Mary C. Corretti

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.

Effect of a Single High-Fat Meal on Endothelial Function in Healthy Subjects

Although there is a well-established relation between serum cholesterol and coronary artery disease risk, individual and national variations in this association suggest that other factors are involved in atherogenesis. High-fat diet associated triglyceride-rich lipoproteins have also been suggested to be atherogenic. To assess the direct effect of postprandial triglyceride-rich lipoproteins on endothelial function, an early factor in atherogenesis--10 healthy, normocholesterolemic volunteers--were studied before and for 6 hours after single isocaloric high- and low-fat meals (900 calorie; 50 and 0 g fat, respectively). Endothelial function, in the form of flow-mediated vasoactivity, was assessed in the brachial artery using 7.5-MHz ultrasound as percent arterial diameter change 1 minute after 5 minutes of upper-arm arterial occlusion. Serum lipoproteins and glucose were determined before eating and 2 and 4 hours postprandially. Serum triglycerides increased from 94 +/- 55 mg/dl preprandially to 147 +/- 80 mg/dl 2 hours after the high-fat meal (p = 0.05). Flow-dependent vasoactivity decreased from 21 +/- 5% preprandially to 11 +/- 4%, 11 +/- 6%, and 10 +/- 3% at 2, 3, and 4 hours after the high-fat meal, respectively (all p <0.05 compared with low-fat meal data). No changes in lipoproteins or flow-mediated vasoactivity were observed after the low-fat meal. Fasting low-density lipoprotein cholesterol correlated inversely (r = -0.47, p = 0.04) with preprandial flow-mediated vasoactivity, but triglyceride level did not. Mean change in postprandial flow-mediated vasoactivity at 2, 3, and 4 hours correlated with change in 2-hour serum triglycerides (r = -0.51, p = 0.02). These results demonstrate that a single high-fat meal transiently impairs endothelial function. These findings identify a potential process by which a high-fat diet may be atherogenic independent of induced changes in cholesterol.

The postprandial effect of components of the Mediterranean diet on endothelial function.

OBJECTIVES This study investigated the postprandial effect of components of the Mediterranean diet on endothelial function, which may be an atherogenic factor. BACKGROUND The Mediterranean diet, containing olive oil, pasta, fruits, vegetables, fish, and wine, is associated with an unexpectedly low rate of cardiovascular events. The Lyon Diet Heart Study found that a Mediterranean diet, which substituted omega-3-fatty-acid-enriched canola oil for the traditionally consumed omega-9 fatty-acid-rich olive oil, reduced cardiovascular events. METHODS We fed 10 healthy, normolipidemic subjects five meals containing 900 kcal and 50 g fat. Three meals contained different fat sources: olive oil, canola oil, and salmon. Two olive oil meals also contained antioxidant vitamins (C and E) or foods (balsamic vinegar and salad). We measured serum lipoproteins and glucose and brachial artery flow-mediated vasodilation (FMD), an index of endothelial function, before and 3 h after each meal. RESULTS All five meals significantly raised serum triglycerides, but did not change other lipoproteins or glucose 3 h postprandially. The olive oil meal reduced FMD 31% (14.3 +/- 4.2% to 9.9 +/- 4.5%, p = 0.008). An inverse correlation was observed between postprandial changes in serum triglycerides and FMD (r = -0.47, p < 0.05). The remaining four meals did not significantly reduce FMD. CONCLUSIONS In terms of their postprandial effect on endothelial function, the beneficial components of the Mediterranean and Lyon Diet Heart Study diets appear to be antioxidant-rich foods, including vegetables, fruits, and their derivatives such as vinegar, and omega-3-rich fish and canola oils.

Changes in flow-mediated brachial artery vasoactivity with lowering of desirable cholesterol levels in healthy middle-aged men

Current National Cholesterol Education Program guidelines consider desirable total and low-density lipoprotein cholesterol levels to be < 200 and < 160 mg/dl, respectively, for healthy individuals without multiple coronary risk factors. To determine the extent to which these levels affect vascular function, we assessed flow-mediated (endothelium-dependent) brachial artery vasoactivity noninvasively before, during, and after cholesterol lowering (simvastatin 10 mg/day) in 7 healthy middle-aged men with cholesterol levels meeting current recommendations. Flow-mediated brachial artery vasoactivity was measured using 7.5 MHz ultrasound and expressed as percent diameter change from baseline to hyperemic conditions (1 minute following 5 minutes of blood pressure cuff arterial occlusion). Flow-mediated vasoactivity rose from 5.0 +/- 3.6% at baseline to 10.5 +/- 5.6%, 13.3 +/- 4.3%, and 15.7 +/- 4.9% (all p < 0.05) as cholesterol fell from 200 +/- 12 to 161 +/- 18, 169 +/- 16, and 153 +/- 11 mg/dl after 2, 4, and 12 weeks, respectively, of cholesterol-lowering therapy. Vasoactivity and cholesterol returned to baseline levels 12 weeks after simvastatin discontinuation. Overall, vasoactivity was found to correlate inversely with cholesterol levels (r = -0.47, p = 0.004). These data suggest that flow-mediated brachial artery vasoactivity responds rapidly to changes in cholesterol levels and that endothelial function improves by lowering cholesterol levels below recommendations of current guidelines.

Effects of exercise rehabilitation on endothelial reactivity in older patients with peripheral arterial disease

Peripheral arterial disease (PAD) is a major cause of morbidity and mortality. Endothelial function, which is a measure of vascular health, is impaired in patients with PAD. We examined the effects of 6 months of aerobic exercise rehabilitation on brachial artery endothelial function, assessed using high-frequency ultrasonography, and calf blood flow in 19 older PAD patients (age 69 +/- 1 years, mean +/- SEM) with intermittent claudication (ankle to brachial artery index of 0.73 +/- 0.04). After exercise, the time to onset of claudication pain increased by 94%, from 271 +/- 49 to 525 +/- 80 seconds (p <0.01), and the time to maximal claudication pain increased by 43%, from 623 +/- 77 to 889 +/- 75 seconds (p <0.05). Exercise rehabilitation increased the flow-mediated brachial arterial diameter by 61%, from 0.18 +/- 0.03 to 0.29 +/- 0.04 mm (p <0.005), as well as the relative change in brachial arterial diameter from the resting state by 60%, from 4.81 +/- 0.82% to 7.97 +/- 1.03% (p <0.005). Maximal calf blood flow (14.2 +/- 1.0 vs 19.2 +/- 2.0 ml/100 ml/min; p = 0.04), and postocclusive reactive hyperemic blood flow (9.8 +/- 0.8 vs 11.3 +/- 0.7 ml/100 ml/min; p = 0.1) increased 35% and 15%, respectively. In conclusion, exercise rehabilitation improved ambulatory function, endothelial-dependent dilation, and calf blood flow in older PAD patients with intermittent claudication.

Ulcerated atherosclerotic plaques in the thoracic aorta are associated with cryptogenic stroke: A multiplane transesophageal echocardiographic study

Atherosclerotic plaque ulcers > or = 2 mm in depth and width in the thoracic aorta have been implicated by autopsy study as a cause of unexplained or cryptogenic ischemic strokes. Transesophageal echocardiography (TEE) allows visualization of complex atherosclerotic lesions of the thoracic aorta. We compared the prevalence of thoracic aorta ulcerated plaques (ulcers > or = 2 mm in both depth and width) in three age-matched groups undergoing multiplane TEE: group 1, 23 patients with cryptogenic ischemic stroke; group 2, 26 patients with known-cause strokes; and group 3, 57 control patients without strokes. TEEs were interpreted in a blinded fashion. Ulcerated plaques were found in 9 (39%) group 1 patients but in only 2 (8%) group 2 patients and in only 4 (7%) group 3 patients (p < 0.001). There was an association between advancing age and the presence of ulcerated plaques (p < 0.02). We conclude that ulcerated atherosclerotic plaques in the thoracic aorta are associated with cryptogenic ischemic stroke and should be considered a potential source of cerebral emboli.

Endothelial reactivity and cardiac risk factors in older patients with peripheral arterial disease

Peripheral arterial disease (PAD) is a major cause of morbidity and mortality. Endothelium-dependent vasoreactivity, which is advocated as a measure of vascular health, is impaired in persons with cardiac risk factors and coronary artery disease. Few studies have examined the degree of endothelial dysfunction in patients with PAD. Using high-resolution external vascular ultrasound, we measured brachial artery diameter and flow at rest, and in response to reactive hyperemia (flow-mediated dilation) in 50 older patients (age 69 +/- 1 year) with PAD (ankle-to-brachial artery index of 0.67 +/- 0.03), and 50 age-matched non-PAD patients. Coronary artery disease was more prevalent in PAD than in non-PAD patients (40% vs 4%, p <0.001). Systolic blood pressure (153 +/- 4 vs 141 +/- 3 mm Hg, p <0.01), fasting glucose (129 +/- 6 vs 109 +/- 5 mg/dl, p <0.001), and pack-years smoked (54 +/- 7 vs 25 +/- 3, p <0.01) were higher in the PAD than in non-PAD patients. There were no differences in baseline brachial artery diameter, blood velocity, or flow between the 2 groups. However, the 1-minute postocclusion percent change in diameter (6.5 +/- 0.7% vs 9.8 +/- 0.7%, p <0.001) and the change in diameter (0.22 +/- 0.02 vs 0.33 +/- 0.02 mm, p <0.001) were lower in PAD than in non-PAD patients, suggesting impaired endothelium-dependent dilation. The postocclusion hyperemic velocity and blood flow were also lower in PAD than in non-PAD patients. In multiple regression analyses the low-density lipoprotein-to-high-density lipoprotein cholesterol ratio, elevated fasting glucose, and high systolic blood pressure were independent predictors of percent change in brachial artery diameter (r2 = 0.37, p <0.001). Thus, older patients with PAD had impaired endothelial dependent vasodilation compared with controls that was associated with the presence of cardiac risk factors. The effect of cardiac risk factor intervention on endothelial function in patients with PAD remains to be determined.

The genetic response to short-term interventions affecting cardiovascular function: Rationale and design of the Heredity and Phenotype Intervention (HAPI) Heart Study

BACKGROUND The etiology of cardiovascular disease (CVD) is multifactorial. Efforts to identify genes influencing CVD risk have met with limited success to date, likely because of the small effect sizes of common CVD risk alleles and the presence of gene by gene and gene by environment interactions. METHODS The HAPI Heart Study was initiated in 2002 to measure the cardiovascular response to 4 short-term interventions affecting cardiovascular risk factors and to identify the genetic and environmental determinants of these responses. The measurements included blood pressure responses to the cold pressor stress test and to a high salt diet, triglyceride excursion in response to a high-fat challenge, and response in platelet aggregation to aspirin therapy. RESULTS The interventions were carried out in 868 relatively healthy Amish adults from large families. The heritabilities of selected response traits for each intervention ranged from 8% to 38%, suggesting that some of the variation associated with response to each intervention can be attributed to the additive effects of genes. CONCLUSIONS Identifying these response genes may identify new mechanisms influencing CVD and may lead to individualized preventive strategies and improved early detection of high-risk individuals.

Effect of supplemental phytonutrients on impairment of the flow-mediated brachialartery vasoactivity after a single high-fat meal

OBJECTIVES Our objective was to determine if long-term daily administration of phytonutrient supplements can prevent the immediate adverse impact of a high-fat meal and increase the production of nitric oxide. BACKGROUND Ingestion of a high-fat meal impairs flow-mediated vasodilation of the brachial artery for at least 4 h; however, co-ingestion of vitamin antioxidants or a green salad has been shown to prevent this effect. METHODS Flow-mediated brachial artery reactivity test (BART) both before and 3 h after a 900 calorie 50 g fat meal was evaluated in 38 healthy volunteers (age 36.4 +/- 10.1 years). Subjects were randomized to four weeks of daily supplementation with a powdered fruit vegetable juice concentrate (Juice Plus [JP]) along with a complex supplement providing nutritional antioxidants and various herbal extracts (Vineyard [V]), JP alone, or a matching placebo. At three and four weeks, BART was repeated both before and after the high-fat meal. Serum nitrate/nitrite concentrations were measured at baseline and at four weeks. RESULTS Four weeks of the JP-V combination blunted the detrimental effect of the high-fat meal (-47.5 +/- 23.4% at baseline vs. -1.7 +/- 9.7% at four weeks [p < 0.05]). Four weeks of JP alone had a similar beneficial effect (-45.1 +/- 19.7% at baseline vs. -16.6 +/- 10.3% at four weeks [p < 0.05]), whereas there was no substantial effect of the placebo. In the subjects treated with supplements, concentrations of serum nitrate/nitrite increased from 78 +/- 39 to 114 +/- 62 microm/l (p < 0.02). CONCLUSIONS Daily ingestion of modest amounts of a fruit/vegetable juice concentrate with or without adjunctive phytonutrient supplementation can reduce the immediate adverse impact of high-fat meals on flow-mediated vasoactivity and increase nitrate/nitrite blood concentration.

Correlation of cold pressor and flow-mediated brachial artery diameter responses with the presence of coronary artery disease

Flow-mediated brachial and coronary artery vasoactivity are abnormal in patients with coronary artery disease (CAD) and cardiac risk factors. Cold pressor coronary artery vasoactivity is abnormal in patients with CAD, but brachial artery responses have not been studied. This study assesses whether cold pressor and flow-mediated brachial artery vasoactivity correlate independently with the presence of CAD. We studied 50 men (27 who were clinically normal, 23 with angiographically proven CAD) aged 23 to 59 years. With use of 7.5 MHz ultrasound, we measured brachial artery diameter and Doppler flow velocity at baseline, during contralateral ice water hand immersion (cold pressor), after 5 minutes of ipsilateral blood pressure cuff occlusion (flow-mediated), and after nitroglycerin administration. During cold pressor stimulation, mean brachial artery diameter increased 0.36 +/- 2.93% in normal subjects but decreased 2.38 +/- 3.32% in the CAD subjects (p = 0.006). Mean flow-mediated diameter increased 9.11 +/- 6.01% and 6.58 +/- 7.50% in normal and CAD subjects, respectively (p = NS). Responses to sublingual nitroglycerin were the same in the 2 groups. Multiple stepwise regression analysis revealed that cold pressor vasoactivity was found to correlate with smoking status (p = 0.0002) and the presence of CAD (p = 0.04). In the 32 nonsmokers undergoing assessment, only the presence of CAD correlated with cold pressor vasoactivity (p = 0.02). The associations of brachial artery vasoactivity with cardiac risk factors and CAD appear to be stimulus-dependent. Cold pressor vasoactivity correlates more closely with the presence of CAD than does flow-mediated vasoactivity.