Gustavo Vazquez

Prospective validation of standardized, 3-dimensional, quantitative coronary computed tomographic plaque measurements using radiofrequency backscatter intravascular ultrasound as reference standard in intermediate coronary arterial lesions: results from the ATLANTA (assessment of tissue characteristics, lesion morphology, and hemodynamics by angiography with fractional flow reserve, intravascular ultrasound and virtual histology, and noninvasive computed tomography in atherosclerotic plaques) I study.

OBJECTIVES This study sought to determine the accuracy of 3-dimensional, quantitative measurements of coronary plaque by computed tomography angiography (CTA) against intravascular ultrasound with radiofrequency backscatter analysis (IVUS/VH). BACKGROUND Quantitative, 3-dimensional coronary CTA plaque measurements have not been validated against IVUS/VH. METHODS Sixty patients in a prospective study underwent coronary X-ray angiography, IVUS/VH, and coronary CTA. Plaque geometry and composition was quantified after spatial coregistration on segmental and slice-by-slice bases. Correlation, mean difference, and limits of agreement were determined. RESULTS There was significant correlation for all pre-specified parameters by segmental and slice-by-slice analyses (r = 0.41 to 0.84; all p < 0.001). On a segmental basis, CTA underestimated minimal lumen diameter by 21% and overestimated diameter stenosis by 39%. Minimal lumen area was overestimated on CTA by 27% but area stenosis was only underestimated by 5%. Mean difference in noncalcified plaque volume and percent and calcified plaque volume and percent were 38%, -22%, 104%, and 64%. On a slice-by-slice basis, lumen, vessel, noncalcified-, and calcified-plaque areas were overestimated on CTA by 22%, 19%, 44%, and 88%. There was significant correlation for percentage of atheroma volume (0.52 vs. 0.54; r = 0.51; p < 0.001). Compositional analysis suggested that high-density noncalcified plaque on CTA best correlated with fibrous tissue and low-density noncalcified plaque correlated with necrotic core plus fibrofatty tissue by IVUS/VH. CONCLUSIONS This is the first validation that standardized, 3-dimensional, quantitative measurements of coronary plaque correlate with IVUS/VH. Mean differences are small, whereas limits of agreement are wide. Low-density noncalcified plaque correlates with necrotic core plus fibrofatty tissue on IVUS/VH.

Quantitative measurements of coronary arterial stenosis, plaque geometry, and composition are highly reproducible with a standardized coronary arterial computed tomographic approach in high-quality CT datasets

BACKGROUND Computed tomographic (CT) coronary angiography provides a noninvasive method for coronary plaque detection and quantification, but data are limited on reproducibility of a quantitative evaluation. METHODS Intrarater and interrater reliability of a semiquantitative and highly standardized, fully quantitative approach was evaluated in 480 coronary segments in 30 patients. Quantitative vessel-wall and plaque geometrical parameters (minimal lumen diameter [MLD], minimal lumen area [MLA], percentage of atheroma volume [PAV], and remodeling index [RI]) and compositional parameters (calcified plaque volume [CAP] and % of CAP [%CAP], noncalcified plaque [NCP] and % of NCP [%NCP], high-density NCP volume [HD-NCP] and % of HD-NCP [%HD-NCP] and low-density NCP volume [LD-NCP] and % of LD-NCP [%LD-NCP]) were measured. Semiquantitative agreement was evaluated by weighted κ; quantitative agreement was evaluated by concordance correlation coefficient (CCC) and Bland-Altman analysis. RESULTS Intraobserver agreement for MLD, MLA, and RI was excellent (CCC: 0.96, 0.96, and 0.84, respectively). Intraobserver agreement for %CAP, %HD-NCP, and %LD-NCP was also excellent (CCC: 0.99, 0.98,and 0.96, respectively). Interobserver agreement for MLD, MLA, PAV and RI was excellent (CCC: 0.98, 0.99, 0.96,and 0.86, respectively). Interobserver agreement for %CAP, % NCP, %HD-NCP, and %LD-NCP was also excellent (CCC: 0.99, 0.99, 0.98,and 0.90, respectively), and mean differences were small. Quantitative analysis showed statistically significant differences in both geometrical and compositional parameters between normal segments and those with plaque. CONCLUSIONS Standardized, quantitative analysis of coronary CTA datasets is reproducible for the measurement of plaque geometrical and compositional parameters and can quantify differences between normal and abnormal segments in high-quality datasets.

Precision phenotyping, panomics, and system-level bioinformatics to delineate complex biologies of atherosclerosis: rationale and design of the "Genetic Loci and the Burden of Atherosclerotic Lesions" study.

BACKGROUND Complex biological networks of atherosclerosis are largely unknown. OBJECTIVE The main objective of the Genetic Loci and the Burden of Atherosclerotic Lesions study is to assemble comprehensive biological networks of atherosclerosis using advanced cardiovascular imaging for phenotyping, a panomic approach to identify underlying genomic, proteomic, metabolomic, and lipidomic underpinnings, analyzed by systems biology-driven bioinformatics. METHODS By design, this is a hypothesis-free unbiased discovery study collecting a large number of biologically related factors to examine biological associations between genomic, proteomic, metabolomic, lipidomic, and phenotypic factors of atherosclerosis. The Genetic Loci and the Burden of Atherosclerotic Lesions study (NCT01738828) is a prospective, multicenter, international observational study of atherosclerotic coronary artery disease. Approximately 7500 patients are enrolled and undergo non-contrast-enhanced coronary calcium scanning by CT for the detection and quantification of coronary artery calcium, as well as coronary artery CT angiography for the detection and quantification of plaque, stenosis, and overall coronary artery disease burden. In addition, patients undergo whole genome sequencing, DNA methylation, whole blood-based transcriptome sequencing, unbiased proteomics based on mass spectrometry, as well as metabolomics and lipidomics on a mass spectrometry platform. The study is analyzed in 3 subsequent phases, and each phase consists of a discovery cohort and an independent validation cohort. For the primary analysis, the primary phenotype will be the presence of any atherosclerotic plaque, as detected by cardiac CT. Additional phenotypic analyses will include per patient maximal luminal stenosis defined as 50% and 70% diameter stenosis. Single-omic and multi-omic associations will be examined for each phenotype; putative biomarkers will be assessed for association, calibration, discrimination, and reclassification.

A peripheral blood gene expression score is associated with plaque volume and phenotype by intravascular ultrasound with radiofrequency backscatter analysis: results from the ATLANTA study

BACKGROUND A composite, peripheral gene expression score based on quantitative RNA-measurements has been validated for detecting stenosis against invasive coronary X-ray angiography. IVUS/VH has been validated for quantitative measurements of coronary plaque volume and composition and has been shown to be predictive of outcomes and treatment effects. The correlation between peripheral gene expression and coronary plaque composition by intravascular ultrasound with radiofrequency backscatter (IVUS/VH) is unknown. METHODS Peripheral blood gene expression score (GES) was prospectively measured in 18 patients undergoing IVUS/VH. Plaque volume and composition [fibrous tissue (FI), fibro-fatty tissue (FF), necrotic core (NC) and dense calcium (DC)] were quantified in 3 dimensions in all plaques within the entire pullback. The relationship to GES was assessed by Spearman rank correlation. RESULTS Mean age was 61.1±8.6 years; 67% were male. 1,158 mm of coronary anatomy was imaged by IVUS/VH. Using a validated scale of 1-40, mean GES was 21.6±9.4. GES was associated with plaque volume (R(2)=0.55; P=0.018), NC volume (R(2)=0.56; P=0.015), DC volume (R(2)=0.60; P=0.007), and non-calcified plaque volume (R(2)=0.50; P=0.036) by Spearman rank correlation. CONCLUSIONS In this preliminary report, increased GES was associated with higher plaque volume and a more vulnerable plaque phenotype as evidenced by NC and DC. This composite GES is not only associated with obstructive coronary disease, but also with higher plaque volume and vulnerable phenotype.

Cardiovascular computed tomographic assessment of the effect of combination lipoprotein therapy on coronary arterial plaque: rationale and design of the AFRICA (Atorvastatin plus Fenofibric acid in the Reduction of Intermediate Coronary Atherosclerosis) study.

Whether combination lipoprotein therapy targeting apolipoprotein B (apoB)- and apoA-containing lipoprotein particles and triglycerides (TGs) in low-risk, asymptomatic subjects with coronary atherosclerosis alters the natural progression of plaques is unknown. This study was designed to compare the progression of coronary atherosclerosis in asymptomatic, low-risk subjects without previously known coronary artery disease but with the presence of plaque on a combination of atorvastatin 40 mg plus fenofibric acid 135 mg daily for 18 months, using cardiovascular computed tomography (CCT). This is an investigator-initiated, single-center, prospective, double-blind, randomized, placebo-controlled, parallel-arm study. Asymptomatic subjects at low risk of cardiovascular events defined as <10% 10-year risk based on the Framingham Risk Score will be recruited, if they do not qualify for lipoprotein-lowering therapy based on the National Cholesterol Education Panel Adult Treatment Panel III guidelines. Subjects will qualify based on lipid parameters if their low-density lipoprotein cholesterol is >/=100 mg/dL and <190 mg/dL, TGs are >150 mg/dL, and the TGs/high-density lipoprotein cholesterol ratio is >3.5. Patients must have nonobstructive plaque based on CCT. Randomization will be 1:1 to either a combination of atorvastatin 40 mg plus fenofibric acid 135 mg daily or placebo for 18 months. Patients will undergo CCT at baseline and at the end of the treatment period. The primary end point will be the between-group difference in percent atheroma volume. Ultimately, this study can guide physicians about the use of a statin-fibric acid derivative combination in asymptomatic, low-risk persons with atherosclerosis.

Abnormal Lipoprotein(a) Levels Predict Coronary Artery Calcification in Southeast Asians but Not in Caucasians: Use of Noninvasive Imaging for Evaluation of an Emerging Risk Factor

Subclinical atherosclerosis can be quantified by coronary artery calcium (CAC) scoring. Due to its high specificity for atherosclerosis, CAC is an excellent phenotypic tool for the evaluation of emerging risk markers. Lipoprotein(a) [Lp(a)] is atherogenic due to the presence of apoB and may be thrombogenic through its apo(a) component. Lp(a) has been linked to cardiovascular events in Caucasians; however, its link to atherosclerosis in various ethnicities remains unclear. We evaluated the ability of Lp(a) mass to predict subclinical atherosclerosis in Southeast Asians and Caucasians, as measured by CAC. Traditional lipid measurements, Lp(a) measurements, and CAC by 64-slice multidetector computed tomography was performed in 103 consecutive patients in the USA and in 104 consecutive patients in Jakarta, Indonesia. Proportion of positive CAC and median CAC in Southeast Asians and in Caucasians was 61.5% and 63.1%, and 23.5 (interquartile range, 0–270) and 13 (interquartile range, 0–388), respectively. Significantly higher proportion of Southeast Asians had elevated Lp(a) levels, compared to Caucasians (51.0% vs. 29.2%; p = 0.005). In Southeast Asians, Lp(a) remained an independent predictor of CAC with an odds ratio of 4.97 (95% confidence interval, 1.56–15.88; p < 0.0001), but not in Caucasians. Receiver operating characteristic analysis showed an improvement in area under the curve from 0.81 to 0.86 (p = 0.05) when including Lp(a) in the predictive model in Southeast Asians. This translated to 7% of Southeast Asians reclassified to correct CAC status. Lp(a) measurements may have a role in risk stratification of Southeast Asians. Ethnic variation should be taken into account when considering the use of Lp(a) measurements in risk assessment.

Relationship between chest lateral width, tube current, image noise, and radiation exposure associated with coronary artery calcium scanning on 320-detector row CT

BACKGROUND The relationship between chest lateral width, tube current, image noise, and radiation exposure on 320-detector row CT has not been reported. OBJECTIVE We investigated the relationships between chest lateral width, estimated radiation exposure (DLPe), and image noise in 300 patients undergoing clinical coronary calcium scanning. METHODS Patients undergoing coronary calcium scanning with 320-detector row CT (prospective, volumetric mode, 120 kV of tube voltage, 100-550 mA of tube current, 0.5-mm detector width) were grouped by chest lateral width (small, medium, and large) from anteroposterior topograms and 100 consecutive patients were selected from each group (n = 300). Tube current, DLPe, and noise were compared among groups with Kruskal-Wallis or one-way ANOVA. Phantom experiments were performed to evaluate the accuracy of calcium quantification as a function of size and tube current. RESULTS Median tube current in small, medium, and large patients was 130, 200, and 250 mA, respectively (P < 0.0001). Despite the use of higher tube current settings, noise levels also increased with size (20.2 ± 4.5 HU, 22.0 ± 3.9 HU, and 25.1 ± 4.9 HU, respectively; global P < 0.001). DLPe was significantly higher with increasing size (54, 83, and 104 mGy · cm, respectively; P < 0.0001). Phantom experiments showed that 50-100 mA, 150-200 mA, and approximately 300 mA in small, medium, and large phantoms were associated with stable estimate of calcium. CONCLUSIONS Increasing chest lateral width is associated with increasing radiation exposure and image noise. The use of 50-100 mA in small and 150-200 mA in medium patients is associated with acceptable noise and stable estimate of coronary artery calcium. In large patients, precise identification of individual calcified lesions remains difficult despite increasing tube current and radiation exposure.

Intermodal registration of CTA and IVUS-VH, and its application on CTA-based plaque composition analysis

Plaque composition analysis is a critical tool in identifying vulnerable atherosclerotic plaques. Intravascular ultrasound with spectral analysis of the backscattered radio frequency (RF) signals (IVUS-VH) is currently considered as the gold standard for the evaluation of coronary plaque composition, while CT coronary angiography (CTA) has been proposed as a potential non-invasive counterpart. In this paper, we have developed a novel intermodal registration framework for IVUS-VH and CTA, which is based on a novel composition-to-appearance transformation technique and a mutual-information-based registration algorithm. A detailed and complete intermodal registration system was presented. In addition, based on the registered images, we have developed a principal component analysis-based plaque composition classification tool, which has been tested and validated on 6 sets of IVUS-VH and CTA images. Experimental results have shown that our approach has the potential of improving the classification accuracy of plaque compositions on CTA.

Optimal cutoff threshold for calcium quantification in isotropic CT calcium scans by validating against registered intravascular ultrasound with radiofrequency backscatter

3D Computed Tomography (CT) provides noninvasive, low-radiation method of coronary artery calcium (CAC) measurement. Conventional CAC images are acquired on multidetector-row CT scanners without contrast, and reconstructed with 3 mm slice thickness. The calcium volume is quantified by registering voxels with attenuation values greater than or equal to 130 Hounsfield Unit (HU). In isotropic CAC images with 0.5 mm slice thickness obtained from 320-detector row CT, the optimal value of attenuation cutoff threshold is unknown. In this paper we find the optimal cutoff threshold for calcium quantification in isotropic CT calcium scans by validating against registered intravascular ultrasound with radiofrequency backscatter (IVUS/VH). From the statistical analysis of calcium data obtained from the images of 9 patients we found a range of optimal thresholds and the conventional threshold of 130 HU was in the range. Further, the optimal values were different for individual patients.

Coronary artery calcium: 0.5 mm slice-thickness reconstruction with adjusted attenuation threshold outperforms 3.0 mm by validating against spatially registered intravascular ultrasound with radiofrequency backscatter.

RATIONALE AND OBJECTIVES Coronary artery calcium (CAC) images can be reconstructed with thinner slice thickness on some modern multidetector-row computed tomography scanners without additional radiation. We hypothesized that the isotropic 0.5-mm CAC reconstruction outperforms the conventional 3.0-mm reconstruction in detecting and quantifying coronary calcium, and we proposed to compare them by validating against spatially registered intravascular ultrasound with radiofrequency backscatter-virtual histology (IVUS-VH). MATERIALS AND METHODS Twenty-seven patients were enrolled, and 5976 mm of coronary arteries were analyzed. A semiautomatic software was developed to coregister CAC and IVUS-VH on a detailed slice-by-slice basis. Calcium detection and calcium volume quantification were evaluated and compared using varying calcium attenuation thresholds. Algorithms for deriving individualized optimal threshold and comparable Agatston score on the 0.5-mm reconstruction were developed. RESULTS The isotropic 0.5-mm reconstruction achieved significantly higher area under receiver-operating curve than the conventional 3.0-mm reconstruction (0.9 vs. 0.74, P < .001). Using the optimal threshold, the 0.5-mm reconstruction had higher sensitivity (0.79 vs. 0.65), specificity (0.85 vs. 0.77), positive predictive value (0.42 vs. 0.29), and negative predictive value (0.97 vs. 0.94) than the 3.0 mm. Individualized optimal threshold was significantly correlated with the image noise (r = 0.66, P < .001) in the 0.5-mm reconstruction. CONCLUSIONS By optimizing the calcium threshold, the 0.5-mm reconstruction is superior to the conventional 3.0-mm in detecting and quantifying calcium, which may improve the clinical value of CAC without additional radiation.