Correlation between endothelial function and hypertension Content Points: The endothelium plays a pivotal role in maintaining hemostasis and tone in blood vessels. The impact of hypertension on endothelial function is seen in these two studies. Panza and colleagues, as seen on the left, showed that hypertensive patients have reduced endothelium-mediated forearm blood flow during cholinergic vasodilation, which was induced by infusion of acetylcholine, as compared with subjects with normal blood pressure.36 Taddei and colleagues showed that endothelium-mediated vasodilation in the forearm is reduced in subjects with a family history of hypertension compared with those who do not have a family history of hypertension.37 Both studies show that hypertension is associated with changes in the endothelium that lead to endothelial dysfunction.

Correlation between endothelial function and atherosclerosis Content Points: Hashimoto and colleagues examined whether endothelial dysfunction in the brachial artery is related to the intima-media thickness of the carotid artery in 34 men with atherosclerosis (mean age 61 years) and 33 age-matched men without atherosclerosis.38 The change in FMD in the brachial artery in reactive hyperemia is widely accepted as a means to evaluate endothelial function. Intima-media thickness of the common carotid artery is used as a surrogate end-point to assess the progression and regression of atherosclerosis. As shown in the slide, the group with atherosclerosis had significantly greater intima-media thickness of the common carotid artery than the control group (P < .05). During reactive hyperemia, the increase in FMD the group with atherosclerosis was significantly smaller than in the control group (P < .01). There was a significant negative correlation between the intima-media thickness of the carotid artery and percent increased FMD. These findings support the concept that endothelial dysfunction is significantly related to atherogenesis. The next few slides will show recent findings regarding the correlation between endothelial function and cardiovascular risk.

Severe endothelial dysfunction associated with increased CV risk in patients with mild CAD Content Points: In this study 157 patients with mildly diseased coronary arteries were studied to determine the association of endothelial dysfunction and future cardiac events.39 Patients were divided into three groups on the basis of their response to acetylcholine. Group 1 (N = 83) included patients with normal coronary endothelial function, which was defined as an increase of > 50% in coronary blood flow in response to acetylcholine. Group 2 (N = 32) included patients with mild endothelial dysfunction, which was defined as a 0% to 50% change in coronary blood flow in response to acetylcholine. Group 3 (N = 42) included patients with severe endothelial dysfunction, which was defined as a decrease in (< 0% change) in coronary blood flow in response to acetylcholine. Over an average 28-month follow-up, none of the patients from groups 1 or 2 had cardiac events. However, 6 (14%) with severe endothelial dysfunction had 10 cardiac events (P < .05 vs groups 1 and 2). Cardiac events included MI, percutaneous or surgical coronary revascularization, and/or cardiac death. Endothelial dysfunction was also evaluated according the epicardial coronary artery diameter response to acetylcholine [% CAD (Ach)]. This division produced results identical to the original classification. This study extends previous observations that early coronary atherosclerosis is associated with endothelial dysfunction. It demonstrates that severe endothelial dysfunction in patients with nonobstructive CAD is associated with increased cardiac events.

Endothelial dysfunction predicts cardiovascular events: 5-year follow-up in patients with angina Content Points: A 5-year follow up of 73 patients with angina pectoris showed endothelial dysfunction, detected by brachial artery ultrasound response to reactive hyperemia, provides prognostic information regarding future cardiac events.40 Cardiac events included MI, or the need for coronary revascularization. Patients with preserved FMD (> 10% change in response to reactive hyperemia, N = 27) and patients with impaired FMD (< 10% change in response to reactive hyperemia, N = 46) differed in their rates of coronary angioplasty (7% vs 37% P = .0003) and bypass surgery (0 vs 15%, P = .009). The groups had similar rates of MI (11% vs 20%, NS), probably due to the low incidence (N = 12) within the 5-year follow-up. FMD evaluation had an 86% sensitivity and a 51% specificity for identifying all cardiac events and a 93% predictive value. After factoring in other risk factors, impaired endothelial function remained independently predictive of cardiac events (P = .0009).

Endothelial function vs clinical outcome in patients with CAD Content Points: In this study, 150 patients with normal or minimally diseased coronary arteries (< 30% diameter stenosis) were studied to determine the relation of endothelial dysfunction to clinical outcomes.41 FMD in the coronary artery was measured following infusion of acetylcholine. Patients were categorized into three groups including low, middle, and upper range of endothelial dysfunction based on the increase in coronary flow with acetylcholine. They were followed for a mean of 24 months. During follow-up, 7 subjects (14%) in the lower third of the study groups developed new symptomatic and angiographically proven CAD, including cardiac death, need for coronary bypass surgery, non-fatal MI, and new or worsening angina (P = .01 for the lower third vs other two groups). Among those with milder endothelial dysfunction, cardiac events occurred in 2% of the patients in the middle group and there were no cardiac events in uppermost group.

Carotid plaque is a marker of CV risk Content Points: This study looked at the associations between carotid-artery intima and media thickness (IMT) and the incidence of new MI or stroke in 4476 subjects aged >65 years without clinical cardiovascular disease.42 The incidence of cardiovascular events correlated with carotid IMT measurements. The relative risk of MI or stroke increased with IMT thickness (P < .001). The estimated cumulative rate of the combined end point for the highest quintile of the combined wall-thickness measure was > 25% at 7 years as compared with < 5% for the lowest quintile. The yearly incidence of the combined end point of MI or stroke increased with increasing quintiles for each of the measures of IMT.

Carotid atherosclerosis and systolic blood pressure Content Points: This study found that hypertensive patients managed in general practice had more advanced atherosclerosis and LVH than matched normotensive patients.43 The case-controlled study included 500 hypertensive cases (systolic BP > 160 mm Hg or diastolic BP > 95 mm Hg) and 506 age- (mean 61 years) and sex- (54% female) matched normotensive controls. Mean systolic BP/diastolic BP levels in 399 treated cases (145/87 mm Hg) were lower than those in untreated cases (158/94 mm Hg) but higher than those in controls (133/82 mm Hg) (P < .0001). Mean carotid artery wall thickness was 10% greater in hypertensive patients than in normotensive controls and LV mass was 14% greater (P < .001), but both were similar in treated and untreated cases of hypertension. Thus hypertensive patients, whether treated with antihypertensive agents or not, had more advanced atherosclerosis and LVH than did matched normotensive patients. Hypertensive patients managed in general practice had persisting atherosclerosis and LVH, despite the fact that the majority were receiving antihypertensive treatment. In multivariate analysis, blood pressure and body mass index were both directly and independently related to carotid wall thickness and LVH (P < .0001). Both obesity and hypertension were cited as potentially modifiable factors to decrease LVH.