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Background: The SPRINT (Systolic Blood Pressure Intervention Trial) demonstrated reductions in major cardiovascular disease events and mortality with an intensive systolic blood pressure (SBP) goal intervention. However, a detailed description of the blood pressure intervention, antihypertensive medication usage, blood pressure levels, and rates and predictors of blood pressure control has not been reported previously. Methods: Hypertensive participants (n=9361) 50 years and older with elevated cardiovascular disease risk were randomized 1:1 to SBP goal Results: Baseline blood pressure (median±interquartile range) was 138±19/78±16 mm Hg. For intensive group participants, percent at goal rose from 8.9% at baseline to 52.4% at 6 months and average antihypertensive medications rose from 2.2 to 2.7; SBP was Conclusions: These results may inform and help replicate the benefits of SPRINT in clinical practice. Registration: URL: http://www.clinicaltrials.gov ; Unique identifier: NCT01206062.

BACKGROUND: In a previously reported randomized trial of standard and intensive systolic blood-pressure control, data on some outcome events had yet to be adjudicated and post-trial follow-up data had not yet been collected. METHODS: We randomly assigned 9361 participants who were at increased risk for cardiovascular disease but did not have diabetes or previous stroke to adhere to an intensive treatment target (systolic blood pressure

Orthostatic hypotension (OH) is frequently observed with hypertension treatment, but its contribution to adverse outcomes is unknown. The SPRINT (Systolic Blood Pressure Intervention Trial) was a randomized trial of adults, age ≥50 years at high risk for cardiovascular disease with a seated systolic blood pressure (BP) of 130 to 180 mm Hg and a standing systolic BP ≥110 mm Hg. Participants were randomized to a systolic BP treatment goal of either Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT01206062.

OBJECTIVES Concern about falling is common among older hypertension patients and could impact decisions to intensify blood pressure therapy. Our aim was to determine whether intensive therapy targeting a systolic blood pressure (SBP) of 120 mm Hg is associated with greater changes in concern about falling when compared with standard therapy targeting an SBP of 140 mm Hg. DESIGN Subsample analysis of participants randomized to either intensive or standard therapy in the Systolic Blood Pressure Intervention Trial (SPRINT). SETTING Approximately 100 outpatient sites. PARTICIPANTS A total of 2313 enrollees in SPRINT; participants were all age 50 or older (mean = 69 y) and diagnosed with hypertension. MEASUREMENTS Concern about falling was described by the shortened version of the Falls Efficacy Scale International as measured at baseline, 6 months, 1 year, and annually thereafter. RESULTS Concern about falling showed a small but significant increase over time among all hypertension patients. No differences were noted, however, among those randomized to intensive vs standard therapy (P = .95). Among participants younger than 75 years, no increase in concern about falling over time was noted, but among participants aged 75 years and older, the mean falls self-efficacy score increased by .3 points per year (P

Thiazides and thiazide-type diuretics are recommended as first-line agents for the treatment of hypertension, but contemporary information on their use in clinical practice is lacking. We examined patterns and correlates of thiazide prescription in a cross-sectional analysis of baseline data from participants enrolled in the Systolic Blood Pressure Intervention Trial (SPRINT). We examined baseline prescription of thiazides in 7582 participants receiving at least 1 antihypertensive medication by subgroup, and used log-binomial regression to calculate adjusted prevalence ratios for thiazide prescription (versus no thiazide). Forty-three percent of all participants were prescribed a thiazide at baseline, but among participants prescribed a single agent, the proportion was only 16%. The prevalence of thiazide prescription differed significantly by demographic factors, with younger participants, women, and blacks all having higher adjusted prevalence of thiazide prescription than other corresponding subgroups. Participants in the lowest category of kidney function (estimated glomerular filtration rate

Advances in the field of carotid ultrasound have been incremental, resulting in a steady decrease in measurement variability. Improvements in edge detection algorithms point toward increasing automation of CIMT measurements. The major advantage of CIMT is that it is completely noninvasive and can be repeated as often as required. It provides a continuous measure since all subjects have a measurable carotid wall. It is also relatively inexpensive to perform, and the technology is widely available. A graded relation between raising LDL cholesterol and increased CIMT is apparent. Increased CIMT has been shown consistently to relate the atherosclerotic abnormalities elsewhere in the arterial system. Moreover, increased CIMT predicts future vascular events in both populations from Caucasian ancestry and those from Asian ancestry. Furthermore, lipid‑lowering therapy has been shown to affect CIMT progression within 12–18 months in properly designed trials with results congruent with clinical events trials. In conclusion, when one wants to evaluate the effect of a pharmaceutical intervention that is to be expected to beneficially affect atherosclerosis progression and to reduce CV event risk, the use of CIMT measurements over time is a valid, suitable, and evidence‑based choice.

BACKGROUND: SPRINT found that treatment of systolic hypertension to a goal of

BACKGROUND There are no proven strategies to prevent atrial fibrillation (AF) in patients with type 2 diabetes (T2DM). We compared standard blood pressure (BP) lowering vs. intensive BP lowering in reducing incidence of AF or P-wave indices (PWI-ECG markers of left atrial abnormality that are considered intermediate phenotypes of AF) in patients with T2DM. METHODS We analyzed data from the ACCORD BP trial-a randomized controlled nonblinded trial (2001-2009) which randomized patients with T2DM and systolic BP (SBP) 130-180mm Hg on ≤3 antihypertensive medications aged 40-79 years with cardiovascular disease (CVD) or aged 55-79 years with subclinical CVD or ≥2 CVD risk factors to standard BP lowering (SBP

BACKGROUND There are few rigorous studies to confirm or refute the commonly cited concern that control of blood pressure to lower thresholds may result in an increased risk of falls and fractures.

OBJECTIVE To compare effects of combinations of standard and intensive treatment of glycemia and either blood pressure (BP) or lipids in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. RESEARCH DESIGN AND METHODS ACCORD enrolled 10,251 type 2 diabetes patients aged 40–79 years at high risk for cardiovascular disease (CVD) events. Participants were randomly assigned to hemoglobin A1c goals of RESULTS In the BP trial, risk of the primary outcome was lower in the groups intensively treated for glycemia (hazard ratio [HR] 0.67; 95% CI 0.50–0.91), BP (HR 0.74; 95% CI 0.55–1.00), or both (HR 0.71; 95% CI 0.52–0.96) compared with combined standard BP and glycemia treatment. For secondary outcomes, MI was significantly reduced by intensive glycemia treatment and stroke by intensive BP treatment; most other HRs were neutral or favored intensive treatment groups. In the lipid trial, the general pattern of results showed no evidence of benefit of intensive regimens (whether single or combined) compared with combined standard lipid and glycemia treatment. The mortality HR was 1.33 (95% CI 1.02–1.74) in the standard lipid/intensive glycemia group compared with the standard lipid/standard glycemia group. CONCLUSIONS In the ACCORD BP trial, compared with combined standard treatment, intensive BP or intensive glycemia treatment alone improved major CVD outcomes, without additional benefit from combining the two. In the ACCORD lipid trial, neither intensive lipid nor glycemia treatment produced an overall benefit, but intensive glycemia treatment increased mortality.

Increasing carotid intima-media thickness (CIMT) is associated with incident heart failure (HF). We investigated whether this association differs by diabetes status.We characterized 13,590 Atherosclerosis Risk in Communities Study participants free of baseline HF into normal fasting glucose (NFG, glucose100mg/dl), impaired fasting glucose (IFG, glucose 100-125mg/dl), and type 2 diabetes (T2D, glucose ≥126mg/dl, self-report, or use of diabetes drugs). CIMT was assessed by B-mode ultrasound. Incident HF was defined using ICD-9 or 10 codes from hospitalizations and death certificates. Cox regression was used to estimate hazard ratios (HR) for incident HF, adjusting for age, sex, race, education, hypertension medication, blood pressure, BMI, waist circumference, HDL, LDL, triglycerides, lipid-lowering medication, smoking, alcohol, serum creatinine, and interim CHD.T2D participants had higher mean CIMT (0.79±0.20mm), compared to IFG (0.75±0.19mm) and NFG (0.70±0.17mm) (p0.0001). Over 20.6years of median follow-up, 15% developed HF. Rates of HF (per 1000 person-years) were substantially higher for those with T2D (24.7), compared to IFG (7.7) and NFG (5.8). In adjusted analyses, the CIMT-HF association was significantly modified by diabetes status (PCIMT is associated with increased risk of HF, particularly among persons without diabetes. Due to a high absolute risk of HF among adults with T2D, CIMT may be a less reliable predictor.

Orthostatic hypotension (OH) is associated with hypertension and diabetes mellitus. However, in populations with both hypertension and diabetes mellitus, its prevalence, the effect of intensive versus standard systolic blood pressure (BP) targets on incident OH, and its prognostic significance are unclear. In 4266 participants in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) BP trial, seated BP was measured 3×, followed by readings every minute for 3 minutes after standing. Orthostatic BP change, calculated as the minimum standing minus the mean seated systolic BP and diastolic BP, was assessed at baseline, 12 months, and 48 months. The relationship between OH and clinical outcomes (total and cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, heart failure hospitalization or death and the primary composite outcome of nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death) was assessed using proportional hazards analysis. Consensus OH, defined by orthostatic decline in systolic BP ≥20 mm Hg or diastolic BP ≥10 mm Hg, occurred at ≥1 time point in 20% of participants. Neither age nor systolic BP treatment target (intensive

Orthostatic changes in systolic blood pressure (SBP) impact cardiovascular outcomes. In this study, we aimed to determine the pattern of orthostatic systolic pressure changes in participants enrolled in the SBP Intervention Trial (SPRINT) at their baseline visit before randomization and sought to understand clinical factors predictive of these changes. Of the 9323 participants enrolled in SPRINT, 8662 had complete data for these analyses. The SBP after 1 minute of standing was subtracted from the mean value of the three preceding seated SBP values. At the baseline visit, medical history, medications, anthropometric measures, and standard laboratory testing were undertaken. The mean age of SPRINT participants was 68 years, two-thirds were male, with 30% black, 11% Hispanic, and 55% Caucasian. The spectrum of SBP changes on standing demonstrated that increases in SBP were as common as declines, and about 5% of participants had an increase, and 5% had a decrease of >20 mm Hg in SBP upon standing. Female sex, taller height, more advanced kidney disease, current smoking, and several drug classes were associated with larger declines in BP upon standing, while black race, higher blood levels of glucose and sodium, and heavier weight were associated with more positive values of the change in BP upon standing. Our cross-sectional results show a significant spectrum of orthostatic SBP changes, reflecting known (eg, age) and less well-known (eg, kidney function) relationships that may be important considerations in determining the optimal target blood pressure in long-term outcomes of older hypertensive patients.

Hypertension is a risk factor for the development of cardiovascular and kidney disease, but treatment can substantially reduce risks. Many patients avoid antihypertensive medications because of fear of side-effects. Although associations between antihypertensives and sexual dysfunction in men have been documented, it remains unclear whether antihypertensives are associated with sexual dysfunction in women. We conducted a cross-sectional analysis of baseline data from women in the Systolic Blood Pressure Intervention Trial (SPRINT) to evaluate the relations among class of antihypertensive medication and the outcomes: sexual activity and sexual function.SPRINT enrolled individuals 50 and older with hypertension at high risk for cardiovascular disease. A subset of participants completed questionnaires regarding quality of life, including sexual function. Antihypertensive class was determined by medications taken at baseline.Of 690 women in the quality of life subset of SPRINT, 183 (26.5%) were sexually active. There were no significant differences in sexual activity among women taking one or more antihypertensives and women not taking any. Women taking an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker had higher odds of sexual activity [odds ratio 1.66 (1.12-4.27), P = 0.011]. Among sexually active women, the prevalence of sexual dysfunction was high (52.5%). No class of medication was associated with sexual dysfunction in the multivariable model.Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use was associated with higher odds of sexual activity. Although prevalence of sexual dysfunction was high, no single class of antihypertensive medication was associated with sexual dysfunction.

Context The evidence that measurement of the common carotid intima-media thickness (CIMT) improves the risk scores in prediction of the absolute risk of cardiovascular events is inconsistent. Objective To determine whether common CIMT has added value in 10-year risk prediction of first-time myocardial infarctions or strokes, above that of the Framingham Risk Score. Data Sources Relevant studies were identified through literature searches of databases (PubMed from 1950 to June 2012 and EMBASE from 1980 to June 2012) and expert opinion. Study Selection Studies were included if participants were drawn from the general population, common CIMT was measured at baseline, and individuals were followed up for first-time myocardial infarction or stroke. Data Extraction Individual data were combined into 1 data set and an individual participant data meta-analysis was performed on individuals without existing cardiovascular disease. Results We included 14 population-based cohorts contributing data for 45 828 individuals. During a median follow-up of 11 years, 4007 first-time myocardial infarctions or strokes occurred. We first refitted the risk factors of the Framingham Risk Score and then extended the model with common CIMT measurements to estimate the absolute 10-year risks to develop a first-time myocardial infarction or stroke in both models. The C statistic of both models was similar (0.757; 95% CI, 0.749-0.764; and 0.759; 95% CI, 0.752-0.766). The net reclassification improvement with the addition of common CIMT was small (0.8%; 95% CI, 0.1%-1.6%). In those at intermediate risk, the net reclassification improvement was 3.6% in all individuals (95% CI, 2.7%-4.6%) and no differences between men and women. Conclusion The addition of common CIMT measurements to the Framingham Risk Score was associated with small improvement in 10-year risk prediction of first-time myocardial infarction or stroke, but this improvement is unlikely to be of clinical importance. JAMA. 2012;308(8):796-803 www.jama.com

IN BRIEF Our study demonstrates strong associations of diabetes symptoms and distress with female sex, higher BMI, history of neuropathy, and current depressive symptoms. Many diabetes-specific symptoms may be significantly shaped by factors such as depression and obesity.

OBJECTIVE The Action to Control Cardiovascular Risk in Diabetes (ACCORD) Blood Pressure Trial reported no differences in most cardiovascular disease (CVD) outcomes between intensive and standard blood pressure therapy in individuals with diabetes mellitus (DM) and hypertension. Many such individuals are centrally obese. Here we evaluate whether the trial outcomes varied by the level of central obesity. RESEARCH DESIGN AND METHODS The cohort included 4,687 people (47.7% women) with DM and hypertension. Mean age was 62.2, and mean follow-up was 4.7 years. Participants were randomly assigned to one of two blood pressure treatment strategies: intensive (systolic RESULTS There was no evidence that the effect of intensively lowering blood pressure differed by quartile of waist-to-height ratio for any of the four outcomes (P > 0.25 in all cases). Controlling for waist-to-height quartile had no significant impact on previously published results for intensive blood pressure therapy. Waist-to-height ratio was significantly related to CVD mortality (hazard ratio 2.32 [95% CI 1.40–3.83], P = 0.0009 comparing the heaviest to lightest quartiles), but not to the other outcomes (P > 0.09 in all cases). CONCLUSIONS Intensive lowering of blood pressure versus standard treatment does not ameliorate CVD risk in individuals with DM and hypertension. These results did not vary by quartile of waist-to-height ratio.

Carotid intima-media thickness (CIMT) is a marker of atherosclerosis that is commonly used to assess the effect of therapeutic interventions. It is currently unclear to what extent biologically implausible values affect treatment effects. We evaluated the impact of biologically implausible CIMT values on the estimated rate of change in CIMT.Data were used from the METEOR (Measuring Effects on Intima-media Thickness: an Evaluation of Rosuvastatin) trial. METEOR was a randomized, placebo-controlled trial showing that rosuvastatin reduced the 2-year change in CIMT among low-risk individuals with subclinical atherosclerosis. In the main METEOR analysis, the data were analyzed without exclusion of biologically implausible data. In this post-hoc analysis, we constructed twelve definitions to define mildly or extremely biologically implausible values using distance from the interquartile range, median or mean. We evaluated the effect of removing implausible values on the estimated rate of change in CIMT.The percentage of biologically implausible CIMT values ranged from 0.6% to 9.7%, depending on the definition used. Across all definitions, removal of biologically implausible CIMT values marginally reduced standard errors and did not change the primary outcome (i.e., a nonsignificant change in the rosuvastatin group, significant progression in the placebo group, and a statistically significant difference between treatment groups).This study was focussed on the impact of implausible values in the analytical part of a CIMT study. Ultrasound images were not re-examined to determine whether an implausible measurement was due to measurement error or temporal morphological thickening,Removal of biologically implausible CIMT values marginally decreased the variability of the estimated rate of change in CIMT without having a large impact on the estimated rate of change.

Peters SAE, Lind L, Palmer MK, Grobbee DE,Crouse JR III, O’Leary DH, Evans GW, Raichlen J,Bots ML, den Ruijter HM, on behalf of the METEORstudygroup(UniversityMedicalCenterUtrecht,Utr-echt, The Netherlands; Uppsala University Hospital,Uppsala, Sweden;KeeleUniversity,Keele, UK; WakeForest University School of Medicine, Winston-Salem, NC, USA; Caritas Carney Hospital, Boston,MA, USA; and AstraZeneca, Wilmington, DE, USA).Increasedage,highbodymassindexandlowHDL-Clevels are related to an echolucent carotid intima–media: the METEOR study. J Intern Med 2012;272:257–266.Introduction. Echolucentplaquesarerelatedtoahighercardiovascular risk. Studies to investigate the rela-tionship between echolucency and cardiovascularriskintheearlystages ofatherosclerosisare limited.We studied the relationship between cardiovascularrisk factors and echolucency of the carotid intima–mediainlow-riskindividuals.Methods. Data were analysed from the Measuring Ef-fects on Intima-Media Thickness: an Evaluation ofRosuvastatin (METEOR) study, a randomized pla-cebo-controlledtrialincluding984individualswhichshowed that rosuvastatin attenuated the rate ofchange of carotid intima–media thickness (CIMT). Inthisposthocanalysis,duplicatebaselineultrasoundimagesfromthefarwalloftheleftandrightcommoncarotid arteries were used for the evaluation of theecholucency of the carotid intima–media, measuredbygrey-scalemedian(GSM)onascaleof0–256.LowGSM values reflect echolucent, whereas high valuesreflect echogenic structures. The relationship be-tween baseline GSM and cardiovascular risk factorswasevaluatedusinglinearregressionmodels.Results. MeanbaselineGSM(± SD)was84 ± 29.LowerGSMofthecarotidintima–mediawasassociatedwitholder age, highbodymass index (BMI) andlow levelsof high-density lipoprotein cholesterol (HDL-C) [beta)4.49, 95% confidence interval (CI) )6.50 to )2.49;beta)4.51,95%CI)6.43to)2.60;beta2.45,95%CI0.47to4.42,respectively].CommonCIMTwasinver-selyrelatedtoGSMofthecarotidintima–media(beta)3.94,95%CI)1.98to)5.89).Conclusion. Olderage,highBMIandlowlevelsofHDL-Carerelatedtoecholucencyofthecarotidintima–med-ia. Hence, echolucency of the carotid intima–mediamaybeusedasamarkerofcardiovascularriskprofiletoprovidemoreinformationthanthicknessalone.Keywords: atherosclerosis, carotid intima–mediathickness, carotid ultrasound, echolucency, riskfactors.IntroductionAtherosclerosis is a chronic and progressive diseaseofthe arterial wallandis theunderlyingcause ofthemajority of cardiovascular events worldwide [1, 2].B-modeultrasoundmeasurements of thecarotidar-teryhavecommonlybeenusedtoassessthepresenceand severity of atherosclerotic disease in a safe, reli-able and reproducible way [3]. Histological studieshave shown that plaques that appear echolucent onB-mode ultrasound are rich in lipids, whereas echo-genic plaqueshavea higher contentoffibrous tissue*

Background Current ultrasound protocols to measure carotid intima-media thickness (CIMT) in trials differ considerably. The best CIMT protocol would be one that combines high reproducibility, a large and precise estimate of the rate of CIMT progression and a large and precise estimate of the treatment effect. We performed a post-hoc analysis to determine the best algorithm for determining CIMT using data from the METEOR study, a randomized double-blind, placebo-controlled study of the effect of rosuvastatin on CIMT progression in 984 low coronary heart disease risk individuals with increased CIMT. Methods CIMT information was collected from two walls (near and far wall), three segments (common carotid, bifurcation and internal carotid artery), five different angles (for the right carotid artery - 60, 90, 120, 150, and 180 degrees on the Meijer's carotid arc; for the left - 300, 270, 240, 210, and 180 degrees) of two sides (left and right carotid artery), resulting in possibly (2 × 3 × 5 × 2 =) 60 measurements. On the basis of combinations of these measurements, we built 66 different ultrasound protocols to estimate a CIMT for each individual (22 protocols for mean common CIMT, 44 protocols for mean maximum CIMT). For each protocol we assessed reproducibility [intraclass correlation (ICC), mean difference of duplicate scans], 2-year progression rate in the placebo group with its corresponding standard error and treatment effect (difference in CIMT progression between rosuvastatin and placebo) and its corresponding standard error. Results Data of duplicate ultrasound examinations at baseline and end of study were available for 688 participants (70% of 984). The ICC based on duplicate baseline examinations ranged from 0.81 to 0.95. CIMT progression rates in the placebo group ranged from 0.0046 to 0.0177 mm/year, with SE ranging from 0.00134 to 0.00337. Treatment effects ranged from 0.0141 to 0.0388 mm/year. The protocols with highest reproducibility, highest CIMT progression/precision ratio and highest treatment effect/precision ratio were those measuring both near and far wall for at least two angles. Conclusion Ultrasound protocols that include CIMT measurements at multiple angles of both near and far wall give the best balance between reproducibility, rate of CIMT progression, treatment effect and their associated precision in this low-risk population with subclinical atherosclerosis.

Peters SAE, den Ruijter HM, Palmer MK, Grobbee DE, Crouse JR, O’Leary DH, Evans GW, Raichlen JS, Lind L, Bots ML, on behalf of the METEOR Study Group (University Medical Center Utrecht, Utrecht, The Netherlands; Keele University, Keele, UK; Wake Forest University School of Medicine, Winston-Salem, NC, USA; Caritas Carney Hospital, Boston, MA, USA; Wake Forest University School of Medicine, Winston-Salem, NC, USA; AstraZeneca, Wilmington, DE, USA; and Uppsala University Hospital, Uppsala, Sweden). Manual or semi-automated edge detection of the maximal far wall common carotid intima–media thickness: a direct comparison. J Intern Med 2012; 271: 247–256. Background. Automated edge detection is thought to be superior to manual edge detection in quantification of the far wall common carotid intima–media thickness (CIMT), yet published evidence making a direct comparison is not available. Methods. Data were used from the METEOR study, a randomized placebo-controlled trial among 984 individuals showing that rosuvastatin attenuated the rate of change of 2 year change in CIMT among low-risk individuals with subclinical atherosclerosis. For this post hoc analysis, CIMT images of the far wall of the common carotid artery were evaluated using manual and semi-automated edge detection and reproducibility, relation to cardiovascular risk factors, rates of change over time and effects of lipid-lowering therapy were assessed. Results. Reproducibility was high for both reading methods. Direction, magnitude and statistical significance of risk factor relations were similar across methods. Rate of change in CIMT in participants assigned to placebo was 0.0066 mm per year (SE: 0.0027) for manually and 0.0072 mm per year (SE: 0.0029) for semi-automatically read images. The effect of lipid-lowering therapy on CIMT changes was −0.0103 mm per year (SE: 0.0032) for manual reading and −0.0111 mm per year (SE: 0.0034) for semi-automated reading. Conclusion. Manual and semi-automated readings of the maximal far wall of the common CIMT images both result in high reproducibility, show similar risk factor relations, rates of change and treatment effects. Hence, choices between semi-automated and manual reading software for CIMT studies likely should be based on logistical and cost considerations rather than differences in expected data quality when the choice is made to use far wall common CIMT measurements.

Objective To evaluate the effect of the number and positioning during follow-up of ultrasound examinations on the rate of change in carotid intima―media thickness (CIMT) using METEOR (Measuring Effects on Intima―Media Thickness: an Evaluation of Rosuvastatin) as an example. Methods METEOR was a randomized, placebo-controlled trial showing that rosuvastatin reduced progression of 2-year change in CIMT among low-risk patients with subclinical atherosclerosis. In the full METEOR protocol, ultrasound examinations were performed twice before randomization, once each at 6, 12, and 18 months after randomization, and then twice at the end of study at 24 months. For the present study, 17 study designs were retrospectively constructed with varying number and position of ultrasound examinations during the study. Differences in the rate of change in maximum CIMT between these study designs were compared. Results Variations in frequency of ultrasound visits gave results in the same direction and magnitude for the change in maximum CIMT for both groups (i.e. nonsignificant change for rosuvastatin and significant progression for placebo, and a significant difference between treatments). However, standard errors were larger when the number of exams reduced. This finding was consistent over different lengths of follow-up, sample sizes, and with CIMT measurements made on different locations. Conclusion Protocols with different number and timing of ultrasound examinations minimally affect the direction and magnitude of treatment effects on the rate of change in CIMT. However, reductions in exam frequency increase standard errors of rates of change, suggesting larger sample sizes would be required to have the same level of statistical power. J.

There is no evidence from randomized trials to support a strategy of lowering systolic blood pressure below 135 to 140 mm Hg in persons with type 2 diabetes mellitus. We investigated whether therapy targeting normal systolic pressure (i.e.,120 mm Hg) reduces major cardiovascular events in participants with type 2 diabetes at high risk for cardiovascular events.A total of 4733 participants with type 2 diabetes were randomly assigned to intensive therapy, targeting a systolic pressure of less than 120 mm Hg, or standard therapy, targeting a systolic pressure of less than 140 mm Hg. The primary composite outcome was nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The mean follow-up was 4.7 years.After 1 year, the mean systolic blood pressure was 119.3 mm Hg in the intensive-therapy group and 133.5 mm Hg in the standard-therapy group. The annual rate of the primary outcome was 1.87% in the intensive-therapy group and 2.09% in the standard-therapy group (hazard ratio with intensive therapy, 0.88; 95% confidence interval [CI], 0.73 to 1.06; P=0.20). The annual rates of death from any cause were 1.28% and 1.19% in the two groups, respectively (hazard ratio, 1.07; 95% CI, 0.85 to 1.35; P=0.55). The annual rates of stroke, a prespecified secondary outcome, were 0.32% and 0.53% in the two groups, respectively (hazard ratio, 0.59; 95% CI, 0.39 to 0.89; P=0.01). Serious adverse events attributed to antihypertensive treatment occurred in 77 of the 2362 participants in the intensive-therapy group (3.3%) and 30 of the 2371 participants in the standard-therapy group (1.3%) (P0.001).In patients with type 2 diabetes at high risk for cardiovascular events, targeting a systolic blood pressure of less than 120 mm Hg, as compared with less than 140 mm Hg, did not reduce the rate of a composite outcome of fatal and nonfatal major cardiovascular events. (ClinicalTrials.gov number, NCT00000620.)

OBJECTIVE Intensive therapy targeting normal blood glucose increased mortality compared with standard treatment in a randomized clinical trial of 10,251 participants with type 2 diabetes at high-risk for cardiovascular disease (CVD) events. We evaluated whether the presence of cardiac autonomic neuropathy (CAN) at baseline modified the effect of intensive compared with standard glycemia treatment on mortality outcomes in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial participants. RESEARCH DESIGN AND METHODS CAN was assessed by measures of heart rate variability (HRV) and QT index (QTI) computed from 10-s resting electrocardiograms in 8,135 ACCORD trial participants with valid measurements (mean age 63.0 years, 40% women). Prespecified CAN definitions included a composite of the lowest quartile of HRV and highest QTI quartile in the presence or absence of peripheral neuropathy. Outcomes were all-cause and CVD mortality. Associations between CAN and mortality were evaluated by proportional hazards analysis, adjusting for treatment group allocation, CVD history, and multiple prespecified baseline covariates. RESULTS During a mean 3.5 years follow-up, there were 329 deaths from all causes. In fully adjusted analyses, participants with baseline CAN were 1.55–2.14 times as likely to die as participants without CAN, depending on the CAN definition used (P < 0.02 for all). The effect of allocation to the intensive group on all-cause and CVD mortality was similar in participants with or without CAN at baseline (Pinteraction > 0.7). CONCLUSIONS Whereas CAN was associated with increased mortality in this high-risk type 2 diabetes cohort, these analyses indicate that participants with CAN at baseline had similar mortality outcomes from intensive compared with standard glycemia treatment in the ACCORD cohort.

Background— Torcetrapib, an inhibitor of cholesteryl ester transfer protein, has been shown to increase the cardiovascular event rate despite conferring a significant high-density lipoprotein cholesterol increase. Using data from the Rating Atherosclerotic Disease Change by Imaging with a New CETP Inhibitor (RADIANCE) trials, which assessed the impact of torcetrapib on carotid intima-media thickness (cIMT), we sought to explore potential mechanisms underlying this adverse outcome. Methods and Results— Data from the RADIANCE 1 and 2 studies, which examined cIMT in 904 subjects with familial hypercholesterolemia and in 752 subjects with mixed dyslipidemia, were pooled. Subjects were randomized to either atorvastatin or torcetrapib combined with atorvastatin. Mean common cIMT progression was increased in subjects receiving torcetrapib plus atorvastatin compared with subjects receiving atorvastatin alone (0.0076±0.0011 versus 0.0025±0.0011 mm/y; P =0.0014). Subjects treated with torcetrapib plus atorvastatin displayed higher postrandomization systolic blood pressure and plasma sodium and bicarbonate levels in conjunction with lower potassium levels. The decrease in potassium levels was associated with the blood pressure increase. Markedly, the use of renin-angiotensin-aldosterone system inhibitors tended to aggravate the blood pressure increase. Subjects receiving torcetrapib plus atorvastatin with the strongest low-density lipoprotein cholesterol reduction showed the smallest cIMT progression, whereas subjects with the highest systolic blood pressure increase showed the largest cIMT progression. High-density lipoprotein cholesterol increase was not associated with cIMT change. Conclusions— These analyses support mineralocorticoid-mediated off-target toxicity in patients receiving torcetrapib as a contributing factor to an adverse outcome. The absence of an inverse relationship between high-density lipoprotein cholesterol change and cIMT progression suggests that torcetrapib-induced high-density lipoprotein cholesterol increase does not mediate atheroprotection. Future studies with cholesteryl ester transfer protein inhibitors without off-target toxicity are needed to settle this issue.

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 (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.A total of 984 individuals aged 45-70 years (men) or 55-70 (women) were randomized. Participants were required to have: maximum CIMTor = 1.2-3.5 mm; 2+ risk factors and 10-year coronary heart disease (CHD) risk10%, or2 CHD risk factors. Demographic characteristics were compared in two groups: USA versus Europe, and individuals with maximum CIMT2 mm versus those with CIMTor = 2 mm.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 withor = 2 CHD risk factors was similar. Increased baseline CIMT (2 mm) was related to increasing age, male gender, smoking, hypertension and lipid levels.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.

Abstract— Left ventricular hypertrophy (LVH), a marker of cardiac end-organ damage, is a common complication of hypertension. Regression of LVH is achievable by sustained lowering of systolic blood pressure (BP). However, it is unknown whether a strategy aimed at lowering BP beyond that recommended would lower the risk of LVH. We examined the effect of intensive (systolic BPP =0.91) and the mean Cornell index (1456 versus 1470 µV; P =0.45) were similar in the intensive (n=2154) and standard (n=2177) BP-lowering arms, respectively. However, after median follow-up of 4.4 years, intensive, compared with standard, BP lowering was associated with a 39% lower risk of LVH (odds ratio [95% confidence interval], 0.61[0.43, 0.88]; P =0.008) and a significantly lower adjusted mean Cornell index (1352 versus 1447 µV; P Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00000620

T o the Editor: In our study showing no increase in the rate of falls with intensive blood pressure (BP) control in the ACCORD trial, Dr. Jolobe inquires whether the prevalence of orthostatic hypotension differed between the intensive and standard BP control groups. He further notes that orthostatic hypotension may not be accompanied by symptoms. The ACCORD BP trial did gather data on orthostatic BP change and dizziness on standing in a subgroup of participants. Of the 3,099 participants included in our analysis, orthostatic BP measurements and reports of dizziness or lightheadedness on standing during the measurement are available on 905 participants at baseline. We also have data on a subgroup of 607 participants who were assessed for health-related quality of life at baseline and 12 months. This included a question about dizziness on standing within the previous month. Seated and standing brachial artery BP was measured using an Omron model HEM-907 automatic sphygmomanometer. After 7 min of seated rest, during which BP was measured 3 times, participants were asked to stand. Standing BPwas taken every minute for 3 min in the same arm. BP change was calculated using the lowest of the standing measurements minus the mean of the seated measurements. Orthostatic hypotension was defined as a decline in either systolic BP ≥20 mmHg or diastolic BP ≥10 mm. Orthostatic hypotension was present in 17 % of standard and 21 % of intensive BP group participants at the baseline visit (p=0.13). Dizziness or lightheadedness during these measurements was uncommon and also did not differ between the groups (5 % of standard and 6 % of intensive BP group participants, p=0.56.) Dizziness on standing within the previous month was more common, but did not differ between the standard and intensive treatment groups either at baseline or at 12months of follow-up in the subgroup of participants in these analyses (Table 1). This is similar to the previous report for the ACCORD BP trial. Our analysis was designed to determine whether intensive BP treatment would affect the risk of falls or fractures, and our findings suggest that intensive treatment is safe with regard to these outcomes. Based on the data presented in this letter, we consider it unlikely that differences in orthostatic hypotension at baseline influenced our results. As Dr. Jolobe notes, an important outstanding question is Bwhether or not orthostatic hypotension (and its severity) might have contributed to falls in either group.^We agree that this is an important question, and we are currently conducting analyses to carefully examine the influence of orthostatic BP change and symptoms on falls and fractures among ACCORD BP trial participants.

Serum uric acid has been positively associated with incident hypertension, but previous studies have had limited ability to explore this relationship across sex and ethnic strata. We sought to evaluate this association in a biethnic cohort of middle-aged men and women. Participants in the Atherosclerosis Risk in Communities (ARIC) study who were free of hypertension at baseline (N=9104) were evaluated for hypertension at 3-year intervals over 4 examinations. Adjusted Cox proportional hazards models evaluated risk of incident hypertension or progression of blood category for each SD higher baseline serum uric acid. At baseline, the mean age was 53.3 years (range: 45 to 64 years), with a mean (SD) systolic blood pressure of 113.8 (12.2) mm Hg, mean diastolic blood pressure of 70.2 (8.6) mm Hg, and mean serum uric acid of 5.7 (1.4). Higher serum uric acid was associated with greater risk of hypertension in the overall cohort (hazard ratio for each SD of higher uric acid [95% CI]: 1.10 [1.04 to 1.15]) and in subgroup analyses (black men: 1.32 [1.14 to 1.54]; black women: 1.16 [1.03 to 1.31]; white men: 1.01 [0.94 to 1.09]; white women: 1.04 [0.96 to 1.11]), after adjustment for age, baseline blood pressure, body mass index, renal function, diabetes, and smoking. The pattern was similar when modeling blood pressure progression (overall: 1.10 [1.05 to 1.14]; black men: 1.26 [1.11 to 1.42]; black women: 1.18 [1.06 to 1.31]; white men: 1.05 [0.99 to 1.11]; white women: 1.05 [1.00 to 1.12]). In conclusion, serum uric acid was positively associated with incident hypertension over 9 years of follow-up, and this relationship was stronger in blacks than in whites. More research is warranted concerning the physiological and clinical consequences of hyperuricemia, especially in blacks.

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.

Objective— Increased carotid artery intima-media thickness (IMT) and increased coronary artery calcium (CAC) are noninvasive surrogate indices of prevalent coronary artery disease (CAD). We compared CAC to IMT for noninvasive detection of prevalent CAD in participants whose coronary status was identified by coronary angiography. Methods and Results— Male and female CAD patients (≥50% stenosis in one or more coronary artery, n=79) and controls (no lumen irregularities, n=93) were identified using coronary angiography. Mean maximum carotid IMT was quantified using B-mode ultrasound and total CAC was measured using ECG-gated helical computed tomography (HCT). Carotid IMT was ≈20% higher in CAD cases compared with controls ( P P P =0.015). CAC scores that exceeded the median score of 92 were associated with 28-fold increase in likelihood of prevalent CAD ( P Conclusion— HCT-measured CAC compares favorably with carotid IMT measured by B-mode ultrasound as a noninvasive index of prevalent CAD.

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 ≥1.2 mm and

Periodontitis has been linked to coronary heart disease (CHD) risk, possibly through providing a systemic inflammatory burden. Few studies have evaluated periodontitis and subclinical measures of atherosclerosis. Coronary artery calcification (CAC) is an emerging marker for atherosclerosis, and past studies suggest that it predicts incident CHD in asymptomatic populations.In 1996-1998, dental examinations were performed on 6,931 participants in the Atherosclerosis Risk in Communities (ARIC) cohort. Extent of periodontitis was measured by the percent of sites with attachment level (AL)or = 3 mm. In 1999-2000, CAC was measured by cardiac gated mechanical or helical computed tomography in 269 dental examinees and edentulous subjects from the Minnesota and North Carolina field centers of ARIC who were free of clinically recognized CHD. A traditional Agatston score for CAC was calculated.Compared to subjects with no or mild periodontitis (10% of sites with ALor = 3 mm), subjects with moderate or severe periodontitis (or = 10% of sites with ALor = 3 mm) were more likely to have CACor = 100, but this difference was not statistically significant (odds ratio [OR]: 1.78; 95% confidence interval [CI]: 0.65 to 4.86). This association was partially but not completely attenuated when adjusted for demographic factors and traditional CHD risk factors (OR: 1.51; 95% CI: 0.54 to 4.23).These results suggest that periodontitis is not strongly associated with CAC. This study offers some reference for the magnitude of the association between CAC and periodontitis and information regarding the minimal power necessary for future studies.

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.

Prolongation of the QT interval is associated with an increased risk of arrhythmia, coronary heart disease (CHD), and mortality. Estrogens and androgens have been proposed as a causal factor in QT lengthening. We tested whether postmenopausal hormone replacement therapy was associated with prolonged QT intervals in a healthy population sample of women (mean age=54).Women (n=3103) were asked about estrogen (ERT) and progestin plus estrogen (PERT) replacement therapy use at 4 examinations over 9 years. Electrocardiographic QT intervals were measured and corrected for heart rate using the QT Index (QTI) and Bazett's correction. QT prolongation was defined as QTI110% and a change from baseline ofor=4%.Heart rate corrected QT length was moderately but significantly (p0.01) greater, and the risk of QT prolongation was nearly twice (Odds Ratio=1.9, 95% Confidence Interval: 1.2-2.0) that in women who used ERT compared with never users. PERT use was not significantly associated with QT length.The potential for slight increases in QT length over time, and an increased risk of QT prolongation with ERT use identified in this observational study, are important concerns that should be further explored in randomized trials.

Hormone replacement therapy is universely associated with coronary heart disease (CHD) in observational studies, but it is unknown whether this association is mediated by the autonomic nervous system. We tested the hypothesis that postmenopausal hormone replacement therapy was associated with more favorable heart rate (HR) and heart rate variability (HRV) in a population sample of women ( n =2,621). Hormone therapy use was measured at four examinations beginning in 1987. Supine HR and HRV indices were measured for 6 minutes at the final examination (1996–1998). In unadjusted linear regression models, hormone therapy was associated with lower HR (hormone use=64.7 vs. never=65.7 beats/min, P =.01) and higher HRV. However, following adjustment for age and CHD risk factors, both associations were eliminated. Results from this observational study suggest that hormone therapy is not associated with HR or HRV. These analyses should be replicated in a randomized trial.

BACKGROUND Effective therapy for chronic heart failure (CHF) is underutilized despite a broad consensus regarding treatment recommendations. METHODS As a quality improvement project designed to reduce preventable hospitalizations associated with CHF, we examined use of angiotensin converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), and beta-adrenergic receptor blockers (BB) in a population of patients enrolled in a managed care plan. Medicare and commercial enrollees were included. Patients with CHF were identified using claims data (International Classification of Disease 9th Clinical Modification code 428) covering January 1, 1998 through December 31, 1998. Drug utilization data were obtained from the plan's pharmacy benefits database. Data were available for 1220 patients. RESULTS The mean age (+/- SD) was 71 +/- 12 years, 53% were female, and 84% were Medicare enrollees. Prescriptions for ACEI, ARB and BB were filled by 52%, 9% and 25% of patients, respectively. Prescriptions for diuretics, digitalis preparations, and calcium channel blockers (CCB) were filled by 69%, 34%, and 32%, respectively. Therefore, almost half of patients with CHF were not receiving ACEI therapy, even though it had been proven to reduce morbidity and mortality related to CHF. Furthermore, three-quarters of patients were not receiving BB therapy, a similarly effective therapy. In contrast, CCB and digitalis have not been convincingly shown to reduce mortality in patients with CHF broadly defined. Utilization of CCB and digitalis exceeded that of BB. CONCLUSIONS Managed care organizations should develop, test, and implement network-level strategies designed to optimize the appropriate utilization of effective drug therapies for patients with CHF.

The objective of this study was to test prospectively in a population sample whether individuals with impaired heart rate variability (HRV) are at increased risk of developing coronary heart disease (CHD) and of non-CHD mortality and to test whether this relationship is more pronounced among individuals with diabetes. We examined the association between HRV and incident CHD and non-CHD mortality in a cohort of 11,654 men and women aged 45–64 years at intake, from the biracial, population-based Atherosclerosis Risk in Communities Study. Supine, resting, 2-min beat-to-beat heart rate data were collected at the baseline examination. High frequency (HF; 0.15–0.40 Hz) and low frequency (LF; 0.04–0.15 Hz) spectral powers, LF/HF ratio, normalized HF and LF, the standard deviation of all normal R-R intervals (SDNN), and the mean of the sum of the squared differences between adjacent normal R-R intervals (MSSD) were used as the conventional indexes of HRV to measure cardiac autonomic control. From this cohort, 635 cases of incident CHD (including 346 cases of incident myocardial infarction [MI] and 82 cases of fatal CHD), and 623 non-CHD deaths were identified and validated after an average of 8 years of follow-up. Among individuals with diabetes, the multivariable adjusted proportional hazards ratios (95% CI) were 2.03 (1.28–3.23), 1.60 (1.12–2.27), 1.50 (0.65–3.42), and 1.27 (0.84–1.91) for incident MI, incident CHD, fatal CHD, and non-CHD deaths, respectively, comparing the lowest quartile to the upper most three quartiles of HF. A similar pattern of associations was found for LF, SDNN, and MSSD. By contrast, there was no consistent pattern of associations among individuals without diabetes. At the population level, a lower HRV (reflective of impaired cardiac autonomic control) is statistically significantly related to the development of CHD among individuals with diabetes, independent of markers of the duration/severity of the glucose metabolism impairment. These data suggest a contribution of an impaired cardiac autonomic control to the risk of CHD among individuals with diabetes.

Objective: To examine associations between changes in body mass index (BMI) and changes in carotid artery intima-media thickness (IMT) in a community-based sample. Research Methods and Procedures: Carotid artery IMT and BMI were assessed at baseline (between 1987 and 1990) and in three subsequent examinations at 3-year intervals in participants in the Atherosclerosis Risk in Communities cohort. The 9316 African-American and white men and women in the analysis were 45 to 64 years of age at baseline. Cross-sectional associations between BMI and IMT were assessed using general linear models. Longitudinal associations were examined using mixed models analysis. Results: Cross-sectional associations between BMI and IMT were confirmed. At baseline, a 1-kg/m2 increase in BMI was associated with an increase in IMT that ranged from 2.5 to 7.5 μm among the ethnic-gender groups examined. Changes in BMI were not associated with changes in IMT in models that adjusted for aging and other covariates. Results were similar across ethnic-gender groups. Discussion: Among free-living, 45- to 64-year-old adults, changes in common carotid artery IMT associated with changes in BMI are either very small or absent.

Purpose: Although human studies have failed to reveal an increased risk of clinical cardiovascular disease in men who undergo vasectomy, the possibility exists that an association may be detectable only after a long followup, or it may be more evident for subclinical than clinical disease. We assessed the association of vasectomy with inflammation and coagulation factors, carotid intimal-medial thickness, carotid plaque, prevalent peripheral arterial disease, and incident coronary heart disease and stroke in the Atherosclerosis Risk in Communities cohort.Materials and Methods: Included in the study were 3,957 white men 45 to 64 years old who were free of coronary heart disease at the Atherosclerosis Risk in Communities (ARIC) baseline examination in 1987 to 1989. Data on vasectomy was collected at baseline by self-reporting. High resolution B-mode ultrasound was done to assess carotid intimal-medial thickness and carotid plaque. The cohort was followed an average of 9 years for incident cardiovascular eve...

Intima-media thickness of the common carotid arteries is a marker of atherosclerosis and has been shown to be associated with prevalent and incident coronary heart disease and with coronary heart disease risk factors. The authors examined the association of baseline risk factors or change in risk factors with change in intima-media thickness over follow-up (1987-1998) in the Atherosclerosis Risk in Communities (ARIC) population-based cohort (baseline: age 45-64 years, n = 15,792). Subjects were members of households sampled in four areas of the United States. Either not adjusting for baseline intima-media thickness or doing so with correction for its measurement error resulted in statistically significant associations of change in intima-media thickness with baseline diabetes, current smoking, high density lipoprotein cholesterol, pulse pressure, white blood cell count, and fibrinogen. The associations were of a similar order of magnitude as anticipated from the authors' cross-sectional findings. Statistically significant associations were found between change in intima-media thickness and change in low density lipoprotein cholesterol and triglycerides and with onset of diabetes and hypertension. In summary, established risk factors for coronary heart disease are associated with the rate of change of subclinical atherosclerosis.

Background Increased carotid intima‐media thickness ( IMT ) is associated with subclinical left ventricular myocardial dysfunction, suggesting a possible role of carotid IMT in heart failure ( HF ) risk determination. Methods and Results Mean far wall carotid IMT , measured by B‐mode ultrasound, was available for 13 590 Atherosclerosis Risk in Communities study participants aged 45 to 64 years and free of HF at baseline. HF was defined using ICD ‐9 428 and ICD ‐10 I‐50 codes from hospitalization records and death certificates. The association between carotid IMT and incident HF was assessed using Cox proportional hazards analysis with models adjusted for demographic variables, major CVD risk factors, and interim CHD . There were 2008 incident HF cases over a median follow‐up of 20.6 years (8.1 cases per 1000 person‐years). Mean IMT was higher in those with HF than in those without (0.81 mm±0.23 versus 0.71 mm±0.17, P HF for the fourth compared with the first quartile of IMT was 15.4 versus 3.9 per 1000 person‐years; P IMT was associated with incident HF ( HR 1.20 [95% CI : 1.16 to 1.25]). After adjustment, the top quartile of IMT was associated with HF ( HR 1.60 [95% CI : 1.37 to 1.87]). Results were similar across race and gender groups. Conclusions Increasing carotid IMT is associated with incident HF in middle‐aged whites and blacks, beyond risks explained by major CVD risk factors and CHD . This suggests that carotid IMT may be associated with HF through mechanisms different from myocardial ischemia or infarction.

PURPOSE: Arterial distensibility decreases with age. This decrease may be associated with the initiation and/or progression of hypertension and atherosclerosis and may be attenuated by positive lifestyle habits, including habitual physical activity. We tested the hypothesis that self-reported sport, leisure, and work physical activity is associated with greater arterial distensibility (i.e., carotid artery pulsatile diameter changes). METHODS: The Atherosclerosis Risk in Communities (ARIC) study assessed left common carotid arterial diameters and intimal-medial wall thickness (IMT) using B-mode ultrasound techniques, in 10,644 African-American and white men and women aged 45-64 yr and free of cardiovascular disease. RESULTS: Work activity, but not sports or leisure activity, was weakly associated with greater arterial distensibility in an ANCOVA model adjusted for blood pressure and other covariates (diastolic arterial diameter, pulse pressure, pulse pressure squared, age, race, sex, smoking, dietary fat intake, height, education, and clinical center) (P for linear trend = 0.03). Vigorous sports activity was weakly positively associated with arterial distensibility (arterial diameter change (mean +/- SE in mm) 0.42 +/- 0.004 vs 0.41 +/- 0.002 for the 12.7% of participants reporting any vs no vigorous activity, P = 0.02), and this association was not attenuated by adjustment for IMT, body mass index, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, or diabetes. Repeated analyses with traditional arterial stiffness indices showed similar findings for vigorous but not work activity. CONCLUSION: In contrast to several smaller studies, these findings do not support the hypothesis that habitual physical activity has a strong, consistent positive effect on arterial distensibility.

The relationship between carotid artery lesions (CALs), with and without acoustic shadowing (AS) as an index of arterial mineralization, and incident coronary heart disease (CHD) was examined in the Atherosclerosis Risk in Communities study cohort. Among 12,375 individuals, ages 45–64 years, free of CHD at baseline, 399 CHD events occurred between 1987–1995. In a 3-cm segment centered at the carotid bifurcation, CALs with and without AS were identified by B-mode ultrasound (US). After adjustment for the major CHD risk factors, the CHD hazard ratio (HR) for women with CAL without AS compared to women without CAL was 1.78 (95% CI: 1.22, 2.60) and the HR comparing women with CAL with AS to women with CAL without AS was 1.73 (95% CI: 1.07, 2.80). Corresponding HRs for men were 1.59 (95% CI: 1.22, 2.07) and 1.04 (95% CI: 0.72, 1.51). CALs predicted CHD events; this association was stronger for mineralized CALs in women, but not men. (E-mail: gerardo_heiss@unc.edu)

Abstract —Cerebral magnetic resonance imaging (MRI) has demonstrated a high prevalence of infarct-like lesions, white matter hyperintensities, and evidence of cerebral atrophy in older adults. While these findings are generally believed to be related to ischemia and atherosclerosis, their relationship to atherosclerosis in the carotid arteries remains to be explored. Study subjects were part of the multicenter Cardiovascular Health Study, a cross-sectional study of 3502 women and men ≥65 years of age undergoing cranial MRI and carotid ultrasonography. MRI infarcts were detected in 1068 participants (29.3%) and measurable carotid plaque in 2745 (75.3%). MRI infarcts, ventricular and sulcal widening, and white matter score were strongly associated with carotid intimal-medial thickness (IMT) and stenosis degree after adjustment for age and sex (all P P P P

SummarySeveral studies have linked higher plasma fibrinogen and plasminogen activator inhibitor (PAI-1) concentrations with increased risk of cardiovascular disease. We studied whether members of families with increased occurrence of coronary heart disease (CHD) have increased levels of fibrinogen and PAI-1 and whether subclinical carotid atherosclerosis is associated with these two hemostatic factors. Contrary to our hypothesis, fibrinogen and PAI-1 antigen levels were not different between high CHD risk families versus random families. Adjusted for age and family type, fibrinogen and PAI-1 were both associated positively with carotid intima-media thickness assessed by B-mode ultrasound. However, adjustment for lifestyle and medical covariates essentially eliminated these associations. These data suggest 1) elevated fibrinogen and PAI-1 do not explain clustering of CHD in families and 2) fibrinogen and PAI-1 may partly mediate the effects of other risk factors on carotid atherosclerosis, though the data are also consistent with them playing no causal role.

The resting ankle-brachial index (ABI) is a non-invasive method to assess the patency of the lower extremity arterial system and to screen for the presence of peripheral occlusive arterial disease. To determine how the ABI is associated with clinical coronary heart disease (CHD), stroke, preclinical carotid plaque and far wall intimal-medial thickness (IMT) of the carotid and popliteal arteries, we conducted analyses in 15 106 middle-aged adults from the baseline examination (1987-1989) of the Atherosclerosis Risk in Communities (ARIC) Study. The prevalence of clinical CHD, stroke/transient ischemic attack (TIA) and preclinical carotid plaque increased with decreasing ABI levels, particularly at those of 0.90 (age-adjusted odds ratio (OR) ranging from 2.2 (95% CI: 1.0-5.1) in African-American men to 3.3 (95% CI: 2.1-5.0) in white men). Men with ABI 0.90 (age-adjusted OR: 4.2 (95% CI: 1.8-9.5) in African-American men and 4.9 (95% CI: 2.6-9.0) in white men). In women the association was weaker and not statistically significant. Among those free of clinical cardiovascular disease, individuals with ABI 0.90 (age-adjusted ORs ranging from 1.5 (95% CI: 1.0-1.9) in white women to 2.6 (95% CI: 1.0-6.6) in african-american men). The ABI was also inversely associated with far wall IMT of the carotid arteries (in both men and women) and the popliteal arteries (in men only). The associations of ABI with clinical CHD, stroke, preclinical carotid plaque and IMT of the carotid and popliteal arteries were attenuated and often not statistically significant after further adjustment for LDL cholesterol, cigarette smoking, hypertension and diabetes. These data demonstrate that low ABI levels, particularly those of < 0.90, are indicative of generalized atherosclerosis.