Background
Worldwide, cardiovascular (CV) disease remains the most common cause of morbidity and mortality. Although effective in predicting CV risk in select populations, the Framingham risk score (FRS) fails to identify many young individuals who experience premature CV events. Accordingly, the aim of this study was to determine the prevalence of high-risk carotid intima-media thickness (CIMT) or plaque, a marker of atherosclerosis and predictor of CV events, in young asymptomatic individuals with low and intermediate FRS (<2% annualized event rate) using the carotid ultrasound protocol recommended by the American Society of Echocardiography and the Society of Vascular Medicine.
Methods
Individuals aged ≤ 65 years not taking statins and without diabetes mellitus or histories of coronary artery disease underwent CIMT and plaque examination for primary prevention. Clinical variables including lipid values, family history of premature coronary artery disease, and FRS and subsequent pharmacotherapy recommendations were retrospectively collected for statistical analysis.
Results
Of 441 subjects (mean age, 49.7 ± 7.9 years), 184 (42%; 95% confidence interval, 37.3%-46.5%) had high-risk carotid ultrasound findings (CIMT ≥ 75th percentile adjusted for age, gender, and race or presence of plaque). Of those with the lowest FRS of ≤5% (n = 336) (mean age, 48.0 ± 7.6 years; mean FRS, 2.5 ± 1.5%), 127 (38%; 95% confidence interval, 32.6%-43.0%) had high-risk carotid ultrasound findings. For individuals with FRS ≤ 5% and high-risk carotid ultrasound findings (n = 127; mean age, 47.3 ± 8.1 years; mean FRS, 2.5 ± 1.5%), lipid-lowering therapy was recommended by their treating physicians in 77 (61%).
Conclusions
Thirty-eight percent of asymptomatic young to middle-aged individuals with FRS ≤ 5% have abnormal carotid ultrasound findings associated with increased risk for CV events. Pharmacologic therapy for CV prevention was recommended in the majority of these individuals. The lack of radiation exposure, relatively low cost, and ability to detect early-stage atherosclerosis suggest that carotid ultrasound for CIMT and plaque detection should continue to be explored as a primary tool for CV risk stratification in young to middle-aged adults with low FRS.
Worldwide, cardiovascular (CV) disease remains the most common cause of morbidity and mortality. Fortunately, preventive strategies are effective at decreasing CV events and mortality in those at highest risk. Because atherosclerosis begins early in life and can progress silently over decades, there has been great interest in identifying asymptomatic high-risk individuals before an acute and sometimes fatal CV event occurs. Population-based risk algorithms, such as the Framingham risk score (FRS), are the primary tools recommended by preventive guidelines to identify at-risk individuals and determine the aggressiveness of preventive therapy. However, these population-based risk algorithms may not include all of the relevant risk factors for each individual patient. For example, the FRS does not incorporate variables such as family history of premature coronary artery disease, remote smoking history, waist circumference, impaired fasting glucose, and triglyceride levels. Population-based risk algorithms also do not quantify atherosclerosis but only provide a probability of CV events over a fixed, usually relatively short (<10 years) time period. This information is very useful in the epidemiology of large populations but has limitations in predicting CV risk in individuals.
Because of these limitations, tests for subclinical atherosclerosis in select individuals have been recommended to add incremental information for more accurate risk stratification. A recently published study of the Coronary Artery Risk Development in Young Adults (CARDIA) and Multi-Ethnic Study of Atherosclerosis (MESA) populations supports this assertion, demonstrating a greater subclinical atherosclerotic burden in those with low 10-year but high lifetime risk for CV disease compared with those with low lifetime risk. The two most commonly used tests are the computed tomographic coronary artery calcium score (CTCS) and carotid ultrasound for the determination of carotid intima-media thickness (CIMT) and the detection of plaque. Both studies are able to detect subclinical atherosclerosis and are independently predictive of future adverse CV events. The advantage of the CTCS is that it correlates directly with coronary artery plaque burden and when positive is a predictor of short-term risk for myocardial infarction. The disadvantage is that it requires ionizing radiation and may be falsely negative in younger individuals whose soft plaque has not yet calcified. Carotid ultrasound may be a more sensitive detector of atherosclerosis in younger adults and does not result in radiation exposure.
In the current study, we tested the hypothesis that a significant number of patients with low (≤5% 10-year risk for first CV event) and intermediate (6%-20% 10-year risk) FRS have increased CV disease risk as determined by carotid plaque or abnormally thickened CIMT. We also evaluated subsequent pharmacologic CV preventive recommendations in these individuals in a primarily internal medicine and family medicine practice.
Methods
Patient Selection
Upon obtaining approval from the Mayo Clinic Institutional Review Board, the medical records of all 688 patients at our institution who underwent CIMT examinations between January 1, 2007, and December 31, 2008, were retrospectively reviewed. Clinical data were collected from the electronic medical records and an FRS was calculated for each subject. Subjects aged > 65 years, those with diabetes mellitus, those with histories of coronary artery disease, and those with incomplete clinical data were excluded from the study (n = 99). No patients had histories of either peripheral vascular or cerebrovascular disease. Furthermore, subjects who were on statin therapy at the time of carotid ultrasound were also excluded (n = 148). The medical records were reviewed to determine referring physicians’ recommendations to patients on the basis of the results of carotid ultrasound examinations. The majority of treating physicians were internists, family physicians, and cardiologists not trained in CIMT interpretation. Patients were referred for CIMT at the discretion of their treating physicians to determine their CV risk.
Carotid Ultrasound
Carotid artery imaging was performed using a Siemens Sequoia ultrasound system with an 8-MHz to 15-MHz linear-array transducer (Siemens Medical Solutions, Mountain View, CA). The protocol used was as recommended by the American Society of Echocardiography and the Society of Vascular Medicine. A depth of 4 cm was used. The examination included a thorough scan of the extracranial carotid arteries for the presence of carotid plaque, defined as focal wall thickening that was ≥50% greater than that of the surrounding vessel wall and CIMT > 1.5 mm ( Figure 1 ). In the absence of identified plaque, CIMT measurements were made of the distal 1 cm of the far wall of the common carotid artery using the Syngo Arterial Health semiautomated border detection program (Siemens Medical Solutions). The best image of the distal 1 cm of the common carotid artery far wall was selected from each of 3 scan planes. A mean value of CIMT was calculated on the basis of 3 separate measures of intima-media thickness on R wave–gated still frames from each of 3 scan planes: anterior, lateral, and posterior from both the right and left common carotid arteries (18 total measurements). Using data from the Athero-sclerosis Risk in Communities (ARIC) study, the composite mean CIMT from the left and right common carotid arteries was used to calculate an age-matched, sex-matched, and race-matched percentile for those individuals aged 40 to 65 years. For individuals aged < 40 years, data from the Bogalusa Heart Study were used to determine quartiles (on the basis of mean-maximum CIMT per Bogalusa Heart Study protocol). When the quartile was discrepant between the right and left common carotid arteries, the highest quartile was assigned. High-risk CIMT was defined as either the presence of plaque or CIMT ≥ 75th percentile for age, race, and gender ( Figure 2 ).
Statistical Methods
Data are summarized as mean ± SD or as frequencies and percentages. For independent groups, the χ 2 test was used to compare categorical variables, while Student’s t test was used for continuous variables. A 95% confidence interval (CI) for the proportion of subjects with atherosclerosis by carotid examination was calculated using the exact binomial method. Interobserver variability was calculated as the absolute difference of the corresponding pair of repeated measurements in percentage of their mean in each patient and then averaged for 18 randomly selected patients.
Results
Subjects (n = 441) had an average age of 49.7 ± 7.9 years, and there was a predominance of men (70%). The average FRS was 4.5 ± 4.2%. Of these subjects, 184 (42%; 95% CI, 37.3%-46.5%) had high-risk carotid ultrasound results; 90 (20%) had carotid plaque and 94 (21%) had CIMT ≥ 75th percentile for age-matched, gender-matched, and race-matched controls. The average body mass index was 27.5 ± 5.3 kg/m 2 , 59 subjects (13%) had family histories of premature coronary artery disease, 34 (8%) were actively smoking cigarettes, 73 (17%) had hypertension, and 169 (38%) had hyperlipidemia ( Table 1 ).
| Variable | Value |
|---|---|
| Age (y) | 49.7 ± 7.9 |
| Men | 310 (70.3%) |
| BMI (kg/m 2 ) | 27.5 ± 5.3 |
| Family history of premature CAD | 59 (13.4%) |
| Current cigarette smoking | 34 (7.7%) |
| Hypertension | 73 (16.6%) |
| Total cholesterol (mg/dL) | 212 ± 42 |
| Triglycerides (mg/dL) | 128 ± 85 |
| HDL (mg/dL) | 57 ± 18 |
| LDL (mg/dL) | 131 ± 38 |
| FRS (%) | 4.5 ± 4.2 |
| FRS ≤ 5% | 336 (76.2%) |
| FRS > 6% | 106 (24.0%) |
| CIMT imaging | |
| CIMT < 75th percentile | 257 (58.3%) |
| High-risk CIMT | 184 (42.0%) |
| Carotid plaque present (>1.5 mm) | 90 (20.4%) |
| Carotid plaque absent but CIMT ≥ 75th percentile | 94 (21.3%) |
Subjects with FRS ≤ 5% (n = 336) had an average age of 48.0 ± 7.6 years; 125 (37%) were women, and the average FRS was 2.5 ± 1.5%. Among this group, 127 (38%; 95% CI, 32.6%-43.0%) had high-risk carotid ultrasound results; 58 (17%) had carotid plaque and 69 (21%) had CIMT ≥ 75th percentile for age-matched, gender-matched, and race-matched controls. The average body mass index was 27.1 ± 5.1 kg/m 2 , 46 subjects (14%) had family histories of premature coronary artery disease, 11 (3%) were actively smoking cigarettes, 46 (14%) had hypertension, and 125 (37%) had hyperlipidemia ( Table 2 ).
| Variable | Low FRS (≤5%) | Higher FRS (>5%) |
|---|---|---|
| Number | 336 (76.0%) | 105 (23.8%) |
| Age (y) | 48.0 ± 7.6 | 55.2 ± 7.1 |
| Men | 125 (62.7%) | 99 (94.3%) |
| BMI (kg/m 2 ) | 27.1 ± 5.1 | 28.8 ± 4.9 |
| Family history of premature CAD | 46 (13.7%) | 13 (12.4%) |
| Current cigarette smoking | 11 (3.3%) | 23 (9.5%) |
| Hypertension | 46 (13.7%) | 26 (24.8%) |
| Total cholesterol (mg/dL) | 209 ± 41 | 222 ± 42 |
| Triglycerides (mg/dL) | 121 ± 90 | 152 ± 74 |
| HDL (mg/dL) | 59 ± 18 | 50 ± 13 |
| LDL (mg/dL) | 128 ± 40 | 141 ± 37 |
| FRS (%) | 2.5 ± 1.5 | 10.1 ± 4.3 |
| FRS 6%-10% | 0 (0%) | 65 (61.9%) |
| FRS > 10% | 0 (0%) | 40 (38.1%) |
| CIMT imaging | ||
| CIMT < 75th percentile | 209 ∗ (62.2%) | 48 ∗ (45.7%) |
| High-risk CIMT | 127 ∗ (37.8%) | 57 ∗ (54.3%) |
| Carotid plaque present (>1.5 mm) | 58 (17.3%) | 32 (30.4%) |
| Carotid plaque absent but CIMT ≥ 75th percentile | 69 (20.5%) | 25 (23.8%) |
The low-FRS (≤5%) groups with and without high-risk carotid ultrasound findings had similar characteristics, with the exception of baseline total cholesterol and low-density lipoprotein values ( Table 3 ). Subjects with FRS ≤ 5% and high-risk carotid ultrasound findings (either presence of plaque or CIMT ≥ 75th percentile; n = 127) had an average age of 47.3 ± 8.1 years and an average FRS of 2.5 ± 1.5%. Following high-risk carotid ultrasound examinations, 58 patients (46%) were recommended the initiation of statin therapy, and 19 (15%) were recommended the initiation of other lipid-lowering therapy (omega-3 fatty acids or niacin). Thirty-four subjects (27%) were recommended the initiation of low-dose aspirin therapy (81 mg/d), and 25 (20%) were already taking aspirin at the time of carotid ultrasound examinations. Thirty-eight patients (30%) were not asked to modify their pharmacologic regimens following carotid ultrasound examinations. Of 155 individuals with CIMT < 50th percentile for age, gender, and race, 12 (8%) were recommended the initiation of statin therapy, and 13 (9%) were started on low-dose aspirin after CIMT was assessed. Patients with CIMT > 75th percentile were more likely to be started on statin therapy than those with CIMT < 50th percentile (46% vs 8%, P < .001; Table 3 ).
| CIMT < 75th percentile | CIMT ≥ 75th percentile or plaque | ||
|---|---|---|---|
| Variable | (n = 209) | (n = 127) | P |
| Age (y) | 48.6 ± 7.1 | 47.3 ± 8.1 | .11 |
| Women | 78 (37%) | 47 (37%) | 1.00 |
| FRS ≤ 5% | 209 (100%) | 127 (100%) | 1.00 |
| BMI (kg/m 2 ) | 27.3 ± 4.9 | 26.7 ± 6.0 | .36 |
| Family history of premature CAD | 25 (12%) | 21 (17%) | .25 |
| Current cigarette smoking | 9 (4%) | 2 (2%) | .22 |
| Hypertension | 27 (13%) | 19 (15%) | .63 |
| Hyperlipidemia | 74 (35%) | 51 (40%) | .15 |
| FRS (%) | 2.5 ± 1.4 | 2.5 ± 1.5 | .79 |
| Total cholesterol (mg/dL) | 204 ± 40 | 217 ± 43 | .003 |
| Triglycerides (mg/dL) | 115 ± 77 | 131 ± 100 | .18 |
| HDL (mg/dL) | 58 ± 17 | 59 ± 20 | .60 |
| LDL (mg/dL) | 125 ± 39 | 133 ± 36 | .04 |
| Statin initiation recommended | — | 58 (46%) | — |
| Other lipid-lowering therapy recommended | — | 19 (15%) | — |
| Aspirin initiation recommended | — | 34 (27%) | — |
| Already taking aspirin | — | 25 (20%) | — |
Subjects with FRS > 6% (n = 105) had an average age of 55.2 ± 7.1 years and an average FRS of 10.1 ± 4.3%. Of these, 57 (54%) had high-risk carotid ultrasound findings, with 32 (30%) having plaque and 25 (24%) having CIMT ≥ 75th percentile. There were 26 patients with CIMT < 50th percentile than would be expected for their age, gender, and race. Table 2 lists detailed characteristics of this group. A higher proportion of subjects with intermediate FRS had high-risk carotid ultrasound findings (62%) compared with subjects with low FRS (43%) ( P = .003; Figure 3 ).
Carotid Ultrasound Findings and Gender
Table 4 summarizes characteristics of men and women who underwent CIMT examinations. The populations were different with respect to many clinical variables (men were younger, had higher body mass indexes, had a lower prevalence of family history of premature coronary artery disease, had lower total cholesterol and high-density lipoprotein, and had higher FRS), but there was no significant difference in the prevalence of high-risk carotid ultrasound findings, CIMT > 75th percentile, or plaque between men and women.
