Assessment of subclinical atherosclerosis and cardiovascular risk.

Conventional cardiac risk factors do not fully explain the incidence of coronary artery disease and coronary events. Risk stratification and therapy based solely on these conventional risk factors may exclude a population who would otherwise benefit from lifestyle and risk factor modification. Recent efforts to improve our ability to recognize individuals and populations at increased risk of coronary events have focused on the noninvasive imaging of atherosclerosis, both in coronary and extracoronary arterial beds, or the identification of "non-traditional" serum markers. We review the complimentary role of these newer methods of risk stratification in the context of conventional risk factor evaluation.

Measurement of endothelial function by brachial artery flow-mediated vasodilation.

In response to physical and chemical stimuli, the endothelium regulates vascular tone through the release of vasodilators, such as nitric oxide, and vasoconstrictors, such as endothelin. Increased blood flow is an important stimulus for endothelium-mediated vasodilation (flow-mediated vasodilation). Brachial artery flow-mediated vasodilation can be assessed using high-frequency ultrasound assessment of changes in brachial artery diameter after a 5-minute blood pressure cuff arterial occlusion. Endothelial dysfunction is demonstrated as reduced vasodilation, which is usually associated with the presence of coronary risk factors. Brachial artery flow-mediated vasodilation correlates with coronary artery flow-mediated vasodilation. Both indexes have been shown to predict long-term cardiovascular events. Whereas the clinical applicability of brachial artery flow-mediated vasodilation is unclear, it has become a frequently employed measure of endothelial function.

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.

A comparison of brachial artery flow-mediated vasodilation using upper and lower arm arterial occlusion in subjects with and without coronary risk factors.

BACKGROUND: The ultrasound assessment of brachial artery flow-mediated vasodilation provides a noninvasive means for measuring endothelial function. The test is performed using either upper or lower arm blood pressure cuff arterial occlusion to induce hyperemia. Upper arm occlusion produces a greater hyperemic stimulus. Brachial artery flow-mediated vasodilation is abnormal in the presence of coronary risk factors. HYPOTHESIS: The study sought to compare the ability of the upper and lower arm occlusion techniques to differentiate endothelial function in subjects with and without risk factors. METHODS: We measured brachial artery flow-mediated vasodilation in 20 subjects, 10 without and 10 with a single risk factor (hypertension, hypercholesterolemia, or cigarette smoking) using both the upper and lower arm occlusion techniques (5 min blood pressure cuff occlusion). Using 11 MHz ultrasound, Doppler blood flow velocities were measured before and immediately after cuff deflation. Brachial artery vasodilation was measured 1 min after cuff deflation, compared with baseline, and expressed as a percent increase. RESULTS: The immediately postocclusion hyperemia (% increase in flow) was significantly greater (p < 0.01) using the upper versus the lower arm technique in both the normal (530 +/- 152 vs. 383 +/- 51%) and the risk factor (583 +/- 153 vs. 409 +/- 114%) groups. Flow-mediated vasodilation was significantly greater (p < 0.01) using the upper arm versus the lower arm occlusion technique in both the normal (13.4 +/- 5.3 vs. 5.6 +/- 3.4%) and risk factor (7.9 +/- 3.6 vs. 3.9 +/- 2.2%) groups. Vasodilation was significantly greater (p < 0.01) in the normal subjects than in the risk factor subjects (13.4 +/- 5.3 vs. 7.9 +/- 3.6%) using the upper arm technique, but was not statistically different in the two groups using the lower arm technique. CONCLUSIONS: Our study demonstrates that upper arm compared with lower arm cuff occlusion undertaken to induce hyperemia for the assessment of brachial artery flow-mediated vasodilation results in significantly greater hyperemia and vasodilation. Flow-mediated vasodilation obtained using the upper arm technique better separates subjects with and without coronary risk factors.

The Mediterranean diet and endothelial function: why some dietary fats may be healthy.

Evidence from both diet and physiologic studies suggests that some dietary fats--but not others--impair endothelial function in the short term, possibly by a mechanism of oxidative stress. This insight may affect our advice to patients about heart-healthy eating.

Noninvasive assessment of cardiovascular risk: from Framingham to the future.

Risk assessment and risk factor modification have become essential tools in the management of cardiovascular disease. While the risk assessment defined by the Framingham Study researchers was a great leap forward, the search for additional and more precise markers of cardiovascular risk continues. Markers of thrombosis, abnormal endothelial function, plaque formation, and other events in atherosclerosis development are being evaluated. Some of the most promising for population screening are high-sensitivity C-reactive protein tests, degree of arterial stiffness (measured directly or as pulse pressure), and ankle-brachial index.

Cholesterol lowering and endothelial function.

The pathophysiology of the association between cholesterol and atherosclerosis has been thought to involve the deposition, modification, and cellular uptake of cholesterol. We now believe that the process begins with vascular injury and involves inflammation and vessel remodeling. The vascular endothelium actively regulates vascular tone, lipid breakdown, thrombogenesis, inflammation, and vessel growth, all of which are important factors in the development of atherosclerosis. Endothelial dysfunction promotes atherosclerosis through vasoconstriction, monocyte and platelet adhesion, thrombogenesis, and cytokine and growth factor stimulation and release. An important component of endothelial dysfunction is reduced availability of nitric oxide, which is caused by low-density lipoproteins, especially if they are oxidized. This reduced availability appears to occur through a combination of decreased production, abnormal signaling, and increased destruction by oxygen-free radicals. Concurrently, endothelium-mediated vasoconstrictors, adhesion molecules, cytokines, growth factors, and thrombogenic factors, such as endothelin, are increased by oxidized low-density lipoprotein. Several studies have shown improvements in endothelial function with cholesterol lowering, which may explain the early and substantial reductions in major cardiovascular events associated with cholesterol lowering.

Brachial artery ultrasound: a noninvasive tool in the assessment of triglyceride-rich lipoproteins.

In recent years, endothelial dysfunction has been identified as an early feature of atherosclerosis. Endothelial function can be measured noninvasively by using brachial artery ultrasound. A variety of factors associated with atherosclerosis also impair endothelial function. Some of these factors are lipoproteins such as various forms of low-density lipoproteins, postprandial chylomicron remnants, fasting triglyceride-rich particles, and free fatty acids. A high-fat diet also has an adverse effect on endothelial function. Several interventions can improve endothelial function and, at the same time, reduce cardiovascular events. Measuring endothelial function may eventually serve as a useful index to determine an individual's risk for coronary artery disease.

Assessing the appropriateness of coronary revascularization: the University of Maryland Revascularization Appropriateness Score (RAS) and its comparison to RAND expert panel ratings and American College of Cardiology/American Heart Association guidelines with regard to assigned appropriateness rating and ability to predict outcome.

BACKGROUND: Significant regional variation in procedural frequencies has led to the development of the RAND and American College of Cardiology/American Heart Association (ACC/AHA) guidelines; however, they may be difficult to apply in clinical practice. The University of Maryland Revascularization Appropriateness Score (RAS) was created to address the need for a simplified point scoring system. HYPOTHESIS: The study was undertaken to compare revascularization appropriateness ratings yielded by the RAND Expert Panel Ratings, ACC/AHA guidelines, and the University of Maryland RAS. METHODS: We applied these three revascularization appropriateness scoring systems to 153 catheterization laboratory patients with a variety of cardiac diagnoses and treatments. For each patient, appropriateness scores assigned by each of the three systems were compared with each other and with the actual treatment delivered. Concordance of care with appropriateness score was then correlated with outcome. RESULTS: There were significant differences among all three scoring systems in their ratings and in the concordance of treatment with appropriateness rating. When treatment provided was concordant with RAND ratings, there was a lower occurrence of subsequent coronary artery bypass grafting (CABG), the composite end point of either CABG or percutaneous transluminal coronary angioplasty (PTCA), and the composite end point of death, myocardial infarction (MI), or revascularization. When treatment was concordant with the ACC/AHA guidelines, there was lower occurrence of all-cause mortality, PTCA, the composite end point of either CABG or PTCA, and the composite end point of death, MI, or revascularization. When treatment provided was concordant with the RAS, there was lower occurrence of cardiac death, all-cause death, CABG, the composite end point of either CABG or PTCA, and the composite end point of death, MI, or revascularization. CONCLUSIONS: The RAS is a simple scoring system to assess revascularization appropriateness. When the RAND, ACC/AHA, and RAS systems are compared in a catheterization laboratory population, they rate the same patient differently and vary in their correlation of appropriateness rating with outcome.

Cholesterol, cholesterol lowering, and endothelial function.

A strong relationship between hypercholesterolemia and atherosclerosis has been established through epidemiological, experimental, and clinical trial data. Traditional theories on the pathophysiology of this relationship involve the deposition, modification, and cellular uptake of cholesterol, and the release of inflammatory and growth factors resulting in smooth muscle cell proliferation and collagen matrix production. The vasculature has recently been found to be an active and complex organ, with the endothelium playing a controlling role in vascular tone, lipid breakdown, thrombogenesis, inflammation, and vessel growth. In the presence of risk factors such as hypercholesterolemia, the endothelium promotes vasoconstriction, monocyte and platelet adhesion, thrombogenesis, and growth factor release. A high-fat diet also directly impairs endothelial function and increases coagulation factors. Endothelial dysfunction is associated with decreased availability of the predominant vasodilator nitric oxide, possibly by increased destruction by oxygen free radicals. This dysfunctional state appears before the earliest anatomic evidence of atherosclerosis and may represent an important initial step in its development. Several studies have shown improvements in endothelial function with cholesterol lowering in both normal individuals and those with coronary heart disease. Short-term improvements in endothelial-dependent vasodilation and adhesion molecule expression have also been reported with antioxidant therapy. These observations suggest that atherosclerosis is at least in part caused by endothelial dysfunction that favors cellular proliferation. This new understanding helps to explain the early and substantial reductions in major cardiovascular events associated with cholesterol lowering.

Effect of beta-blockade on mortality among high-risk and low-risk patients after myocardial infarction.

BACKGROUND: Long-term administration of beta-adrenergic blockers to patients after myocardial infarction improves survival. However, physicians are reluctant to administer beta-blockers to many patients, such as older patients and those with chronic pulmonary disease, left ventricular dysfunction, or non-Q-wave myocardial infarction. METHODS: The medical records of 201,752 patients with myocardial infarction were abstracted by the Cooperative Cardiovascular Project, which was sponsored by the Health Care Financing Administration. Using a Cox proportional-hazards model that accounted for multiple factors that might influence survival, we compared mortality among patients treated with beta-blockers with mortality among untreated patients during the two years after myocardial infarction. RESULTS: A total of 34 percent of the patients received beta-blockers. The percentage was lower among the very elderly, blacks, and patients with the lowest ejection fractions, heart failure, chronic obstructive pulmonary disease, elevated serum creatinine concentrations, or type 1 diabetes mellitus. Nevertheless, mortality was lower in every subgroup of patients treated with beta-blockade than in untreated patients. In patients with myocardial infarction and no other complications, treatment with beta-blockers was associated with a 40 percent reduction in mortality. Mortality was also reduced by 40 percent in patients with non-Q-wave infarction and those with chronic obstructive pulmonary disease. Blacks, patients 80 years old or older, and those with a left ventricular ejection fraction below 20 percent, serum creatinine concentration greater than 1.4 mg per deciliter (124 micromol per liter), or diabetes mellitus had a lower percentage reduction in mortality. Given, however, the higher mortality rates in these subgroups, the absolute reduction in mortality was similar to or greater than that among patients with no specific risk factors. CONCLUSIONS: After myocardial infarction, patients with conditions that are often considered contraindications to beta-blockade (such as heart failure, pulmonary disease, and older age) and those with nontransmural infarction benefit from beta-blocker therapy.

Improving the quality of care for Medicare patients with acute myocardial infarction: results from the Cooperative Cardiovascular Project.

CONTEXT: Medicare has a legislative mandate for quality assurance, but the effectiveness of its population-based quality improvement programs has been difficult to establish. OBJECTIVE: To improve the quality of care for Medicare patients with acute myocardial infarction. DESIGN: Quality improvement project with baseline measurement, feedback, remeasurement, and comparison samples. SETTING: All acute care hospitals in the United States. PATIENTS: Preintervention and postintervention samples included all Medicare patients in Alabama, Connecticut, Iowa, and Wisconsin discharged with principal diagnoses of acute myocardial infarctions during 2 periods, June 1992 through December 1992 and August 1995 through November 1995. Indicator comparisons were made with a random sample of Medicare patients in the rest of the nation discharged with acute myocardial infarctions from August 1995 through November 1995. Mortality comparisons involved all Medicare patients nationwide with inpatient claims for acute myocardial infarctions during 2 periods, June 1992 through May 1993 and August 1995 through July 1996. INTERVENTION: Data feedback by peer review organizations. MAIN OUTCOME MEASURES: Quality indicators derived from clinical practice guidelines, length of stay, and mortality. RESULTS: Performance on all quality indicators improved significantly in the 4 pilot states. Administration of aspirin during hospitalization in patients without contraindications improved from 84% to 90% (P< .001), and prescription of beta-blockers at discharge improved from 47% to 68% (P < .001). Mortality at 30 days decreased from 18.9% to 17.1% (P = .005) and at 1 year from 32.3% to 29.6% (P < .001). These improvements in quality occurred during a period when median length of stay decreased from 8 days to 6 days. Performance on all quality indicators except reperfusion was better in the pilot states than in the rest of the nation in 1995, and the differences were statistically significant for aspirin use at discharge (P < .001), beta-blocker use (P < .001), and smoking cessation counseling (P = .02). Postinfarction mortality was not significantly different between the pilot states and the rest of the nation during the baseline period, although it was slightly but significantly better in the pilot states during the follow-up period (absolute mortality difference at 1 year, 0.9%; P = .004). CONCLUSIONS: The quality of care for Medicare patients with acute myocardial infarction has improved in the Cooperative Cardiovascular Project pilot states. Performance on the defined quality indicators appeared to be better in the pilot states than in the rest of the nation in 1995 and was associated with reduced mortality.

Smoking correlates with flow-mediated brachial artery vasoactivity but not cold pressor vasoactivity in men with coronary artery disease.

Impaired endothelial function is observed as altered vasomotion in both the peripheral and coronary circulation in the presence of cardiovascular risk factors and early atherogenesis. An improvement in endothelium-dependent vasoactivity has been reported with both cholesterol reduction and smoking cessation. This study was performed to determine whether smoking status in coronary artery disease (CAD) effects both flow-mediated and cold pressor vasoactivity. We studied 25 men (ages 30-59), 12 smokers and 13 nonsmokers with angiographically documented coronary artery disease and cardiac risk factors who were grouped as smokers and nonsmokers. Using 7.5 MHz ultrasound, we measured brachial artery diameter and Doppler flow velocity at baseline, following 5 mins of ipsilateral blood pressure cuff occlusion and release (flow-mediated), during contralateral ice water hand immersion (cold pressor test) and after sublinqual nitroglycerin administration (an endothelium-independent vasodilator). Flow-mediated percent diameter change was significantly less in the smokers than nonsmokers (1.9 +/- 5.7% vs 11.4 +/- 7.2%, p < 0.001). Both smokers and nonsmokers responded similarly to the cold pressor test (-3.9 +/- 2.3 vs -1.2 +/- 0.2%) and nitroglycerin (15.1 +/- 7.6 vs 17.5 +/- 8.3%). Cholesterol level did not appear to be an independent determinant of flow-mediated vasoactivity when smoking status was taken into account. Flow-mediated vasoactivity is associated with smoking status in the presence of coronary artery disease but cold pressor induced vasoactivity is not.

The management of hypercholesterolemia in patients with coronary artery disease: guidelines for primary care.

More than 10 million individuals in the United States currently have symptomatic coronary artery disease (CAD). Asymptomatic CAD is even more prevalent. CAD in the United States is responsible for approximately 1.5 million myocardial infarctions, 500,000 deaths, and a total economic burden in excess of $120 billion annually. Fortunately, CAD is preventable in many individuals. Our understanding of CAD has steadily progressed throughout the 20th century, and now several lines of evidence support the importance of cholesterol in both the genesis and management of coronary atherosclerosis. Following identification of the presence of cholesterol in atheromas, Anitschkov early this century demonstrated that atherosclerotic lesions can be induced in susceptible animals by high-saturated-fat and cholesterol diets. These lesions regressed when low-fat and cholesterol diets were resumed. In the 1970s and 1980s, findings from the landmark Framingham Heart, Seven Countries, and Multiple Risk Factor Intervention Trial studies firmly established that hypercholesterolemia was a major risk factor for cardiovascular morbidity and mortality. During the 1980s and 1990s, 21 of 22 angiographic trials demonstrated reduced progression of coronary and/or carotid artery disease using lifestyle, drug, and surgical means for reducing cholesterol. The later trials commonly employed hydroxymethylglutaryl coenzyme A reductase inhibitors (statins), reflecting increasing clinical use of these drugs. In 1988, the Adult Treatment Panel of the National Cholesterol Education Program (NCEP) published guidelines on testing and treating hypercholesterolemic patients, which outlined a more aggressive approach to cholesterol lowering than was currently in practice. Since 1994, five large cardiovascular event trials and a large angiographic trial have shown that aggressive cholesterol lowering reduces both cardiac morbidity and mortality, largely substantiating the NCEP guidelines. Although important clinical questions remain regarding patient subsets and treatment goals, lifestyle changes and appropriate drug therapy have proved to be highly effective in preventing initial and recurrent cardiovascular events.