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1.  Progress in atherosclerotic plaque imaging 
World Journal of Radiology  2012;4(8):353-371.
Cardiovascular diseases are the primary cause of mortality in the industrialized world, and arterial obstruction, triggered by rupture-prone atherosclerotic plaques, lead to myocardial infarction and cerebral stroke. Vulnerable plaques do not necessarily occur with flow-limiting stenosis, thus conventional luminographic assessment of the pathology fails to identify unstable lesions. In this review we discuss the currently available imaging modalities used to investigate morphological features and biological characteristics of the atherosclerotic plaque. The different imaging modalities such as ultrasound, magnetic resonance imaging, computed tomography, nuclear imaging and their intravascular applications are illustrated, highlighting their specific diagnostic potential. Clinically available and upcoming methodologies are also reviewed along with the related challenges in their clinical translation, concerning the specific invasiveness, accuracy and cost-effectiveness of these methods.
doi:10.4329/wjr.v4.i8.353
PMCID: PMC3430733  PMID: 22937215
Atherosclerosis; Diagnostic imaging; Plaque characterization
2.  Molecular Imaging of Inflammation in Atherosclerosis 
Theranostics  2013;3(11):865-884.
Acute rupture of vulnerable plaques frequently leads to myocardial infarction and stroke. Within the last decades, several cellular and molecular players have been identified that promote atherosclerotic lesion formation, maturation and plaque rupture. It is now widely recognized that inflammation of the vessel wall and distinct leukocyte subsets are involved throughout all phases of atherosclerotic lesion development. The mechanisms that render a stable plaque unstable and prone to rupture, however, remain unknown and the identification of the vulnerable plaque remains a major challenge in cardiovascular medicine. Imaging technologies used in the clinic offer minimal information about the underlying biology and potential risk for rupture. New imaging technologies are therefore being developed, and in the preclinical setting have enabled new and dynamic insights into the vessel wall for a better understanding of this complex disease. Molecular imaging has the potential to track biological processes, such as the activity of cellular and molecular biomarkers in vivo and over time. Similarly, novel imaging technologies specifically detect effects of therapies that aim to stabilize vulnerable plaques and silence vascular inflammation. Here we will review the potential of established and new molecular imaging technologies in the setting of atherosclerosis, and discuss the cumbersome steps required for translating molecular imaging approaches into the clinic.
doi:10.7150/thno.5771
PMCID: PMC3841337  PMID: 24312156
Molecular imaging; Inflammation; Atherosclerosis
3.  Screening of ruptured plaques in patients with coronary artery disease by intravascular ultrasound 
Heart  1999;81(6):621-627.
AIM—To visualise the characteristics of ruptured plaques by intravascular ultrasound (IVUS) and to correlate plaque characteristics with clinical symptoms to establish a quantitative index of plaque vulnerability.
METHODS—144 consecutive patients with angina were examined using IVUS. Ruptured plaques, characterised by a plaque cavity and a tear on the thin fibrous cap, were identified in 31 patients (group A), of whom 23 (74%) presented with unstable angina. Plaque rupture was confirmed by injecting contrast medium filling the plaque cavity during IVUS examination. Of the patients without plaque rupture (group B, n = 108), only 19 (18%) had unstable angina.
RESULTS—No significant differences were found between groups A and B in relation to plaque and vessel area (p > 0.05). Mean (SD) per cent stenosis in group A was less than in group B, at 56.2 (16.5)% v 67.9 (13.4)%; p < 0.001. Area of the emptied plaque cavity in group A (4.1 (3.2) mm2) was larger than the echolucent zone in group B (1.32 (0.79) mm2) (p < 0.001). The plaque cavity to plaque ratio in group A (38.5 (17.1)%) was larger than the echolucent area to plaque ratio in group B (11.2 (8.9)%) (p < 0.001). The thickness of the fibrous cap in group A was less than in group B, at 0.47 (0.20) mm v 0.96 (0.94) mm; p < 0.001.
CONCLUSIONS—Plaques seem to be prone to rupture when the echolucent area is larger than 4.1 (3.2) mm2, when the echolucent area to plaque ratio is greater than 38.5 (17.1)%, and when the fibrous cap is thinner than 0.7 mm. IVUS can identify plaque rupture and vulnerable plaques. This may influence patient management and treatment.


Keywords: intravascular ultrasound; atherosclerosis; unstable angina; myocardial infarction; plaque rupture
PMCID: PMC1729066  PMID: 10336922
4.  Intravascular Ultrasound to Guide Percutaneous Coronary Interventions 
Executive Summary
Objective
The objective of this health technology policy assessment was to determine the effectiveness and cost-effectiveness of using intravascular ultrasound (IVUS) as an adjunctive imaging tool to coronary angiography for guiding percutaneous coronary interventions.
Background
Intravascular Ultrasound
Intravascular ultrasound is a procedure that uses high frequency sound waves to acquire 3-dimensional images from the lumen of a blood vessel. The equipment for performing IVUS consists of a percutaneous transducer catheter and a console for reconstructing images. IVUS has been used to study the structure of the arterial wall and nature of atherosclerotic plaques, and obtain measurements of the vessel lumen. Its role in guiding stent placement is also being investigated. IVUS is presently not an insured health service in Ontario.
Clinical Need
Coronary artery disease accounts for approximately 55% of cardiovascular deaths, the leading cause of death in Canada. In Ontario, the annual mortality rate due to ischemic heart disease was 141.8 per 100,000 population between 1995 and 1997. Percutaneous coronary intervention (PCI), a less invasive approach to treating coronary artery disease, is used more frequently than coronary bypass surgery in Ontario. The number of percutaneous coronary intervention procedures funded by the Ontario Ministry of Health and Long-term Care is expected to increase from approximately 17, 780 in 2004/2005 to 22,355 in 2006/2007 (an increase of 26%), with about 95% requiring the placement of one or more stents. Restenosis following percutaneous coronary interventions involving bare metal stents occurs in 15% to 30% of the cases, mainly because of smooth muscle proliferation and migration, and production of extracellular matrix. In-stent restenosis has been linked to suboptimal stent expansion and inadequate lesion coverage, while stent thrombosis has been attributed to incomplete stent-to-vessel wall apposition. Since coronary angiography (the imaging tool used to guide stent placement) has been shown to be inaccurate in assessing optimal stent placement, and IVUS can provide better views of the vessel lumen, the clinical utility of IVUS as an imaging tool adjunctive to coronary angiography in coronary intervention procedures has been explored in clinical studies.
Method
A systematic review was conducted to answer the following questions:
What are the procedure-related complications associated with IVUS?
Does IVUS used in conjunction with angiography to guide percutaneous interventions improve patient outcomes compared to angiographic guidance without IVUS?
Who would benefit most in terms of clinical outcomes from the use of IVUS adjunctive to coronary angiography in guiding PCIs?
What is the effectiveness of IVUS guidance in the context of drug-eluting stents?
What is the cost-effectiveness ratio and budget impact of adjunctive IVUS in PCIs in Ontario?
A systematic search of databases OVID MEDLINE, EMBASE, MEDLINE In-Process & Other Non-Indexed Citations, The Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) database for the period beginning in May 2001 until the day of the search, November 4, 2005 yielded 2 systematic reviews, 1 meta-analysis, 6 randomized controlled trials, and 2 non-randomized studies on left main coronary arteries. The quality of the studies ranged from moderate to high. These reports were combined with reports from a previous systematic review for analysis. In addition to qualitative synthesis, pooled analyses of data from randomized controlled studies using a random effect model in the Cochrane Review Manager 4.2 software were conducted when possible.
Findings of Literature Review & Analysis
Safety
Intravascular ultrasound appears to be a safe tool when used in coronary interventions. Periprocedural complications associated with the use of IVUS in coronary interventions ranged from 0.5% in the largest study to 4%. Coronary rupture was reported in 1 study (1/54). Other complications included prolonged spasms of the artery after stenting, dissection, and femoral aneurysm.
Effectiveness
Based on pooled analyses of data from randomized controlled studies, the use of intravascular ultrasound adjunctive to coronary intervention in percutaneous coronary interventions using bare metal stents yielded the following findings:
For lesions predominantly at low risk of restenosis:
There were no significant differences in preintervention angiographic minimal lumen diameter between the IVUS-guided and angiography-guided groups.
IVUS guidance resulted in a significantly larger mean postintervention angiographic minimal lumen diameter (weighted mean difference of 0.11 mm, P = .0003) compared to angiographic guidance alone.
The benefit in angiographic minimal lumen diameter from IVUS guidance was not maintained at 6-month follow-up, when no significant difference in angiographic minimal lumen diameter could be detected between the two arms (weighted mean difference 0.08, P = .13).
There were no statistically significant differences in angiographic binary restenosis rates between IVUS-guidance and no IVUS guidance (Odds ratio [OR] 0.87 in favour of IVUS, 95% Confidence Interval [CI] [0.64–1.18], P = 0.37).
IVUS guidance resulted in a reduction in the odds of target lesion revascularization (repeat percutaneous coronary intervention or coronary bypass graft) compared to angiographic guidance alone. The reduction was statistically significant at a follow-up period of 6 months to 1 year, and at a follow-up period of 18 month to 2 years (OR 0.52 in favour of IVUS, 95% CI [0.33–0.81], P = .004).
Total revascularization rate (either target lesion or target vessel revascularization) was significantly lower for IVUS-guided patients at 18 months to 2.5 years after intervention (OR 0.43 in favour of IVUS, 95% CI [0.29–0.63], p < .0001).
There were no statistically significant differences in the odds of death (OR 1.36 in favour of no IVUS, P =0.65) or myocardial infarction (OR 0.95 in favour of IVUS, P = 0.93) between IVUS-guidance and angiographic guidance alone at up to 2.5 years of follow-up
The odds of having a major cardiac event (defined as death, myocardial infarction, and target lesion or target vessel revascularization) were significantly lower for patients with IVUS guidance compared to angiographic guidance alone during follow-up periods of up to 2.5 years (OR 0.53, 95% CI [0.36–0.78], P = 0.001). Since there were no significant reductions in the odds of death or myocardial infarction, the reduction in the odds of combined events reflected mainly the reduction in revascularization rates.
For lesions at High Risk of Restenosis:
There is evidence from one small, randomized controlled trial (n=150) that IVUS-guided percutaneous coronary intervention in long de novo lesions (>20 mm) of native coronary arteries resulted in statistically significant larger minimal lumen Diameter, and statistically significant lower 6-month angiographic binary restenosis rate. Target vessel revascularization rate and the rate of combined events were also significantly reduced at 12 months.
A small subgroup analysis of a randomized controlled trial reported no benefit in clinical or angiographic outcomes for IVUS-guided percutaneous coronary interventions in patients with diabetes compared to those guided by angiography. However, due to the nature and size of the analysis, no firm conclusions could be reached.
Based on 2 small, prospective, non-randomized controlled studies, IVUS guidance in percutaneous coronary interventions of left main coronary lesions using bare metal stents or drug-eluting stents did not result in any benefits in angiographic or clinical outcomes. These findings need to be confirmed.
Interventions Using Drug-Eluting Stents
There is presently no evidence on whether the addition of IVUS guidance during the implantation of drug-eluting stents would reduce incomplete stent apposition, or improve the angiographic or clinical outcomes of patients.
Ontario-Based Economic Analysis
Cost-effectiveness analysis showed that PCIs using IVUS guidance would likely be less costly and more effective than PCIs without IVUS guidance. The upfront cost of adjunctive use of IVUS in PCIs ranged from $1.56 million at 6% uptake to $13.04 million at 50% uptake. Taking into consideration cost avoidance from reduction in revascularization associated with the use of IVUS, a net saving of $0.63 million to $5.2 million is expected. However, since it is uncertain whether the reduction in revascularization rate resulting from the use of IVUS can be generalized to clinical settings in Ontario, further analysis on the budget impact and cost-effectiveness need to be conducted once Ontario-specific revascularization rates are verified.
Factors to be Considered in the Ontario Context
Applicability of Findings to Ontario
The interim analysis of an Ontario field evaluation that compared drug-eluting stents to bare metal stents showed that the revascularization rates in low-risk patients with bare metal stents were much lower in Ontario compared to rates reported in randomized controlled trials (7.2% vs >17 %). Even though IVUS is presently not routinely used in the stenting of low-risk patients in Ontario, the revascularization rates in these patients in Ontario were shown to be lower than those reported for the IVUS groups reported in published studies. Based on this information and previous findings from the Ontario field evaluation on stenting, it is uncertain whether the reduction in revascularization rates from IVUS guidance can be generalized to Ontario. In light of the above findings, it is advisable to validate the reported benefits of IVUS guidance in percutaneous coronary interventions involving bare metal stents in the Ontario context.
Licensing Status
As of January 16, 2006, Health Canada has licensed 10 intravascular ultrasound imaging systems/catheters for transluminal intervention procedures, most as class 4 medical devices.
Current Funding
IVUS is presently not an insured procedure under the Ontario Health Insurance Plan and there are no professional fees for this procedure. All costs related to the use of IVUS are covered within hospitals’ global budgets. A single use IVUS catheter costs approximately $900CDN and the procedure adds approximately 20 minutes to 30 minutes to a percutaneous coronary intervention procedure.
Diffusion
According to an expert consultant, current use of IVUS in coronary interventions in Ontario is probably limited to high-risk cases such as interventions in long lesions, small vessels, and bifurcated lesions for which images from coronary angiography are indeterminate. It was estimated that IVUS is being used in about 6% of all percutaneous coronary interventions at a large Ontario cardiac centre.
Expert Opinion
IVUS greatly enhances the cardiac interventionists’ ability to visualize and assess high-risk lesions such as long lesions, narrow lesions, and bifurcated lesions that may have indeterminate angiographic images. Information from IVUS in these cases facilitates the choice of the most appropriate approach for the intervention.
Conclusion
The use of adjunctive IVUS in PCIs using bare metal stents in lesions predominantly at low risk for restenosis had no significant impact on survival, myocardial infarction, or angiographic restenosis rates up to 2.5 years after intervention.
The use of IVUS adjunctive to coronary angiography in percutaneous coronary interventions using bare metal stents in lesions predominantly at low risk for restenosis significantly reduced the target lesion and target vessel revascularization at a follow-up period of 18 months to 2.5 years.
One small study suggests that adjunctive IVUS in PCIs using bare metal stents in long lesions (>20 mm) significantly improved the 6-month angiographic restenosis rate and one-year target lesion revascularization rate. These results need to be confirmed with large randomized controlled trials.
Based on information from the Ontario field evaluation on stenting, it is uncertain whether the reduction in revascularization rate resulting from the use of IVUS in the placement of bare metal stents can be generalized to clinical settings in Ontario.
There is presently insufficient evidence available to determine the impact of adjunctive IVUS in percutaneous interventions in high-risk lesions (other than long lesions) or in PCIs using drug-eluting stents.
PMCID: PMC3379536  PMID: 23074482
5.  Vascular ultrasound for atherosclerosis imaging 
Interface Focus  2011;1(4):565-575.
Cardiovascular disease is a leading cause of death in the Western world. Therefore, detection and quantification of atherosclerotic disease is of paramount importance to monitor treatment and possible prevention of acute events. Vascular ultrasound is an excellent technique to assess the geometry of vessel walls and plaques. The high temporal as well as spatial resolution allows quantification of luminal area and plaque size and volume. While carotid arteries can be imaged non-invasively, scanning of coronary arteries requires invasive intravascular catheters. Both techniques have already demonstrated their clinical applicability. Using linear array technology, detection of disease as well as monitoring of pharmaceutical treatment in carotid arteries are feasible. Data acquired with intravascular ultrasound catheters have proved to be especially beneficial in understanding the development of atherosclerotic disease in coronary arteries. With the introduction of vascular elastography not only the geometry of plaques but also the risk for rupture of plaques might be identified. These so-called vulnerable plaques are frequently not flow-limiting and rupture of these plaques is responsible for the majority of cerebral and cardiac ischaemic events. Intravascular ultrasound elastography studies have demonstrated a high correlation between high strain and vulnerable plaque features, both ex vivo and in vivo. Additionally, pharmaceutical intervention could be monitored using this technique. Non-invasive vascular elastography has recently been developed for carotid applications by using compound scanning. Validation and initial clinical evaluation is currently being performed. Since abundance of vasa vasorum (VV) is correlated with vulnerable plaque development, quantification of VV might be a unique tool to even prevent this from happening. Using ultrasound contrast agents, it has been demonstrated that VV can be identified and quantified. Although far from routine clinical application, non-invasive and intravascular ultrasound VV imaging might pave the road to prevent atherosclerotic disease in an early phase. This paper reviews the conventional vascular ultrasound techniques as well as vascular ultrasound strain and vascular ultrasound VV imaging.
doi:10.1098/rsfs.2011.0024
PMCID: PMC3262270  PMID: 22866231
ultrasound imaging; vascular; elastography; vulnerable plaque; contrast-enhanced ultrasound
6.  Imaging of the unstable plaque: how far have we got? 
European Heart Journal  2009;30(21):2566-2574.
Rupture of unstable plaques may lead to myocardial infarction or stroke and is the leading cause of morbidity and mortality in western countries. Thus, there is a clear need for identifying these vulnerable plaques before the rupture occurs. Atherosclerotic plaques are a challenging imaging target as they are small and move rapidly, especially in the coronary tree. Many of the currently available imaging tools for clinical use still provide minimal information about the biological characteristics of plaques, because they are limited with respect to spatial and temporal resolution. Moreover, many of these imaging tools are invasive. The new generation of imaging modalities such as magnetic resonance imaging, nuclear imaging such as positron emission tomography and single photon emission computed tomography, computed tomography, fluorescence imaging, intravascular ultrasound, and optical coherence tomography offer opportunities to overcome some of these limitations. This review discusses the potential of these techniques for imaging the unstable plaque.
doi:10.1093/eurheartj/ehp419
PMCID: PMC2771148  PMID: 19833636
Atherosclerosis; Molecular imaging; Vulnerable plaque
7.  Intravascular Ultrasound of Symptomatic Intracranial Stenosis Demonstrates Atherosclerotic Plaque with Intraplaque Hemorrhage: A Case Report 
BACKGROUND
Intracranial artery stenosis is assumed to represent atherosclerotic plaque. Catheter cerebral arteriography shows that intracranial stenosis may progress, regress, or remain unchanged. It is counterintuitive that atherosclerotic plaque should spontaneously regress, raising questions about the composition of intracranial stenoses. Little is known about this disease entity in vivo. We provide the first demonstration of in vivo atherosclerotic plaque with intraplaque hemorrhage using intravascular ultrasound (IVUS).
CASE DESCRIPTION
A 35-year-old man with multiple vascular risk factors presented with recurrent stroke failing medical therapy. Imaging demonstrated left internal carotid artery occlusion, severe intracranial right internal carotid artery stenosis, and cerebral perfusion failure. Cerebral arteriography with IVUS confirmed 85% stenosis of the petrous right carotid artery due to atherosclerotic plaque with intraplaque hemorrhage. Intracranial stent-supported angioplasty was performed with IRB approval. The patient recovered without complication.
CONCLUSIONS
This case supports the premise that symptomatic intracranial stenosis can be caused by atherosclerotic plaque complicated by intraplaque hemorrhage similar to coronary artery plaque. IVUS provides additional characteristics that define intracranial atherosclerosis and high-risk features. To our knowledge, this is the first report of stroke due to unstable atherosclerotic plaque with intraplaque hemorrhage in vivo.
doi:10.1111/j.1552-6569.2008.00278.x
PMCID: PMC2710422  PMID: 19021843
Intracranial atherosclerosis; IVUS; atheroma; intraplaque hemorrhage
8.  High Platelet Reactivity on Clopidogrel Therapy Correlates With Increased Coronary Atherosclerosis and Calcification: A Volumetric Intravascular Ultrasound Study 
JACC. Cardiovascular imaging  2012;5(5):540-549.
OBJECTIVES
To evaluate the relationship between platelet reactivity and atherosclerotic burden in patients undergoing percutaneous coronary intervention (PCI) with pre-intervention volumetric intravascular ultrasound (IVUS) imaging.
BACKGROUND
Atherosclerosis progresses by the pathologic sequence of sub-clinical plaque rupture, thrombosis and healing. In this setting, increased platelet reactivity may lead to more extensive arterial thrombosis at the time of plaque rupture, leading to a more rapid progression of the disease. Alternatively, abnormal vessel wall biology with advanced atherosclerosis is known to enhance platelet reactivity. Therefore, it is possible that by either mechanism, increased platelet reactivity may be associated with greater atherosclerotic burden.
METHODS
We analyzed patients who underwent PCI with pre-intervention IVUS imaging and platelet reactivity functional assay (P2Y12 reaction-units [PRU]) performed >16 hours post-PCI after stabilization of clopidogrel therapy (administered pre-PCI). A PRU value of >230 defined high on-treatment platelet reactivity (HPR).
RESULTS
Among 335 patients (mean age 65.0; 71% male), there were 109 patients with HPR (32.5%) and 226 without HPR (67.5%), with HPR being associated with diabetes and chronic renal insufficiency. By IVUS analysis, HPR patients had significantly greater target lesion calcium length, calcium arc, and calcium index. Furthermore, HPR patients tended to have longer lesions and greater volumetric dimensions, indicating higher plaque volume, larger total vessel volume and also greater lumen volume, despite similar plaque burden. By multivariable analysis controlling for baseline clinical variables, HPR was the single consistent predictor of all IVUS parameters examined, including plaque volume, calcium length and calcium arc.
CONCLUSIONS
Increased platelet reactivity on clopidogrel treatment, as defined by a PRU value of >230, is associated with greater coronary artery atherosclerotic disease burden and plaque calcification.
doi:10.1016/j.jcmg.2011.12.019
PMCID: PMC3753810  PMID: 22595163
atherosclerosis; clopidogrel; plaque progression; platelets; platelet reactivity
9.  Plaque regression and plaque stabilisation in cardiovascular diseases 
Atherosclerosis is characterized by formation of plaques on the inner walls of arteries that threatens to become the leading cause of death worldwide via its sequelae of myocardial infarction and stroke. Endothelial dysfunction leads to cholesterol uptake and accumulation of inflammatory markers within the plaque. The stability of a plaque eventually depends on the balance between vascular smooth muscle cells that stabilize it and the inflammatory cells like macrophages and T lymphocytes that make it prone to rupture. The current approach to manage atherosclerosis focuses on the treatment of a ruptured plaque and efforts have been made to reduce the risk of plaque rupture by identifying vulnerable plaques and treating them before they precipitate into clinical events. New diagnostic approaches such as IVUS and CIMT ultrasound are now being preferred over traditional coronary angiography because of their better accuracy in measuring plaque volume rather than the level of stenosis caused. The present review highlights the literature available on two prevalent approaches to manage a vulnerable plaque, namely, plaque stabilization and plaque regression, and their validation through various treatment modalities in recent plaque management studies. Plaque stabilization focuses on stabilizing the content of plaque and strengthening the overlying endothelium, while plaque regression focuses on the overall reduction in plaque volume and to reverse the arterial endothelium to its normal functional state. Although earlier studies contemplated the practicality of plaque regression and focused greatly on stabilization of a vulnerable plaque, our review indicated that, aided by the use of superior diagnostics tools, more intensive lipid modifying therapies have resulted in actual plaque regression.
doi:10.4103/2230-8210.122604
PMCID: PMC3872716  PMID: 24381872
Atherosclerotic plaque; plaque regression; plaque stabilisationstabilization; vulnerable plaque
10.  Focus on the research utility of intravascular ultrasound - comparison with other invasive modalities 
Intravascular ultrasound (IVUS) is an invasive modality which provides cross-sectional images of a coronary artery. In these images both the lumen and outer vessel wall can be identified and accurate estimations of their dimensions and of the plaque burden can be obtained. In addition, further processing of the IVUS backscatter signal helps in the characterization of the type of the plaque and thus it has been used to study the natural history of the atherosclerotic evolution. On the other hand its indigenous limitations do not allow IVUS to assess accurately stent struts coverage, existence of thrombus or exact site of plaque rupture and to identify some of the features associated with increased plaque vulnerability. In order this information to be obtained, other modalities such as optical coherence tomography, angioscopy, near infrared spectroscopy and intravascular magnetic resonance imaging have either been utilized or are under evaluation. The aim of this review article is to present the current utilities of IVUS in research and to discuss its advantages and disadvantages over the other imaging techniques.
doi:10.1186/1476-7120-9-2
PMCID: PMC3039561  PMID: 21276268
11.  Small coronary calcifications are not detectable by 64-slice contrast enhanced computed tomography 
Recently, small calcifications have been associated with unstable plaques. Plaque calcifications are both in intravascular ultrasound (IVUS) and multi-slice computed tomography (MSCT) easily recognized. However, smaller calcifications might be missed on MSCT due to its lower resolution. Because it is unknown to which extent calcifications can be detected with MSCT, we compared calcification detection on contrast enhanced MSCT with IVUS. The coronary arteries of patients with myocardial infarction or unstable angina were imaged by 64-slice MSCT angiography and IVUS. The IVUS and MSCT images were registered and the arteries were inspected on the presence of calcifications on both modalities independently. We measured the length and the maximum circumferential angle of each calcification on IVUS. In 31 arteries, we found 99 calcifications on IVUS, of which only 47 were also detected on MSCT. The calcifications missed on MSCT (n = 52) were significantly smaller in angle (27° ± 16° vs. 59° ± 31°) and length (1.4 ± 0.8 vs. 3.7 ± 2.2 mm) than those detected on MSCT. Calcifications could only be detected reliably on MSCT if they were larger than 2.1 mm in length or 36° in angle. Half of the calcifications seen on the IVUS images cannot be detected on contrast enhanced 64-slice MSCT angiography images because of their size. The limited resolution of MSCT is the main reason for missing small calcifications.
doi:10.1007/s10554-010-9662-8
PMCID: PMC3035782  PMID: 20602171
MSCT; IVUS; Calcification; Coronary arteries
12.  Effect of Folic Acid Supplementation on Levels of Circulating Monocyte Chemoattractant Protein-1 and the Presence of Intravascular Ultrasound Derived Virtual Histology Thin-Cap Fibroatheromas in Patients with Stable Angina Pectoris 
PLoS ONE  2013;8(7):e70101.
Background
Virtual Histology Intravascular Ultrasound (VH–IVUS) may be used to detect early signs of unstable coronary artery disease. Monocyte Chemoattractant Protein-1 (MCP-1) is linked with coronary atherosclerosis and plaque instability and could potentially be modified by folic acid treatment.
Methods
In a randomized, prospective study, 102 patients with stable angina pectoris (SAP) received percutaneous coronary intervention and established medical treatment as well as either homocysteine-lowering folic acid/vitamin B12 (±B6) or placebo (±B6) for 1 year before VH–IVUS was performed. The presence of VH-Thin-Cap Fibroatheroma (VH-TCFA) in non-intervened coronary vessels was registered and serum levels of MCP-1 were measured. The patients were subsequently followed for incident myocardial infarction (MI).
Results
Patients treated with folic acid/vitamin B12 had a geometric mean (SD) MCP-1 level of 79.95 (1.49) versus 86.00 (1.43) pg/mL for patients receiving placebo (p-value 0.34). VH-TCFA lesions were present in 7.8% of patients and did not differ between intervention arms (p-value 0.47). Serum levels of MCP-1 were 1.46 (95% CI 1.12 to 1.92) times higher in patients with VH-TCFA lesions than in those without (p-value 0.005). Afterwards, patients were followed for median 2.1 years and 3.8% experienced a myocardial infarction (MI), which in post-hoc Cox regression analyses was independently predicted by both MCP-1 (P-value 0.006) and VH-TCFA (p-value 0.01).
Conclusions
In patients with SAP receiving established medical treatment, folic acid supplementation is not associated with either presence of VH-TCFA or levels of MCP-1. MCP-1 is however associated with VH-TCFA, a finding corroborated by increased risk for future MI.
ClinicalTrials.gov Identifier: NCT00354081.
doi:10.1371/journal.pone.0070101
PMCID: PMC3723764  PMID: 23936148
13.  Evaluation of Peripheral Atherosclerosis: A Comparative Analysis of Angiography and Intravascular Ultrasound 
Objective
Angiography remains a critical component for diagnostic imaging and therapeutic intervention in peripheral arterial disease (PAD). The goal of this study was to compare angiography to corresponding intravascular ultrasound (IVUS) imaging of the same vessels in patients with PAD.
Methods
From 2004–2008, patients undergoing angiography for PAD (n=93) were recruited in a prospective observational analysis. At the time of angiography, diseased lower extremities were interrogated via a 10-cm IVUS pullback with registration points. IVUS data were analyzed with radiofrequency techniques for vessel and lumen diameter, plaque volume, plaque composition, and cross-sectional area (VH™, Volcano Corp). Similarly, vascular surgeons (n=3) blinded to the IVUS data graded corresponding angiographic images according to vessel diameter, degree of stenosis, degree of calcification, and extent of eccentricity. Statistical analyses of matched IVUS/angiograms were performed utilizing SPSS 16.0 (Chicago, IL).
Results
The distribution of demographic and risk variables were typical for PAD: 54% male, 96% hypertension, 78% hyperlipidemia, 44% diabetic, 87% tobacco history, 65% coronary artery disease, and 10% end-stage renal disease. Symptoms precipitating the angiographic evaluation included claudication (53%), rest pain (18%), and tissue loss (29%). Angiographic and IVUS interpretation were similar for luminal diameters, but external vessel diameter was greater via IVUS (7.0 ± 0.7 vs. 5.2 ± 0.8 mm, P < 0.05). There was a significant correlation for stenosis determination (r=0.84) utilizing the two-dimensional diameter method; however, IVUS determination of vessel area stenosis was greater by 10% (95% confidence interval = 0.3–21%, P<0.05). IVUS indicated that a higher proportion of plaques were concentric. Grading of calcification was moderate/severe in 40% by angiography, but only 7% by IVUS (P < 0.05).
Conclusions
In the evaluation of peripheral arterial disease, angiography and IVUS provide similar luminal diameters and diameter-reducing stenosis measurements. Determination of overall vessel diameter, and interpretation of plaque morphology by angiography are discordant from IVUS derived data.
doi:10.1016/j.jvs.2009.11.034
PMCID: PMC2847042  PMID: 20080002
14.  Optical Coherence Tomography Analysis of Attenuated Plaques Detected by Intravascular Ultrasound in Patients with Acute Coronary Syndromes 
Background. Recent intravascular ultrasound (IVUS) studies have demonstrated that hypoechoic plaque with deep ultrasound attenuation despite absence of bright calcium is common in acute coronary syndrome. Such “attenuated plaque” may be an IVUS characteristic of unstable lesion. Methods. We used optical coherence tomography (OCT) in 104 patients with unstable angina to compare lesion characteristics between IVUS-detected attenuated plaque and nonattenuated plaque. Results. IVUS-detected attenuated plaque was observed in 41 (39%) patients. OCT-detected lipidic plaque (88% versus 49%, P < 0.001), thin-cap fibroatheroma (48% versus 16%, P < 0.001), plaque rupture (44% versus 11%, P < 0.001), and intracoronary thrombus (54% versus 17%, P < 0.001) were more often seen in IVUS-detected attenuated plaques compared with nonattenuated plaques. Conclusions. IVUS-detected attenuated plaque has many characteristics of unstable coronary lesion. The presence of attended plaque might be an important marker of lesion instability.
doi:10.4061/2011/687515
PMCID: PMC3173965  PMID: 21941667
15.  Symptomatic and asymptomatic carotid artery plaque 
Carotid atherosclerotic plaques represent both stable and unstable atheromatous lesions. Atherosclerotic plaques that are prone to rupture owing to their intrinsic composition such as a large lipid core, thin fibrous cap and intraplaque hemorrhage are associated with subsequent thromboembolic ischemic events. At least 15–20% of all ischemic strokes are attributable to carotid artery atherosclerosis. Characterization of plaques may enhance the understanding of natural history and ultimately the treatment of atherosclerotic disease. MRI of carotid plaque and embolic signals during transcranial Doppler have identified features beyond luminal stenosis that are predictive of future transient ischemic attacks and stroke. The value of specific therapies to prevent stroke in symptomatic and asymptomatic patients with severe carotid artery stenosis are the subject of current research and analysis of recently published clinical trials that are discussed in this article.
doi:10.1586/erc.11.120
PMCID: PMC3243497  PMID: 21985544
carotid atherosclerosis; carotid endarterectomy; diagnostic studies; medical therapy; stenting; stroke
16.  Safety of embolic protection device-assisted and unprotected intravascular ultrasound in evaluating carotid artery atherosclerotic lesions 
Summary
Background
Significant atherosclerotic stenosis of internal carotid artery (ICA) origin is common (5–10% at ≥60 years). Intravascular ultrasound (IVUS) enables high-resolution (120 μm) plaque imaging, and IVUS-elucidated features of the coronary plaque were recently shown to be associated with its symptomatic rupture/thrombosis risk. Safety of the significant carotid plaque IVUS imaging in a large unselected population is unknown.
Material/Methods
We prospectively evaluated the safety of embolic protection device (EPD)-assisted vs. unprotected ICA-IVUS in a series of consecutive subjects with ≥50% ICA stenosis referred for carotid artery stenting (CAS), including 104 asymptomatic (aS) and 187 symptomatic (S) subjects (age 47–83 y, 187 men). EPD use was optional for IVUS, but mandatory for CAS.
Results
Evaluation was performed of 107 ICAs (36.8%) without EPD and 184 with EPD. Lesions imaged under EPD were overall more severe (peak-systolic velocity 2.97±0.08 vs. 2.20±0.08m/s, end-diastolic velocity 1.0±0.04 vs. 0.7±0.03 m/s, stenosis severity of 85.7±0.5% vs. 77.7±0.6% by catheter angiography; mean ±SEM; p<0.01 for all comparisons) and more frequently S (50.0% vs. 34.6%, p=0.01). No ICA perforation or dissection, and no major stroke or death occurred. There was no IVUS-triggered cerebral embolization. In the procedures of (i) unprotected IVUS and no CAS, (ii) unprotected IVUS followed by CAS (filters – 39, flow reversal/blockade – 3), (iii) EPD-protected (filters – 135, flow reversal/blockade – 48) IVUS+CAS, TIA occurred in 1.5% vs. 4.8% vs. 2.7%, respectively, and minor stroke in 0% vs. 2.4% vs. 2.1%, respectively. EPD intolerance (on-filter ICA spasm or flow reversal/blockade intolerance) occurred in 9/225 (4.0%). IVUS increased the procedure duration by 7.27±0.19 min.
Conclusions
Carotid IVUS is safe and, for the less severe lesions in particular, it may not require mandatory EPD use. High-risk lesions can be safely evaluated with IVUS under flow reversal/blockade.
doi:10.12659/MSM.882452
PMCID: PMC3560589  PMID: 22293887
intravascular ultrasound; carotid artery stenosis; embolic protection device
17.  Radionuclide imaging - A molecular key to the atherosclerotic plaque 
Despite primary and secondary prevention, serious cardiovascular events like unstable angina or myocardial infarction still account for one third of all deaths worldwide. Therefore, identifying individual patients with vulnerable plaques at high risk for plaque rupture is a central challenge in cardiovascular medicine. Several non-invasive techniques, such as MRI, multislice computed tomography and electron beam tomography are currently being tested for their ability to identify such patients by morphological criteria. In contrast, molecular imaging techniques use radiolabeled molecules to detect functional aspects in atherosclerotic plaques by visualizing its biological activity. Based upon the knowledge about the pathophysiology of atherosclerosis, various studies in vitro, in vivo and the first clinical trials have used different tracers for plaque imaging studies, including radioactive labelled lipoproteins, components of the coagulation system, cytokines, mediators of the metalloproteinase system, cell adhesion receptors and even whole cells. This review gives an update on the relevant non-invasive plaque imaging approaches using nuclear imaging techniques to detect atherosclerotic vascular lesions.
doi:10.1016/j.jacc.2008.03.036
PMCID: PMC2683742  PMID: 18582628
Plaque imaging; atherosclerosis; radionuclide imaging; vulnerable plaque; thrombogenicity
18.  In vivo characterisation of coronary plaques with conventional grey-scale intravascular ultrasound: correlation with optical coherence tomography 
Aims
Although intravascular ultrasound (IVUS) is widely used, there is limited published data on its accuracy in defining plaque characteristics in vivo. Optical coherence tomography (OCT) is a high-resolution imaging technique that takes advantage of the pronounced optical contrast between the components of normal and diseased vessels. The aim of this study was to evaluate the ability of conventional grey-scale IVUS in identifying in vivo coronary plaque characteristics, in particular lipid content as a marker of the vulnerable plaque, when compared to OCT.
Methods and results
In patients undergoing cardiac catheterisation, IVUS and OCT imaging was performed. Detailed qualitative analysis of lipid-rich plaque, calcific plaque, and plaque disruption were performed at corresponding sites using both modalities. A total of 146 matched sites were available for analysis. When compared to OCT, sensitivity of IVUS for identification of lipid pools was low (24.1%) but specificity was high (93.9%). The sensitivity and specificity of IVUS for detection of calcific plaque and plaque disruption were respectively 92.9%; 66.4%, and 66.7%; 96.1%.
Conclusions
Conventional grey-scale IVUS may not be a reliable imaging modality for detection of lipid-rich and hence vulnerable plaques. This has important implications in using conventional grey-scale IVUS to identify the vulnerable plaque.
PMCID: PMC3425358  PMID: 19378684
Intravascular; ultrasound; optical; coherence tomography; coronary plaques
19.  Plasma osteopontin levels are elevated in non-ST-segment elevation acute coronary syndromes. 
BACKGROUND: The regions of ruptured atherosclerotic plaques have numerous macrophages. Osteopontin that modulates macrophage function has been shown in atherosclerotic plaques. We aimed to study the plasma levels of osteopontin in patients with unstable angina or non-ST-seg ment elevation myocardial infarction (NSTEMI) and the rela tionship between osteopontin and the extent of the coronary artery disease (CAD). METHODS: We studied 65 patients with unstable angina or NSTEMI, 25 patients with stable angina and 18 patients as the control group. The extent of coronary artery stenosis was determined by the number of vessels with >50% stenosis. Plasma osteopontin concentrations were measured from the blood samples that were drawn immediately after admission to the emergency department in unstable angina/NSTEMI patients and before the coronary angiograph in the stable angina and control groups. RESULTS: The plasma osteopontin concentration was (495 118 ng/ml) significantly higher in the patients with unstable angina/NSTEMI compared to the stable angina group (319 106 ng/ml) and control group (125+/-54 ng/ml) (p=0.0001 The plasma osteopontin levels were lower in the patients with stable angina pectoris who had one-vessel disease compared to those with two-vessel disease (p=0.01). How ever, in the unstable angina/NSTEMI group, the plasma osteopontin levels were statistically not different among the patients with one-vessel, and two-vessel and three-vessel disease (p=NS). There was no correlation between the plasma osteopontin levels and the extent of coronary stenosis. CONCLUSIONS: The plasma osteopontin levels are elevatedin patients with unstable angina/NSTEMI, but there appears to be no correlation with the extent of CAD. These results ma suggest that osteopontin may have a role in the pathobiology of ACS.
PMCID: PMC2569782  PMID: 17128682
20.  Evaluation of collagen in atherosclerotic plaques: the use of two coherent laser-based imaging methods 
Lasers in medical science  2008;24(3):439-445.
Acute coronary events such as myocardial infarction are frequently caused by the rupture of unstable atherosclerotic plaque. Collagen plays a key role in determining plaque stability. Methods to measure plaque collagen content are invaluable in detecting unstable atherosclerotic plaques. Recently, novel coherent laser-based imaging techniques, such as polarization-sensitive optical coherence tomography (PSOCT) and laser speckle imaging (LSI) have been investigated, and they provide a wealth of information related to collagen content and plaque stability. Additionally, given their potential for intravascular use, these technologies will be invaluable for improving our understanding of the natural history of plaque development and rupture and, hence, enable the detection of unstable plaques. In this article we review recent developments in these techniques and potential challenges in translating these methods into intra-arterial use in patients.
doi:10.1007/s10103-007-0535-x
PMCID: PMC2776077  PMID: 18386093
Lasers; Atherosclerosis; Collagen; Smooth muscle cells; Optical coherence tomography; Laser speckle imaging
21.  IVUS-Based Computational Modeling and Planar Biaxial Artery Material Properties for Human Coronary Plaque Vulnerability Assessment 
Image-based computational modeling has been introduced for vulnerable atherosclerotic plaques to identify critical mechanical conditions which may be used for better plaque assessment and rupture predictions. In vivo patient-specific coronary plaque models are lagging due to limitations on non-invasive image resolution, flow data, and vessel material properties. A framework is proposed to combine intravascular ultrasound (IVUS) imaging, biaxial mechanical testing and computational modeling with fluid-structure interactions and anisotropic material properties to acquire better and more complete plaque data and make more accurate plaque vulnerability assessment and predictions. Impact of pre-shrink-stretch process, vessel curvature and high blood pressure on stress, strain, flow velocity and flow maximum principal shear stress was investigated.
PMCID: PMC3313454  PMID: 22428362
Coronary artery; cardiovascular; fluid-structure interaction; atherosclerotic plaque rupture; IVUS
22.  Detection of High-Risk Atherosclerotic Plaque 
JACC. Cardiovascular imaging  2012;5(9):941-955.
The leading cause of major morbidity and mortality in most countries around the world is atherosclerotic cardiovascular disease, most commonly caused by thrombotic occlusion of a high-risk coronary plaque resulting in myocardial infarction or cardiac death, or embolization from a high-risk carotid plaque resulting in stroke. The lesions prone to result in such clinical events are termed vulnerable or high-risk plaques, and their identification may lead to the development of pharmacological and mechanical intervention strategies to prevent such events. Autopsy studies from patients dying of acute myocardial infarction or sudden death have shown that such events typically arise from specific types of atherosclerotic plaques, most commonly the thin-cap fibroatheroma. However, the search in human beings for vulnerable plaques before their becoming symptomatic has been elusive. Recently, the PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree) study demonstrated that coronary plaques that are likely to cause future cardiac events, regardless of angiographic severity, are characterized by large plaque burden and small lumen area and/or are thin-cap fibroatheromas verified by radiofrequency intravascular ultrasound imaging. This study opened the door to identifying additional invasive and noninvasive imaging modalities that may improve detection of high-risk atherosclerotic lesions and patients. Beyond classic risk factors, novel biomarkers and genetic profiling may identify those patients in whom noninvasive imaging for vulnerable plaque screening, followed by invasive imaging for risk confirmation is warranted, and in whom future pharmacological and/or device-based focal or regional therapies may be applied to improve long-term prognosis.
doi:10.1016/j.jcmg.2012.07.007
PMCID: PMC3646061  PMID: 22974808
cardiovascular event; high-risk plaque; imaging; prognosis; vulnerable plaque
23.  Electrochemical Impedance Spectroscopy to Characterize Inflammatory Atherosclerotic Plaques 
Biosensors & bioelectronics  2011;30(1):165-173.
Despite advances in diagnosis and therapy, atherosclerotic cardiovascular disease remains the leading cause of morbidity and mortality in the Western world. Predicting metabolically active atherosclerotic lesions has remained an unmet clinical need. We hereby developed an electrochemical strategy to characterize the inflammatory states of high-risk atherosclerotic plaques. Using the concentric bipolar microelectrodes, we sought to demonstrate distinct Electrochemical Impedance Spectroscopic (EIS) measurements for unstable atherosclerotic plaques that harbored active lipids and inflammatory cells. Using equivalent circuits to simulate vessel impedance at the electrode-endoluminal tissue interface, we demonstrated specific electric elements to model working and counter electrode interfaces as well as the tissue impedance. Using explants of human coronary, carotid, and femoral arteries at various Stary stages of atherosclerotic lesions (n = 15), we performed endoluminal EIS measurements (n = 147) and validated with histology and immunohistochemistry. We computed the vascular tissue resistance using the equivalent circuit model and normalized the resistance to the lesion-free regions. Tissue resistance was significantly elevated in the oxLDL-rich thin-cap atheromas (1.57±0.40, n = 14, p < 0.001) and fatty streaks (1.36±0.28, n = 33, p < 0.001) as compared with lesion-free region (1.00±0.18, n = 82) or oxLDL-absent fibrous atheromas (0.86±0.30, n = 12). Tissue resistance was also elevated in the calcified core of fibrous atheroma (2.37±0.60, n = 6, p < 0.001). Despite presence of fibrous structures, tissue resistance between ox-LDL-absent fibroatheroma and the lesion-free regions was statistically insignificant (0.86±0.30, n = 12, p > 0.05). Hence, we demonstrate that the application of EIS strategy was sensitive to detect fibrous cap oxLDL-rich lesions and specific to distinguish oxLDL-absent fibroatheroma.
doi:10.1016/j.bios.2011.09.007
PMCID: PMC3210389  PMID: 21959227
Inflammatory atherosclerotic plaque; Electrochemical Impedance Spectroscopy; Concentric bipolar microelectrodes; oxLDL; Fibrous atheroma; Calcification
24.  Impact of Medical Therapy on Atheroma Volume Measured by Different Cardiovascular Imaging Modalities 
Atherosclerosis is a systemic disease that affects most vascular beds. The gold standard of atherosclerosis imaging has been invasive intravascular ultrasound (IVUS). Newer noninvasive imaging modalities like B-mode ultrasound, cardiac computed tomography (CT), positron emission tomography (PET), and magnetic resonance imaging (MRI) have been used to assess these vascular territories with high accuracy and reproducibility. These imaging modalities have lately been used for the assessment of the atherosclerotic plaque and the response of its volume to several medical therapies used in the treatment of patients with cardiovascular disease. To study the impact of these medications on atheroma volume progression or regression, imaging modalities have been used on a serial basis providing a unique opportunity to monitor the effect these antiatherosclerotic strategies exert on plaque burden. As a result, studies incorporating serial IVUS imaging, quantitative coronary angiography (QCA), B-mode ultrasound, electron beam computed tomography (EBCT), and dynamic contrast-enhanced magnetic resonance imaging have all been used to evaluate the impact of therapeutic strategies that modify cholesterol and blood pressure on the progression/regression of atherosclerotic plaque. In this review, we intend to summarize the impact of different therapies aimed at halting the progression or even result in regression of atherosclerotic cardiovascular disease evaluated by different imaging modalities.
doi:10.4061/2010/134564
PMCID: PMC2909714  PMID: 20672024
25.  Intravascular Photoacoustic Imaging 
Intravascular photoacoustic (IVPA) imaging is a catheter-based, minimally invasive, imaging modality capable of providing high-resolution optical absorption map of the arterial wall. Integrated with intravascular ultrasound (IVUS) imaging, combined IVPA and IVUS imaging can be used to detect and characterize atherosclerotic plaques building up in the inner lining of an artery. In this paper, we present and discuss various representative applications of combined IVPA/IVUS imaging of atherosclerosis, including assessment of the composition of atherosclerotic plaques, imaging of macrophages within the plaques, and molecular imaging of biomarkers associated with formation and development of plaques. In addition, imaging of coronary artery stents using IVPA and IVUS imaging is demonstrated. Furthermore, the design of an integrated IVUS/IVPA imaging catheter needed for in vivo clinical applications is discussed.
doi:10.1109/JSTQE.2009.2037023
PMCID: PMC3045110  PMID: 21359138
Atherosclerosis; contrast agent; imaging catheter; intravascular photoacoustic (IVPA) imaging; intravascular ultrasound (IVUS) imaging; molecular imaging; stent; vulnerable plaque

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