Early evidence of endothelial vasodilator dysfunction at coronary branch points

Intracoronary acetylcholine produces endothelium-dependent dilation of normal coronary arteries and paradoxical constriction of atherosclerotic vessels. Regional differences in endothelium-dependent vasomotion, however, have not been studied in relation to the nonuniform development of atherosclerosis. We compared the vasomotor response to increasing doses of acetylcholine of angiographically smooth coronary artery segments prone to atherosclerosis (coronary branch points) with segments remote from branch points (straight segments). In patients with entirely smooth coronary arteries and a dilator response to acetylcholine (group 1, n = 7), branch points and straight segments demonstrated equal and significant dose-dependent dilation to acetylcholine (14.7 +/- 8.9% and 12.3 +/- 12.7%, respectively; p identical to NS). In patients with early atherosclerosis as manifest by luminal coronary irregularities, the lowest dose of acetylcholine (10(-8) M) produced constriction at branch points and slight dilation at straight segments (-6.3 +/- 7.4% vs. +2.2 +/- 7.3%, p less than 0.05). At higher doses of acetylcholine, both branch point and straight segments constricted, but constriction remained more pronounced at branch points. Both branch point and straight segments, however, retained the ability to dilate to the non-endothelium-dependent agent, nitroglycerin. In a third group of patients with angiographically entirely smooth coronary arteries but without dilation to acetylcholine, constriction to acetylcholine again occurred first at branch points. Thus, coronary branch points demonstrate increased sensitivity to acetylcholine-induced constriction in patients with angiographic evidence of early coronary atherosclerosis and in middle-aged patients with smooth coronary arteries. These segments, however, retain the ability to dilate to nitroglycerin. Whether this early evidence of defective endothelium-dependent vasodilation predicts the later development of occlusive atherosclerosis is not yet known.     

Relation of the level of high-density lipoprotein subfractions to the presence and extent of coronary artery disease.

Plasma lipid profiles, including high-density lipoprotein (HDL) subfractions HDL2 and HDL3, were obtained in 115 men undergoing coronary angiography to assess the relation of lipid levels to coronary artery disease (CAD). CAD was present in 87 patients (76%) and absent in 28 (24%). The largest difference between the 2 groups were observed for HDL2 cholesterol, with a mean of 0.13 mmol/liter (5 mg/dl) in patients with CAD compared with 0.25 mmol/liter (10 mg/dl) in those without CAD (p less than 0.005). Smaller differences were found for HDL3 (1.02 mmol/liter [39 mg/dl] vs 1.19 mmol/liter [46 mg/dl]; p less than 0.005) and HDL (1.15 vs 1.42 mmol/liter [45 vs 55 mg/dl]; p less than 0.001) cholesterol, and apolipoprotein A-1 (1.37 vs 1.50 g/liter; p less than 0.01) and plasma triglycerides (1.79 vs 1.38 mmol/liter [159 vs 122 mg/dl]; p less than 0.05). No significant difference was found for plasma and low-density lipoprotein cholesterol, and apolipoprotein B levels. Simple regression analysis revealed that the most powerful independent variable associated with the extent of CAD was HDL2 cholesterol (Spearman rho = 0.311; p less than 0.001). Stepwise multiple regression analysis proved HDL2 cholesterol and age to be the strongest predictors of extent of CAD. The level of HDL2 cholesterol was reasonably well correlated with HDL cholesterol (r2 = 0.6; p less than 0.0001), but less so with plasma apolipoprotein A-1 (r2 = 0.4; p less than 0.0001). The data add to the growing body of information demonstrating an important association of HDL (and more specifically HDL2) with CAD in men.     

Low density lipoprotein cholesterol and coronary microvascular dysfunction in hypercholesterolemia

OBJECTIVES: The present study evaluates the impact of total cholesterol (TC) and its subfractions on coronary flow reserve (CFR), an index of the integrated function of the coronary circulation, in asymptomatic subjects. BACKGROUND: Endothelial dysfunction of the coronary microcirculation has been reported in asymptomatic subjects with hypercholesterolemia. METHODS: Using oxygen-15-labeled water and positron emission tomography, myocardial blood flow (MBF, in ml/min per g) was measured at rest and during intravenous adenosine (140 microg/kg body weight per min) in 80 asymptomatic nonsmoking men: group 1 (n = 61; age 45 +/- 7 years) had normal TC (< or =6.5 mmol/liter or < or =250 mg/dl) and group 2 (n = 19; age 48 +/- 10 years) had elevated TC. RESULTS: Total cholesterol were 5.1 +/- 0.8 and 7.2 +/- 0.7 mmol/liter in groups 1 and 2 (p < 0.0005), respectively; low density lipoprotein (LDL) cholesterol levels were 3.2 +/- 0.8 and 4.9 +/- 0.7 mmol/liter (p < 0.0005); high density lipoprotein (HDL) cholesterol levels were 1.1 +/- 0.3 and 1.0 +/- 0.4 mmol/liter (p = NS); and triglyceride levels were 1.8 +/- 1.3 and 3.0 +/- 1.8 mmol/liter (p < 0.005). Groups 1 and 2 did not differ with regard to MBF at rest (0.87 +/- 0.14 vs. 0.84 +/- 0.14), MBF during adenosine (3.63 +/- 1.02 vs. 3.30 +/- 0.86) or CFR (4.23 +/-1.29 vs. 3.95 +/- 0.93). A significant but weak correlation was found between CFR and HDL in group 1 (r = 0.29, p < 0.05), but not in group 2. In contrast, a significant inverse correlation between LDL and CFR was found in group 2 (r = -0.61, p < 0.05), but not in group 1. CONCLUSIONS: Low density lipoprotein cholesterol but not TC correlated inversely with CFR in hypercholesterolemic subjects. Thus, LDL-induced coronary microvascular dysfunction could play an important role in the pathogenesis of coronary artery disease and its complications.     

Predictive value for coronary heart disease of baseline high-density and low-density lipoprotein cholesterol among Fredrickson type IIa subjects in the Helsinki Heart Study

In the Helsinki Heart Study 2,590 subjects (63.5% of total) had a type IIa hyperlipoproteinemia at screening. Baseline low-density lipoprotein (LDL) cholesterol (mean 193 mg/dl; 5 mmol/liter) and high-density lipoprotein (HDL) cholesterol (mean 50.2 mg/dl; 1.3 mmol/liter) showed no statistical correlation (r = 0.046). Both the placebo (1,293 patients) and gemfibrozil groups (1,297 patients) were divided into tertiles by baseline HDL and LDL cholesterol to determine the relative predictive risk of developing coronary artery disease. In a population with elevated LDL cholesterol, it is significant that the lipoprotein fraction with the greatest predictive value was HDL cholesterol. The severity of LDL cholesterol elevation did not provide any differential predictive value for coronary artery disease.     

Lipoprotein cholesterol, apolipoprotein A-I and B and lipoprotein (a) abnormalities in men with premature coronary artery disease.

The prevalence of abnormalities of lipoprotein cholesterol and apolipoproteins A-I and B and lipoprotein (a) [Lp(a)] was determined in 321 men (mean age 50 +/- 7 years) with angiographically documented coronary artery disease and compared with that in 901 control subjects from the Framingham Offspring Study (mean age 49 +/- 6 years) who were clinically free of coronary artery disease. After correction for sampling in hospital, beta-adrenergic medication use and effects of diet, patients had significantly higher cholesterol levels (224 +/- 53 vs. 214 +/- 36 mg/dl), triglycerides (189 +/- 95 vs. 141 +/- 104 mg/dl), low density lipoprotein (LDL) cholesterol (156 +/- 51 vs. 138 +/- 33 mg/dl), apolipoprotein B (131 +/- 37 vs. 108 +/- 33 mg/dl) and Lp(a) levels (19.9 +/- 19 vs. 14.9 +/- 17.5 mg/dl). They also had significantly lower high density lipoprotein (HDL) cholesterol (36 +/- 11 vs. 45 +/- 12 mg/dl) and apolipoprotein A-I levels (114 +/- 26 vs. 136 +/- 32 mg/dl) (all p less than 0.005). On the basis of Lipid Research Clinic 90th percentile values for triglycerides and LDL cholesterol and 10th percentile values for HDL cholesterol, the most frequent dyslipidemias were low HDL cholesterol alone (19.3% vs. 4.4%), elevated LDL cholesterol (12.1% vs. 9%), hypertriglyceridemia with low HDL cholesterol (9.7% vs. 4.2%), hypertriglyceridemia and elevated LDL cholesterol with low HDL cholesterol (3.4% vs. 0.2%) and Lp(a) excess (15.8% vs. 10%) in patients versus control subjects, respectively (p less than 0.05). Stepwise discriminant analysis indicates that smoking, hypertension, decreased apolipoprotein A-I, increased apolipoprotein B, increased Lp(a) and diabetes are all significant (p less than 0.05) factors in descending order of importance in distinguishing patients with coronary artery disease from normal control subjects. Not applying a correction for beta-adrenergic blocking agents, sampling bias and diet effects leads to a serious underestimation of the prevalence of LDL abnormalities and an overestimation of HDL abnormalities in patients with coronary artery disease. However, 35% of patients had a total cholesterol level less than 200 mg/dl after correction; of those patients, 73% had an HDL cholesterol level less than 35 mg/dl.     

Cholesterol lowering with pravastatin improves resistance artery endothelial function: report of six subjects with normal coronary arteriograms

STUDY OBJECTIVES: Improvement in coronary artery endothelial function has been demonstrated after cholesterol lowering in hypercholesterolemic patients with significant atherosclerosis. However, to our knowledge, no previous study has shown improvement in resistance artery function in subjects with normal coronary arteries after cholesterol lowering. The purpose of our study was to investigate the effect of cholesterol lowering with pravastatin on coronary resistance artery endothelial function in the setting of angiographically normal coronary arteries. METHODS: Invasive testing of coronary endothelial and vasomotor function was performed at baseline and after 6 months of pravastatin treatment in six patients with normal coronary arteriograms. RESULTS: After 6 months of pravastatin treatment, low-density lipoprotein cholesterol level dropped from 157+/-11 to 117+/-8 mg/dL (p = 0.02) and percent increase in coronary blood flow after acetylcholine improved from 97+/-13% to 160+/-16% (p = 0.01). There was a trend (p = 0.17) toward enhanced epicardial dilation in response to acetylcholine after pravastatin treatment when compared with the baseline study. CONCLUSIONS: Our study demonstrates significant improvement in coronary resistance artery endothelial function after 6 months of cholesterol lowering with pravastatin in six subjects presenting with chest pain who were found to have normal coronary arteriograms. A trend toward improved epicardial vasomotion was also observed.     

Endothelium-dependent dilator response to substance P in patients with coronary spastic angina.

OBJECTIVE. This study was designed to examine whether patients with coronary spastic angina have an impaired coronary artery dilator response to substance P, an endothelium-dependent vasodilator. BACKGROUND. Impairment of the endothelium-dependent vasodilator response has been suggested to be involved in the pathogenesis of coronary spasm. METHODS. In 11 patients with coronary spastic angina and 11 control patients, substance P was infused into the coronary artery at 20 pmol/min for 5 min. Incremental doses of acetylcholine were then injected into the coronary artery. The effects of these drugs and nitroglycerin on the coronary artery diameter were quantitatively analyzed. RESULTS. Heart rate, systolic blood pressure and rate-pressure product did not change after substance P infusion. In 12 coronary arteries of the patients with coronary spastic angina, spasm was induced with acetylcholine. At the site of coronary spasm documented, the lumen diameter, which was 1.6 +/- 0.5 mm at baseline, increased to 2.1 +/- 0.7 mm after substance P infusion (p less than 0.01). It decreased to 0.2 +/- 0.3 mm during acetylcholine-induced spasm (p less than 0.001) and increased to 2.3 +/- 0.8 mm after nitroglycerin administration (p less than 0.001 vs. baseline and p = NS vs. after substance P infusion). Of the 12 arteries with spasm, 5 were angiographically normal and the other 7 were minimally or moderately atherosclerotic: the diameter change after substance P was +28 +/- 20% and +30 +/- 22%, respectively (p = NS). In control patients, the diameter of the middle portion of the left anterior descending artery, which was 2.0 +/- 0.4 mm at baseline, increased to 2.5 +/- 0.4 mm after substance P infusion (p less than 0.001). The diameter changes after substance P infusion were not different between the patients with coronary spastic angina and control patients. CONCLUSIONS. Substance P dilated the artery with spasm of the patients with coronary spastic angina to a degree similar to that in control patients, indicating the preserved endothelium-dependent dilator response at the site of coronary spasm by way of substance P receptor.     

High-density lipoprotein cholesterol in coronary artery disease patients: is it as low as expected?

OBJECTIVE: Epidemiological studies demonstrated that the high-density lipoprotein (HDL) cholesterol levels in Turkish people are lower compared to other populations. In the present study, the HDL cholesterol levels in subjects with or without angiographically documented coronary artery disease (CAD) were compared to assess whether HDL cholesterol levels were as low as expected. METHODS: A total of 420 consecutive patients with age of > or =40 years (160 female, 260 male) undergoing coronary angiography were included in the study. Patients receiving fibric acid derivatives or niacin were excluded. Coronary artery disease group consisted of those patients with any atherosclerotic lesions in coronary angiography, and non-CAD group consisted of patients with no such lesions. RESULTS: Average HDL cholesterol levels were 45.0+/-10.5 mg/dl (44.4+/-10.9 mg/dl in men, 46.5+/-9.6 mg/dl in women) in CAD group, and 47.7+/-9.0 mg/dl (45.5+/-8.4 mg/dl in men, 48.9+/-9.2 mg/dl in women) in non-CAD group (p<0.05). CONCLUSION: Compared to non-CAD patients, patients with CAD had lower HDL cholesterol levels, but in general HDL cholesterol levels were not as low as to be expected from epidemiological studies.     

Insulin resistance affects endothelium-dependent acetylcholine-induced coronary artery response.

AIMS: This study was designed to investigate the relationship between insulin resistance and the acetylcholine-induced endothelium-dependent coronary artery response in patients without angiographically significant atherosclerotic coronary artery disease and to elucidate the pathophysiological significance of insulin resistance in the early stages of coronary atherosclerosis. METHODS AND RESULTS: Insulin resistance was calculated from fasting plasma glucose and insulin concentration using homeostasis model assessment in 40 patients suspected of having ischaemic heart disease, but without angiographic evidence of atherosclerotic coronary artery disease defined as a discrete stenosis or intimal irregularity. They were selected for an acetylcholine provocation test in both left and right coronary arteries. The homeostasis model assessment level was higher in 16 acetylcholine-positive patients than in 24 acetylcholine-negative patients (1.84+/-1.24 vs 0.72+/-0.62, P<0.01). Comparisons of the percentage change in vessel lumen diameter after the acetylcholine test in each of proximal, mid and distal segments of three coronary arteries among the three groups of low (less than 0.7; n=13), intermediate (0.7 to 1.4; n=13), and high homeostasis model assessment level (more than 1.4; n=14) revealed that a higher level resulted in a worse acetylcholine-induced constrictive response in coronary arteries. CONCLUSION: These results suggest that there is an association between high insulin resistance and coronary vascular endothelial cell dysfunction, and that insulin resistance may be an indicator of early stage coronary artery atherosclerosis not detectable by angiography.     

Effects of estrogen replacement therapy on serum lipid values and angiographically defined coronary artery disease in postmenopausal women.

To examine the effects of estrogen replacement on lipids and angiographically defined coronary artery disease (CAD) in postmenopausal women, lipid profiles were obtained in 90 consecutive postmenopausal women undergoing diagnostic coronary angiography. Eighteen women (20%) were receiving estrogen and 72 (80%) were not. CAD (defined as greater than or equal to 25% luminal diameter narrowing in a major coronary artery) was present in only 22% of women (4 of 18) receiving estrogen and in 68% (49 of 72) who were not (p less than 0.001), with an odds ratio of 0.13. Mean high-density lipoprotein (HDL) cholesterol level was significantly higher (63 +/- 6 vs 48 +/- 2; p less than 0.01) and mean total/HDL cholesterol ratio significantly lower in women receiving estrogen than in those who were not (4.2 +/- 0.5 vs 5.1 +/- 0.2; p less than 0.05). The other lipid values were similar in both groups. On multiple logistic regression analysis, absence of estrogen use was the most powerful independent predictor of the presence of CAD (p less than 0.001), with total/HDL cholesterol ratio as the only other variable selected (p less than 0.01). Thus, among 90 consecutive postmenopausal women undergoing diagnostic coronary angiography, estrogen replacement therapy was associated with an 87% reduction in the prevalence of CAD, and those receiving estrogen had a significantly higher mean HDL cholesterol level and lower mean total/HDL cholesterol ratio.     

Evidence of endothelial dysfunction in angiographically normal coronary arteries of patients with coronary artery disease

Acetylcholine causes endothelium-dependent dilation of normal arteries in most animal species. The effect of acetylcholine on normal human coronary arteries is controversial. Pathologic studies and epicardial echocardiography have shown that diffuse atherosclerosis is often present despite angiographic evidence of discrete coronary artery disease (CAD). Therefore, we postulated that acetylcholine would cause vasoconstriction of coronary arteries that are angiographically normal in patients with CAD. Coronary artery diameter, measured by automated quantification of digitized cineangiograms, was determined before and after the intracoronary infusion of 0.2 mM acetylcholine at 0.8-1.6 ml/min. The diameter of stenotic or irregular segments of six atherosclerotic coronary arteries decreased from 1.80 +/- 0.42 mm before acetylcholine to 1.26 +/- 0.46 mm after acetylcholine (p = 0.0025). Acetylcholine had a significantly different effect on the diameter of two groups of coronary arteries that are angiographically normal. Acetylcholine caused a 0.16 +/- 0.09-mm increase in the diameter of 14 normal coronary arteries in patients without CAD, whereas it caused a 0.26 +/- 0.12-mm decrease in the diameter of 14 normal coronary arteries in patients with CAD (p less than 0.01). Thus, the normal response to intracoronary acetylcholine is vasodilation, suggesting that endothelium-derived relaxing factor is released from normal human coronary endothelium. The vasoconstrictive effect of acetylcholine in the angiographically normal coronary arteries of patients with CAD suggests the presence of a diffuse abnormality of endothelial function.     

Coronary vasomotor response to acetylcholine relates to risk factors for coronary artery disease

In animals, acetylcholine dilates normal arteries and produces vasoconstriction in the presence of hypercholesterolemia, hypertension, or atherosclerosis, reflecting endothelial cell dysfunction. In patients with angiographically smooth coronary arteries, acetylcholine has been reported to produce both vasodilation and constriction. To test the hypothesis that the acetylcholine response relates to risk factors for coronary artery disease, acetylcholine 10(-8) to 10(-6) M was infused into the left anterior descending or circumflex coronary artery, and diameter changes were assessed with quantitative angiography in 34 patients with angiographically smooth coronary arteries. The acetylcholine response ranged from +37% (dilation) to -53% (constriction) at the peak acetylcholine dose. All coronary arteries dilated in response to nitroglycerin (26 +/- 17%), suggesting an abnormality of endothelial function in the patients with a constrictor response to acetylcholine. By multiple stepwise regression analysis, serum cholesterol (p less than 0.01), male gender (p less than 0.001), family history (p less than 0.05), age (p less than 0.05), cholesterol level (p less than 0.01), and total number of risk factors (p less than 0.0001) were independently associated with the acetylcholine response. Thus, coronary risk factors are associated with loss of endothelium-dependent vasodilation. The development of vasoconstriction is likely to be an abnormality of endothelial function that precedes atherosclerosis or an early marker of atherosclerosis not detectable by angiography.     

Coronary vasomotion in response to sympathetic stimulation in humans: importance of the functional integrity of the endothelium

The coronary vasomotor response to the cold pressor test was studied with use of quantitative coronary angiography in 32 patients without evidence of coronary artery disease and 55 patients with such disease; in a subset of 22 patients (9 with normal coronary arteries and 13 with coronary artery disease), the effects of the cold pressor test were compared with the effects of the endothelium-dependent vasodilator acetylcholine with simultaneous intracoronary Doppler flow velocity measurements to assess the influence of endothelial dysfunction. The cold pressor test induced vasodilation of 8.9 +/- 5.7% in all 77 analyzed vessel segments of the group with normal arteries (p less than 0.01). In contrast, in patients with coronary artery disease, the 52 analyzed stenotic segments were constricted by -12.1 +/- 9.5% (p less than 0.01), the 57 analyzed vessel segments with luminal irregularities were constricted by -8.9 +/- 5.2% (p less 0.01) and 40 (85%) of 47 angiographically normal segments also were constricted by -7.0 +/- 4.9% (p less than 0.05). Preserved vasodilating capability was demonstrated by intracoronary nitroglycerin in all analyzed segments. In nine patients with normal coronary arteries, the analyzed vessel segments were dilated in response to both the cold pressor test and intracoronary acetylcholine by 10.9 +/- 5.4% and 13.4 +/- 4.7%, respectively. In contrast, in all 13 patients with coronary artery disease, vasoconstriction of identical vessel segments by -9.1 +/- 3.7% and -23 +/- 10.4%, respectively, was observed after both the cold pressor test and intracoronary acetylcholine. Intracoronary propranolol did not significantly affect either the vasodilative response in 11 normal coronary arteries (11.3 +/- 4.4% before and 8.6 +/- 4.3% after beta-blockade) or the vasoconstrictor response in 8 atherosclerotic coronary arteries (-11.4 +/- 4.6% before and -14.6 +/- 5.3% after beta-blockade). The dilation of normal and the constriction of atherosclerotic coronary arteries with cold pressor testing exactly mirror the response to the endothelium-dependent dilator acetylcholine. Endothelial dysfunction in coronary atherosclerosis resulted in a loss of normal dilator function and permitted vasoconstrictor responses to sympathetic stimulation. Thus, coronary vasomotion of large epicardial arteries in response to sympathetic stimulation by the cold pressor test in humans is intimately related to the integrity of endothelial function.     

Epidemiology of triglycerides: a view from Framingham.

New analyses from the Framingham Heart Study are presented showing that men and women who have high triglyceride levels (> 1.7 mmol/liter) and a low high-density lipoprotein (HDL) level (< 1.03 mmol/liter) run a significantly higher rate of coronary artery disease and can be identified, and that this risk group (high triglyceride-low HDL) is, independently of the major risk factors (including low HDL), related to occurrence of coronary artery disease. Further, this trait appears to be common in our society, producing twice as many cases of coronary artery disease during the 14 years of the Framingham study as the next highest disease-producing lipid abnormality. This trait of high triglyceride-low HDL is associated in the medical literature with increased insulin resistance, higher blood sugars (within the normal range), higher uric acid levels, hypertension, and centrally mediated obesity. Because total cholesterol in people with these traits may be less than or just slightly greater than 5.2 mmol/liter, they are missed or neglected by most cholesterol screening programs.     

Relation of coronary calcium progression and control of lipids according to National Cholesterol Education Program guidelines

Tracking of coronary artery calcium (CAC) has been suggested for monitoring the effects of lipid control, but it is not known whether lipid control decreases progression of CAC. Seven hundred sixty-one subjects (mean age 64.5 +/- 7.3 years; 91% men; 69% positive for CAC) in an ongoing cohort study underwent baseline and follow-up (after 7.0 +/- 0.5 years) computed tomography for CAC. Subjects were stratified into low-risk (<2 risk factors), intermediate-risk (> or =2 risk factors but <20% risk of coronary heart disease over 10 years), or high-risk (> or =2 risk factors and >20% risk of coronary heart disease in 10 years or diabetes) groups. Lipid control was defined according to criteria of the National Cholesterol Education Program. Two-way analysis of covariance was used to examine the relation of low-density lipoprotein (LDL) cholesterol and risk group to change in CAC volume score. Control of levels of high-density lipoprotein (HDL) cholesterol and triglycerides was also examined in relation to progression of CAC. After adjustment for other risk factors and baseline CAC volume, CAC progression was similar between those with adequate and those with inadequate control of LDL cholesterol (p = 0.68) and across categories of optimal, intermediate, and higher risk LDL cholesterol (p = 0.40). However, higher levels of HDL cholesterol (> or =1.5 mmol/L [60 mg/dl]) were associated with less progression of CAC volume (151 vs 203 mm(3) in those with HDL cholesterol <1.0 mmol/L [40 mg/dl], p = 0.03). There was no relation between triglycerides and CAC progression (p = 0.54). Our findings do not support the use of CAC assessment for monitoring the control of LDL cholesterol, but greater progression of CAC may occur in those in whom HDL cholesterol is not controlled.     

Reactivity of proximal and distal angiographically normal and stenotic coronary segments in chronic stable angina pectoris

To assess whether vasoreactivity of significant coronary stenosis (greater than 50% intraluminal diameter reduction) and that of angiographically normal coronary segments differs in proximal and distal locations, 53 patients (40 men, 13 women, mean +/- standard deviation age 55 +/- 11 years) with chronic stable angina and angiographically documented coronary artery disease were studied. While abstaining from antianginal therapy, all 53 patients underwent coronary arteriography before and after 1 mg of intracoronary isosorbide dinitrate and 21 of the 53 also before and after 20 to 30 micrograms intracoronary ergonovine. Computerized quantitative angiography was used to assess changes in the intraluminal diameter of 126 normal coronary segments (63 proximal, 63 distal) and 43 significant coronary stenoses. Nitrates dilated proximal normal coronary segments by 7.4 +/- 1.2% and distal normal coronary segments by 15 +/- 1.7% (p less than 0.01). Significant proximal coronary stenoses dilated by 11 +/- 2.5% and distal stenoses by 23 +/- 2.8% (p less than 0.01) after nitrates. Ergonovine reduced the diameter of proximal normal coronary segments by 9.3 +/- 1.7% and that of normal distal segments by 15.5 +/- 1.4% (p less than 0.01). Proximal stenoses constricted by 11 +/- 2.2% and distal stenoses by 18.4 +/- 2.8% (p = 0.06). Analysis of segments showed that nitrates dilated 19 of 63 (30%) proximal normal segments by (greater than or equal to 10%), 31 of 63 (49%) distal (p less than 0.05) and 21 of 43 (49%) stenoses.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evidence that high-density lipoprotein cholesterol is an independent predictor of acute platelet-dependent thrombus formation

Plasma total and low-density lipoprotein (LDL) cholesterol are established risk factors for atherosclerotic vascular disease and may also contribute to a prothrombotic risk via enhanced platelet reactivity. This study examines whether high-density lipoprotein (HDL) cholesterol, which is inversely correlated with coronary artery disease, is associated with a reduced thrombogenic potential. Platelet thrombus formation was evaluated by exposing porcine aortic media placed in Badimon perfusion chambers to flowing nonanticoagulated venous blood for 5 minutes at a shear rate of 1,000 s(-1). Forty-five subjects, 23 normal (LDL 104 +/- 31, HDL 50 +/- 15 mg/dl) and 22 hypercholesterolemic (LDL 181 +/- 45, HDL 41 +/- 10 mg/dl) patients without coronary artery disease were studied. Platelet aggregation and CD62 antigen expression, and assay for circulating prothrombotic factors were also performed. In univariate analysis platelet thrombus formation correlated with weight (r = 0.33, p = 0.03), diastolic blood pressure (r = 0.39, p = 0.01), HDL cholesterol (r = -0.45, p = 0.003), total/HDL cholesterol (r = 0.43, p = 0.004) and LDL/HDL (r = 0.38, p = 0.01) ratios, and platelet CD62 expression (r = 0.41, p = 0.02). In multiple regression analysis only HDL cholesterol showed significant correlation with platelet thrombus formation (p = 0.03). Platelet aggregation and circulating prothrombotic factors did not correlate with platelet thrombus formation. A comparison between normal and hypercholesterolemic subjects revealed enhanced thrombus area (0.026 +/- 0.20 vs 0.045 +/- 0.039 mm2/mm; p = 0.04), resting CD62 expression (6 +/- 7% vs 15 +/- 10% positive platelets, p = 0.02), and platelet aggregation (16.7 +/- 5.2 vs 21.7 +/- 6.7 ohms, p = 0.04) in hypercholesterolemic subjects. Our results demonstrate that HDL cholesterol is a significant independent predictor of ex vivo platelet thrombus formation.     

A study on coronary hemodynamics during acetylcholine-induced coronary spasm in patients with variant angina: endothelium-dependent dilation in the resistance vessels.

The epicardial coronary artery of patients with variant angina is hyperreactive to the constrictive effect of acetylcholine, but it is not known whether the coronary microvasculature also constricts in response to acetylcholine. Incremental doses of acetylcholine were injected into the left coronary artery of 57 patients with variant angina and with spasm in this artery. By measuring coronary sinus blood flow, coronary hemodynamic status just before angiographic documentation of spasm was examined. Acetylcholine induced spasm in the left coronary artery in all patients. It also decreased the diameter of the nonspasm artery by 36 +/- 19% from baseline. For all patients, coronary sinus blood flow was 89 +/- 38 ml/min at baseline and increased to 104 +/- 61 ml/min during an acetylcholine-induced anginal attack (p less than 0.01). In 10 patients with spasm in both the left anterior descending and left circumflex arteries (that is, multivessel spasm), coronary sinus blood flow decreased from 84 +/- 21 to 52 +/- 26 ml/min (p less than 0.01). In the other 47 patients with spasm in only one of these two arteries (that is, single-vessel spasm), coronary sinus blood flow increased from 90 +/- 41 to 115 +/- 61 ml/min (p less than 0.01) without change in the rate-pressure product. It is concluded that in patients with variant angina, acetylcholine induces spasm and constriction in the epicardial coronary artery, whereas it dilates the resistance vessels presumably through the release of the endothelium-dependent relaxing factor.     

Endothelium-dependent relaxation by acetylcholine is impaired in hypertriglyceridemic humans with normal levels of plasma LDL cholesterol

OBJECTIVES: Patients with high triglyceride (of which very low density lipoproteins [VLDL] are the main carriers), but with normal low density lipoprotein (LDL) cholesterol levels, were examined for in vivo endothelium function status. BACKGROUND: Very low density lipoproteins inhibit endothelium-dependent, but not -independent, vasorelaxation in vitro. METHODS: Three groups were studied: 1) healthy volunteers (n = 10; triglyceride 1.24+/-0.14 mmol/liter, LDL cholesterol 2.99+/-0.24 mmol/liter); 2) hypertriglyceridemic (n = 11; triglyceride 6.97+/-1.19 mmol/liter, LDL cholesterol 2.17+/-0.2 mmol/liter, p < 0.05); and 3) hypercholesterolemic (n = 10; triglyceride 2.25+/-0.29 mmol/liter, LDL cholesterol 5.61+/-0.54 mmol/liter; p < 0.05) patients. Vasoactive responses to acetylcholine, sodium nitroprusside, noradrenaline, N(G)-monomethyl-L-arginine and postischemic hyperemia were determined using forearm venous occlusion plethysmography. RESULTS: Responses to acetylcholine (37 microg/min) were significantly dampened both in hypercholesterolemic (% increase in forearm blood flow: 268.2+/-62) and hypertriglyceridemic patients (232.6+/-45.2) when compared with controls (547.8+/-108.9; ANOVA p < 0.05). Responses to sodium nitroprusside (at 1.6 microg/min: controls vs. hypercholesterolemics vs. hypertriglyceridemic: 168.7+/- 25.1 vs. 140.6+/-38.9 vs. 178.5+/-54.5% increase), noradrenaline, N(G)-monomethyl-L-arginine and postischemic hyperemic responses were not different among the groups examined. CONCLUSIONS: Acetylcholine responses are impaired in patients with pathophysiologic levels of plasma triglycerides but normal plasma levels of LDL cholesterol. The impairment observed was comparable to that obtained in hypercholesterolemic patients. We conclude that impaired responses to acetylcholine normally associated with hypercholesterolemia also occur in hypertriglyceridemia. These findings identify a potential mechanism by which high plasma triglyceride levels may be atherogenic independent of LDL cholesterol levels.     

Possible relationship between insulin resistance and remnant-like lipoprotein particles in coronary endothelial dysfunction

BACKGROUND: High insulin resistance and elevated remnant lipoprotein levels both correlate with impaired coronary vascular endothelial function. Hyperinsulinemia induces abnormalities of lipid metabolism. However, the correlation among insulin resistance, remnant lipoproteins, and endothelial function has not been clinically elucidated. HYPOTHESIS: This study was designed to elucidate the correlation among insulin resistance, remnant lipoproteins, and acetylcholine (ACh)-induced coronary artery response. METHODS: Forty-nine patients suspected of having ischemic heart disease, but without angiographically significant atherosclerotic coronary artery disease, underwent an ACh provocation test. Fasting venous blood was taken early in the morning on the day coronary angiography was performed. The insulin resistance index (IR) was determined from fasting plasma glucose and insulin concentrations, using the homeostasis model assessment (HOMA). Serum levels of remnant-like lipoprotein particle cholesterol (RLP-C) were measured. RESULTS: Homeostasis model assessment IR was significantly higher (3.65 +/- 1.38 vs. 0.75 +/- 0.14, p < 0.05) and log-transformed HOMA (Log HOMA) was even more significantly higher (0.20 +/- 0.12 vs. -0.29 +/- 0.08, p < 0.001) in the ACh-positive group (n = 23) than in the ACh-negative group (n = 26). The serum RLP-C level was also higher in the ACh-positive group than in the ACh-negative group (4.37 +/- 0.63 vs. 2.52 +/- 0.18 mg/dl, p < 0.01). Log HOMA and RLP-C levels correlated with each other (R = 0.54, p < 0.001). Multiple regression analysis indicated that only the RLP-C level was a dependent predictor of Log HOMA in various lipid profiles. CONCLUSIONS: Both high insulin resistance and elevated remnant lipoprotein levels correlated and might have a crucial role in the impairment of coronary vascular endothelial function, even in patients without angiographically significant coronary artery disease.