The inflammatory biomarker high-sensitivity C-reactive protein (hs-CRP) has emerged as a predictor of future cardiovascular events. Screening for coronary artery calcium (CAC) is an alternative method for stratifying subjects by their cardiovascular risk. It is unclear, however, how hs-CRP compares with CAC scoring for the detection of obstructive coronary artery stenoses. We, thus, evaluated the association, if any, between hs-CRP and CAC scores for the detection of obstructive stenoses in a low-risk population with well-controlled traditional cardiovascular risk factors. In the present study of 1,079 stable subjects, 38 (3.5%) severely obstructive stenoses were found initially by coronary computed tomographic angiography and confirmed subsequently using invasive coronary angiography. The univariate predictors of severely obstructive coronary artery disease included the use of antihypertensive agents (p = 0.03), angina (p <0.001), and an elevated CAC score (p <0.001). The biomarker hs-CRP was not significantly associated with the presence of a severely obstructive stenosis. As the CAC scores increased, the frequency of obstructive stenosis also increased (p for trend <0.001). In contrast, the frequency of obstructive stenoses was low when CAC was not detected. This relation remained significant after adjustment for antihypertensive medication use and angina. In conclusion, hs-CRP was not useful for the prediction of obstructive stenoses in stable subjects. CAC was found to be a better predictor of obstructive heart disease than hs-CRP.
The identification of significant coronary artery disease in subjects with well-controlled cardiovascular risk factors is problematic. Such subjects have, by consensus, a low risk of cardiovascular events. However, adverse cardiovascular events do occur in this group, although at a relatively low frequency. Ideally, it would be better to identify such subjects before complications related to their coronary artery disease occur.
Recently, the inflammatory biomarker, high-sensitivity C-reactive protein (hs-CRP), has emerged as a predictor of future cardiovascular events. Screening for coronary artery calcium (CAC) has also become a method of stratifying subjects’ cardiovascular risk. It is unclear, however, how hs-CRP compares with CAC scoring for the detection of obstructive coronary artery stenoses. We, thus, evaluated the association, if any, of hs-CRP and CAC scores for the detection of obstructive stenoses in a low-risk, stable population with well-controlled traditional cardiovascular risk factors.
Methods
The study population consisted of 1,079 subjects who were referred to the Cooper Clinic for coronary computed tomographic angiography (CTA). These referrals were at the discretion of their preventive medicine physician. Common referral indications included equivocal exercise stress test findings, significant atherosclerosis (defined as an Agatston CAC score >400 and/or ≥75th percentile), and the presence of ≥2 traditional cardiovascular risk factors. Patients with atrial fibrillation, significant renal insufficiency, or a history of significant iodinated contrast allergy were excluded. In addition, we excluded those with a history of revascularization with stents or coronary artery bypass grafting. All study subjects had given written permission to be included in the present study, which was approved by the local institutional review board.
A detailed medical history and physical examination were performed on all study participants. The evaluation included obtaining a complete medication and supplement history, performing an exercise treadmill stress test to assess for obstructive heart disease, and performing a noncontrast-enhanced, multidetector CT scan to determine the CAC score. In addition, fasting blood work measuring total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, glucose, and hs-CRP was done. Diabetes was defined as a fasting blood glucose ≥126 mg/dl or treatment with antidiabetic medication. Hypertension was defined as a systolic blood pressure of ≥140 mm Hg or a diastolic blood pressure of ≥90 mm Hg (or both) or current hypertension treatment. Hyperlipidemia was defined as total cholesterol ≥200 mg/dl or concurrent treatment for such.
All study participants underwent CAC score determination initially and contrast-enhanced coronary CTA subsequently, as previously described. The total CAC burden was quantified using the Agatston scoring method. In brief, contrast-enhanced CTA was performed with a 64-slice scanner system (Lightspeed VCT, GE Healthcare, Waukesha, Wisconsin). Unless clinically contraindicated, intravenous metoprolol and/or verapamil was given by way of an antecubital vein to achieve a goal heart rate of 50 to 65 beats/min. No rate-lowering medications were given to those with a baseline heart rate <60 beats/min. In addition, a low-dose automatic timing bolus protocol (100 kV, 50 mA, 20 ml contrast [5 ml/s] followed by a 20-ml saline chaser [5 ml/s] using a twin injector) was used to optimize the delay from the start of injection to the start of scanning at the level of the left main origin. Approximately 90 to 100 ml of iodinated contrast (Visipaque or Omnipaque, GE Healthcare) was administered at a flow rate of 5 to 6 ml/s for the CT angiographic images. Participants underwent CTA with the following scan parameters: tube voltage 100 kV, effective tube current 300 to 450 mA, 64- × 0.6-mm collimation, rotation time of 350 ms, and pitch 0.18 to 0.22. The effective tube current was selected as a function of the body mass index (BMI <20 kg/m 2 , 300 mA; BMI ≥20 but <25 kg/m 2 , 350 mA; BMI ≥25 but <30 kg/m 2 , 400 mA; and BMI ≥30, 450 mA). In addition, to minimize radiation exposure, prospective, “step and shoot” technology was used.
Source image data sets were loaded to reconstruct both thin-slab maximum intensity projections and curved multiplanar reconstructions. Transaxial images were reconstructed at a slice width of 0.6 mm. Reconstructions were performed at 75% of the R-R interval. Both a cardiologist and a radiologist experienced with coronary CTA reviewed all scans independently, and any discrepancies were resolved after additional joint review and discussion. A semiquantitative assessment was performed on any detected coronary artery stenoses, with an estimate of stenosis severity calculated as the ratio of the minimum contrast lumen to the normal reference lumen of an unaffected distal portion. Severe stenosis was defined as ≥50% of the left main artery or ≥70% luminal compromise elsewhere.
Patients with ≥1 severe stenosis as defined were referred for invasive coronary angiography and possible revascularization. Those in whom the invasive coronary angiogram corroborated the CTA findings were categorized as having true-positive findings for severe coronary artery disease. However, those in whom the invasive coronary angiogram did not corroborate the CTA findings were classified as having negative (false-positive) findings for severe coronary artery disease.
The clinical, anthropometric, and biochemical data of the study population are reported as proportions, mean ± SD, or median values with interquartile ranges, as appropriate. We compared the descriptive characteristics and scan parameters between patients classified by the obstructive stenosis category using Wilcoxon rank sum tests, t tests, or chi-square analysis. We conducted all data analyses using SAS, version 9.1, statistical software (SAS Institute, Cary, North Carolina).
Results
The baseline characteristics of the study population are listed in Table 1 . The study patients were primarily older, overweight men. The frequency of hypertension (40.0%) and hyperlipidemia (45.0%) was relatively high, and the prevalence of current tobacco use (7.0%) and diabetes (6.0%) was low. The use of antihypertensive (55%) and statin (52%) medications approximated the corresponding frequency of the appropriate cardiovascular risk factor. The control of these risk factors appeared to be excellent, with good blood pressure (mean 126/79 mm Hg), lipid profiles (mean low-density lipoprotein 95 mg/dl), and glucose levels (mean 102 mg/dl) at study enrollment. The median hs-CRP of the study group was also normal at 0.98 mg/dl (interquartile range 0.50 to 2.29). Nevertheless, the atherosclerosis burden of the overall study group was severe, with a median CAC score of 424 (interquartile range 95 to 954).
| Variable | Value |
|---|---|
| Total | 1,079 |
| Age (yrs) | 62.7 ± 9.5 |
| Men | 878 (81.4%) |
| Body mass index (kg/m 2 ) | 27.9 ± 4.5 |
| Hypertension | 432 (40.0%) |
| Diabetes mellitus | 65 (6.0%) |
| Hyperlipidemia | 483 (44.8%) |
| Current smoker | 84 (7.8%) |
| Systolic blood pressure (mm Hg) | 126.0 ± 15.0 |
| Diastolic blood pressure (mm Hg) | 78.7 ± 9.1 |
| Total cholesterol (mg/dl) | 171.7 ± 41.7 |
| High-density lipoprotein (mg/dl) | 54.0 ± 15.8 |
| Low-density lipoprotein (mg/dl) | 95.4 ± 36.6 |
| Triglycerides (mg/dl) | 111.6 ± 63.6 |
| Glucose (mg/dl) | 101.7 ± 20.9 |
| C-reactive protein (mg/L) | 0.98 (0.50–2.29) |
| Coronary artery calcium score | 424 (95–954) |
| Medications | |
| Antihypertensives | 590 (54.7%) |
| Statins | 565 (52.4%) |
| Antidiabetic | 86 (8.0%) |
| Test indications | |
| Angina | 7 (0.6%) |
| Chest pain, atypical | 162 (15.0%) |
| Abnormal/equivocal exercise stress test findings | 349 (32.3%) |
| Abnormal/equivocal myocardial perfusion test findings | 33 (3.1%) |
| Hypertension | 565 (52.4%) |
| Diabetes mellitus | 87 (8.1%) |
| Hyperlipidemia | 887 (82.2%) |
| Tobacco history | 446 (41.3%) |
| Body mass index ≥30 kg/m 2 | 281 (26.0%) |
| Family history of heart disease | 383 (35.5%) |
| Atherosclerosis | 846 (78.4%) |
The indications prompting referral for coronary CTA are also listed in Table 1 . The study population was largely asymptomatic, with a very low frequency of angina (<1.0%) and a relatively low rate of atypical chest pain (15.0%). The most frequent referral indication was the presence of significant atherosclerosis, defined as a CAC score >400 and/or ≥75th percentile. Other relatively common referral indications included abnormal or equivocal exercise treadmill stress test findings, equivocal myocardial perfusion study findings, a family history of premature heart disease, and the presence of multiple cardiovascular risk factors.
Despite the apparent control of the cardiovascular risk factors seen in this population, severely obstructive coronary artery disease was found in 38 participants (3.5%). The parameters associated with the presence of these stenoses are listed in Table 2 . The univariate predictors of severely obstructive coronary artery disease included the use of antihypertensive agents (p = 0.03), angina (p <0.001), and an elevated CAC score (p <0.001). After excluding those with angina, we still had 32 patients (3.0%) with apparently asymptomatic severely obstructive coronary artery disease. hs-CRP was not significantly associated with obstructive coronary artery disease.
| Variable | Severely Obstructive Stenoses | p Value | |
|---|---|---|---|
| No (n = 1,041) | Yes (n = 38) | ||
| Age (yrs) | 62.6 ± 9.4 | 64.3 ± 9.9 | 0.31 |
| Men | 843 (81.0%) | 35 (92.1%) | 0.13 |
| Body mass index (kg/m 2 ) | 27.9 ± 4.5 | 28.2 ± 3.9 | 0.70 |
| Hypertension | 416 (40.0%) | 16 (42.1%) | 0.87 |
| Diabetes mellitus | 63 (6.1%) | 2 (5.3%) | 0.75 |
| Hyperlipidemia | 468 (45.0%) | 15 (39.5%) | 0.51 |
| Current smoker | 83 (8.0%) | 1 (2.6%) | 0.51 |
| Systolic blood pressure (mm Hg) | 125.9 ± 14.9 | 129.6 ± 18.0 | 0.22 |
| Diastolic blood pressure (mm Hg) | 78.7 ± 9.0 | 79.0 ± 11.0 | 0.86 |
| Glucose (mg/dl) | 101.7 ± 21.1 | 100.0 ± 12.0 | 0.41 |
| Total cholesterol (mg/dl) | 171.9 ± 41.5 | 165.0 ± 46.7 | 0.37 |
| High-density lipoprotein (mg/dl) | 54.1 ±15.9 | 51.8 ± 11.9 | 0.26 |
| Low-density lipoprotein (mg/dl) | 95.4 ± 36.4 | 93.3 ± 40.9 | 0.74 |
| Triglycerides (mg/dl) | 112.0 ± 64.1 | 100.3 ± 46.3 | 0.14 |
| C-reactive protein (mg/L) | 0.98 (0.51–2.30) | 0.76 (0.37–1.69) | 0.13 |
| Coronary artery calcium score | 405 (91–911) | 1,140 (553–1,988) | <0.001 |
| Medications | |||
| Antihypertensive | 562 (54.0%) | 28 (73.7%) | 0.03 |
| Statins | 541 (52.0%) | 24 (63.2%) | 0.24 |
| Antidiabetic | 83 (8.0%) | 3 (7.9%) | 0.76 |
| Test indication | |||
| Angina | 1 (0.01%) | 6 (15.8%) | <0.001 |
| Chest pain, atypical | 156 (15.0%) | 6 (15.8%) | 0.66 |
| Abnormal/equivocal exercise treadmill test findings | 333 (32.0%) | 16 (42.1%) | 0.24 |
| Abnormal/equivocal myocardial perfusion test findings | 31 (3.0%) | 2 (5.3%) | 0.37 |
| Hypertension | 541 (52.0%) | 24 (63.2%) | 0.20 |
| Diabetes mellitus | 83 (8.0%) | 4 (10.5%) | 0.77 |
| Hyperlipidemia | 854 (82.0%) | 33 (86.8%) | 0.53 |
| Tobacco history | 427 (41.0% | 19 (50.0%) | 0.20 |
| Body mass index ≥30 kg/m 2 | 271 (26.0%) | 10 (26.3%) | 0.86 |
| Family history of heart disease | 364 (35.0%) | 19 (50.0%) | 0.09 |
| Atherosclerosis | 812 (78.0%) | 34 (89.5%) | 0.08 |
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