement of the maternal innate immune system in severe hypertensive disorders of pregnancy.

Atherosclerotic lesion development and Toll like receptor 2 and 4 responsiveness (Article)

2008-03-01T00:00:00Z

Background: Toll like receptors (TLR) have been recognized for their role in atherosclerotic lesion development and progression. Endogenous TLR ligands that are also expressed in atherosclerotic tissues have been shown to promote atherosclerosis in mice. Since repetitive stimulation of TLR induces an attenuated inflammatory response, we hypothesized that the TLR response is altered during atherosclerosis development, due to chronic exposure to endogenous ligands. Methods and Results: We examined five groups of both ApoE-/- and C57Bl/6 mice aged 5, 10, 15, 25 and 40 weeks. In ApoE-/- mice with advanced stages of atherosclerosis, levels of mRNA encoding TLR2 and TLR4, the endogenous TLR ligands EDA and hsp60 as well as intracellular TLR-regulating mediators, like IRAK-M, were increased. Systemic TLR cell surface expression on circulating monocytes and EDA plasma levels were significantly increased in ApoE-/- mice with advanced atherosclerosis. We also observed that the endogenous TLR ligand EDA was capable of activating the TLR-signaling pathway in white blood cells. During the plaque progression stage however, stimulation of TLR2 and TLR4 in blood samples attenuated MIP-1α and RANTES release in atherosclerotic mice. Conclusion: During atherosclerotic lesion development, TLR2 and TLR4 expression increases in atherosclerotic plaques and on circulating blood cells. However, with advanced stages of atherosclerotic disease, circulating blood cells become less responsive to TLR ligation, which may be due to chronic TLR engagement by endogenous EDA.

Peptidoglycan increases firm adhesion of monocytes under flow conditions and primes monocyte chemotaxis (Article)

2007-04-01T00:00:00Z

The Toll-like receptor (TLR) 2/nucleotide-binding oligomerization domain ligand peptidoglycan (PG) has been shown to be present in macrophage-rich regions within atherosclerotic lesions, and stimulation of TLR2 promotes atherosclerotic plaque and intima formation in in vivo mouse models. We determined the effect of a PG preparation and Pam3Cys-SK4, a synthetic TLR2 activator, on (1) adhesion molecule expression by flow cytometry; (2) monocyte adhesion under flow conditions, and (3) monocyte migration. The total adhesion (rolling and firm adhesion) of the PG-preparation-stimulated monocytes to L cells, constitutively expressing ICAM-1 (intercellular adhesion molecule-1) and E-selectin, was decreased. This was most likely due to the L-selectin shedding, since monocyte incubation with a blocking L-selectin antibody resulted in a comparable number of adherent monocytes as PG-stimulated cells. The PG preparation induced an increased percentage of firmly adherent, polarized cells and a β2- integrin-dependent binding to ICAM-1-coated beads. Interestingly, the PG preparation induced a priming of the monocytes for increased migration towards the chemoattractant C5a which was TLR2 and β2-integrin dependent. Pam3Cys-SK4gave comparable results to the PG preparation in all assays tested. This study demonstrates that PG activation of monocytes results in an increase in adhesive and migratory capacities of these cells. This might be a mechanism by which PG promotes atherosclerotic disease in vivo. Copyright

In vivo temperature heterogeneity is associated with plaque regions of increased MMP-9 activity. (Article)

2005-10-01T00:00:00Z

AIMS: Plaque rupture has been associated with a high matrix metalloproteinase (MMP) activity. Recently, regional temperature variations have been observed in atherosclerotic plaques in vivo and ascribed to the presence of macrophages. As macrophages are a major source of MMPs, we examined whether regional temperature changes are related to local MMP activity and macrophage accumulation. METHODS AND RESULTS: Plaques were experimentally induced in rabbit (n=11) aortas, and at the day of sacrifice, a pull-back was performed with a thermography catheter. Hot (n=10), cold (n=10), and reference (n=11) regions were dissected and analysed for smooth muscle cell (SMC), lipids (L), collagen (COL), and macrophage (MPhi) cell densities (%); a vulnerability index (VI) was calculated as VI=MPhi+L/(SMC+COL). In addition, accumulation and activity of MMP-2 and MMP-9 were determined with zymography. Ten hot regions were identified with an average temperature of 0.40+/-0.03 degrees C (P<0.05 vs. reference) and 10 cold regions with 0.07+/-0.03 degrees C (P<0.05 vs. hot). In the hot regions, a higher macrophage density (173%), less SMC density (77%), and a higher VI (100%) were identified. In addition, MMP-9 (673%) activity was increased. A detailed regression analysis revealed that MMP-9 predicted hot regions better than macrophage accumulation alone. CONCLUSION: In vivo temperature measurements enable to detect plaques that contain more macrophages, less SMCs, and a higher MMP-9 activity.

Characterizing vulnerable plaque features with intravascular elastography. (Article)

2003-11-25T00:00:00Z

BACKGROUND: In vivo detection of vulnerable plaques is presently limited by a lack of diagnostic tools. Intravascular ultrasound elastography is a new technique based on intravascular ultrasound and has the potential to differentiate between different plaques phenotypes. However, the predictive value of intravascular elastography to detect vulnerable plaques had not been studied. METHODS AND RESULTS: Postmortem coronary arteries were investigated with intravascular elastography and subsequently processed for histology. In histology, a vulnerable plaque was defined as a plaque consisting of a thin cap (<250 microm) with moderate to heavy macrophage infiltration and at least 40% of atheroma. In elastography, a vulnerable plaque was defined as a plaque with a high strain region at the surface with adjacent low strain regions. In 24 diseased coronary arteries, we studied 54 cross sections. In histology, 26 vulnerable plaques and 28 nonvulnerable plaques were found. Receiver operator characteristic analysis revealed a maximum predictive power for a strain value threshold of 1.26%. The area under the receiver operator characteristic curve was 0.85. The sensitivity was 88%, and the specificity was 89% to detect vulnerable plaques. Linear regression showed high correlation between the strain in caps and the amount of macrophages (P<0.006) and an inverse relation between the amount of smooth muscle cells and strain (P<0.0001). Plaques, which are declared vulnerable in elastography, have a thinner cap than nonvulnerable plaques (P<0.0001). CONCLUSIONS: Intravascular elastography has a high sensitivity and specificity to detect vulnerable plaques in vitro.

From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part II. (Article)

2003-10-14T00:00:00Z

Atherosclerotic cardiovascular disease results in >19 million deaths annually, and coronary heart disease accounts for the majority of this toll. Despite major advances in treatment of coronary heart disease patients, a large number of victims of the disease who are apparently healthy die suddenly without prior symptoms. Available screening and diagnostic methods are insufficient to identify the victims before the event occurs. The recognition of the role of the vulnerable plaque has opened new avenues of opportunity in the field of cardiovascular medicine. This consensus document concludes the following. (1) Rupture-prone plaques are not the only vulnerable plaques. All types of atherosclerotic plaques with high likelihood of thrombotic complications and rapid progression should be considered as vulnerable plaques. We propose a classification for clinical as well as pathological evaluation of vulnerable plaques. (2) Vulnerable plaques are not the only culprit factors for the development of acute coronary syndromes, myocardial infarction, and sudden cardiac death. Vulnerable blood (prone to thrombosis) and vulnerable myocardium (prone to fatal arrhythmia) play an important role in the outcome. Therefore, the term "vulnerable patient" may be more appropriate and is proposed now for the identification of subjects with high likelihood of developing cardiac events in the near future. (3) A quantitative method for cumulative risk assessment of vulnerable patients needs to be developed that may include variables based on plaque, blood, and myocardial vulnerability. In Part I of this consensus document, we cover the new definition of vulnerable plaque and its relationship with vulnerable patients. Part II of this consensus document will focus on vulnerable blood and vulnerable myocardium and provide an outline of overall risk assessment of vulnerable patients. Parts I and II are meant to provide a general consensus and overviews the new field of vulnerable patient. Recently developed assays (eg, C-reactive protein), imaging techniques (eg, CT and MRI), noninvasive electrophysiological tests (for vulnerable myocardium), and emerging catheters (to localize and characterize vulnerable plaque) in combination with future genomic and proteomic techniques will guide us in the search for vulnerable patients. It will also lead to the development and deployment of new therapies and ultimately to reduce the incidence of acute coronary syndromes and sudden cardiac death. We encourage healthcare policy makers to promote translational research for screening and treatment of vulnerable patients.

From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part I. (Article)

2003-10-07T00:00:00Z

Atherosclerotic cardiovascular disease results in >19 million deaths annually, and coronary heart disease accounts for the majority of this toll. Despite major advances in treatment of coronary heart disease patients, a large number of victims of the disease who are apparently healthy die suddenly without prior symptoms. Available screening and diagnostic methods are insufficient to identify the victims before the event occurs. The recognition of the role of the vulnerable plaque has opened new avenues of opportunity in the field of cardiovascular medicine. This consensus document concludes the following. (1) Rupture-prone plaques are not the only vulnerable plaques. All types of atherosclerotic plaques with high likelihood of thrombotic complications and rapid progression should be considered as vulnerable plaques. We propose a classification for clinical as well as pathological evaluation of vulnerable plaques. (2) Vulnerable plaques are not the only culprit factors for the development of acute coronary syndromes, myocardial infarction, and sudden cardiac death. Vulnerable blood (prone to thrombosis) and vulnerable myocardium (prone to fatal arrhythmia) play an important role in the outcome. Therefore, the term "vulnerable patient" may be more appropriate and is proposed now for the identification of subjects with high likelihood of developing cardiac events in the near future. (3) A quantitative method for cumulative risk assessment of vulnerable patients needs to be developed that may include variables based on plaque, blood, and myocardial vulnerability. In Part I of this consensus document, we cover the new definition of vulnerable plaque and its relationship with vulnerable patients. Part II of this consensus document focuses on vulnerable blood and vulnerable myocardium and provide an outline of overall risk assessment of vulnerable patients. Parts I and II are meant to provide a general consensus and overviews the new field of vulnerable patient. Recently developed assays (eg, C-reactive protein), imaging techniques (eg, CT and MRI), noninvasive electrophysiological tests (for vulnerable myocardium), and emerging catheters (to localize and characterize vulnerable plaque) in combination with future genomic and proteomic techniques will guide us in the search for vulnerable patients. It will also lead to the development and deployment of new therapies and ultimately to reduce the incidence of acute coronary syndromes and sudden cardiac death. We encourage healthcare policy makers to promote translational research for screening and treatment of vulnerable patients.

Identification of Atherosclerotic Plaque Components With Intravascular Ultrasound Elastography In Vivo: A Yucatan Pig Study (Article)

2002-04-09T00:00:00Z

BACKGROUND: Intravascular ultrasound elastography assesses the local strain of the atherosclerotic vessel wall. In the present study, the potential to identify different plaque components in vivo was investigated. METHODS AND RESULTS: Atherosclerotic external iliac and femoral arteries (n=24) of 6 Yucatan pigs were investigated. Before termination, elastographic data were acquired with a 20-MHz Visions catheter. Two frames acquired at end-diastole with a pressure differential of approximately 4 mm Hg were acquired to obtain the elastograms. Before dissection, x-ray was used to identify the arterial segments that had been investigated by ultrasound. Specimens were stained for collagen, fat, and macrophages. Plaques were classified as absent, early fibrous lesion, early fatty lesion, or advanced fibrous plaque. The average strains in the plaque-free arterial wall (0.21%) and the early (0.24%) and advanced fibrous plaques (0.22%) were similar. Higher average strain values were observed in fatty lesions (0.46%) compared with fibrous plaques (P=0.007). After correction for confounding by lipid content, no additional differences in average strain were found between plaques with and without macrophages (P=0.966). Receiver operating characteristic analysis revealed a sensitivity and a specificity of 100% and 80%, respectively, to identify fatty plaques. The presence of a high-strain spot (strain >1%) has 92% sensitivity and 92% specificity to identify macrophages. CONCLUSIONS: To the best of our knowledge, this is the first time that intravascular ultrasound elastography has been validated in vivo. Fatty plaques have an increased mean strain value. High-strain spots are associated with the presence of macrophages.

Shear-stress and wall-stress regulation of vascular remodeling after balloon angioplasty: effect of matrix metalloproteinase inhibition (Article)

2001-01-01T00:00:00Z

BACKGROUND: Constrictive vascular remodeling (VR) is the most significant component of restenosis after balloon angioplasty (PTA). Whereas in physiological conditions VR is associated with normalization of shear stress (SS) and wall stress (WS), after PTA the role of SS and WS in VR is unknown. Furthermore, whereas matrix metalloproteinase inhibition (MMPI) has been shown to modulate VR after PTA, its effect on the SS and WS control mechanisms after PTA is unknown. METHODS AND RESULTS: PTA was performed in external iliac arteries of 12 atherosclerotic Yucatan pigs, of which 6 pigs (7 vessels) received the MMPI batimastat and 6 pigs (10 vessels) served as controls. Before and after the intervention and at 6-week follow-up, intravascular ultrasound pullback was performed, allowing 3D reconstruction of the treated segment and computational fluid dynamics to calculate the media-bounded area and SS. WS was derived from the Laplace formula. Immediately after PTA, media-bounded area, WS, and SS changed by 20%, 16%, and -49%, respectively, in both groups. VR was predicted by SS and WS. In the control group, SS and WS had been normalized at follow-up with respect to the reference segment. In contrast, for the batimastat group, the SS had been normalized, but not the WS. The latter is attributed to an increase in wall area at follow-up. CONCLUSIONS: Vascular remodeling after PTA is controlled by both SS and WS. MMPI inhibited the WS control system.

No relationship between compensatory arterial remodeling of focal stenotic atherosclerotic lesions and tortuosity of the arterial segment involved (Article)

2001-01-01T00:00:00Z

Videodensitometric quantitative angiography after coronary balloon angioplasty, compared to edge-detection quantitative angiography and intracoronary ultrasound imaging. (Article)

2000-04-05T00:00:00Z

AIMS: To assess the value of videodensitometric quantification of the coronary lumen after angioplasty by comparison to two other techniques of coronary artery lumen quantification. METHODS AND RESULTS: Videodensitometric quantitative angiography, edge detection quantitative angiography and 30 MHz intracoronary ultrasound imaging were performed after successful balloon angioplasty in 161 patients. Lumen cross-sectional areas were mean (SD) 2.82 (1.15) mm(2)for edge detection quantitative angiography, 3.67 (1.5) mm(2)for videodensitometric quantitative angiography and 5.32 (1.75) mm(2)for intracoronary ultrasound imaging (P<0.001). The correlation between intracoronary ultrasound imaging and videodensitometric quantitative angiography (r=0.44) was almost similar to that of intracoronary ultrasound imaging and edge detection quantitative angiography (r=0. 47). The correlation between the three techniques was not significantly influenced by the presence of ruptures and dissections on intracoronary ultrasound imaging. The absence of calcifications improved the correlation between videodensitometry and intracoronary ultrasound imaging. CONCLUSIONS: The luminal dimensions as measured by videodensitometric quantitative angiography matched intracoronary ultrasound imaging derived dimensions more closely than edge detection quantitative angiography. Videodensitometric quantitative angiography represents an on-line alternative to intracoronary ultrasound imaging for quantitative analysis regardless of the degree of vessel damage.

Characterization of plaque components with intravascular ultrasound elastography in human femoral and coronary arteries in vitro (Article)

2000-01-01T00:00:00Z

BACKGROUND: The composition of plaque is a major determinant of coronary-related clinical syndromes. Intravascular ultrasound (IVUS) elastography has proven to be a technique capable of reflecting the mechanical properties of phantom material and the femoral arterial wall. The aim of this study was to investigate the capability of intravascular elastography to characterize different plaque components. METHODS AND RESULTS: Diseased human femoral (n=9) and coronary (n=4) arteries were studied in vitro. At each location (n=45), 2 IVUS images were acquired at different intraluminal pressures (80 and 100 mm Hg). With the use of cross-correlation analysis on the high-frequency (radiofrequency) ultrasound signal, the local strain in the tissue was determined. The strain was color-coded and plotted as an additional image to the IVUS echogram. The visualized segments were stained on the presence of collagen, smooth muscle cells, and macrophages. Matching of elastographic data and histology were performed with the use of the IVUS echogram. The cross sections were segmented in regions (n=125) that were based on the strain value on the elastogram. The dominant plaque types in these regions (fibrous, fibro-fatty, or fatty) were obtained from histology and correlated with the average strain and echo intensity. The strain for the 3 plaque types as determined by histology differed significantly (P=0.0002). This difference was mainly evident between fibrous and fatty tissue (P=0.0004). The plaque types did not reveal echo-intensity differences in the IVUS echogram (P=0.882). CONCLUSIONS: Different strain values are found between fibrous, fibro-fatty, and fatty plaque components, indicating the potential of intravascular elastography to distinguish different plaque morphologies.

Prediction of Restenosis After Coronary Balloon Angioplasty (Article)

1997-01-01T00:00:00Z

Background Intracoronary ultrasound (ICUS) imaging is potentially suitable to identify lesions at high risk of restenosis after percutaneous transluminal coronary angioplasty (PTCA), but it has not been studied systematically. Methods and Results We recruited 200 patients in whom ICUS studies were performed after successful PTCA and related their ICUS parameters to 6-month follow-up quantitative coronary angiography. This was performed in 164 patients (82%), yielding 170 lesions for analysis. The overall incidence of a 50% diameter stenosis at follow-up (categorical restenosis) was 29.4%. Quantitative ICUS parameters were weakly but significantly related to follow-up minimal luminal diameter on quantitative coronary angiography (lumen area: R2=.36, P=.0001; vessel area: R2=.29, P=.0002; plaque area: R2=-.18, P=.021; percent obstruction: R2=-.15, P=.05), but categorical restenosis was not significantly related to these parameters (P=.63, .77, .38, and .08, respectively). There were no significant predictors of restenosis in ICUS parameters of plaque morphology: eccentric versus concentric (P=1.0), plaque type (hard, soft, or calcific, P=.98), or the number of calcified quadrants (P=.41). There were no significant predictors of restenosis in two predefined types of vessel-wall disruptions: (1) rupture: presence (P=.79), depth (partial versus complete, P=.85), or extent in quadrants (P=.6), and (2) dissection: presence (P=.31), depth (P=.82), or extent (P=.38). Conclusions Qualitative ICUS parameters after PTCA did not predict restenosis. A larger lumen and vessel area and a smaller plaque area by ICUS were associated with a larger angiographic minimal lumen diameter at follow-up, but these parameters were not significantly related to categorical restenosis.