David M. Herrington

Guidelines for the Ultrasound Assessment of Endothelial-Dependent Flow-Mediated Vasodilation of the Brachial Artery A Report of the International Brachial Artery Reactivity Task Force

Endothelial function is thought to be an important factor in the pathogenesis of atherosclerosis, hypertension and heart failure. In the 1990s, high-frequency ultrasonographic imaging of the brachial artery to assess endothelium-dependent flow-mediated vasodilation (FMD) was developed. The technique provokes the release of nitric oxide, resulting in vasodilation that can be quantitated as an index of vasomotor function. The noninvasive nature of the technique allows repeated measurements over time to study the effectiveness of various interventions that may affect vascular health. However, despite its widespread use, there are technical and interpretive limitations of this technique. State-of-the-art information is presented and insights are provided into the strengths and limitations of high-resolution ultrasonography of the brachial artery to evaluate vasomotor function, with guidelines for its research application in the study of endothelial physiology.

Effects of estrogen replacement on the progression of coronary-artery atherosclerosis

Background Heart disease is a major cause of illness and death in women. To understand better the role of estrogen in the treatment and prevention of heart disease, more information is needed about its effects on coronary atherosclerosis and the extent to which concomitant progestin therapy may modify these effects. Methods We randomly assigned a total of 309 women with angiographically verified coronary disease to receive 0.625 mg of conjugated estrogen per day, 0.625 mg of conjugated estrogen plus 2.5 mg of medroxyprogesterone acetate per day, or placebo. The women were followed for a mean (±SD) of 3.2±0.6 years. Base-line and follow-up coronary angiograms were analyzed by quantitative methods. Results Estrogen and estrogen plus medroxyprogesterone acetate produced significant reductions in low-density lipoprotein cholesterol levels (9.4 percent and 16.5 percent, respectively) and significant increases in high-density lipoprotein cholesterol levels (18.8 percent and 14.2 percent, respectively); however,...

Brachial Flow-Mediated Dilation Predicts Incident Cardiovascular Events in Older Adults The Cardiovascular Health Study

Background— The relationship between impaired brachial flow-mediated dilation (FMD) and subsequent clinical cardiovascular events is not well established, especially in older adults whose FMD is often diminished. We assessed the hypothesis that FMD predicts incident cardiovascular events in a population-based cohort of older adults. Methods and Results— FMD was measured at the 1997 to 1998 Cardiovascular Health Study clinic visit in 2792 adults aged 72 to 98 years (82.7% white, 58.6% women) recruited at 4 clinic sites in the United States. Log-rank test and Cox proportional hazard models were used to examine the association between FMD and adjudicated cardiovascular events. A total of 674 subjects (24.1%) had an adjudicated event over the 5-year follow-up period. Event-free survival rates for cardiovascular events were significantly higher in subjects with FMD greater than the sex-specific medians than in subjects with FMD less than or equal to the sex-specific medians (78.3% versus 73.6%, log-rank P=0.006). FMD remained a significant predictor of cardiovascular events after adjustment for age, gender, diabetes mellitus, cigarette smoking, systolic and diastolic blood pressure, baseline cardiovascular disease status, and total cholesterol (hazard ratio, 0.91 [95% CI, 0.83 to 0.99], P=0.02 per unit SD of FMD) but added only ≈1% to the prognostic accuracy of the best Cox model. Brachial artery diameter was also predictive of CV events in the adjusted Cox proportional hazard model (hazard ratio, 1.12 [95% CI, 1.02 to 1.28], P=0.025) and also added ≈1% to the accuracy of our best Cox model. Conclusions— FMD is a predictor of future cardiovascular events but adds very little to the prognostic accuracy of traditional cardiovascular risk scores/factors in older adults. FMD and brachial artery diameter may have similar predictive values for cardiovascular events in older adults.

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

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

Predictive Value of Brachial Flow-Mediated Dilation for Incident Cardiovascular Events in a Population-Based Study The Multi-Ethnic Study of Atherosclerosis

Background— Although brachial artery flow-mediated dilation (FMD) predicts recurrent cardiovascular events, its predictive value for incident cardiovascular disease (CVD) events in adults free of CVD is not well established. We assessed the predictive value of FMD for incident CVD events in the Multi-Ethnic Study of Atherosclerosis (MESA). Methods and Results— Brachial artery FMD was measured in a nested case-cohort sample of 3026 of 6814 subjects (mean±SD age, 61.2±9.9 years) in MESA, a population-based cohort study of adults free of clinical CVD at baseline recruited at 6 clinic sites in the United States. The sample included 50.2% female, 34.3% white, 19.7% Chinese, 20.8% black, and 25.1% Hispanic subjects. Probability-weighted Cox proportional hazards analysis was used to examine the association between FMD and 5 years of adjudicated incident CVD events, including incident myocardial infarction, definite angina, coronary revascularization (coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, or other revascularization), stroke, resuscitated cardiac arrest, and CVD death. Mean (SD) FMD of the cohort was 4.4% (2.8). In probability-weighted Cox models, FMD/unit SD was significantly associated with incident cardiovascular events in the univariate model (adjusted for age and sex) (hazard ratio, 0.79; 95% confidence interval, 0.65 to 0.97; P=0.01), after adjustment for the Framingham Risk Score (FRS) (hazard ratio, 0.80; 95% confidence interval, 0.62 to 0.97; P=0.025), and in the multivariable model (hazard ratio, 0.84; 95% confidence interval, 0.71 to 0.99; P=0.04) after adjustment for age, sex, diabetes mellitus, cigarette smoking status, systolic blood pressure, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, heart rate, statin use, and blood pressure medication use. The c statistic (area under the curve) values of FMD, FRS, and FRS+FMD were 0.65, 0.74, and 0.74, respectively. Compared with the FRS alone, the addition of FMD to the FRS net correctly reclassifies 52% of subjects with no incident CVD event but net incorrectly reclassifies 23% of subjects with an incident CVD event, an overall net correct reclassification of 29% (P<0.001). Conclusions— Brachial FMD is a predictor of incident cardiovascular events in population-based adults. Even though the addition of FMD to the FRS did not improve discrimination of subjects at risk of CVD events in receiver operating characteristic analysis, it improved the classification of subjects as low, intermediate, and high CVD risk compared with the FRS.

Comparison of Novel Risk Markers for Improvement in Cardiovascular Risk Assessment in Intermediate-Risk Individuals

CONTEXT Risk markers including coronary artery calcium, carotid intima-media thickness, ankle-brachial index, brachial flow-mediated dilation, high-sensitivity C-reactive protein (CRP), and family history of coronary heart disease (CHD) have been reported to improve on the Framingham Risk Score (FRS) for prediction of CHD, but there are no direct comparisons of these markers for risk prediction in a single cohort. OBJECTIVE We compared improvement in prediction of incident CHD/cardiovascular disease (CVD) of these 6 risk markers within intermediate-risk participants (FRS >5%-<20%) in the Multi-Ethnic Study of Atherosclerosis (MESA). DESIGN, SETTING, AND PARTICIPANTS Of 6814 MESA participants from 6 US field centers, 1330 were intermediate risk, without diabetes mellitus, and had complete data on all 6 markers. Recruitment spanned July 2000 to September 2002, with follow-up through May 2011. Probability-weighted Cox proportional hazard models were used to estimate hazard ratios (HRs). Area under the receiver operator characteristic curve (AUC) and net reclassification improvement were used to compare incremental contributions of each marker when added to the FRS, plus race/ethnicity. MAIN OUTCOME MEASURES Incident CHD defined as myocardial infarction, angina followed by revascularization, resuscitated cardiac arrest, or CHD death. Incident CVD additionally included stroke or CVD death. RESULTS After 7.6-year median follow-up (IQR, 7.3-7.8), 94 CHD and 123 CVD events occurred. Coronary artery calcium, ankle-brachial index, high-sensitivity CRP, and family history were independently associated with incident CHD in multivariable analyses (HR, 2.60 [95% CI, 1.94-3.50]; HR, 0.79 [95% CI, 0.66-0.95]; HR, 1.28 [95% CI, 1.00-1.64]; and HR, 2.18 [95% CI, 1.38-3.42], respectively). Carotid intima-media thickness and brachial flow-mediated dilation were not associated with incident CHD in multivariable analyses (HR, 1.17 [95% CI, 0.95-1.45] and HR, 0.95 [95% CI, 0.78-1.14]). Although addition of the markers individually to the FRS plus race/ethnicity improved AUC, coronary artery calcium afforded the highest increment (0.623 vs 0.784), while brachial flow-mediated dilation had the least (0.623 vs 0.639). For incident CHD, the net reclassification improvement with coronary artery calcium was 0.659, brachial flow-mediated dilation was 0.024, ankle-brachial index was 0.036, carotid intima-media thickness was 0.102, family history was 0.160 and high-sensitivity CRP was 0.079. Similar results were obtained for incident CVD. CONCLUSIONS Coronary artery calcium, ankle-brachial index, high-sensitivity CRP, and family history were independent predictors of incident CHD/CVD in intermediate-risk individuals. Coronary artery calcium provided superior discrimination and risk reclassification compared with other risk markers.

Glycemic Effects of Postmenopausal Hormone Therapy: The Heart and Estrogen/progestin Replacement Study: A Randomized, Double-Blind, Placebo-Controlled Trial

Context In observational studies, postmenopausal hormone therapy has been associated with lower fasting glucose levels. No prospective, controlled trial has evaluated the effect of postmenopausal hormone therapy on the development of diabetes mellitus. Contribution Among the 2029 women in the Heart and Estrogen/progestin Replacement Study who had coronary disease but no diabetes at baseline, 6.2% of those receiving 0.625 mg of conjugated estrogen plus 2.5 mg of medroxyprogesterone acetate and 9.5% of those receiving placebo developed diabetes. Implications Recommendations about combination postmenopausal hormone therapy should consider that for every 30 women treated for 4 years, therapy might prevent one case of diabetes. The Editors Several clinical studies have evaluated the effect of postmenopausal hormone therapy on glucose metabolism and have had disparate results. Results from randomized, controlled trials performed primarily in women without diabetes have found decreased mean fasting glucose or insulin levels among those assigned to hormone therapy (1-5) or no difference between those assigned to hormones and those assigned to placebo (6-10). Fewer clinical trials have evaluated the effect of postmenopausal hormones on fasting glucose and insulin levels among women with type 2 diabetes mellitus, but again, the results have been mixed (11-16). Observational studies have more consistently found that postmenopausal women taking hormone therapy have lower fasting glucose or hemoglobin A1c levels than those not taking hormones (17-24). In addition, some (25, 26) but not all (24, 27) observational studies have noted a decreased incidence of diabetes among users of postmenopausal hormone therapy. No randomized, controlled trial has evaluated the long-term effect of hormone therapy on diabetes incidence. To determine the effect of hormone therapy on subsequent diabetes, we analyzed data from the Heart and Estrogen/progestin Replacement Study (HERS), in which 2763 postmenopausal women with documented coronary heart disease (CHD) were randomly assigned to daily estrogen plus progestin therapy or to placebo. We evaluated the effect of hormone therapy on fasting glucose levels and incident diabetes over 4 years of follow-up. Methods Study Setting, Participants, and Design The design, methods, baseline characteristics (28), and main findings (29) of HERS have been published elsewhere. Briefly, HERS was a randomized, double-blind, placebo-controlled trial performed to evaluate daily doses of 0.625 mg of conjugated estrogen plus 2.5 mg of medroxyprogesterone acetate for the prevention of coronary events in postmenopausal women with established CHD. The trial enrolled 2763 women at 20 clinical centers in the United States between January 1993 and September 1994 and followed participants for a mean of 4.1 years. To be included in the trial, women had to be younger than 80 years of age and have CHD, as evidenced by previous myocardial infarction, coronary artery bypass graft surgery, mechanical revascularization, or angiographic evidence of coronary stenosis. Women who reported a CHD event within 6 months of randomization or who had used postmenopausal hormone therapy within 3 months of the initial screening were excluded. Those with serum triglyceride levels of 3.39 mmol/L or greater ( 300 mg/dL), fasting blood glucose levels of 16.5 mmol/L or greater ( 300 mg/dL), or uncontrolled hypertension (systolic blood pres sure 200 mg Hg or diastolic blood pressure 105 mm Hg) were also excluded. Computer-generated random numbers were used to specify the allocation sequence. Women were randomly assigned to the two treatment groups by use of a tamper-proof blocked randomization stratified by clinical center. Participants, investigators, and staff at the clinical centers; Wyeth-Ayerst Research; and those adjudicating study outcomes were blinded to medication assignment. Additional details about sample size calculations, randomization, and blinding procedures have been published elsewhere (29). For our analysis, women were classified as having diabetes at the baseline visit if they reported a physician diagnosis of diabetes, were taking diabetes medication, or had a fasting plasma glucose level of 6.9 mmol/L or greater ( 126 mg/dL). Women were classified as having impaired fasting glucose if they had a fasting glucose level of 6.0 to 6.9 mmol/L (110 to 125 mg/dL) at baseline. The remaining women were considered to have normal glucose metabolism. Data Collection At baseline, participants completed a questionnaire to ascertain age, race or ethnicity, education, smoking habits (current, former, or never), alcohol consumption (drinks per week), and exercise or walking activity. Physical examination variables measured at baseline were body weight, height, waist and hip circumference, and systolic and diastolic blood pressure. At baseline, at year 1, and at the end-of-trial visit, participants had fasting blood tests for levels of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, and lipoprotein(a) measured by the Lipoprotein Analytical Laboratory at Johns Hopkins Hospital, Baltimore, Maryland. Fasting serum glucose level was measured at baseline, at year 1, and at the end-of-trial visit. Venous blood was obtained in the morning after a 12-hour fast, and SmithKline Beecham Clinical Laboratory, Van Nuys, California, analyzed the samples using the hexokinase enzymatic method. We determined coefficients of variation by using ChemTrac (Medical Analysis Systems, Inc., Camarillo, California) control. The coefficient of variation for serum glucose level was 1.6% at a mean value (SD) of 4.2 0.05 mmol/L (77 1.0 mg/dL) and 1.1% at a mean value (SD) of 14.6 0.16 mmol/L (266 3.0 mg/dL). Adherence to study medication was reassessed every 4 months, at each visit. Ascertainment of Outcomes Diabetes incidence was not a secondary end point of the main HERS trial, but blood glucose level was prespecified as a variable that may mediate the effects of hormone therapy on CHD outcomes. We defined incident cases of diabetes by the presence of a fasting glucose level of 6.9 mmol/L or greater ( 126 mg/dL) at year 1 or at the end-of-trial visit, self-report of new diabetes or a complication directly related to diabetes, or initiation of hypoglycemic medication at any point during follow-up. Self-reported complications included diabetic neuropathy, diabetic retinopathy, diabetic foot ulcer, and diabetic renal disease. Hypoglycemia was considered a complication of diabetes if a participant taking an antidiabetic medication reported it to the study staff as an adverse event. Statistical Analysis To compare fasting glucose levels by treatment assignment at baseline, at year 1, and at the end-of-trial visit, t-tests were used. In addition, mixed linear models for repeated measures were used to assess treatment effects on fasting glucose level measured at year 1 and at the end-of-trial visit. Since mean values changed little after the year 1 visit, treatment effects were modeled by using the interaction between treatment assignment and an indicator for follow-up compared with baseline. These analyses were repeated after stratification by baseline diabetes status (diabetes, impaired fasting glucose, or normal glucose metabolism). We calculated the number needed to treat for benefit by taking the inverse of the absolute risk reduction of incident diabetes between the treatment groups. The effect of treatment assignment on incident diabetes was assessed by using Cox proportional-hazards models. Primary analyses used unadjusted intention-to-treat models; in supplementary analyses, we adjusted first for age and then for a range of potential confounders selected a priori, including age; ethnicity; education; current smoking; alcohol use; exercise; body mass index; waist circumference; and baseline use of diuretics, -blockers, angiotensin-converting enzyme inhibitors, and statins. In addition to intention-to-treat analyses, we also performed as treated analyses to determine whether the observed effect of hormone therapy on glucose levels and incident diabetes was also seen among women who adhered to the study medication. In these analyses, follow-up was censored at the beginning of the first 2-week period in which participants did not adhere to medication. To minimize potential confounding, these analyses were adjusted for baseline variables that differed between adherent and nonadherent women. We hypothesized that certain characteristics (body mass index, waist circumference, weight change, smoking, triglyceride level, high-density lipoprotein cholesterol level, hypertension, and certain cardiac medications) may mediate the effect of hormone therapy on fasting glucose level and diabetes incidence. To test this theory, we added postrandomization values of one or more hypothesized mediators as covariates to Cox regression models for incident diabetes. All analyses were conducted by using SAS software, version 8.02 (SAS Institute, Inc., Cary, North Carolina). A P value less than 0.05 was considered statistically significant. Role of the Funding Sources The funding sources had no role in the design or conduct of this analysis or in the decision to submit the paper for publication. Results Characteristics of women enrolled in HERS did not differ substantially between the hormone therapy group and the placebo group (Table 1). At the baseline examination, 734 women (26.6%) were classified as diabetic based on self-report of diagnosis or medication use (n = 640 [87.2%]) or by a fasting serum glucose level of 6.9 mmol/L or greater ( 126 mg/dL) (n = 101 [13.8%]). Impaired fasting glucose (fasting serum glucose level, 6.0 to 6.9 mmol/L [110 to 125 mg/dL]) was noted in 218 women (7.9%), and 1811 women (65.5%) were classified as nondiabetic (Table 2). Women with diabetes had higher body mass index, waist circumference, systolic

Short-term administration of estrogen and vascular responce of atherosclerotic coronary arteries

OBJECTIVES This experiment sought to determine the effect of short-term administration of estrogen on endothelium-dependent dilation in the coronary arteries of 13 surgically postmenopausal female cynomolgus monkeys. BACKGROUND Long-term estrogen replacement therapy prevents impaired endothelium-dependent dilation of atherosclerotic coronary arteries in postmenopausal female monkeys. However, it remains unclear whether this action of estrogen is due to long-term effects on plasma lipids and atherogenesis or to direct short-term effects on the endothelium. METHODS The monkeys consumed an atherogenic diet for 18 months after bilateral ovariectomy. Vascular responses were measured just before euthanasia and necropsy. Dextrose in water (control), acetylcholine, 10(-6)M, and nitroglycerin were infused for 2.5 min each both before and 20 min after intravenous injection of 54 ng ethinyl estradiol. RESULTS Quantitative coronary angiography revealed that the arteries constricted (-17 +/- 3%) in response to intracoronary infusion of acetylcholine before estrogen treatment but dilated (+5 +/- 3%) 20 min after intravenous injection of ethinyl estradiol (p less than 0.05). Coronary arteries dilated in response to nitroglycerin both before and after administration of estrogen (p greater than 0.05). Vascular responses of coronary arteries, both before and after administration of estrogen, were not associated with variation in plasma lipid concentrations, blood pressure, heart rate or plaque size. CONCLUSIONS Estrogen affects endothelium-dependent coronary dilation within 20 min of administration and may have rapid direct effects on the vascular endothelium.

Pravastatin Has Cholesterol-Lowering Independent Effects on the Artery Wall of Atherosclerotic Monkeys☆

OBJECTIVES This study examined the direct effects of pravastatin on the artery wall of atherosclerotic monkeys after dietary lipid lowering. BACKGROUND Clinical trials suggest that hepatic hydroxymethylglutaryl coenzyme A reductase inhibitors may reduce the risk of coronary heart disease out of proportion to their effect on angiographically assessed lumen stenosis. METHODS Thirty-two cynomolgus monkeys were fed an atherogenic diet for 2 years (progression phase) and then fed a lipid-lowering diet either containing (n = 14) or not containing (n = 18) pravastatin in the diet for an additional 2 years (treatment phase). As designed, total plasma cholesterol and high density lipoprotein concentrations did not differ between groups at the beginning of or during the treatment phase of the experiment (p > 0.05). RESULTS Quantitative angiography revealed that coronary arteries of the pravastatin-treated monkeys dilated 10 +/- 3%, whereas those from untreated control monkeys constricted -2 +/- 2% in response to acetylcholine (p < 0.05). There were no treatment effects on plaque size of coronary arteries measured at the end of the treatment phase of the study (0.110 +/- 0.048 mm2 [untreated] vs. 0.125 +/- 0.051 mm2 [pravastatin]; p > 0.05) or on the amount of reduction in plaque size in common iliac arteries during the treatment phase of the study (48 +/- 5% [untreated] vs. 45 +/- 6% [pravastatin]; p > 0.05). However, histochemical analysis of the atherosclerotic lesions indicated that the arteries from pravastatin-treated monkeys had significantly fewer macrophages in the intima and media, less calcification and less neovascularization in the intima (p < 0.05). CONCLUSIONS We conclude that compared with control monkeys, the arteries of pravastatin-treated monkeys had better dilator function and plaque characteristics more consistent with plaque stability than those of monkeys not receiving pravastatin. These beneficial arterial effects of pravastatin occurred independently of plasma lipoprotein concentrations and despite similar changes in plaque size between the groups.

Utility of Fast Cine Magnetic Resonance Imaging and Display for the Detection of Myocardial Ischemia in Patients Not Well Suited for Second Harmonic Stress Echocardiography

BACKGROUND Some patients referred for pharmacological stress testing with transthoracic echocardiography (TTE) are unable to undergo testing owing to poor acoustic windows. Fast cine MRI can be used to assess left ventricular contraction, but its utility for detection of myocardial ischemia in patients poorly suited for echocardiography is unknown. METHODS AND RESULTS One hundred fifty-three patients (86 men and 67 women aged 30 to 88 years) with poor acoustic windows that prevented adequate second harmonic TTE imaging were consecutively referred for MRI to diagnose inducible myocardial ischemia during intravenous dobutamine and atropine. Diagnostic studies were completed in an average of 53 minutes. No patients experienced myocardial infarction, ventricular fibrillation, exacerbation of congestive heart failure, or death. In patients who underwent computer-assisted quantitative coronary angiography, the sensitivity and specificity for detecting a >50% luminal diameter narrowing were 83% and 83%, respectively. In the 103 patients with a negative MRI examination, the cardiovascular occurrence-free survival rate was 97%. CONCLUSIONS Fast cine cardiac MRI provides a mechanism to assess left ventricular contraction and diagnose inducible myocardial ischemia in patients not well suited for stress echocardiography.