Thomas S. Hatsukami

Association Between Carotid Plaque Characteristics and Subsequent Ischemic Cerebrovascular Events A Prospective Assessment With MRI—Initial Results

Background and Purpose— MRI is able to quantify carotid plaque size and composition with good accuracy and reproducibility and provides an opportunity to prospectively examine the relationship between plaque features and subsequent cerebrovascular events. We tested the hypothesis that the characteristics of carotid plaque, as assessed by MRI, are possible predictors of future ipsilateral cerebrovascular events. Methods— A total of 154 consecutive subjects who initially had an asymptomatic 50% to 79% carotid stenosis by ultrasound with ≥12 months of follow-up were included in this study. Multicontrast-weighted carotid MRIs were performed at baseline, and participants were followed clinically every 3 months to identify symptoms of cerebrovascular events. Results— Over a mean follow-up period of 38.2 months, 12 carotid cerebrovascular events occurred ipsilateral to the index carotid artery. Cox regression analysis demonstrated a significant association between baseline MRI identification of the following plaque characteristics and subsequent symptoms during follow-up: presence of a thin or ruptured fibrous cap (hazard ratio, 17.0; P≤0.001), intraplaque hemorrhage (hazard ratio, 5.2; P=0.005), larger mean intraplaque hemorrhage area (hazard ratio for 10 mm2 increase, 2.6; P=0.006), larger maximum %lipid-rich/necrotic core (hazard ratio for 10% increase, 1.6; P=0.004), and larger maximum wall thickness (hazard ratio for a 1-mm increase, 1.6; P=0.008). Conclusions— Among patients who initially had an asymptomatic 50% to 79% carotid stenosis, arteries with thinned or ruptured fibrous caps, intraplaque hemorrhage, larger maximum %lipid-rich/necrotic cores, and larger maximum wall thickness by MRI were associated with the occurrence of subsequent cerebrovascular events. Findings from this prospective study provide a basis for larger multicenter studies to assess the risk of plaque features for subsequent ischemic events.

Classification of Human Carotid Atherosclerotic Lesions With In Vivo Multicontrast Magnetic Resonance Imaging

Background—Recent studies demonstrated that in vivo and ex vivo MRI can characterize the components of the carotid atherosclerotic plaque, such as fibrous tissue, lipid/necrotic core, calcium, hemorrhage, and thrombus. The purpose of this study was to determine whether in vivo high-resolution multicontrast MRI could accurately classify human carotid atherosclerotic plaque according to the American Heart Association classification. Methods and Results—Sixty consecutive patients (mean age 70 years; 54 males) scheduled for carotid endarterectomy were imaged with a 1.5-T scanner after informed consent was obtained. A standardized protocol was used to obtain 4 different contrast-weighted images (time of flight and T1-, PD-, and T2-weighted) of the carotid arteries. Best voxel size was 0.25×0.25×1 mm3. Carotid plaques were removed intact and processed for histological examination. Both MR images and histological sections were independently reviewed, categorized, and compared. Overall, the classification obtained by MRI and the American Heart Association classifications showed good agreement, with Cohen’s &kgr; (95% CI) of 0.74 (0.67 to 0.82) and weighted &kgr; of 0.79. The sensitivity and specificity, respectively, of MRI classification were as follows: type I-II lesions, 67% and 100%; type III lesions, 81% and 98%; type IV-V lesions, 84% and 90%; type VI lesions, 82% and 91%; type VII lesions, 80% and 94%; and type VIII lesions, 56% and 100%. Conclusions—In vivo high-resolution multicontrast MRI is capable of classifying intermediate to advanced atherosclerotic lesions in the human carotid artery and is also capable of distinguishing advanced lesions from early and intermediate atherosclerotic plaque.

Visualization of Fibrous Cap Thickness and Rupture in Human Atherosclerotic Carotid Plaque In Vivo With High-Resolution Magnetic Resonance Imaging

BackgroundThe results of studies of advanced lesions of atherosclerosis suggest that the thickness of the fibrous cap that overlies the necrotic core distinguishes the stable lesion from one that is at high risk for rupture and thromboembolic events. We have developed a high-resolution MRI technique that can identify the fine structure of the lesion, including the fibrous cap, in vivo. The aim of the present study was to determine the agreement between in vivo MRI and lesion architecture as seen on histology and gross tissue examination to identify fibrous cap thickness and rupture. Methods and ResultsTwenty-two subjects who were scheduled for carotid endarterectomy underwent MRI with a 3-dimensional multiple overlapping thin slab angiography protocol. The appearance of the fibrous cap was categorized as (1) an intact, thick, (2) an intact, thin, or (3) a ruptured fibrous cap on MRI, gross, and histological sections. Thirty-six sites were available for comparison between MRI and histology. There was a high level of agreement between MRI and histological findings: 89% agreement, &kgr; (95% CI)=0.83 (0.67 to 1.0), weighted &kgr;=0.87. Spearman’s correlation coefficient was 0.88 (significant to the 0.01 level). ConclusionsThese findings indicate that high-resolution MRI with a 3-dimensional multiple overlapping thin slab angiography protocol is capable of distinguishing intact, thick fibrous caps from intact thin and disrupted caps in atherosclerotic human carotid arteries in vivo. This noninvasive technique has the potential to permit studies that examine the relationship between fibrous cap changes and clinical outcome and to permit trials that evaluate therapy intended to “stabilize” the fibrous cap.

Presence of Intraplaque Hemorrhage Stimulates Progression of Carotid Atherosclerotic Plaques A High-Resolution Magnetic Resonance Imaging Study

Background—Previous studies suggest that erythrocyte membranes from intraplaque hemorrhage into the necrotic core are a source of free cholesterol and may become a driving force in the progression of atherosclerosis. We have shown that MRI can accurately identify carotid intraplaque hemorrhage and precisely measure plaque volume. We tested the hypothesis that hemorrhage into carotid atheroma stimulates plaque progression. Methods and Results—Twenty-nine subjects (14 cases with intraplaque hemorrhage and 15 controls with comparably sized plaques without intraplaque hemorrhage at baseline) underwent serial carotid MRI examination with a multicontrast weighted protocol (T1, T2, proton density, and 3D time of flight) over a period of 18 months. The volumes of wall, lumen, lipid-rich necrotic core, calcification, and intraplaque hemorrhage were measured with a custom-designed image analysis tool. The percent change in wall volume (6.8% versus −0.15%; P=0.009) and lipid-rich necrotic core volume (28.4% versus −5.2%; P=0.001) was significantly higher in the hemorrhage group than in controls over the course of the study. Furthermore, those with intraplaque hemorrhage at baseline were much more likely to have new plaque hemorrhages at 18 months compared with controls (43% versus 0%; P=0.006). Conclusions—Hemorrhage into the carotid atherosclerotic plaque accelerated plaque progression in an 18-month period. Repeated bleeding into the plaque may produce a stimulus for the progression of atherosclerosis by increasing lipid core and plaque volume and creating new destabilizing factors.

In Vivo Quantitative Measurement of Intact Fibrous Cap and Lipid-Rich Necrotic Core Size in Atherosclerotic Carotid Plaque: Comparison of High-Resolution, Contrast-Enhanced Magnetic Resonance Imaging and Histology

Background— Previous studies with contrast-enhanced magnetic resonance imaging (CEMRI) have shown that the fibrous cap (FC) in atherosclerotic carotid plaques enhances with gadolinium-based contrast agents. Conversely, the lipid-rich necrotic core (LR-NC), lacking both vasculature and matrix, shows no or only slight enhancement. The goal of this study was to assess whether CEMRI can be used to accurately measure the dimensions of the intact FC and LR-NC. Methods and Results— Twenty-one patients scheduled for carotid endarterectomy were imaged with a 1.5-T scanner. Precontrast images and CEMRI were obtained. One hundred eight locations with an intact FC were matched between MRI and the excised histology specimens. Quantitative measurements of FC length along the lumen circumference, FC area, and LR-NC area were collected from CEMRI images and histology sections. Blinded comparison of corresponding MR images and histology slices showed moderate to good correlation for length (r=0.73, P<0.001) and area (r=0.80, P<0.001) of the intact FC. The mean percentage LR-NC areas (LR-NC area/wall area) measured by CEMRI and histology were 30.1% and 32.7%, respectively, and were strongly correlated across locations (r=0.87, P<0.001). Conclusions— In vivo high-resolution CEMRI is capable of quantitatively measuring the dimensions of the intact FC and LR-NC. These new parameters may be useful to evaluate plaque vulnerability and provide continuous variables for characterizing the intact FC and LR-NC in progression and regression studies.

Contrast-enhanced high resolution MRI for atherosclerotic carotid artery tissue characterization.

To determine if a gadolinium‐based contrast agent provides additional information for characterization of human plaque tissues, particularly neovasculature. Although high‐resolution magnetic resonance imaging (MRI) has been used to identify plaque constituents in advanced atherosclerosis, some constituents, such as neovascularized tissue, defy detection.

Hemorrhage in the Atherosclerotic Carotid Plaque: A High-Resolution MRI Study

Background and Purpose— High-resolution, multicontrast magnetic resonance imaging (MRI) has developed into an effective tool for the identification of carotid atherosclerotic plaque components, such as necrotic core, fibrous matrix, and hemorrhage/thrombus. Factors that may lead to plaque instability are lipid content, thin fibrous cap, and intraplaque hemorrhage. Determining the age of intraplaque hemorrhage can give insight to the history and current condition of the biologically active plaque. The aim of this study was to develop criteria for the identification of the stages of intraplaque hemorrhage using high-resolution MRI. Methods— Twenty-seven patients, scheduled for carotid endarterectomy (CEA), were imaged on a 1.5-T GE SIGNA scanner (sequences: 3-dimensional time of flight, double-inversion recovery, T1-weighted (T1W), PDW and T2W). Two readers, blinded to histology, reviewed MR images and grouped hemorrhage into fresh, recent, and old categories using a modified cerebral hemorrhage criteria. The CEA specimens were serially sectioned and graded as to presence and stage of hemorrhage. Results— Hemorrhage was histologically identified and staged in 145/189 (77%) of carotid artery plaque locations. MRI detected intraplaque hemorrhage with high sensitivity (90%) but moderate specificity (74%). Moderate agreement in classifying stages occurred between MRI and histology (Cohen κ = 0.7, 95% CI: 0.5 to 0.8 for reviewer 1 and 0.4, 95% CI: 0.2 to 0.6 for reviewer 2), with moderate agreement between the 2 MRI readers (κ = 0.4, 95% CI: 0.3 to 0.6). Conclusion— Multicontrast MRI can detect and classify carotid intraplaque hemorrhage with high sensitivity and moderate specificity.

Quantitative Magnetic Resonance Imaging Analysis of Neovasculature Volume in Carotid Atherosclerotic Plaque

Background—Neovasculature within atherosclerotic plaques is believed to be associated with infiltration of inflammatory cells and plaque destabilization. The aim of the present investigation was to determine whether the amount of neovasculature present in advanced carotid plaques can be noninvasively measured by dynamic, contrast-enhanced MRI. Methods and Results—A total of 20 consecutive patients scheduled for carotid endarterectomy were recruited to participate in an MRI study. Images were obtained at 15-second intervals, and a gadolinium contrast agent was injected coincident with the second of 10 images in the sequence. The resulting image intensity within the plaque was tracked over time, and a kinetic model was used to estimate the fractional blood volume. For validation, matched sections from subsequent endarterectomy were stained with ULEX and CD-31 antibody to highlight microvessels. Finally, all microvessels within the matched sections were identified, and their total area was computed as a fraction of the plaque area. Results were obtained from 16 participants, which showed fractional blood volumes ranging from 2% to 41%. These levels were significantly higher than the histological measurements of fractional vascular area. Nevertheless, the 2 measurements were highly correlated, with a correlation coefficient of 0.80 (P <0.001). Conclusions—Dynamic contrast-enhanced MRI provides an indication of the extent of neovasculature within carotid atherosclerotic plaque. MRI therefore provides a means for prospectively studying the link between neovasculature and plaque vulnerability.

Measurement of Atherosclerotic Carotid Plaque Size In Vivo Using High Resolution Magnetic Resonance Imaging

BACKGROUND Current imaging modalities, such as contrast angiography, accurately determine the degree of luminal narrowing but provide no direct information on plaque size. Magnetic resonance imaging (MRI), however, has potential for noninvasively determining arterial wall area (WA). This study was conducted to determine the accuracy of in vivo MRI for measuring the cross-sectional maximum wall area (MaxWA) of atherosclerotic carotid arteries in a group of patients undergoing carotid endarterectomy. METHODS AND RESULTS Fourteen patients scheduled for carotid endarterectomy underwent preoperative carotid MRI using a custom-made phased-array coil. The plaques were excised en bloc and scanned using similar imaging parameters. MaxWA measurements from the ex vivo MRI were used as the reference standard and compared with MaxWA measurements from the corresponding in vivo MR study. Agreement between the in vivo and ex vivo measurement was analyzed using the Bland-Altman method. The paired in vivo and ex vivo MaxWA measurements strongly agreed: the mean difference (in vivo minus ex vivo) in MaxWA was 13.1+/-6.5 mm2 for T1-weighted (T1W) imaging (mean MaxWA in vivo=94.7 mm2, ex vivo=81.6 mm2) and 14.1+/-11.7 mm2 for proton density-weighted (PDW) imaging (mean MaxWA in vivo=93.4 mm2, ex vivo=79.3 mm2). Intraobserver and interobserver variability was small, with intraclass correlation coefficients ranging from 0.90 to 0.98. CONCLUSIONS MRI is highly accurate for in vivo measurement of artery WA in atherosclerotic carotid lesions. This imaging technique has potential application monitoring lesion size in studies examining plaque progression and/or regression.

Paraoxonase (PON1) Phenotype Is a Better Predictor of Vascular Disease Than Is PON1192 or PON155 Genotype

The paraoxonase (PON1) PON1-Q192R and PON1-L55M polymorphisms have been inconsistently associated with vascular disease. Plasma PON1 activity phenotypes vary markedly within genotypes and were, therefore, expected to add to the informativeness of genotype for predicting vascular disease. The case-control sample included 212 age- and race-matched men (mean age 66.4 years). The 106 carotid artery disease (CAAD) cases had >80% carotid stenosis, and the 106 controls had <15%. Two PON1 substrate hydrolysis rates (paraoxon [POase] and diazoxon [DZOase]) were significantly lower in cases than in controls and were significant predictors of CAAD by use of logistic regression (POase, P =0.005; DZOase, P =0.019). DZOase predicted vascular disease independently of lipoprotein profile, high density lipoprotein subfractions, apolipoprotein A-I, and smoking. PON1-192 and PON1-55 genotypes or haplotypes did not predict case-control status unless the activity phenotype was also included as a predictor by use of logistic regression. When phenotype was included as a predictor, PON1-192 and PON1-55 genotypes or combined haplotypes were significant predictors (P <0.05). In conclusion, examining PON1-192 and/or PON1-55 genotypes alone may mistakenly lead to the conclusion that there is no role of PON1 in CAAD. These results support the benefit of a “level crossing” approach that includes intervening phenotypes in the study of complexly inherited disease.