Daniel R. Obaid

Association Between IVUS Findings and Adverse Outcomes in Patients With Coronary Artery Disease The VIVA (VH-IVUS in Vulnerable Atherosclerosis) Study

OBJECTIVES The purpose of this study was to determine whether thin-capped fibroatheromata (TCFA) identified by virtual histology intravascular ultrasound (VH-IVUS) are associated with major adverse cardiac events (MACE) on individual plaque or whole patient analysis. BACKGROUND Post-mortem studies have identified TCFA as the substrate for most myocardial infarctions. However, little is known about the natural history of individual TCFA and their link with MACE. VH-IVUS provides a method of identifying plaques in vivo that are similar (although not identical) to histologically defined TCFA, and has been validated in human atherectomy and post-mortem studies. METHODS One hundred seventy patients with stable angina or troponin-positive acute coronary syndrome referred for percutaneous coronary intervention (PCI) were prospectively enrolled and underwent 3-vessel VH-IVUS pre-PCI and also post-PCI in the culprit vessel. MACE consisted of death, myocardial infarction, or unplanned revascularization. RESULTS In all, 30,372 mm of VH-IVUS were analyzed. Eighteen MACE occurred in 16 patients over a median follow-up of 625 days (interquartile range: 463 to 990 days); 1,096 plaques were classified, and 19 lesions resulted in MACE (13 nonculprit lesions and 6 culprit lesions). Nonculprit lesion factors associated with nonrestenotic MACE included VHTCFA (hazard ratio [HR]: 7.53, p = 0.038) and plaque burden >70% (HR: 8.13, p = 0.011). VHTCFA (HR: 8.16, p = 0.007), plaque burden >70% (HR: 7.48, p < 0.001), and minimum luminal area <4 mm(2) (HR: 2.91, p = 0.036) were associated with total MACE. On patient-based analysis, the only factor associated with nonrestenotic MACE was 3-vessel noncalcified VHTCFA (HR: 1.79, p = 0.004). CONCLUSIONS VH-IVUS TCFA was associated with nonrestenotic and total MACE on individual plaque analysis, and noncalcified VHTCFA was associated with nonrestenotic and total MACE on whole-patient analysis, demonstrating that VH-IVUS can identify plaques at increased risk of subsequent events. The preservation of the association between VHTCFA and MACE despite various analyses emphasizes its biological importance.

Mitochondrial DNA Damage Can Promote Atherosclerosis Independently of Reactive Oxygen Species Through Effects on Smooth Muscle Cells and Monocytes and Correlates With Higher-Risk Plaques in Humans

Background— Mitochondrial DNA (mtDNA) damage occurs in both circulating cells and the vessel wall in human atherosclerosis. However, it is unclear whether mtDNA damage directly promotes atherogenesis or is a consequence of tissue damage, which cell types are involved, and whether its effects are mediated only through reactive oxygen species. Methods and Results— mtDNA damage occurred early in the vessel wall in apolipoprotein E–null (ApoE−/−) mice, before significant atherosclerosis developed. mtDNA defects were also identified in circulating monocytes and liver and were associated with mitochondrial dysfunction. To determine whether mtDNA damage directly promotes atherosclerosis, we studied ApoE−/− mice deficient for mitochondrial polymerase-&ggr; proofreading activity (polG−/−/ApoE−/−). polG−/−/ApoE−/− mice showed extensive mtDNA damage and defects in oxidative phosphorylation but no increase in reactive oxygen species. polG−/−/ApoE−/− mice showed increased atherosclerosis, associated with impaired proliferation and apoptosis of vascular smooth muscle cells, and hyperlipidemia. Transplantation with polG−/−/ApoE−/− bone marrow increased the features of plaque vulnerability, and polG−/−/ApoE−/− monocytes showed increased apoptosis and inflammatory cytokine release. To examine mtDNA damage in human atherosclerosis, we assessed mtDNA adducts in plaques and in leukocytes from patients who had undergone virtual histology intravascular ultrasound characterization of coronary plaques. Human atherosclerotic plaques showed increased mtDNA damage compared with normal vessels; in contrast, leukocyte mtDNA damage was associated with higher-risk plaques but not plaque burden. Conclusions— We show that mtDNA damage in vessel wall and circulating cells is widespread and causative and indicates higher risk in atherosclerosis. Protection against mtDNA damage and improvement of mitochondrial function are potential areas for new therapeutics.

Atherosclerotic plaque composition and classification identified by coronary computed tomography: assessment of computed tomography-generated plaque maps compared with virtual histology intravascular ultrasound and histology.

Background— Computed tomography (CT) is used routinely for coronary angiography, and higher-risk features of plaques can also be identified. However, the ability of CT to discriminate individual plaque components and classify plaques according to accepted histological definitions is unknown. Methods and Results— We first determined CT attenuation ranges for individual plaque components using combined in vivo CT coregistered with virtual histology intravascular ultrasound (VH-IVUS) in 108 plaques from 57 patients. Comparison with contrast attenuation created plaque/contrast attenuation ratios that were significantly different for each component. In a separate validation cohort of 47 patients, these Plaque Maps correlated significantly with VH-IVUS–determined plaque component volumes (necrotic core: r=0.41, P=0.002; fibrous plaque: r=0.54, P<0.001; calcified plaque: r=0.59, P<0.001; total plaque: r=0.62, P<0.001). We also assessed VH-IVUS and CT Plaque Maps against coregistered histology in 72 (VH-IVUS) and 87 (CT) segments from 8 postmortem coronary arteries. The diagnostic accuracy of CT to detect calcified plaque (83% versus 92%), necrotic core (80% versus 65%), and fibroatheroma (80% versus 79%) was comparable with VH-IVUS. However, although VH-IVUS could identify thin-cap fibroatheromas (TCFA) with a diagnostic accuracy of between 74% and 82% (depending on the TCFA definition used), the spatial resolution of CT prevented direct identification of TCFA. Conclusions— CT-derived Plaque Maps based on contrast-adjusted attenuation ranges can define individual plaque components with a similar accuracy to VH-IVUS ex vivo. However, coronary CT Plaque Maps could not reliably classify plaques and identify TCFA, such that high-risk plaques may be misclassified or overlooked.

Coronary Plaque Structural Stress Is Associated With Plaque Composition and Subtype and Higher in Acute Coronary Syndrome The BEACON I (Biomechanical Evaluation of Atheromatous Coronary Arteries) Study

Background—Atherosclerotic plaques underlying most myocardial infarctions have thin fibrous caps and large necrotic cores; however, these features alone do not reliably identify plaques that rupture. Rupture occurs when plaque structural stress (PSS) exceeds mechanical strength. We examined whether PSS could be calculated in vivo based on virtual histology (VH) intravascular ultrasound and whether PSS varied according to plaque composition, subtype, or clinical presentation. Methods and Results—A total of 4429 VH intravascular ultrasound frames from 53 patients were analyzed, identifying 99 584 individual plaque components. PSS was calculated by finite element analysis in whole vessels, in individual plaques, and in higher-risk regions (plaque burden ≥70%, mean luminal area ⩽4 mm2, noncalcified VH-defined thin-cap fibroatheroma). Plaque components including total area/arc of calcification (R2=0.33; P<0.001 and R2=0.28; P<0.001) and necrotic core (R2=0.18; P<0.001 and R2=0.15; P<0.001) showed complex, nonlinear relationships with PSS. PSS was higher in noncalcified VH-defined thin-cap fibroatheroma compared with thick-cap fibroatheromas (median [Q1–Q3], 8.44 [6.97–10.64] versus 7.63 [6.37–9.68]; P=0.002). PSS was also higher in patients with an acute coronary syndrome, where mean luminal area ⩽4 mm2 (8.24 [7.06–9.93] versus 7.72 [6.33–9.34]; P=0.03), plaque burden ≥70% (9.18 [7.44–10.88] versus 7.93 [6.16–9.46]; P=0.02), and in noncalcified VH-defined thin-cap fibroatheroma (9.23 [7.33–11.44] versus 7.65 [6.45–8.62]; P=0.02). Finally, PSS increased the positive predictive value for VH intravascular ultrasound to identify clinical presentation. Conclusions—Finite element analysis modeling demonstrates that structural stress is highly variable within plaques, with increased PSS associated with plaque composition, subtype, and higher-risk regions in patients with acute coronary syndrome. PSS may represent a novel tool to analyze the dynamic behavior of coronary plaques with the potential to improve prediction of plaque rupture.

Non-invasive imaging of atherosclerosis

Atherosclerosis is an inflammatory disease that causes most myocardial infarctions, strokes, and acute coronary syndromes. Despite the identification of multiple risk factors and widespread use of drug therapies, it still remains a global health concern with associated costs. It is well known that the risks of atherosclerotic plaque rupture are not well correlated with stenosis severity. Lumenography has a central place for defining the site and severity of vascular stenosis as a prelude to intervention for relief of symptoms due to blood flow limitation. Atherosclerosis develops within the arterial wall; this is not imaged by lumenography and hence it provides no information regarding underlying processes that may lead to plaque rupture. For this, we must rely on other imaging modalities such as ultrasound, computed tomography, magnetic resonance imaging, and nuclear imaging methods. These are capable of reporting on the underlying pathology, in particular the presence of inflammation, calcification, neovascularization, and intraplaque haemorrhage. Additionally, non-invasive imaging can now be used to track the effect of anti-atherosclerosis therapy. Each modality alone has positives and negatives and this review will highlight these, as well as speculating on future developments in this area.

Leukocyte Telomere Length Is Associated With High-Risk Plaques on Virtual Histology Intravascular Ultrasound and Increased Proinflammatory Activity

Objective— Leukocyte telomere length (LTL), a marker of cellular senescence, is inversely associated with cardiovascular events. However, whether LTL reflects plaque extent or unstable plaques, and the mechanisms underlying any association are unknown. Methods and Results— One hundred seventy patients with stable angina or acute coronary syndrome referred for percutaneous coronary intervention underwent 3-vessel virtual histology intravascular ultrasound; 30 372 mm of intravascular ultrasound pullback and 1096 plaques were analyzed. LTL was not associated with plaque volume but was associated with calcified thin-capped fibroatheroma (OR, 1.24; CI, 1.01–1.53; P=0.039) and total fibroatheroma numbers (OR, 1.19; CI, 1.02–1.39; P=0.027). Monocytes from coronary artery disease patients showed increased secretion of proinflammatory cytokines. To mimic leukocyte senescence, we disrupted telomeres and binding and expression of the telomeric protein protection of telomeres protein-1, inducing DNA damage. Telomere disruption increased monocyte secretion of monocyte chemoattractant protein-1, IL-6, and IL-1&bgr; and oxidative burst, similar to that seen in coronary artery disease patients, and lymphocyte secretion of IL-2 and reduced lymphocyte IL-10. Conclusion— Shorter LTL is associated with high-risk plaque morphology on virtual histology intravascular ultrasound but not total 3-vessel plaque burden. Monocytes with disrupted telomeres show increased proinflammatory activity, which is also seen in coronary artery disease patients, suggesting that telomere shortening promotes high-risk plaque subtypes by increasing proinflammatory activity.

Dual-energy computed tomography imaging to determine atherosclerotic plaque composition: A prospective study with tissue validation

Background Identifying vulnerable coronary plaque with coronary CT angiography is limited by overlap between attenuation of necrotic core and fibrous plaque. Using x-rays with differing energies alters attenuation values of these components, depending on their material composition. Objectives We sought to determine whether dual-energy CT (DECT) improves plaque component discrimination compared with single-energy CT (SECT). Methods Twenty patients underwent DECT and virtual histology intravascular ultrasound (VH-IVUS). Attenuation changes at 100 and 140 kV for each plaque component were defined, using 1088 plaque areas co-registered with VH-IVUS. Hounsfield unit thresholds that best detected necrotic core were derived for SECT (conventional attenuation values) and for DECT (using dual-energy indices, defined as difference in Hounsfield unit values at the 2 voltages/their sum). Sensitivity of SECT and DECT to detect plaque components was determined in 77 segments from 7 postmortem coronary arteries. Finally, we examined 60 plaques in vivo to determine feasibility and sensitivity of clinical DECT to detect VH-IVUS–defined necrotic core. Results In contrast to conventional SECT, mean dual-energy indices of necrotic core and fibrous tissue were significantly different with minimal overlap of ranges (necrotic core, 0.007 [95% CI, –0.001 to 0.016]; fibrous tissue, 0.028 [95% CI, 0.016–0.050]; P < .0001). DECT increased diagnostic accuracy to detect necrotic core in postmortem arteries (sensitivity, 64%; specificity, 98%) compared with SECT (sensitivity, 50%; specificity, 94%). DECT sensitivity to detect necrotic core was lower when analyzed in vivo, although still better than SECT (45% vs 39%). Conclusions DECT improves the differentiation of necrotic core and fibrous plaque in ex vivo postmortem arteries. However, much of this improvement is lost when translated to in vivo imaging because of a reduction in image quality.

Direct Comparison of Virtual-Histology Intravascular Ultrasound and Optical Coherence Tomography Imaging for Identification of Thin-Cap Fibroatheroma

Background—Although rupture of thin-cap fibroatheroma (TCFA) underlies most myocardial infarctions, reliable TCFA identification remains challenging. Virtual-histology intravascular ultrasound (VH-IVUS) and optical coherence tomography (OCT) can assess tissue composition and classify plaques. However, direct comparisons between VH-IVUS and OCT are lacking and it remains unknown whether combining these modalities improves TCFA identification. Methods and Results—Two hundred fifty-eight regions-of-interest were obtained from autopsied human hearts, with plaque composition and classification assessed by histology and compared with coregistered ex vivo VH-IVUS and OCT. Sixty-seven regions-of-interest were classified as fibroatheroma on histology, with 22 meeting criteria for TCFA. On VH-IVUS, plaque (10.91±4.82 versus 8.42±4.57 mm2; P=0.01) and necrotic core areas (1.59±0.99 versus 1.03±0.85 mm2; P=0.02) were increased in TCFA versus other fibroatheroma. On OCT, although minimal fibrous cap thickness was similar (71.8±44.1 &mgr;m versus 72.6±32.4; P=0.30), the number of continuous frames with fibrous cap thickness ⩽85 &mgr;m was higher in TCFA (6.5 [1.75–11.0] versus 2.0 [0.0–7.0]; P=0.03). Maximum lipid arc on OCT was an excellent discriminator of fibroatheroma (area under the curve, 0.92; 95% confidence interval, 0.87–0.97) and TCFA (area under the curve, 0.86; 95% confidence interval, 0.81–0.92), with lipid arc ≥80° the optimal cut-off value. Using existing criteria, the sensitivity, specificity, and diagnostic accuracy for TCFA identification was 63.6%, 78.1%, and 76.5% for VH-IVUS and 72.7%, 79.8%, and 79.0% for OCT. Combining VH-defined fibroatheroma and fibrous cap thickness ⩽85 &mgr;m over 3 continuous frames improved TCFA identification, with diagnostic accuracy of 89.0%. Conclusions—Both VH-IVUS and OCT can reliably identify TCFA, although OCT accuracy may be improved using lipid arc ≥80° and fibrous cap thickness ⩽85 &mgr;m over 3 continuous frames. Combined VH-IVUS/OCT imaging markedly improved TCFA identification.

Identification of Coronary Plaque Sub-Types Using Virtual Histology Intravascular Ultrasound Is Affected by Inter-Observer Variability and Differences in Plaque Definitions

Background— Recent studies show that virtual histology intravascular ultrasound (VH-IVUS) can identify plaques at high risk of rupture, such as thin-capped fibroatheromata, raising the possibility of immediate targeted intervention. However, plaque classification entails border recognition and subjective assessment of plaque architecture, introducing inter-observer variability without confirmation by core-labs. Furthermore, the accuracy of local versus core-laboratory VH-IVUS plaque classification and effects of different plaque definitions have not been examined. Methods and Results— Local observers classified 100 VH-IVUS-defined coronary plaques to determine single center inter-observer variability; multi-center variability was determined by comparison with VH-IVUS core-laboratory analysis, and compared with gray-scale IVUS. Frequency of plaque types using different published plaque definitions also was determined. Single-center VH-IVUS inter-observer agreement was strong (kappa=0.86), but lower for thin-capped fibroatheromatas (k=0.59) because of observer judgments on presence and location of confluent necrotic core. Multi-center inter-observer agreement for plaque classification was lower again (k=0.71), particularly for thin-capped fibroatheromatas (k=0.56). Different plaque definitions further reduced VH-IVUS-defined thin-capped fibroatheromata numbers by 44%. The diagnostic accuracy of gray-scale IVUS to identify thin-capped fibroatheromata was poor for both observers (21 and 29% correct), with low inter-observer agreement (k=0.14). Conclusions— VH-IVUS plaque classification, and particularly VH-IVUS-defined thin-capped fibroatheromata identification, varies significantly between local observers, and particularly in comparison with core-laboratory analysis. Differences in VH-IVUS plaque definitions introduce further variability between studies. These factors reduce the use of VH-IVUS plaque classification to guide intervention in a “live” clinical setting, and also affect comparison of diagnostic accuracy and natural history of plaques between studies.

Plaque Structural Stress Estimations Improve Prediction of Future Major Adverse Cardiovascular Events After Intracoronary Imaging

Background—Although plaque rupture is responsible for most myocardial infarctions, few high-risk plaques identified by intracoronary imaging actually result in future major adverse cardiovascular events (MACE). Nonimaging markers of individual plaque behavior are therefore required. Rupture occurs when plaque structural stress (PSS) exceeds material strength. We therefore assessed whether PSS could predict future MACE in high-risk nonculprit lesions identified on virtual-histology intravascular ultrasound. Methods and Results—Baseline nonculprit lesion features associated with MACE during long-term follow-up (median: 1115 days) were determined in 170 patients undergoing 3-vessel virtual-histology intravascular ultrasound. MACE was associated with plaque burden ≥70% (hazard ratio: 8.6; 95% confidence interval, 2.5–30.6; P<0.001) and minimal luminal area ⩽4 mm2 (hazard ratio: 6.6; 95% confidence interval, 2.1–20.1; P=0.036), although absolute event rates for high-risk lesions remained <10%. PSS derived from virtual-histology intravascular ultrasound was subsequently estimated in nonculprit lesions responsible for MACE (n=22) versus matched control lesions (n=22). PSS showed marked heterogeneity across and between similar lesions but was significantly increased in MACE lesions at high-risk regions, including plaque burden ≥70% (13.9±11.5 versus 10.2±4.7; P<0.001) and thin-cap fibroatheroma (14.0±8.9 versus 11.6±4.5; P=0.02). Furthermore, PSS improved the ability of virtual-histology intravascular ultrasound to predict MACE in plaques with plaque burden ≥70% (adjusted log-rank, P=0.003) and minimal luminal area ⩽4 mm2 (P=0.002). Plaques responsible for MACE had larger superficial calcium inclusions, which acted to increase PSS (P<0.05). Conclusions—Baseline PSS is increased in plaques responsible for MACE and improves the ability of intracoronary imaging to predict events. Biomechanical modeling may complement plaque imaging for risk stratification of coronary nonculprit lesions.