M. Gene Bond

Prevention Conference V Beyond Secondary Prevention : Identifying the High-Risk Patient for Primary Prevention : Noninvasive Tests of Atherosclerotic Burden : Writing Group III

Writing Group I of Prevention Conference V considered the role of routine office-based measures for assessing global risk in asymptomatic persons. With the physician-directed office risk assessment as a foundation, further risk stratification may be valuable, especially when the risk estimate is neither clearly low risk nor high risk (intermediate risk). For the intermediate-risk patient, further testing might include ≥1 noninvasive measure of atherosclerotic burden. Pathology studies have documented that levels of traditional risk factors are associated with the extent and severity of atherosclerosis. However, at every level of risk factor exposure, there is substantial variation in the amount of atherosclerosis. This variation in disease is probably due to genetic susceptibility; combinations and interactions with other risk factors, including life habits; duration of exposure to the specific level of the risk factors; and such factors as biological and laboratory variability. Thus, subclinical disease measurements, representing the end result of risk exposures, may be useful for improving coronary heart disease (CHD) risk prediction. Noninvasive tests such as carotid artery duplex scanning, electron beam–computed tomography (EBCT), ultrasound-based endothelial function studies, ankle/brachial blood pressure ratios, and magnetic resonance imaging (MRI) techniques offer the potential for directly or indirectly measuring and monitoring atherosclerosis in asymptomatic persons. High-sensitivity testing for C-reactive protein (hs-CRP) may also represent a measure of atherosclerosis “burden” and may therefore be considered another potential marker of atherosclerosis disease risk. The Prevention Conference V participants considered the status of several measures of subclinical disease in CHD risk assessment. The discussion that follows is a summary of the data reviewed and discussed at Prevention Conference V. During the discussion groups at Prevention Conference V, the ankle-brachial blood pressure index (ABI) was considered as a means of predicting CHD events. The ABI is a simple, inexpensive diagnostic test for lower-extremity peripheral arterial disease (PAD). …

pravastatin, Lipids, and Atherosclerosis in the Carotid Arteries (PlAC-II)

We randomized 151 coronary patients to placebo or pravastatin and treated them for 3 years. B-mode ultrasound quantification of carotid artery intimal-medial thickness (IMT) was obtained at baseline and sequentially during this period. The primary outcome was the change in the mean of the maximal IMT measurements across time. Effects on individual carotid artery segments (common, bifurcation, and internal carotid) and on clinical events were also investigated. Plasma concentrations of total cholesterol were lower with active treatment than with placebo (4.80 vs 6.07 mmol/L [186 vs 235 mg/dl], respectively) as were concentrations of low-density lipoprotein cholesterol (3.11 vs 4.30 mmol/L [120 vs 167 mg/dl], respectively). Plasma concentrations of high-density lipoprotein2 cholesterol were higher with active treatment (0.16 vs 0.14 mmol/L [6.1 vs 5.5 mg/dl], respectively). Active treatment resulted in a nonsignificant 12% reduction in progression of the mean-maximum IMT (from 0.068 to 0.059 mm/year) and a statistically significant 35% reduction in IMT progression in the common carotid. Active treatment was also associated with a reduction in fatal and nonfatal coronary events [corrected] (p = 0.09) and of any fatal event plus nonfatal myocardial infarction (p = 0.04).

Calcium Antagonist Lacidipine Slows Down Progression of Asymptomatic Carotid Atherosclerosis Principal Results of the European Lacidipine Study on Atherosclerosis (ELSA), a Randomized, Double-Blind, Long-Term Trial

Background—Most cardiovascular events associated with hypertension are complications of atherosclerosis. Some antihypertensive agents influence experimental models of atherosclerosis through mechanisms independent of blood pressure lowering. Methods and Results—The European Lacidipine Study on Atherosclerosis (ELSA) was a randomized, double-blind trial in 2334 patients with hypertension that compared the effects of a 4-year treatment based on either lacidipine or atenolol on an index of carotid atherosclerosis, the mean of the maximum intima-media thicknesses (IMT) in far walls of common carotids and bifurcations (CBMmax). This index has been shown by epidemiological studies to be predictive of cardiovascular events. A significant (P <0.0001) effect of lacidipine was found compared with atenolol, with a treatment difference in 4-year CBMmax progression of −0.0227 mm (intention-to-treat population) and −0.0281 mm (completers). The yearly IMT progression rate was 0.0145 mm/y in atenolol-treated and 0.0087 mm/y in lacidipine-treated patients (completers, 40% reduction;P =0.0073). Patients with plaque progression were significantly less common, and patients with plaque regression were significantly more common in the lacidipine group. Clinic blood pressure reductions were identical with both treatments, but 24-hour ambulatory systolic/diastolic blood pressure changes were greater with atenolol (−10/−9 mm Hg) than with lacidipine (−7/−5 mm Hg). No significant difference between treatments was found in any cardiovascular events, although the relative risk for stroke, major cardiovascular events, and mortality showed a trend favoring lacidipine. Conclusion—The greater efficacy of lacidipine on carotid IMT progression and number of plaques per patient, despite a smaller ambulatory blood pressure reduction, indicates an antiatherosclerotic action of lacidipine independent of its antihypertensive action.

Association of Coronary Disease With Segment-Specific Intimal-Medial Thickening of the Extracranial Carotid Artery

BACKGROUND Several investigators have evaluated relations between risk factors and intimal-medial thickness (IMT) of the extracranial carotid arteries and between IMT and clinical cardiovascular disease. Different indexes of IMT have been used as referents. We compared the strength of association of various IMT measurements with coronary artery disease as measured at coronary angiography. METHODS AND RESULTS We quantified the mean of the IMT for 12 sites of the extracranial carotid arteries (common carotid, bifurcation, internal carotid, near and far walls, and left and right sides [mean aggregate]) as well as for various combinations of sites (eg, segment-specific means, far walls only, maximum of any site) in 270 patients with or free of coronary artery disease. Models including age and all the indexes of IMT identified the mean aggregate as the only variable independently associated with the status of coronary atherosclerosis for the group as a whole. Next most strongly correlated was the mean common plus bifurcation. When classification algorithms were tested for ability to correctly classify case patients and control subjects, the mean bifurcation, mean common plus bifurcation, and mean aggregate were most strongly related to case-control status; however, the predictive power of the mean common was also strong. CONCLUSIONS These data support use of the mean aggregate extracranial carotid IMT for correlation with the status of coronary atherosclerosis; however, the data also support use of the mean common plus bifurcation, since there is little increase in predictive power of the mean aggregate over this index. Use of the common carotid alone is also justifiable and may be preferable for certain analyses.

Pravastatin reduces carotid intima-media thickness progression in an asymptomatic hypercholesterolemic Mediterranean population: The Carotid Atherosclerosis Italian Ultrasound Study

PURPOSE The Carotid Atherosclerosis Italian Ultrasound Study (CAIUS) was performed to test the effects of lipid lowering on the progression of carotid intima-media thickness (IMT) in 305 asymptomatic patients from a Mediterranean country. PATIENTS AND METHODS Eligibility included hypercholesterolemia (baseline means: low-density lipoprotein [LDL] = 4.68 mmol/L, high-density lipoprotein [HDL] = 1.37 mmol/L), and at least one 1.3 < IMT < 3.5 mm in the carotid arteries. Patients (mean age 55 years, 53% male) were assigned to pravastatin (40 mg/day, n = 151) or placebo (n not equal to 154). Ultrasound imaging was used to quantify IMT at baseline, and semiannually thereafter for up to 3 years. The mean of the 12 maximum IMTs (MMaxIMT), was calculated for each patient visit, and used to determine each patients longitudinal progression slope. The intention-to-treat group difference in the MMaxIMT progression was chosen a priori as the primary end point. RESULTS Five serious cardiovascular events (1 fatal myocardial infarction), and 7 drop-outs for cancer were registered. In the pravastatin group, LDL decreased -0.22 after 3 months versus -0.01 in the placebo group, and remained substantially unchanged afterward (-0.23 versus +0.01 at 36 months, respectively). Progression of the MMaxIMT was 0.009 +/- 0.0027 versus -0.0043 +/- 0.0028 mm/year (mean +/- SE, P < 0.0007) in the placebo and pravastatin groups, respectively. IMT progression slopes diverged after 6 months of treatment. CONCLUSIONS Pravastatin stops the progression of carotid IMT in asymptomatic, moderately hypercholesterolemic men and women. This finding extends the beneficial effects of cholesterol lowering to the primary prevention of atherosclerosis in a population with relatively low cardiovascular event rates, and suggests that this benefit is mediated by specific morphological effects on early stages of plaque development.

Impact of multiple coronary risk factors on the intima-media thickness of different segments of carotid artery in healthy young adults (The Bogalusa Heart Study)

Although risk factors for coronary artery disease are also associated with increased carotid artery intima-media thickness (IMT) as measured by B-mode ultrasonography in middle-aged and older persons, information on the impact of multiple risk factors on the IMT of different segments of the carotid artery in young adults is limited. This relation was examined in a sample of 518 black and white subjects (mean age 32 years; 71% white, 39% male) enrolled in the Bogalusa Heart Study. IMT was thicker and more skewed in the bulb compared with other carotid segments. Race differences (blacks more than whites) were noted for the common carotid (p <0.001) and carotid bulb (bifurcation) IMT (women only, p <0.001). Men had a greater IMT in the common carotid (p <0.05), internal carotid (p <0.05), and carotid bulb (whites only, p <0.001). In a multivariate analysis, systolic blood pressure, race, age, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol weree entered into a model in that order and accounted for the 16.7% variance in the common carotid IMT; age, systolic blood pressure, HDL cholesterol, LDL cholesterol, race, and insulin levels explained the 19.4% variance in the carotid bulb IMT. Gender and body mass index (BMI) accounted for the 4.7% variance in the internal carotid IMT. Increases in IMT with increasing number of risk factors (cigarette smoking, higher total cholesterol to HDL cholesterol ratio, higher systolic blood pressure, greater waist circumference, and higher insulin level) were noted for the common carotid and carotid bulb segments (p for trend <0.001 for both). The observed deleterious trend of increasing IMT at different carotid segments with increasing number of risk factors in free-living, asymptomatic young subjects underscores the importance of profiling multiple risk factors early in life. Ultrasonography of carotid arteries, especially at the bifurcation, may be helpful along with measurements of risk factors for evaluation of asymptomatic atherosclerotic disease.

Association of Obesity and Central Fat Distribution With Carotid Artery Wall Thickening in Middle-Aged Women

Background and Purpose— The association between obesity and atherosclerotic disease is controversial. In the present analysis, we evaluated whether common carotid intima-media thickness (IMT) and area, 2 markers of preclinical atherosclerosis, were increased in obese subjects. Methods— More than 5000 middle-aged women (n=5062; age, 30 to 69 years) living in the area of Naples, Southern Italy, were recruited for a prospective, currently ongoing study on the etiology of cardiovascular disease and cancer in the female population (the Progetto ATENA study). A subsample of 310 participants underwent high-resolution B-mode ultrasound examination, and the IMTs, intima-media areas, and lumen diameters of common carotid arteries were measured with a semiautomated computerized program. Subjects were divided into 3 groups on the basis of the recently published obesity guidelines for body mass index (BMI), a marker of general obesity, and tertiles of waist-to-hip ratio (WHR), a marker of regional obesity. Results— Women with a BMI ≥30 kg/m2 showed higher systolic and diastolic blood pressures, triglycerides, and fasting glucose and insulin, as well as lower high-density lipoprotein concentrations, than subjects with lower BMI. A gradual increase in common carotid IMT and intima-media area was observed when lean women (0.94±0.01 mm and 19.8±0.5 mm2, respectively) were compared with overweight (0.98±0.01 mm and 21.0±0.4 mm2) and obese (1.02±0.02 mm and 22.6±0.8 mm2, P <0.005 for linear trend) individuals. Similarly, women in the highest tertile of WHR (>0.85) had adverse risk factor profiles and thicker carotid intima-media complex than those in the first 2 tertiles (P <0.01 and P <0.05 for IMT and intima-media area, respectively). In multivariate analyses, BMI and WHR were significant predictors of carotid wall thickness, independently of other traditional and nontraditional cardiovascular risk factors (age, blood pressure, lipid abnormalities, fasting insulin). Conclusions— The present results indicate a graded and independent association between general and abdominal obesity—reflected by high BMI and WHR—and carotid artery wall thickening in a population of middle-aged women.

High-Resolution B-Mode Ultrasound Reading Methods in the Atherosclerosis Risk in Communities (ARIC) Cohort

To measure the association of cardiovascular disease risk factors with carotid artery diameter and thickness of the intima and media in the general population, standardized ultrasound scanning and reading protocols were performed on 15,800 individuals in the multicenter Atherosclerosis Risk in Communities (ARIC) Study. In a randomly selected subset of 855 participants, the mean artery diameter, minimum lumen diameter, and maximum near‐and far‐wall thicknesses were measured at a core laboratory from B‐mode image recordings of the common carotid, bifurcation, and internal carotid arteries to determine both within‐reader and between‐reader variability. Measurements associated with the wall thickness are sensitive indicators of reader reproducibility, with between‐reader reliability coefficients ranging from 0. 78 to 0.93 and coefficients of variation ranging from 13.1 to 18.3%. The percent of paired readings in the three carotid segments for which the absolute difference of the far‐wall thickness measured by different readers was no greater than one image pixel (0.067 mm) was 58% (common carotid), 53% (internal carotid), and 42% (bifurcation). Highly reproducible measurements of carotid artery dimensions can be achieved with standardized training and performance of ultrasound scanning and reading protocols.

Arterial abnormalities in the offspring of patients with premature myocardial infarction.

BACKGROUND Findings from epidemiologic and autopsy studies suggest that the offspring of patients with premature coronary disease may be at increased risk for atherosclerosis. We undertook a study to determine whether changes in brachial-artery reactivity and thickness of the carotid intima and media, two markers of early atherosclerosis, are present in adolescents and young adults with a parental history of premature myocardial infarction. METHODS We enrolled 40 healthy young people whose parents had had premature myocardial infarction (48 percent male; mean [+/-SD] age, 19.0+/-5.2 years) and 40 control subjects who were matched with the first group according to age and sex. All the subjects underwent high-resolution B-mode ultrasound examinations for the measurement of the brachial-artery vasodilatory response after arterial occlusion (i.e., reactive hyperemia) and the intima-media thickness of the distal common carotid arteries. Lipid profiles, blood pressure while at rest, body-mass index, and smoking status were also determined. RESULTS As compared with the control subjects, the offspring of patients with premature myocardial infarction had lower flow-mediated reactivity of the brachial arteries (5.7+/-5.0 percent, vs. 10.2+/-6.6 percent in the control subjects; P=0.001) and greater mean intima-media thickness of the common carotid artery (0.49+/-0.08 mm, vs. 0.44+/-0.07 mm in the control subjects, P=0.004). In the subjects with a parental history of premature myocardial infarction, an inverse association was found between brachial-artery reactivity and carotid intima-media thickness (r=-0.46, P=0.003). In a conditional logistic-regression analysis, both brachial-artery reactivity and carotid intima-media thickness were significantly and independently correlated with a parental history of premature myocardial infarction. CONCLUSIONS Structural and functional changes are present at an early age in the arteries of persons with a parental history of premature myocardial infarction.

Different effects of antihypertensive regimens based on fosinopril or hydrochlorothiazide with or without lipid lowering by pravastatin on progression of asymptomatic carotid atherosclerosis: Principal results of PHYLLIS - A randomized double-blind trial

Background and Purpose— The Plaque Hypertension Lipid-Lowering Italian Study (PHYLLIS) tested whether (1) the angiotensin-converting enzyme (ACE) inhibitor fosinopril (20 mg per day) was more effective on carotid atherosclerosis progression than the diuretic hydrochlorothiazide (25 mg per day), (2) pravastatin (40 mg per day) was more effective than placebo when added to either hydrochlorothiazide or fosinopril, and (3) there were additive effects of ACE inhibitor and lipid-lowering therapies. Methods— A total of 508 hypertensive, hypercholesterolemic patients with asymptomatic carotid atherosclerosis were randomized to: (A) hydrochlorothiazide; (B) fosinopril; (C) hydrochlorothiazide plus pravastatin; and (D) fosinopril plus pravastatin, and followed up blindly for 2.6 years. B-Mode carotid scans were performed yearly by certified sonographers in 13 hospitals and read centrally. Corrections for drift were calculated from readings repeated at study end. Primary outcome was change in mean maximum intima-media thickness of far and near walls of common carotids and bifurcations bilaterally (CBMmax). Results— CBMmax significantly progressed (0.010±0.004 mm per year; P=0.01) in group A (hydrochlorothiazide alone) but not in groups B, C, and D. CBMmax changes in groups B, C, and D were significantly different from changes in group A. Changes in group A were concentrated at the bifurcations. “Clinic” and “ambulatory” blood pressure reductions were not significantly different between groups, but total and low-density lipoprotein cholesterol decreased by ≈1 mmol/L in groups C and D. Conclusions— Progression of carotid atherosclerosis occurred with hydrochlorothiazide but not with fosinopril. Progression could also be avoided by associating pravastatin with hydrochlorothiazide.