Rainer Seibel

Coronary Risk Stratification, Discrimination, and Reclassification Improvement Based on Quantification of Subclinical Coronary Atherosclerosis: The Heinz Nixdorf Recall Study

OBJECTIVES The purpose of this study was to determine net reclassification improvement (NRI) and improved risk prediction based on coronary artery calcification (CAC) scoring in comparison with traditional risk factors. BACKGROUND CAC as a sign of subclinical coronary atherosclerosis can noninvasively be detected by CT and has been suggested to predict coronary events. METHODS In 4,129 subjects from the HNR (Heinz Nixdorf Recall) study (age 45 to 75 years, 53% female) without overt coronary artery disease at baseline, traditional risk factors and CAC scores were measured. Their risk was categorized into low, intermediate, and high according to the Framingham Risk Score (FRS) and National Cholesterol Education Panel Adult Treatment Panel (ATP) III guidelines, and the reclassification rate based on CAC results was calculated. RESULTS After 5 years of follow-up, 93 coronary deaths and nonfatal myocardial infarctions occurred (cumulative risk 2.3%; 95% confidence interval: 1.8% to 2.8%). Reclassifying intermediate (defined as 10% to 20% and 6% to 20%) risk subjects with CAC <100 to the low-risk category and with CAC ≥400 to the high-risk category yielded an NRI of 21.7% (p = 0.0002) and 30.6% (p < 0.0001) for the FRS, respectively. Integrated discrimination improvement using FRS variables and CAC was 1.52% (p < 0.0001). Adding CAC scores to the FRS and National Cholesterol Education Panel ATP III categories improved the area under the curve from 0.681 to 0.749 (p < 0.003) and from 0.653 to 0.755 (p = 0.0001), respectively. CONCLUSIONS CAC scoring results in a high reclassification rate in the intermediate-risk cohort, demonstrating the benefit of imaging of subclinical coronary atherosclerosis. Our study supports its application, especially in carefully selected individuals with intermediate risk.

Comparison of Electron Beam Computed Tomography With Intracoronary Ultrasound and Coronary Angiography for Detection of Coronary Atherosclerosis

OBJECTIVES This analysis compared the results of electron beam computed tomography (EBCT) with those of coronary angiography and intracoronary ultrasound (ICUS) for the in vivo detection of coronary atherosclerotic plaques. BACKGROUND EBCT is a new imaging modality for identification of coronary calcifications. Coronary angiography depicts advanced changes in coronary morphology, whereas ICUS is an established diagnostic tool that detects the early stages of coronary artery disease. METHODS In 57 patients (54 +/- 9 years old), 267 coronary segments were analyzed with EBCT (3-mm slices, acquisition time 100 ms, threshold definition of coronary calcification at 130 Hounsfield units in an area > or = 1 mm2, Agatston calcium score), coronary angiography and ICUS. The analysis was based on the number and extent of coronary calcifications on EBCT, coronary lumen reduction on coronary angiography and plaque formation with and without ultrasound signs of calcifications on ICUS. RESULTS Compared with coronary angiography, EBCT yielded a sensitivity of 66%, a specificity of 78%, a positive predictive value of 39% and a negative predictive value of 91%. Compared with ICUS, EBCT yielded an overall sensitivity of 66%, a specificity of 88% and an overall accuracy of 81%. For plaques with and without ultrasound signs of calcifications, the sensitivity of EBCT was 97% and 47%, specificity 80% and 75% and overall accuracy 82% and 69%, respectively. CONCLUSIONS This in vivo correlation between ICUS and EBCT demonstrates that EBCT is a noninvasive method that helps to visualize the atherosclerotic process by localization and quantification of coronary artery calcifications. EBCT detects calcified plaques with high accuracy. Plaques without ultrasound signs of calcifications can be detected by EBCT but with lower sensitivity but equivalent specificity.

Coronary Artery Calcium in Acute Coronary Syndromes A Comparative Study of Electron-Beam Computed Tomography, Coronary Angiography, and Intracoronary Ultrasound in Survivors of Acute Myocardial Infarction and Unstable Angina

BACKGROUND Quantification of coronary artery calcified plaques by electron-beam CT (EBCT) may predict cardiovascular events. However, whereas advanced coronary atherosclerotic plaques can be identified, mildly stenotic lipid-rich (soft) plaques may be difficult to detect. The value of EBCT in a subgroup of patients has therefore been questioned. To investigate this, we evaluated patients with acute coronary syndromes by EBCT and compared the results with coronary angiography and, in patients with an indeterminate angiogram, intracoronary ultrasound (ICUS). METHODS AND RESULTS EBCT was performed in 118 consecutive patients (57+/-11 years of age) with previous myocardial infarction (n=101) or unstable angina (n=17). A standard protocol requiring a CT density >130 Hounsfield units in an area > or =1.03 mm2 was used for the definition of coronary artery calcium. We found that 110 patients had moderate to severe coronary artery disease by coronary angiography, and 8 had either mildly stenotic plaques at a single site (4 patients, confirmed by ICUS) or nonatherosclerotic causes of the unstable coronary syndrome (4 patients). One hundred and five of the 110 patients (96%) with moderate to severe angiographic disease but only 1 of the 8 other patients (13%) had a positive EBCT. Patients with acute coronary syndromes and negative EBCTs were significantly younger than patients with positive EBCTs (46+/-12 versus 58+/-10 years, P<.001), and a higher percentage was actively smoking (100% of the smokers versus 46%, P<.05). CONCLUSIONS The vast majority of patients with acute coronary syndromes and at least moderate angiographic disease have identifiable coronary calcium by EBCT. Those patients with negative EBCTs have minimal or no atherosclerotic plaque formation. They are younger and tend to be active cigarette smokers.

Natural History and Topographic Pattern of Progression of Coronary Calcification in Symptomatic Patients An Electron-Beam CT Study

Abstract —Electron-beam CT may assess the progression of coronary atherosclerosis by visualizing changes in calcification. The present investigation analyzes (1) the rate of progression of calcification in symptomatic patients, (2) the topographic pattern, and (3) the influence of baseline plaque burden and risk factors. Progression of calcification during a mean (median) interval of 18 (15) months was measured in 102 symptomatic outpatients (aged 59±9 years, 80% male) with calcification. In 4 patient groups with a baseline total score (Agatston criteria) of 1 to 30, >30 to 100, >100 to 400, and >400, the median was 3.1, 26.1, 58.9, and 109.7, respectively, for absolute annual progression of the score (P <0.05) and 57%, 49%, 32%, and 15%, respectively, for relative progression (P <0.05). On the coronary segmental level, changes were largely restricted to typical predilection sites of coronary atherosclerosis. The presence of angiographically defined coronary narrowing influenced absolute, but not relative, progression. Of the risk factors, only low density lipoprotein cholesterol levels showed a trend, although not significant, for predicting progression. These data indicate that baseline plaque burden determines the rate of progression of calcification. This appears to be a coronary systemic process, reflecting the natural history of coronary atherosclerosis.

Association of pericoronary fat volume with atherosclerotic plaque burden in the underlying coronary artery: A segment analysis

OBJECTIVE We aimed to determine, whether the amount of local pericoronary fat volume is associated with the presence of plaque burden in the underlying coronary artery segment. METHODS We assessed 311 coronary segments from ECG-gated contrast-enhanced dual-source computed tomography for presence of plaque as well as segmental pericoronary fat volume. For pericoronary fat evaluation, regions of interest were manually traced containing any fat surrounding a coronary artery segment, with the myocardial wall, the pericardial sac and other coronary segments as outer border. RESULTS Per each doubling of pericoronary fat volume, we observed an 2.5-fold increase in the presence of plaque in the underlying coronary segment in unadjusted models (95% confidence interval [CI] 1.87-3.27, p<0.001), which remained after adjustment for traditional cardiovascular risk factors (odds ratio [OR] 3.07 [2.16-4.35], p<0.001) and when additionally accounting for overall pericardial fat volume (OR 2.68 [1.90-3.79], p<0.001). Associations were similar in all coronary artery segments and not related to the type of plaque (calcified or non-calcified, p<0.01 for all). CONCLUSION Pericoronary fat is associated with atherosclerosis in the coronary arteries. Our results support the hypothesis that perivascular fat depots may function as a local endocrine risk factor in atherosclerosis development.

Measuring the Effect of Risk Factors on Coronary Atherosclerosis: Coronary Calcium Score Versus Angiographic Disease Severity

OBJECTIVES This study sought to determine whether noninvasive quantification of coronary calcium is comparable to selective coronary angiography in measuring the effect of cardiovascular risk factors on coronary atherosclerosis. BACKGROUND Electron beam computed tomography (EBCT) allows the delineation of anatomic coronary atherosclerotic disease and may be useful for noninvasively defining the role of established and new cardiovascular risk factors in selected patient groups. METHODS A total of 211 consecutive patients, 26 to 79 years old, referred for evaluation of suspected or recently diagnosed coronary artery disease were examined. Selective coronary angiography was used to define five angiographic disease categories: normal coronary arteries, nonobstructive disease and one-, two- or three-vessel disease. EBCT was used to calculate coronary calcium scores, and cardiovascular risk, including lipid variables and fibrinogen levels, was assessed. RESULTS Coronary calcium score and angiographic disease severity categories were largely predicted by identical risk factors (i.e., age, male gender, total/high density lipoprotein cholesterol ratio, fibrinogen) and, to a lesser degree, hypertension. Only smoking predicted angiographic disease severity but not calcium scores. The risk factors together explained a comparable proportion of the variability in angiographic disease categories and in calcium score quintiles (33% vs. 41%, p=0.16 by bootstrap analysis). An overall risk score composed of these risk factors separated angiographic disease categories and calcium score quintiles with a similar area under the receiver operating characteristic curve ([mean+/-SE] 0.81+/-0.03 vs. 0.83+/-0.03, p=NS). CONCLUSIONS Quantification of coronary calcium is comparable to selective coronary angiography in measuring the effect of established cardiovascular risk factors on coronary atherosclerosis. Thus, EBCT may be useful for the noninvasive evaluation of the relations between conventional or developing cardiovascular risk factors and coronary atherosclerosis.

Comparison of electron-beam computed tomography and intracoronary ultrasound in detecting calcified and noncalcified plaques in patients with acute coronary syndromes and no or minimal to moderate angiographic coronary artery disease

We compared intracoronary ultrasound (ICUS) and electron-beam computed tomography (EBCT) on a coronary segmental basis in 40 consecutive patients with acute coronary syndromes and no or minimal to moderate angiographic disease (53+/-10 years; 34 men, 6 women). ICUS was used to define plaques, and EBCT was used to quantify coronary calcium (using a threshold of a CT density > 130 Hounsfield units in an area > 1.03 mm2). In a site-by-site analysis, coronary segments were defined as normal if both methods were negative, as containing noncalcified plaques if only ICUS was positive, and as containing calcified plaques if both methods were positive. A total of 222 coronary segments were analyzed (5.6+/-1.9 segments per patient). In 36 patients (90%), a total of 95 segments with plaques were identified, whereas in 4 patients (10%), only normal segments were seen. Of the 95 segments with plaques, 61 (64%) were calcified, and 34 (36%) were noncalcified. There was a linear relationship between the number of segments with calcified and with noncalcified plaques (r = 0.86, p <0.0001), but the mean relative frequency of segments with calcified plaques (55+/-38%) was highly variable. Calcium was found in 15 of 16 patients (93%) with 3 or more segments with plaques, while it was found in only 12 of 20 patients (60%) with one or 2 segments with plaques (p = 0.026). Younger age, higher low-density lipoprotein-cholesterol levels, diabetes, and active smoking predicted a higher relative frequency of segments with noncalcified plaques. Thus, in patients with acute coronary syndromes but no angiographically critical stenoses, there is a linear relationship between segments with calcified plaques versus segments with noncalcified plaques. However, while the mean ratio of these segments is close to 1:1, it is highly variable among individual patients.

Prognostic value of extensive coronary calcium quantities in symptomatic males—a 5-year follow-up study

AIMS Coronary calcium scores (CSs) have been shown to predict future events in patients presenting for first-time evaluation of CAD. Long-term outcome data on symptomatic subjects with advanced CAD are limited. In this study, we evaluated the prognostic value of very high coronary CSs in symptomatic males undergoing angiography and analyzed the impact of event definitions on identification of risk predictors. METHODS AND RESULTS Fifty consecutive symptomatic males with electron beam computed tomography (EBT)-based CSs >1000 were matched 1:2 by age with symptomatic males with scores between 400-1000 and 100-400. All 150 patients underwent coronary angiography. CAD risk factors were ascertained. Events were analyzed after 5 years for: (1) hard coronary events (coronary death and myocardial infarction); (2) overall hard events (adding stroke and non-coronary deaths); and (3) all events (including long-term revascularizations). During follow-up, 17 deaths, two infarctions and three strokes occurred in 21 patients; 38 patients underwent 43 revascularizations. Events occurred earlier and more frequently in patients with scores >1000. Left main disease was the only independent predictor of hard coronary events (hazard ratio, 4.5; 95% confidence interval, 1.1-17.8). Left main disease (4.3; 1.4-13.0) and CSs (1.7; 1.1-2.5) independently predicted overall hard events. Only CSs>90th percentile independently predicted all events (2.5; 1.3-4.8). CONCLUSIONS Symptomatic males with extensive CSs carry an even higher risk for future events than other symptomatic males with advanced CAD. In these patients, EBT-based calcified plaque burden and angiographic indices of disease severity may have a complementary role in predicting future cardiovascular events.

Effect of smoking and other traditional risk factors on the onset of coronary artery calcification: Results of the Heinz Nixdorf recall study

BACKGROUND Coronary artery calcium (CAC) indicates coronary atherosclerosis and can be present in very early stages of the disease. The conversion from no CAC to any CAC reflects an important step of the disease process as cardiovascular risk is increased in persons even with mildly elevated CAC. We sought to identify risk factors that determined incident CAC>0 in men and women from an unselected general population with a special focus on the role of smoking. METHODS All 4814 persons that were initially studied in the Heinz Nixdorf Recall Study were invited to participate in the follow-up examination after 5.1 ± 0.3 years. All traditional Framingham risk factors were quantified using standard techniques. Smokers were categorized in never, former and present smokers. The CAC scores were measured from EBCT using the Agatston method. RESULTS Overall, out of 342 men and 919 women with zero CAC at baseline, 107 (31.3%) men and 210 (22.9%) women had CAC>0 at second examination. In multivariable analysis, age (OR estimate per 5 years: 1.34 (95%CI: 1.21-1.47)), LDL cholesterol (per 10 mg/dL: 1.05 (95%CI: 1.01-1.10)), systolic blood pressure (per 10 mmHg: 1.19 (95%CI: 1.11-1.28)) and current smoking (1.49 (95%CI: 1.04-2.15)) were independent predictors of CAC onset. The probability of CAC onset steadily increased with age from 23.3% (men) and 15.3% (women) at age 45-49 years to 66.7% (men) and 42.9% (women) at age 70-74 years. The difference in age-dependent conversion rates was quantified by years between reaching a given level of CAC onset probability. We found a consistent pattern with respect to smoking status: presently (formerly) smoking middle-aged men convert to positive CAC 10 (5) years earlier than never smokers, for women (middle-aged to elderly) this time span is 8 (5) years. CONCLUSION Several traditional CVD risk factors are associated with CAC onset during 5 years follow-up. CAC onset is accelerated by approximately 10 (5) years for present (former) compared to never smokers.

Minimally invasive evaluation of coronary stents with electron beam computed tomography: In vivo and in vitro experience.

We sought to describe the value of electron beam computed tomography (EBCT) to detect stent restenoses at follow‐up and to identify characteristic EBCT features of coronary stents. Six coronary stents (GRII, Jostent, NIR, PS, Micro, Wiktor) were scanned in vitro (10 1.5‐mm‐thick slices, 15‐cm FoV, 100‐ms AT) before and after inflation with 3.0‐, 3.5‐, and 4.0‐mm balloons to study intensity values and different stent dimensions in comparison to caliper measurements. In 44 patients (60 ± 10 years, 4 females) we prospectively compared EBCT findings [eight 8‐mm‐thick slices in the flow mode, 26‐cm field of view (FoV), 50 ms acquisition time (AT)] with 6‐month angiographic outcome after placement of 86 stents in 49 vessels. For the detection of significant angiographic luminal narrowing (≥75%) that occurred in 17/49 vessels (35%), we found a sensitivity of 65%, a specificity of 84%, and a positive and negative predictive value of 69% and 82%, respectively. The in vitro data show significant differences in image intensity between the stents and a significant gradual decrease in image intensity with increasing stent diameters. The mean differences between EBCT and caliper measurements for the length and diameter were 0.17 ± 0.18 mm and −0.32 ± 0.25mm, respectively. EBCT is currently the only noninvasive technique that allows the assessment of stent dimensions and stent geometry, which may prove useful in patients when intravascular ultrasound cannot be performed. Contrast‐enhanced EBCT is a promising tool for minimally invasive stent patency evaluation at follow‐up, especially in patients that are unable to exercise. Cathet. Cardiovasc. Intervent. 48:39–47, 1999.