The impact of cardiovascular risk factors on subclinical left main coronary artery disease: An intravascular ultrasound study
Article Outline
Background
The impact of cardiovascular risk factors on subclinical but measurable left main coronary artery (LMCA) atherosclerosis is not well known.
Methods
We analyzed 150 consecutive patients with first-time coronary artery disease presentation undergoing intervention of a left anterior descending coronary artery or left circumflex lesion with motorized intravascular ultrasound transducer pullback that included a nonstenotic LMCA. Framingham, PROCAM, and European SCORE risk assessments were determined in 107 patients <65 years of age (because the Framingham, PROCAM, and European SCORE studies excluded patients >65 years old). Intravascular ultrasound measurements were compared in patients with <10% vs 10% to 20% risk of events.
Results
Plaque volumes were greater in patients with higher risk scores: P = .007 in patients with 10% to 20% PROCAM risk, P = .063 in patients with 10% to 20% Framingham risk, and P = .059 in patients with 10% to 20% SCORE risk (P = .059). The mean arc of LMCA calcium (12° ± 25° overall) correlated with plaque volume (51 ± 28 mm3, r = 0.30, P = .0001) and with the number of coronary risk factors (P = .048) and ranged from 0.28° ± 0.74° in patients with 0 to 1 risk factors to 9.95° ± 21.55° in patients with 2 to 4 risk factors to 19.38° ± 32.51° in patients with 5 to 7 risk factors. Regression analysis showed obesity and age were the most important factors contributing to LMCA calcium.
Conclusion
Intravascular ultrasound measurable atherosclerosis in nonstenotic LMCA correlates with conventional primary coronary risk scores. Left main coronary artery calcium correlates both with LMCA plaque volume and risk factors. Thus, subclinical LMCA atherosclerosis may be a marker for events that are predicted by commonly used primary risk-assessment algorithms.
The left main coronary artery (LMCA) may be the most important site of coronary atherosclerosis from the standpoint of clinical events.1, 2, 3, 4, 5, 6, 7, 8 Risk scores from the European SCORE Project,9 the German PROCAM Study,10 and the US Framingham Heart and Offspring Studies11 were developed with an eye for primary prevention and have been shown to predict hard events (ie, cardiac death, myocardial infarction, etc). Recently, these 3 established, primary prevention risk score algorithms were correlated with LMCA plaque progression, as measured by serial intravascular ultrasound (IVUS).12
Coronary artery calcium (CAC) is another predictor of cardiac events.13, 14 It correlates with the extent and severity of atherosclerosis; increasing patient age; and the presence of primary or secondary chronic hypercalcemia, hyperlipidemia, chronic renal insufficiency, or obesity.15, 16, 17, 18, 19, 20, 21, 22, 23, 24 That significant left main disease correlates with future events in these studies, however, is not proof that it causes these events.
The goal of the current study used IVUS (1) to compare LMCA atherosclerosis versus primary-event risk scores, (2) to assess the factors responsible for measurable coronary artery atherosclerosis, and (3) to evaluate the relationship between these risk factors and coronary calcification.
Methods
Study population
We evaluated 150 consecutive patients undergoing a first intervention of a left anterior descending coronary artery or left circumflex lesion with motorized IVUS transducer pullback that included a nonintervened, nonstenotic LMCA. All patients met the following criteria: (1) imaging of an entire left main artery that was at least 4 mm in length, (2) no evidence of significant left main disease (angiographic lumen diameter stenosis <50% by “worst view” visual assessment), and (3) calcifications that did not limit quantitative assessment of vessel cross-sectional area (CSA).
Cardiovascular risk factors
Standard coronary risk factors were collected including age, sex, hypertension (medication-treated only), diabetes mellitus (known diabetes or repeated fasting blood glucose levels >120 gm/dL), hypercholesterolemia (medication treated or a measured >240 mg/dL), current smoking (past 12 months), and family history of coronary artery disease (myocardial infarction of first-degree relative <60 years of age). Body mass index (BMI) was calculated from a person's weight in kilograms divided by height in meters squared (BMI = kg/m2), as recommended by the World Health Organization Expert Committee.25 Obesity was defined as BMI ≥30 kg/m2. Baseline laboratory tests were performed in all patients and were analyzed in the clinical laboratory of Washington Hospital Center according to international standards. Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol (LDLC), high-density lipoprotein cholesterol (HDLC), and triglycerides were measured using standard enzymatic methods. Medications were also tabulated.
Cardiovascular risk assessment
PROCAM scoreThe PROCAM score was evaluated as previously described10 using sex, age, LDLC, HDLC, triglycerides, systolic blood pressure, smoking, diabetes mellitus, and family history. The categories for continuous variables of age, systolic blood pressure, LDLC, and HDLC were based on the National Cholesterol Education Program III guidelines26; the categories for triglycerides were based on the guidelines of the International Task Force for Prevention of coronary heart disease.27 For each patient, 10-year risk of coronary events (fatal/nonfatal myocardial infarction, or sudden death) was predicted.
SCORE risk scoreThe SCORE risk was determined from a risk assessment algorithm previously described.9 The SCORE risk assessment system considers sex, age, total cholesterol, systolic blood pressure, and smoking. We used the table for populations at high cardiovascular disease risk, based on total cholesterol/HDLC levels.
Framingham risk scoreThe Framingham score was calculated using an algorithm previously described26 and considers sex, age, total cholesterol, HDLC, systolic blood pressure, and smoking. The Framingham score is based on data from a sample of the Framingham Heart and Offspring studies.11 It was used to predict the 10-year risk of coronary events (fatal/nonfatal myocardial infarction or sudden death).
IVUS imaging and analysis
All IVUS examinations were performed before any intervention and after intracoronary administration of 200 μg of nitroglycerin using a commercially available IVUS system (Boston Scientific Corporation/SCIMED, Maple Grove, MN) and either 30- or 40-Mhz transducers. The IVUS catheter was advanced distal to the target lesion, and imaging was performed retrograde back to the aorto-ostial junction at an automatic pullback speed of 0.5 mm/s.
Standard IVUS measures were performed each 1 mm within the LMCA; volumes were calculated using Simpson's rule. The distal end of LMCA was the first (distal-most) image slice in which the contralateral vessel (ie, the left circumflex, if the IVUS catheter was positioned in the left anterior descending artery) was no longer seen. The proximal end of the LMCA was the last (proximal most) image slice in which the entire circumference of the LMCA was seen just before the entering the aorta. Qualitative analysis was performed according to criteria of the American College of Cardiology clinical expert consensus document on IVUS.28 Using planimetry software (TapeMeasure, INDEC Systems Inc, Mountain View, CA), we measured external elastic membrane (EEM) CSA and lumen CSA. Plaque and media CSA was calculated as EEM CSA minus lumen CSA. The EEM CSA is measured by tracing the leading edge of the adventitia. Plaque and media CSA was used as a measure of atherosclerotic plaque.
Calcium was brighter than the adventitia with acoustic shadowing. Plaque calcification of the LMCA was measured with an electronic protractor centered on the lumen. If there was >1 deposit of calcium per image slice, the total arc of lesion calcium for the image slice was obtained by adding the arcs of each individual deposit. The mean arc of calcium within the LMCA was obtained by adding the total arcs of calcium divided by the number of IVUS image slices.
Statistics
Statistical analysis was performed using the SPSS statistical package, version 13.0 (SPSS Inc, Chicago, IL). Continuous variables are presented as the mean value ± 1 SD and compared using Student t test. Discrete variables are presented as percentages or relative frequencies and compared using χ2 statistics. Multiple linear regression analysis was used to identify independent clinical predictors of CAC. P <. 05 was considered statistically significant.
Results
Clinical findings
Demographics and clinical characteristics are shown in Table I, Table II. Forty-three patients were >65 years of age; because published risk scores were not validated on patients >65 years old, these patients were excluded from the comparison of risk scores versus measured atherosclerosis. Therefore, 107 patients <65 years of age were analyzed for the relationship between LMCA disease and the 3 risk scores. There were 74 men and 33 women with a mean patient age of 55.0 ± 6.7 years. Twenty-nine patients (27%) were diabetic, 77 (72%) were hypertensive, and 87 (81%) had hypercholesterolemia.
Table I. Clinical demographics
| Age (y) | 55 ± 6.7 |
| Male sex (%) | 74 (69) |
| Diabetes mellitus (%) | 29 (27) |
| Hypertension(%) | 77 (72) |
| Smoker (%) | 33 (31) |
| Hypercholesterolemia (%) | 87 (81) |
| Family history of coronary disease (%) | 66 (61) |
| Previous myocardial infarction (%) | 36 (33) |
| Systolic blood pressure (mm Hg) | 124 ± 13 |
| BMI (kg/m2) | 29 ± 6.7 |
| Total cholesterol (mg/dL) | 187 ± 43 |
| LDLC (mg/dL) | 112 ± 39 |
| HDL-cholesterol (mg/dL) | 42 ± 11 |
| Triglyceride (mg/dL) | 186 ± 118 |
| No. of vessels diseased (%) | |
 1-Vessel disease | 38 (35) |
| 2-Vessel disease | 39 (36) |
| 3-Vessel disease | 30 (29) |
| Clinical syndrome | |
| Stable angina | 26 (25) |
| Unstable angina | 65 (61) |
| Acute myocardial infarction | 16 (14) |
Table II. Medication
| Medication | (n = 107) |
|---|---|
| Acetylsalicylic acid (%) | 106 (99) |
| Angiotensin-converting enzyme inhibitors (%) | 58 (54) |
| β-Blockers (%) | 85 (79) |
| Calcium-channel blockers (%) | 17 (16) |
| Diuretics (%) | 23 (21) |
| Fibrates (%) | 2 (2) |
| Insulin (%) | 8 (7) |
| Nitrates (%) | 23 (21) |
| Oral hypoglycemic agent (%) | 21 (19) |
| Statins (%) | 98 (92) |
Risk scores versus LMCA plaque mass
As shown in Table III, plaque volumes were greater in patients with a higher risk score (10%-20%), compared to <10% risk of events: P = .007 using the PROCAM risk score, P = .063 in the patients with a 10% to 20% using the Framingham risk score, and P = .059 according to the SCORE risk (Figure 1). External elastic membrane and lumen volumes and LMCA lengths were similar in relatively higher-versus relatively lower-risk patients.
Table III. Risk scores and IVUS analyses
| Framingham | PROCAM | SCORE | ||||
|---|---|---|---|---|---|---|
| <10% (n = 57) | 10-20% (n = 46) | <10% (n = 80) | 10-20%(n = 20) | <10%(n = 101) | 10-20%(n = 6) | |
| Length (mm) | 7.45 ± 3.20 | 8.26 ± 3.54 | 7.3 ± 2.88 | 9.3 ± 4.01 | 7.69 ± 3.35 | 8.16 ± 3.31 |
| EEM volume (mm3) | 152 ± 85 | 175 ± 74 | 152 ± 78 | 189 ± 72 | 159 ± 79 | 192 ± 75 |
| Plaque volume (mm3) | 44 ± 28 | 54 ± 25 | 44 ± 26 | 62 ± 23⁎ | 47 ± 26 | 69 ± 26 |
| Lumen volume (mm3) | 108 ± 63 | 121 ± 56 | 108 ± 59 | 127 ± 55 | 112 ± 59 | 123 ± 55 |
⁎P < .05. |
Figure 1.
The change of plaque volume depends on clinical risk score. Left main coronary artery plaque volume is larger in patients with higher risk scores.
Calcium deposition versus plaque mass
The relation between mean calcium arc and plaque volume is shown in Figure 2. The mean arc of LMCA calcification (12° ± 25° overall) correlated with LMCA plaque volume (51 ± 28 mm3, r = 0.30, P = .0001). No patient had to be excluded because of LMCA calcification severity.
Figure 2.
The correlation between LMCA plaque volume and mean LMCA calcium arc.
The relationship of mean LMCA calcium arc to individual risk factors is shown in Table IV. The extents of LMCA calcium correlated with the number of coronary risk factors (P = .048) and ranged from 0.28° ± 0.74° in patients with 0 to 1 risk factors to 9.95° ± 21.55° in patients with 2 to 4 risk factors to 19.38° ± 32.51° in patients with 5 to 7 risk factors. Of the clinical risk factors, linear regression analysis identified obesity and age to be the most important factors contributing to the mean arc of LMCA calcium (Table IV).
Table IV. The clinical risk factors and coronary calcification
| Risk factors | P |
|---|---|
| Age ≥59 y (59%) | .047 |
| Male sex (69%) | .272 |
| Diabetes mellitus (29%) | .31 |
| Hypertension (72%) | .273 |
| Current smoker (25%) | .785 |
| Hypercholesterolemia (79%) | .925 |
| Obesity (40%) | .004 |
| Family history (55%) | .137 |
| Prior myocardial infarction (33%) | .399 |
Discussion
Significant LMCA disease is known to have a poor long-term prognosis.1, 2, 3, 4 But the clinical significance of subclinical LMCA disease has been undervalued. Even when it is angiographically silent, LMCA disease detected by IVUS is an independent predictor of cardiac events.4, 7 Furthermore, necropsy studies have shown that the severity of coronary artery stenoses in mildly (angiographically) diseased arteries may be underestimated, especially in the LMCA.29, 30 The presence of diabetes mellitus has a strong additive impact on prognosis.4 Studies have shown that LMCA disease has a poor prognosis, in part, because it is related to a high frequency of coexisting disease elsewhere in the coronary tree.1, 2, 31
Guidelines on coronary disease prevention use the predicted 10-year risk of coronary events to identify candidates for risk factor modification.26, 32, 33, 34 The current study indicates that these published risk scores correlate with the LMCA plaque mass measured at the first clinical presentation of coronary disease, further justifying their use.
Risk assessments in LMCA
The risk-scoring methods studied in the current report were derived from the European SCORE Project,9 the German PROCAM Study,10 and the US Framingham Heart and Offspring Studies.11 von Birgelen et al12 correlated these risk scores, not with baseline LMCA disease but with LMCA disease progression, as assessed by IVUS. For all 3 algorithms, patients at highest estimated risk of events showed greatest plaque progression and lumen decreaser, as measured with serial IVUS. Importantly, the risk of clinical events not related to the LMCA had a positive linear relationship with plaque progression (r = .41-0.60; P < .002 to <.0001); patients with adverse events (n = 18) had more annual plaque and media CSA progression than the rest of the population (25.2% ± 19.4% vs 5.9% ± 15.6%, P < .001). The present study extends the findings of von Birgelen et al by also relating these risk scores to the baseline LMCA plaque volume at the time of first clinical presentation. Plaque volumes were significantly greater in patients with higher risk scores whether using the PROCAM, SCORE, or Framingham analyses. However, it is difficult to directly compare the 3 risk scores because they studied different populations and used different end points (risk of cardiac events vs cardiovascular mortality; fatal vs combined fatal and nonfatal end points, etc).
Risk factors and LMCA calcification
Intravascular ultrasound analyses have shown that CAC can be detected in >70% of lesions.13 The presence and extent of CAC is associated with a worse prognosis.14 Previous IVUS and other studies have shown that lesion-associated CAC increases with the extent and severity of atherosclerosis; increasing patient age; and the presence of primary or secondary chronic hypercalcemia, hyperlipidemia, chronic renal insufficiency, or obesity.15, 16, 17, 18, 19, 20, 21, 22, 23, 24 Prior IVUS analysis showed that CAC correlated with plaque burden but not with degree of lumen compromise.
Noninvasive detection of CAC is also predictive of future cardiac events.35 The presence of CAC provides incremental prognostic information in addition to age and other risk factors. Kondos et al16 reported that cardiac events were significantly associated with the presence of CAC. In men, events were associated with the presence of CAC (relative risk [RR] 10.5, P < .001), diabetes (RR 1.98, P = .008), and smoking (RR 1.4, P = .025), whereas in women, events were linked to the presence of CAC (RR 2.6, P = .037) alone and not the other risk factors. The presence of any CAC (a total calcium score of >0) and increasing score quartiles were related to the occurrence of new myocardial infarction, the need for revascularization, and total cardiovascular events. Those with scores at or above the median (score of 5) had a relative risk of 4.5 (P < .01) for new events.17 Abizaid et al4 described that patients with cardiac events had larger arcs of LMCA calcium than in patients without event.
The current study extends the results of these previous reports by showing that the mean arc of LMCA calcium had a positive correlation with (1) LMCA plaque volume and (2) the number of coronary risk factors—in particular, patient age and obesity. There are only a few reports about the relation between CAC and obesity. Beddhu36 reported that obesity (high BMI, high fat mass) is associated with inflammation and atherosclerosis. Underlying risk factors were incrementally associated with advanced CAC in low- and intermediate-risk individuals23; and obesity was associated with increased progression of CAC in patients at a lower risk of coronary heart disease.24 Asymptomatic individuals with insulin resistance have elevated coronary calcium scores. The association between insulin resistance and coronary calcification persists with impaired glucose tolerance and normal fasting serum glucose. Central/visceral adiposity may be a determinant of insulin resistance and atherosclerosis even in asymptomatic nondiabetic persons37 In the current study, despite its relationship to coronary disease mortality, chronic renal insufficiency was not tested because it was not included in the various risk factor models.
Limitation
This study was a retrospective analysis of consecutively imaged patients who underwent intervention of an left anterior descending coronary artery or left circumflex lesion. We cannot assess the effects of medication because most of the patients were being treated with statins at the time of imaging. Some LMCA were excluded because the size was larger than the IVUS region of interest. The correlation between left main coronary plaque volume and mean calcium is statistically significant, but an r value was not high.
Conclusions
Intravascular ultrasound measurable atherosclerosis in nonstenotic LMCAs correlated with conventional primary coronary risk scores, and LMCA calcification correlated both with LMCA plaque volume and with coronary risk factors. This may help to explain the relationship of risk analysis (including published primary risk scores and coronary calcification) and clinical events.
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PII: S0002-8703(06)00663-6
doi:10.1016/j.ahj.2006.07.012
© 2006 Mosby, Inc. All rights reserved.
