Heidi Gransar

Impact of Coronary Artery Calcium Scanning on Coronary Risk Factors and Downstream Testing: The EISNER (Early Identification of Subclinical Atherosclerosis by Noninvasive Imaging Research) Prospective Randomized Trial

OBJECTIVES We conducted a prospective randomized trial to compare the clinical impact of conventional risk factor modification to that associated with the addition of coronary artery calcium (CAC) scanning. BACKGROUND Although CAC scanning predicts cardiac events, its impact on subsequent medical management and coronary artery disease risk is not known. METHODS We assigned 2,137 volunteers to groups that either did undergo CAC scanning or did not undergo CAC scanning before risk factor counseling. The primary end point was 4-year change in coronary artery disease risk factors and Framingham Risk Score. We also compared the groups for differences in downstream medical resource utilization. RESULTS Compared with the no-scan group, the scan group showed a net favorable change in systolic blood pressure (p = 0.02), low-density lipoprotein cholesterol (p = 0.04), and waist circumference for those with increased abdominal girth (p = 0.01), and tendency to weight loss among overweight subjects (p = 0.07). While there was a mean rise in Framingham Risk Score (FRS) in the no-scan group, FRS remained static in the scan group (0.7 ± 5.1 vs. 0.002 ± 4.9, p = 0.003). Within the scan group, increasing baseline CAC score was associated with a dose-response improvement in systolic and diastolic blood pressure (p < 0.001), total cholesterol (p < 0.001), low-density lipoprotein cholesterol (p < 0.001), triglycerides (p < 0.001), weight (p < 0.001), and Framingham Risk Score (p = 0.003). Downstream medical testing and costs in the scan group were comparable to those of the no-scan group, balanced by lower and higher resource utilization for subjects with normal CAC scans and CAC scores ≥400, respectively. CONCLUSIONS Compared with no scanning, randomization to CAC scanning was associated with superior coronary artery disease risk factor control without increasing downstream medical testing. Further study of CAC scanning, including pre-specified treatment recommendations, to assess its impact of cardiovascular outcomes is warranted.

Temporal Trends in the Frequency of Inducible Myocardial Ischemia During Cardiac Stress Testing: 1991 to 2009

OBJECTIVES This study sought to assess whether the frequency of inducible myocardial ischemia during stress-rest single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) has changed over time. BACKGROUND The prevalence of cardiac death and other clinical cardiac events have declined in recent decades, but heretofore no study has examined if there has been a temporal change in the frequency of inducible myocardial ischemia during cardiac stress testing. METHODS We assessed 39,515 diagnostic patients undergoing stress-rest MPI between 1991 and 2009. Patients were assessed for change in demographics, clinical symptoms, risk factors, and frequency of abnormal and ischemic SPECT-MPI. RESULTS There was a marked progressive decline in the prevalence of abnormal SPECT studies, from 40.9% in 1991 to 8.7% in 2009 (p < 0.001). Similarly, the prevalence of ischemic SPECT-MPI declined, from 29.6% to 5.0% (p < 0.001), as did the prevalence of severe ischemia. The decline of SPECT-MPI abnormality occurred among all age and symptom subgroups, falling to only 2.9% among recent exercising patients without typical angina. We also noted a progressive trend toward performing more pharmacological rather than exercise stress in all age and weight groups, and pharmacological stress was more likely than exercise to be associated with SPECT-MPI abnormality (odds ratio: 1.43, 95% confidence interval: 1.3 to 1.5; p < 0.001). CONCLUSIONS Over the past 2 decades, the frequency and severity of abnormal stress SPECT-MPI studies has progressively decreased. Notably, the frequency of abnormal SPECT-MPI is now very low among exercising patients without typical angina. These findings suggest the need for developing more cost-effective strategies for the initial work-up of patients who are presently at low risk for manifesting inducible myocardial ischemia during cardiac imaging procedures.

Pericardial Fat Burden on ECG-Gated Noncontrast CT in Asymptomatic Patients Who Subsequently Experience Adverse Cardiovascular Events

OBJECTIVES We aimed to evaluate whether pericardial fat has value in predicting the risk of future adverse cardiovascular outcomes. BACKGROUND Pericardial fat volume (PFV) and thoracic fat volume (TFV) can be routinely measured from noncontrast computed tomography (NCT) performed for calculating coronary calcium score (CCS) and may predict major adverse cardiac event (MACE) risk. METHODS From a registry of 2,751 asymptomatic patients without known cardiac artery disease and 4-year follow-up for MACE (cardiac death, myocardial infarction, stroke, late revascularization) after NCT, we compared 58 patients with MACE with 174 same-sex, event-free control subjects matched by a propensity score to account for age, risk factors, and CCS. The TFV was automatically calculated, and PFV was calculated with manual assistance in defining the pericardial contour, within which fat voxels were automatically identified. Independent relationships of PFV and TFV to MACE were evaluated using conditional multivariable logistic regression. RESULTS Patients experiencing MACE had higher mean PFV (101.8 +/- 49.2 cm(3) vs. 84.9 +/- 37.7 cm(3), p = 0.007) and TFV (204.7 +/- 90.3 cm(3) vs. 177 +/- 80.3 cm(3), p = 0.029) and higher frequencies of PFV >125 cm(3) (33% vs. 14%, p = 0.002) and TFV >250 cm(3) (31% vs. 17%, p = 0.025). After adjustment for Framingham risk score (FRS), CCS, and body mass index, PFV and TFV were significantly associated with MACE (odds ratio [OR]: 1.74, 95% confidence interval [CI]: 1.03 to 2.95 for each doubling of PFV; OR: 1.78, 95% CI: 1.01 to 3.14 for TFV). The area under the curve from receiver-operator characteristic analyses showed a trend of improved MACE prediction when PFV was added to FRS and CCS (0.73 vs. 0.68, p = 0.058). Addition of PFV, but not TFV, to FRS and CCS improved estimated specificity (0.72 vs. 0.66, p = 0.008) and overall accuracy (0.70 vs. 0.65, p = 0.009) in predicting MACE. CONCLUSIONS Asymptomatic patients who experience MACE exhibit greater PFV on pre-MACE NCT when they are compared with event-free control subjects with similar cardiovascular risk profiles. Our preliminary findings suggest that PFV may help improve prediction of MACE.

Noninvasive Fractional Flow Reserve Derived From Computed Tomography Angiography for Coronary Lesions of Intermediate Stenosis Severity Results From the DeFACTO Study

Background—Fractional flow reserve derived from computed tomography angiography (FFRCT) is a noninvasive method for diagnosis of ischemic coronary lesions. To date, the diagnostic performance of FFRCT for lesions of intermediate stenosis severity remains unexamined. Methods and Results—Among 407 vessels from 252 patients at 17 centers who underwent CT, FFRCT, invasive coronary angiography, and invasive FFR, we identified 150 vessels of intermediate stenosis by CT, defined as 30% to 69% stenosis. FFRCT, FFR, and CT were interpreted in blinded fashion by independent core laboratories. FFRCT and FFR ⩽0.80 were considered hemodynamically significant, whereas CT stenosis ≥50% was considered obstructive. Diagnostic performance of FFRCT versus CT was assessed for accuracy, sensitivity, specificity, positive predictive values, and negative predictive values. Area under the receiver operating characteristic curve and net reclassification improvement were evaluated. For lesions of intermediate stenosis severity, accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of FFRCT were 71%, 74%, 67%, 41%, and 90%, whereas accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of CT stenosis were 63%, 34%, 72%, 27%, and 78%. FFRCT demonstrated superior discrimination compared with CT stenosis on per-patient (area under the receiver operating characteristic curve, 0.81 versus 0.50; P=0.0001) and per-vessel basis (area under the receiver operating characteristic curve, 0.79 versus 0.53; P<0.0001). FFRCT demonstrated significant reclassification of CT stenosis for lesion-specific ischemia (net reclassification improvement, 0.45; 95% confidence interval, 0.25–0.65; P=0.01). Conclusions—FFRCT possesses high diagnostic performance for diagnosis of ischemic for lesions of intermediate stenosis severity. Notably, the high sensitivity and negative predictive value suggest the ability of FFRCT to effectively rule out intermediate lesions that cause ischemia.

Non-invasive Fractional Flow Reserve Derived from CT Angiography (FFRCT) for Coronary Lesions of Intermediate Stenosis Severity: Results from the DeFACTO study

Background—Fractional flow reserve derived from computed tomography angiography (FFRCT) is a noninvasive method for diagnosis of ischemic coronary lesions. To date, the diagnostic performance of FFRCT for lesions of intermediate stenosis severity remains unexamined. Methods and Results—Among 407 vessels from 252 patients at 17 centers who underwent CT, FFRCT, invasive coronary angiography, and invasive FFR, we identified 150 vessels of intermediate stenosis by CT, defined as 30% to 69% stenosis. FFRCT, FFR, and CT were interpreted in blinded fashion by independent core laboratories. FFRCT and FFR ⩽0.80 were considered hemodynamically significant, whereas CT stenosis ≥50% was considered obstructive. Diagnostic performance of FFRCT versus CT was assessed for accuracy, sensitivity, specificity, positive predictive values, and negative predictive values. Area under the receiver operating characteristic curve and net reclassification improvement were evaluated. For lesions of intermediate stenosis severity, accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of FFRCT were 71%, 74%, 67%, 41%, and 90%, whereas accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of CT stenosis were 63%, 34%, 72%, 27%, and 78%. FFRCT demonstrated superior discrimination compared with CT stenosis on per-patient (area under the receiver operating characteristic curve, 0.81 versus 0.50; P=0.0001) and per-vessel basis (area under the receiver operating characteristic curve, 0.79 versus 0.53; P<0.0001). FFRCT demonstrated significant reclassification of CT stenosis for lesion-specific ischemia (net reclassification improvement, 0.45; 95% confidence interval, 0.25–0.65; P=0.01). Conclusions—FFRCT possesses high diagnostic performance for diagnosis of ischemic for lesions of intermediate stenosis severity. Notably, the high sensitivity and negative predictive value suggest the ability of FFRCT to effectively rule out intermediate lesions that cause ischemia.

Increased Pericardial Fat Volume Measured From Noncontrast CT Predicts Myocardial Ischemia by SPECT

OBJECTIVES We evaluated the association between pericardial fat and myocardial ischemia for risk stratification. BACKGROUND Pericardial fat volume (PFV) and thoracic fat volume (TFV) measured from noncontrast computed tomography (CT) performed for calculating coronary calcium score (CCS) are associated with increased CCS and risk for major adverse cardiovascular events. METHODS From a cohort of 1,777 consecutive patients without previously known coronary artery disease (CAD) with noncontrast CT performed within 6 months of single photon emission computed tomography (SPECT), we compared 73 patients with ischemia by SPECT (cases) with 146 patients with normal SPECT (controls) matched by age, gender, CCS category, and symptoms and risk factors for CAD. TFV was automatically measured. Pericardial contours were manually defined within which fat voxels were automatically identified to compute PFV. Computer-assisted visual interpretation of SPECT was performed using standard 17-segment and 5-point score model; perfusion defect was quantified as summed stress score (SSS) and summed rest score (SRS). Ischemia was defined by: SSS - SRS ≥4. Independent relationships of PFV and TFV to ischemia were examined. RESULTS Cases had higher mean PFV (99.1 ± 42.9 cm(3) vs. 80.1 ± 31.8 cm(3), p = 0.0003) and TFV (196.1 ± 82.7 cm(3) vs. 160.8 ± 72.1 cm(3), p = 0.001) and higher frequencies of PFV >125 cm(3) (22% vs. 8%, p = 0.004) and TFV >200 cm(3) (40% vs. 19%, p = 0.001) than controls. After adjustment for CCS, PFV and TFV remained the strongest predictors of ischemia (odds ratio [OR]: 2.91, 95% confidence interval [CI]: 1.53 to 5.52, p = 0.001 for each doubling of PFV; OR: 2.64, 95% CI: 1.48 to 4.72, p = 0.001 for TFV). Receiver operating characteristic analysis showed that prediction of ischemia, as indicated by receiver-operator characteristic area under the curve, improved significantly when PFV or TFV was added to CCS (0.75 vs. 0.68, p = 0.04 for both). CONCLUSIONS Pericardial fat was significantly associated with myocardial ischemia in patients without known CAD and may help improve risk assessment.

Computer-aided Non-contrast CT-based Quantification of Pericardial and Thoracic Fat and Their Associations with Coronary Calcium and Metabolic Syndrome

INTRODUCTION Pericardial fat is emerging as an important parameter for cardiovascular risk stratification. We extended previously developed quantitation of thoracic fat volume (TFV) from non-contrast coronary calcium (CC) CT scans to also quantify pericardial fat volume (PFV) and investigated the associations of PFV and TFV with CC and the Metabolic Syndrome (METS). METHODS TFV is quantified automatically from user-defined range of CT slices covering the heart. Pericardial fat contours are generated by spline interpolation between 5-7 control points, placed manually on the pericardium within this cardiac range. Contiguous fat voxels within the pericardium are identified as pericardial fat. PFV and TFV were measured from non-contrast CT for 201 patients. In 105 patients, abdominal visceral fat area (VFA) was measured from an additional single-slice CT. In 26 patients, images were quantified by two readers to establish inter-observer variability. TFV and PFV were examined in relation to Body Mass Index (BMI), waist circumference and VFA, standard coronary risk factors (RF), CC (Agatston score >0) and METS. RESULTS PFV and TFV showed excellent correlation with VFA (R=0.79, R=0.89, p<0.0001), and moderate correlation with BMI (R=0.49, R=0.48, p<0.0001). In 26 scans, the inter-observer variability was greater for PFV (8.0+/-5.3%) than for TFV (4.4+/-3.9%, p=0.001). PFV and TFV, but not RF, were associated with CC [PFV: p=0.04, Odds Ratio 3.1; TFV: p<0.001, OR 7.9]. PFV and TFV were also associated with METS [PFV: p<0.001, OR 6.1; TFV p<0.001, OR 5.7], unlike CC [OR=1.0 p=NS] or RF. PFV correlated with low-HDL and high-glucose; TFV correlated with low-HDL, low-adiponectin, and high glucose and triglyceride levels. CONCLUSIONS PFV and TFV can be obtained easily and reproducibly from routine CC scoring scans, and may be important for risk stratification and monitoring.

Aggregate Plaque Volume by Coronary Computed Tomography Angiography Is Superior and Incremental to Luminal Narrowing for Diagnosis of Ischemic Lesions of Intermediate Stenosis Severity

OBJECTIVES This study examined the performance of percent aggregate plaque volume (%APV), which represents cumulative plaque volume as a function of total vessel volume, by coronary computed tomography angiography (CTA) for identification of ischemic lesions of intermediate stenosis severity. BACKGROUND Coronary lesions of intermediate stenosis demonstrate significant rates of ischemia. Coronary CTA enables quantification of luminal narrowing and %APV. METHODS We identified 58 patients with intermediate lesions (30% to 69% diameter stenosis) who underwent invasive angiography and fractional flow reserve. Coronary CTA measures included diameter stenosis, area stenosis, minimal lumen diameter (MLD), minimal lumen area (MLA) and %APV. %APV was defined as the sum of plaque volume divided by the sum of vessel volume from the ostium to the distal portion of the lesion. Fractional flow reserve ≤ 0.80 was considered diagnostic of lesion-specific ischemia. Area under the receiver operating characteristic curve and net reclassification improvement (NRI) were also evaluated. RESULTS Twenty-two of 58 lesions (38%) caused ischemia. Compared with nonischemic lesions, ischemic lesions had smaller MLD (1.3 vs. 1.7 mm, p = 0.01), smaller MLA (2.5 vs. 3.8 mm(2), p = 0.01), and greater %APV (48.9% vs. 39.3%, p < 0.0001). Area under the receiver operating characteristic curve was highest for %APV (0.85) compared with diameter stenosis (0.68), area stenosis (0.66), MLD (0.75), or MLA (0.78). Addition of %APV to other measures showed significant reclassification over diameter stenosis (NRI 0.77, p < 0.001), area stenosis (NRI 0.63, p = 0.002), MLD (NRI 0.62, p = 0.001), and MLA (NRI 0.43, p = 0.01). CONCLUSIONS Compared with diameter stenosis, area stenosis, MLD, and MLA, %APV by coronary CTA improves identification, discrimination, and reclassification of ischemic lesions of intermediate stenosis severity.

Moving beyond binary grading of coronary arterial stenoses on coronary computed tomographic angiography: insights for the imager and referring clinician.

OBJECTIVES We evaluated the technical and clinical utility of visual 5-point coronary stenosis grading on coronary computed tomographic angiography (CCTA). BACKGROUND The binary approach used to assess coronary stenoses on CCTA does not adequately describe borderline obstructive lesions and limits full expression of clinically useful information. METHODS From 84 patients who underwent CCTA and invasive angiography, we identified 278 native coronary segments with > or =25% stenosis on CCTA after excluding all <25% stenotic, stented, and uninterpretable segments. Fifty <25% stenotic segments were randomly selected as controls. Segmental stenosis severity on CCTA was consensually graded using a 0 to 5 scale (grade 0 = none, grade 1 = 1% to 24%, grade 2 = 25% to 49%, grade 3 = 50% to 69%, grade 4 = 70% to 89%, grade 5 = 90% to 100%) by 2 readers, using visual inspection and computed tomography-based quantification (CTQCA). Invasive angiography-based stenosis quantification (IQCA) was performed for all segments, using the same 0 to 5 scale to score stenosis severity. RESULTS On CCTA, 185 (56%) segments had intermediate stenoses (grade 2 or grade 3). Stenosis severity by IQCA increased significantly with each step-up in CCTA grade (p < 0.001). CTQCA did not perform better than visual inspection. Visual CCTA stenosis grading differed from IQCA by >1 grade in only 4% of grade 2 to grade 5 segments (10 of 278; 2% of CCTA grade 2 segments, 4% of grade 3, 8% of grade 4, 2% of grade 5). Overall quantitative correlation was strong (r = 0.82) with high variability in agreement between CTQCA and IQCA for individual segments (95% of differences between 27.2% and 34.6%). CONCLUSIONS With current CCTA technology, experienced readers should consider adopting a visually based, multitiered grading approach to evaluate coronary stenoses. A < or =49% lesion on CCTA can be considered virtually exclusive of > or =70% stenosis by invasive angiography.

Increase in epicardial fat volume is associated with greater coronary artery calcification progression in subjects at intermediate risk by coronary calcium score: A serial study using non-contrast cardiac CT

OBJECTIVE Epicardial fat volume (EFV) is related to calcified coronary plaques. However, it is unknown whether baseline EFV or changes in EFV affect the progression of coronary artery calcification over time. METHODS We identified 375 consecutive asymptomatic subjects with an intermediate risk of developing coronary artery disease, who underwent serial non-contrast CT at least 3-5 years apart. Subjects were divided into tertiles of CCS progression (% increase) between the 2 scans. Subjects from the upper tertile (High Progressors) were matched by age and gender to 81 subjects from the lower tertile (Low Progressors). All subjects underwent serial measurements of CCS and EFV. Relationships between EFV and CCS progression, and change in plaque number were examined. RESULTS At baseline, there was no difference in EFV, and EFV indexed to body surface area (EFVi) between the groups. At follow-up, EFV, EFVi and percent increase in EFVi-change were higher in High Progressors than Low Progressors (EFV, 102 ± 38 cm(3) vs. 90 ± 35 cm(3), p=0.03; EFVi, 50 ± 16cm(3)/m(2) vs. 46 ± 15 cm(3)/m(2), p=0.03; percent increase in EFVi-change, 15 ± 22% vs. 7 ± 20%, p=0.02). On multivariate analysis, after adjusting for conventional risk factors, EFVi increase ≥15% [odds ratio (OR) 2.3, p<0.05], log (baseline CCS) [OR 0.3, p<0.0001] and scan interval time [p=0.003, OR 1.0] were predictive of being a High Progressor. EFVi increase ≥ 15% (β=3.0, p=0.02) and hypertension (β=3.1, p=0.01) were independent predictors of number of new calcified plaques on follow-up. CONCLUSION Increase in EFV is associated with greater progression of coronary artery calcification in intermediate-risk subjects.