Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, double-blind trial.

BACKGROUND: Patients with mixed dyslipidaemia have raised triglycerides, low high-density lipoprotein (HDL) cholesterol, and high low-density lipoprotein (LDL) cholesterol. Augmentation of HDL cholesterol by inhibition of the cholesteryl ester transfer protein (CETP) could benefit these patients. We aimed to investigate the effect of the CETP inhibitor, torcetrapib, on carotid atherosclerosis progression in patients with mixed dyslipidaemia. METHODS: We did a randomised double-blind trial at 64 centres in North America and Europe. 752 eligible participants completed an atorvastatin-only run-in period for dose titration, after which they all continued to receive atorvastatin at the titrated dose. 377 of these patients were randomly assigned to receive 60 mg of torcetrapib per day and 375 to placebo. We made carotid ultrasound images at baseline and at 6-month intervals for 24 months. The primary endpoint was the yearly rate of change in the maximum intima-media thickness of 12 carotid segments. Analysis was restricted to 683 patients who had at least one dose of treatment and had at least one follow-up carotid intima-media measurement; they were analysed as randomised. Mean follow-up for these patients was 22 (SD 4.8) months. This trial is registered with ClinicalTrials.gov, number NCT00134238. FINDINGS: The change in maximum carotid intima-media thickness was 0.025 (SD 0.005) mm per year in patients given torcetrapib with atorvastatin and 0.030 (0.005) mm per year in those given atorvastatin alone (difference -0.005 mm per year, 95% CI -0.018 to 0.008, p=0.46). Patients in the combined-treatment group had a 63.4% relative increase in HDL cholesterol (p<0.0001) and an 17.7% relative decrease in LDL cholesterol (p<0.0001), compared with controls. Systolic blood pressure increased by 6.6 mm Hg in the combined-treatment group and 1.5 mm Hg in the atorvastatin-only group (difference 5.4 mm Hg, 95% CI 4.3-6.4, p<0.0001). INTERPRETATION: Although torcetrapib substantially raised HDL cholesterol and lowered LDL cholesterol, it also increased systolic blood pressure, and did not affect the yearly rate of change in the maximum intima-media thickness of 12 carotid segments. Torcetrapib showed no clinical benefit in this or other studies, and will not be developed further.

Designs of RADIANCE 1 and 2: carotid ultrasound studies comparing the effects of torcetrapib/atorvastatin with atorvastatin alone on atherosclerosis.

OBJECTIVE: The RADIANCE studies were designed to assess the effects of torcetrapib/atorvastatin (T/A) compared with atorvastatin alone on slowing atherosclerotic progression in patients with heterozygous familial hypercholesterolemia (RADIANCE 1) or mixed hyperlipidemia (RADIANCE 2), as measured by change in carotid intima-media thickness (CIMT). RESEARCH DESIGN AND METHODS: RADIANCE 1 and 2 were randomized, double-blind, controlled trials with a duration of 2 years. In both studies, eligible subjects began treatment with atorvastatin during a run-in period and were titrated to target LDL-C levels defined by NCEP ATP III guidelines. Subjects then proceeded to a double-blind randomized treatment period where they received one of two regimens: (i) fixed combination T/A (torcetrapib dose, 60 mg), or (ii) atorvastatin alone. In both regimens, the dose of atorvastatin was established during the run-in period (20-80 mg, RADIANCE 1; 10-80 mg RADIANCE 2). B-mode ultrasonography was performed in duplicate at baseline and at end of study, and every 6 months in between. MAIN OUTCOME MEASURES: The primary efficacy measure in both studies was the annualized rate of change in maximum CIMT of 12 pre-defined carotid segments. Further outcome measures included lipid and safety assessments. CURRENT STATUS: The number of subjects randomized was 904 in RADIANCE 1 and 752 in RADIANCE 2. Results are anticipated in 2007.

Carotid intima-media thickness in low-risk individuals with asymptomatic atherosclerosis: baseline data from the METEOR study.

OBJECTIVE: Carotid intima-media thickness (CIMT) is an index for changes in atherosclerosis burden and changes in CIMT may relate to clinical events. We present baseline data from the METEOR study, a randomized, placebo-controlled trial evaluating the efficacy of rosuvastatin 40 mg on changes in CIMT. We set out to compare differences in CIMT between several subgroups of individuals. DESIGN AND METHODS: A total of 984 individuals aged 45-70 years (men) or 55-70 (women) were randomized. Participants were required to have: maximum CIMT > or = 1.2-< 3.5 mm; 2+ risk factors and 10-year coronary heart disease (CHD) risk < 10%, or < 2 CHD risk factors. Demographic characteristics were compared in two groups: USA versus Europe, and individuals with maximum CIMT < 2 mm versus those with CIMT > or = 2 mm. BASELINE DATA: Overall, mean age was 57 years and mean low-density lipoprotein cholesterol was 152 mg/dL (3.9 mmol/L). Body mass index (BMI), triglyceride and high-sensitivity C-reactive protein levels were all higher in US individuals, whereas smoking, hypertension and high-density lipoprotein cholesterol levels were higher in Europeans. Mean CIMT levels were the same in both populations, and the percentage of individuals with > or = 2 CHD risk factors was similar. Increased baseline CIMT (> 2 mm) was related to increasing age, male gender, smoking, hypertension and lipid levels. CONCLUSIONS: In this global trial, differences in baseline characteristics between participants from the USA and Europe are apparent. However, a strong association between CIMT and several cardiovascular risk factors was observed across the two continents.

Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia.

BACKGROUND: Torcetrapib, an inhibitor of cholesteryl ester transfer protein, may reduce atherosclerotic vascular disease by increasing levels of high-density lipoprotein (HDL) cholesterol. METHODS: A total of 850 patients with heterozygous familial hypercholesterolemia underwent B-mode ultrasonography at baseline and at follow-up to measure changes in carotid intima-media thickness. The patients completed an atorvastatin run-in period and were subsequently randomly assigned to receive either atorvastatin monotherapy or atorvastatin combined with 60 mg of torcetrapib for 2 years. RESULTS: After 24 months, in the atorvastatin-only group, the mean (+/-SD) HDL cholesterol level was 52.4+/-13.5 mg per deciliter and the mean low-density lipoprotein (LDL) cholesterol level was 143.2+/-42.2 mg per deciliter, as compared with 81.5+/-22.6 mg per deciliter and 115.1+/-48.5 mg per deciliter, respectively, in the torcetrapib-atorvastatin group. During the study, average systolic blood pressure increased by 2.8 mm Hg in the torcetrapib-atorvastatin group, as compared with the atorvastatin-only group. The increase in maximum carotid intima-media thickness, the primary measure of efficacy, was 0.0053+/-0.0028 mm per year in the atorvastatin-only group and 0.0047+/-0.0028 mm per year in the torcetrapib-atorvastatin group (P=0.87). The secondary efficacy measure, annualized change in mean carotid intima-media thickness for the common carotid artery, indicated a decrease of 0.0014 mm per year in the atorvastatin-only group, as compared with an increase of 0.0038 mm per year in the torcetrapib-atorvastatin group (P=0.005). CONCLUSIONS: In patients with familial hypercholesterolemia, the use of torcetrapib with atorvastatin, as compared with atorvastatin alone, did not result in further reduction of progression of atherosclerosis, as assessed by a combined measure of carotid arterial-wall thickness, and was associated with progression of disease in the common carotid segment. These effects occurred despite a large increase in HDL cholesterol levels and a substantial decrease in levels of LDL cholesterol and triglycerides. (ClinicalTrials.gov number, NCT00136981 [ClinicalTrials.gov].).

Effect of rosuvastatin on progression of carotid intima-media thickness in low-risk individuals with subclinical atherosclerosis: the METEOR Trial.

CONTEXT: Atherosclerosis is often advanced before symptoms appear and it is not clear whether treatment is beneficial in middle-aged individuals with a low Framingham risk score (FRS) and mild to moderate subclinical atherosclerosis. OBJECTIVE: To assess whether statin therapy could slow progression and/or cause regression of carotid intima-media thickness (CIMT) over 2 years. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo-controlled study (Measuring Effects on Intima-Media Thickness: an Evaluation of Rosuvastatin [METEOR]) of 984 individuals, with either age (mean, 57 years) as the only coronary heart disease risk factor or a 10-year FRS of less than 10%, modest CIMT thickening (1.2-<3.5 mm), and elevated LDL cholesterol (mean, 154 mg/dL); conducted at 61 primary care centers in the United States and Europe between August 2002 and May 2006. INTERVENTION: Participants received either a 40-mg dose of rosuvastatin or placebo. MAIN OUTCOME MEASURES: Rate of change in maximum CIMT (assessed with B-mode ultrasound) for 12 carotid sites; changes in maximum CIMT of the common carotid artery, carotid bulb, and internal carotid artery sites and in mean CIMT of the common carotid artery sites. CIMT regression was assessed in the rosuvastatin group only. RESULTS: Among participants in the rosuvastatin group, the mean (SD) baseline LDL cholesterol level of 155 (24.1) mg/dL declined to 78 (27.5) mg/dL, a mean reduction of 49% (P<.001 vs placebo group). The change in maximum CIMT for the 12 carotid sites was -0.0014 (95% CI, -0.0041 to 0.0014) mm/y for the rosuvastatin group vs 0.0131 (95% CI, 0.0087-0.0174) mm/y for the placebo group (P<.001). The change in maximum CIMT for the rosuvastatin group was -0.0038 (95% CI, -0.0064 to -0.0013) mm/y for the common carotid artery sites (P<.001), -0.0040 (95% CI, -0.0090 to 0.0010) mm/y for the carotid bulb sites (P<.001), and 0.0039 (95% CI, -0.0009 to 0.0088) mm/y for the internal carotid artery sites (P = .02). The change in mean CIMT for the rosuvastatin group for the common carotid artery sites was 0.0004 (95% CI, -0.0011 to 0.0019) mm/y (P<.001). All P values are vs placebo group. Overall, rosuvastatin was well tolerated with infrequent serious adverse cardiovascular events (6 participants [0.86%] had 8 events [1.1%] over 2 years). CONCLUSIONS: In middle-aged adults with an FRS of less than 10% and evidence of subclinical atherosclerosis, rosuvastatin resulted in statistically significant reductions in the rate of progression of maximum CIMT over 2 years vs placebo. Rosuvastatin did not induce disease regression. Larger, longer-term trials are needed to determine the clinical implications of these findings. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00225589

Carotid intima-media thickness and coronary atherosclerosis: weak or strong relations?

AIMS: Measurement of change in carotid intima-media thickness (CIMT) has been proposed as an alternative for the occurrence of cardiovascular (CV) events in the assessment of therapeutic interventions. Nevertheless, criticism has been voiced based on observations indicating a weak relation between CIMT and coronary atherosclerosis as well as on the virtual absence of data showing that progression of CIMT indeed predicts coronary artery disease (CAD) and stroke. METHODS AND RESULTS: We set out to review the evidence on these issues by performing a literature search on these topics. Of the 34 studies on the relation of CIMT with coronary atherosclerosis, as assessed by angiography (n=33) or intravascular ultrasound (n=1), 30 showed a modest positive relationship; the magnitude of which was similar to that found in autopsy studies. Of all studies on CIMT and future CV events (n=18), 17 showed graded positive relationships. At present, only one study has provided evidence on the relation of change in CIMT and future CV events, showing an increased risk with CIMT progression. The paucity of data on progression and future CV risk is partly attributable to time windows required to complete these studies. CONCLUSION: The modest relation between CIMT and coronary atherosclerosis most likely reflects variability in atherosclerosis development between the vascular beds rather than limitations of CIMT measurements. Additional data on the relation between change in CIMT and future CV events is required and currently is in progress.

Do mutations causing low HDL-C promote increased carotid intima-media thickness?

BACKGROUND: Although observational data support an inverse relationship between high-density lipoprotein (HDL) cholesterol and coronary heart disease (CHD), genetic HDL deficiency states often do not correlate with premature CHD. METHODS: Carotid intima-media thickness (cIMT) measurements were obtained in cases comprising 10 different mutations in LCAT, ABCA1 and APOA1 to further evaluate the relationship between low HDL resulting from genetic variation and early atherosclerosis. RESULTS: In a 1:2 case-control study of sex and age-related (+/-5 y) subjects (n=114), cIMT was nearly identical between cases (0.66+/-0.17 cm) and controls (0.65+/-0.18 cm) despite significantly lower HDL cholesterol (0.67 vs. 1.58 mmol/l) and apolipoprotein A-I levels (96.7 vs. 151.4 mg/dl) (P<0.05) CONCLUSIONS: Genetic variants identified in the present study may be insufficient to promote early carotid atherosclerosis.

From vulnerable plaque to vulnerable patient--Part III: Executive summary of the Screening for Heart Attack Prevention and Education (SHAPE) Task Force report.

Screening for early-stage asymptomatic cancers (eg, cancers of breast and colon) to prevent late-stage malignancies has been widely accepted. However, although atherosclerotic cardiovascular disease (eg, heart attack and stroke) accounts for more death and disability than all cancers combined, there are no national screening guidelines for asymptomatic (subclinical) atherosclerosis, and there is no government- or healthcare-sponsored reimbursement for atherosclerosis screening. Part I and Part II of this consensus statement elaborated on new discoveries in the field of atherosclerosis that led to the concept of the "vulnerable patient." These landmark discoveries, along with new diagnostic and therapeutic options, have set the stage for the next step: translation of this knowledge into a new practice of preventive cardiology. The identification and treatment of the vulnerable patient are the focuses of this consensus statement. In this report, the Screening for Heart Attack Prevention and Education (SHAPE) Task Force presents a new practice guideline for cardiovascular screening in the asymptomatic at-risk population. In summary, the SHAPE Guideline calls for noninvasive screening of all asymptomatic men 45-75 years of age and asymptomatic women 55-75 years of age (except those defined as very low risk) to detect and treat those with subclinical atherosclerosis. A variety of screening tests are available, and the cost-effectiveness of their use in a comprehensive strategy must be validated. Some of these screening tests, such as measurement of coronary artery calcification by computed tomography scanning and carotid artery intima-media thickness and plaque by ultrasonography, have been available longer than others and are capable of providing direct evidence for the presence and extent of atherosclerosis. Both of these imaging methods provide prognostic information of proven value regarding the future risk of heart attack and stroke. Careful and responsible implementation of these tests as part of a comprehensive risk assessment and reduction approach is warranted and outlined by this report. Other tests for the detection of atherosclerosis and abnormal arterial structure and function, such as magnetic resonance imaging of the great arteries, studies of small and large artery stiffness, and assessment of systemic endothelial dysfunction, are emerging and must be further validated. The screening results (severity of subclinical arterial disease) combined with risk factor assessment are used for risk stratification to identify the vulnerable patient and initiate appropriate therapy. The higher the risk, the more vulnerable an individual is to a near-term adverse event. Because <10% of the population who test positive for atherosclerosis will experience a near-term event, additional risk stratification based on reliable markers of disease activity is needed and is expected to further focus the search for the vulnerable patient in the future. All individuals with asymptomatic atherosclerosis should be counseled and treated to prevent progression to overt clinical disease. The aggressiveness of the treatment should be proportional to the level of risk. Individuals with no evidence of subclinical disease may be reassured of the low risk of a future near-term event, yet encouraged to adhere to a healthy lifestyle and maintain appropriate risk factor levels. Early heart attack care education is urged for all individuals with a positive test for atherosclerosis. The SHAPE Task Force reinforces existing guidelines for the screening and treatment of risk factors in younger populations. Cardiovascular healthcare professionals and policymakers are urged to adopt the SHAPE proposal and its attendant cost-effectiveness as a new strategy to contain the epidemic of atherosclerotic cardiovascular disease and the rising cost of therapies associated with this epidemic.

The effect of tibolone and continuous combined conjugated equine oestrogens plus medroxyprogesterone acetate on progression of carotid intima-media thickness: the Osteoporosis Prevention and Arterial effects of tiboLone (OPAL) study.

AIMS: At the time of the design of the Osteoporosis Prevention and Arterial effects of tiboLone (OPAL) study in 1996, oral hormone therapy (HT) was assumed to reduce cardiovascular risk. The evidence mainly came from the effects of combined conjugated equine oestrogens plus medroxyprogesterone acetate (CEE/MPA) therapy. Other HT regimes had not been studied widely. Tibolone, a selective tissue oestrogenic activity regulator, has several effects on cardiovascular risk factors, one of which is HDL lowering. Because the overall effect of tibolone on cardiovascular risk was unknown, the OPAL study was designed. METHODS AND RESULTS: The OPAL study was a three-arm, randomized, placebo-controlled, double-blind study to determine the effect of tibolone (2.5 mg daily) and of CEE/MPA (0.625/2.5 mg daily) over 3 years on progression of carotid intima-media thickness (CIMT) in 866 healthy post-menopausal women. The women were recruited from six US and five European centres. The primary outcome was change in mean common CIMT. Annual common CIMT progression rates in the tibolone and CEE/MPA groups were higher than in the placebo group: 0.0077 mm [95% confidence interval (CI) 0.0051-0.0103] in the tibolone group, 0.0074 mm (0.0048-0.0099) in the CEE/MPA group, and 0.0035 mm (0.009-0.0061) in the placebo group. The differences with placebo (0.0042 mm/year for tibolone and 0.0039 mm/year for CEE/MPA) were statistically significant. HDL cholesterol increased in CEE/MPA group and was lowered in the tibolone group. CONCLUSION: Both tibolone and CEE/MPA showed increased progression of common CIMT. Translation of the increased common CIMT progression of the CEE/MPA group into cardiovascular disease risk could not fully explain the observed increased cardiovascular risk as observed in the Women's Health Initiative study. This suggests that the net effect of tibolone and CEE/MPA on cardiovascular events may depend on the combined effects on the arterial wall, clotting factors, and possibly inflammation.

Measuring Effects on intima media Thickness: an Evaluation Of Rosuvastatin in subclinical atherosclerosis--the rationale and methodology of the METEOR study.

BACKGROUND: Increased carotid intima media thickness (IMT) is associated with established coronary heart disease (CHD) and is a marker of atherosclerosis. Statins are an effective treatment for dyslipidaemia, and have been shown to retard progression or promote carotid IMT regression in patients at high risk of CHD. Rosuvastatin is a highly efficacious statin, and the Measuring Effects on intima media Thickness: an Evaluation Of Rosuvastatin (METEOR) study is designed to assess the impact of rosuvastatin on carotid IMT progression in low risk subjects with signs of subclinical atherosclerosis. METHODS: In this randomised, parallel-group study, asymptomatic subjects at low risk of cardiovascular disease, but with evidence of atherosclerosis (defined as carotid IMT >or=1.2 mm and <3.5 mm), will receive rosuvastatin (40 mg/day) or placebo for 104 weeks. The study will enrol 840 European and US subjects randomised 5:2 between rosuvastatin and placebo. The primary end point will be the change in carotid IMT from baseline to study end, measured using B-mode ultrasonography. Other efficacy end points include changes in the serum lipid profile and C-reactive protein. Safety parameters will also be assessed. CONCLUSION: The METEOR study will evaluate whether long-term rosuvastatin treatment promotes regression, or slows progression, of subclinical atherosclerosis in asymptomatic subjects at low risk of cardiovascular disease.

Race-specific relationships between coronary and carotid artery calcification and carotid intimal medial thickness.

BACKGROUND AND PURPOSE: Calcified arterial plaque has been proposed as a subclinical marker of atherosclerosis. We compared it to a well-validated surrogate--carotid intimal medial thickness (IMT). METHODS: Calcified arterial plaque was measured in 2 vascular beds (coronary and carotid) by computed tomography, and common carotid artery IMT was measured by B-mode ultrasonography, in 438 participants. RESULTS: Calcium was positively associated with IMT (r=0.36 for coronary and r=0.45 for carotid, both P<0.0001). Correlations were attenuated with adjustment for age, sex, and diabetes. CONCLUSIONS: Calcified plaque in the coronary and carotid arteries is moderately associated with subclinical atherosclerosis.

Cardiovascular risk assessment in individual patients from carotid intimal-medial thickness measurements.

Carotid intimal-medial thickness measurements are a low-cost, noninvasive method to assess atherosclerotic burden in the general population. A large evidence base exists to validate estimates of absolute cardiovascular risk obtained from measurements of carotid intimal-medial thickness. Precise and reliable carotid intimal-medial thickness measurements from several ultrasonic interrogation angles and anatomic sites are required to obtain the most valid estimates of cardiovascular risk in an individual patient. This paper reviews basic measurement concepts and outlines important considerations in the clinical assessment of absolute cardiovascular risk in individual patients from measurements of carotid intimal-medial thickness.

The Osteoporosis Prevention and Arterial effects of tiboLone (OPAL) study: design and baseline characteristics.

The Osteoporosis Prevention and Arterial effects of tiboLone (OPAL) trial is a three-arm, randomized, placebo-controlled, double-blind study to determine the effect of tibolone 2.5 mg (Org OD 14) and continuous combined conjugated equine estrogens plus medroxyprogesterone acetate (0.625 mg/2.5 mg respectively) on progression of intima-media thickness of the carotid arteries and bone mineral density of the lumbar vertebrae and proximal femur in postmenopausal women. A total of 866 healthy postmenopausal women were recruited in six U.S. centers and five European centers. Duplicate carotid ultrasound examinations of the common carotid artery, the carotid bifurcation, and the internal carotid artery were performed at baseline. Single measurements of bone mineral density of the lumbar vertebrae and proximal femur were obtained at baseline. After randomization, ultrasound examinations were repeated every 6 months for 36 months following baseline, with a duplicate examination at the end of the study. Bone mineral density was measured every 12 months throughout the trial. The primary outcome is change in mean common carotid intima-media thickness (CIMT), defined as the average of the intima-media thickness measurements performed circumferentially at predefined angles for the near and far wall of 10-mm segments of the right and left distal common carotid arteries. Unique new features of the OPAL study are the specifically developed OPAL ultrasound protocol, yielding highly reproducible CIMT measurements, and the use of two experienced core laboratories for CIMT readings (one in the United States and one in Europe) with one common quality assurance and control program. The OPAL study is a large, placebo-controlled trial evaluating the effects of tibolone, as well as one of the first large randomized studies to determine the effects of continuous combined estrogen-progestin therapy on carotid atherosclerosis in healthy postmenopausal women. The OPAL study results are expected to complement other studies on atherosclerosis progression in healthy postmenopausal women.

Carotid intima-media thickness measurements in intervention studies: design options, progression rates, and sample size considerations: a point of view.

BACKGROUND: Carotid intima-media thickness (CIMT) measurements are currently widely used in randomized controlled trials (RCTs) to study the efficacy of interventions. In designing a RCT with CIMT as a primary outcome, several ultrasound options may be considered. We discuss the various options and provide a pooled estimate of CIMT progression. In addition, we quantify the effect of these choices on the sample size for a RCT. SUMMARY OF COMMENT: To estimate the average CIMT progression rate, we performed a pooled analysis using CIMT progression rates of control groups from published RCTs. The pros and cons of the following ultrasound options are discussed: which arterial segments may be studied; whether near and far wall CIMT measurements should be performed; whether a single image (1 angle of interrogation) or multiple images (more angles of interrogation) should be used; whether a manual or an automated edge detection reading system should be used; and whether images should be read in a random fashion or in batches. The pooled analysis showed an annual rate of change in mean common CIMT of 0.0147 mm (95% CI, 0.0122 to 0.0173) and in mean maximum CIMT of 0.0176 mm (95% CI, 0.0149 to 0.0203). CONCLUSIONS: Given the current evidence together with our experience with recently developed ultrasound protocols, we favor the use of mean maximum CIMT rather than mean common CIMT as the primary outcome measure in RCTs designed to evaluate the efficacy of pharmacological and nonpharmacological interventions in carotid artery atherosclerosis.

Effect of estrogen plus progestin on progression of carotid atherosclerosis in postmenopausal women with heart disease: HERS B-mode substudy.

OBJECTIVE: The Heart and Estrogen/Progestin Replacement Study (HERS) found no overall effect of estrogen plus progestin (compared with placebo) on coronary event rates in 2763 postmenopausal women with established coronary disease (mean 4.1 years of follow-up). In addition to the events trial, a carotid ultrasound substudy was established in 1993 to be conducted concurrently to determine whether hormone therapy affects the progression of the underlying atherosclerotic process. METHODS AND RESULTS: Within the larger HERS, a subset of 362 participants underwent carotid B-mode ultrasound examinations at baseline and the end of follow-up. Progression of carotid atherosclerosis was measured as the temporal change in intimal-medial thickness (IMT). CONCLUSIONS: IMT progressed in the hormone treatment and placebo groups, although there was no statistical difference between the rates: IMT progressed 26 microm/y (95% CI 18 to 34 microm/y) in the hormone group and 31 microm/y (95% CI 21 to 40 microm/y) in the placebo group (P=0.44). There were also no significant treatment effects when the results were examined by carotid segment or were adjusted for covariates. These data support the American Heart Association recommendation that women with established coronary disease should not initiate hormone therapy with an expectation of atherosclerotic benefit.

Lack of association between increased carotid intima-media thickening and decreased HDL-cholesterol in a family with a novel ABCA1 variant, G2265T.

Low HDL-cholesterol (HDL-C) concentrations are inversely correlated with cardiovascular disease, and previous studies have demonstrated that variants in the ATP-binding cassette transporter, ABCA1, are responsible for a proportion of HDL-C deficiency states. We identified a novel variant in ABCA1 in a kindred with decreased HDL-C. This variant was not identified in >200 chromosomes of healthy individuals. The proband, a heterozygote for G2265T, developed premature coronary artery disease. In addition to low HDL-C, six biological family members heterozygous for the ABCA1 variant exhibited low HDL-C concentrations compared with unaffected family members (0.83 +/- 0.32 vs 1.33 +/- 0.36 mmol/L; P = 0.009). Despite the decreased HDL-C, carotid artery B-mode ultrasound studies failed to reveal increased intima-media thickening in affected individuals compared with age- and sex-matched controls. Although these data extend previous observations that a single defective ABCA1 allele may lead to decreased HDL-C, associated evidence of early atherosclerosis was not confirmed.

Heritability of carotid artery intima-medial thickness in type 2 diabetes.

BACKGROUND AND PURPOSE: Carotid artery intima-medial thickness (IMT), a marker of subclinical atherosclerosis, is a strong predictor of subsequent cardiovascular morbidity. The role of genetic factors in thickening of the carotid wall remains largely unknown. We hypothesize that in families with multiple members having diabetes, carotid IMT is likely to be associated with both inherited and environmental factors. METHODS: To determine the extent of the familial aggregation of carotid IMT in the presence of type 2 diabetes, we studied 252 individuals with type 2 diabetes (mean age 60.6 years) from 122 families. Common carotid artery IMT was measured by high-resolution B-mode ultrasonography. Other measured factors included lipid levels, body mass index, fasting glucose, hemoglobin A1c, albumin/creatinine ratio, and self-reported medical history. Heritability estimates were obtained by using variance component methodology, as implemented in the SOLAR software package. Tests for association between carotid IMT and variables were performed by using mixed model analysis while accounting for the correlation due to family structure. RESULTS: The age-, sex-, and race-adjusted heritability estimate for carotid IMT was 0.32 (SE 0.17, P=0.02). Further adjustment for total cholesterol, hypertension status, and current smoking status resulted in a heritability estimate of 0.41 (SE 0.16, P=0.004). The strongest predictors of carotid IMT, after adjusting for age and sex, were ethnicity (African American versus white), total cholesterol, and smoking status. CONCLUSIONS: These data provide empirical evidence that subclinical cardiovascular disease has a significant genetic component and merits a search for the genes involved in susceptibility to the atherosclerotic complications of diabetes.