The effect of atherosclerosis on the vasomotor response of coronary arteries to mental stress

BACKGROUND. Mental stress can cause angina in patients with coronary artery disease, but its effects on coronary vasomotion and blood flow are poorly understood. Because atherosclerosis affects the reactivity of coronary arteries to various stimuli, such as exercise, we postulated that atherosclerosis might also influence the vasomotor response of coronary arteries to mental stress. METHODS. We studied 26 patients who performed mental arithmetic under stressful conditions during cardiac catheterization. (An additional four patients who did not perform the mental arithmetic served as controls.) Coronary segments were classified on the basis of angiographic findings as smooth, irregular, or stenosed. In 15 of the patients without focal stenoses in the left anterior descending artery, acetylcholine (10(-8) to 10(-6) mol per liter) was infused into the artery to test endothelium-dependent vasodilation. Changes in coronary blood flow were measured with an intracoronary Doppler catheter in these 15 patients. RESULTS. The response of the coronary arteries to mental stress varied from 38 percent constriction to 29 percent dilation, whereas the change in coronary blood flow varied from a decrease of 48 percent to an increase of 42 percent. The direction and magnitude of the change in the coronary diameter were not predicted by the changes in the heart rate, blood pressure, or plasma norepinephrine level. Segments with stenoses (n = 7) were constricted by a mean (+/- SE) of 24 +/- 4 percent, and irregular segments (n = 20) by 9 +/- 3 percent, whereas smooth segments (n = 25) did not change significantly (dilation, 3 +/- 3 percent; P less than 0.0002). Coronary blood flow increased by 10 +/- 10 percent in smooth vessels, whereas the flow in irregular vessels decreased by 27 +/- 5 percent. The degree of constriction or dilation during mental stress correlated with the response to the infusions of acetylcholine (P less than 0.0003, r = 0.58). CONCLUSIONS. Atherosclerosis disturbs the normal vasomotor response (no change or dilation) of large coronary arteries to mental stress; in patients with atherosclerosis paradoxical constriction occurs during mental stress, particularly at points of stenosis. This vasomotor response correlates with the extent of atherosclerosis in the artery and with the endothelium-dependent response to an infusion of acetylcholine. These data suggest that in atherosclerosis unopposed constriction caused by a local failure of endothelium-dependent dilation causes the coronary arteries to respond abnormally to mental stress.     

Impaired vascular reactivity following angioplasty is mainly due to endothelial injury.

Vasoconstriction occurs frequently following coronary angioplasty and is implicated in the pathogenesis of abrupt closure and restenosis. Control of vasomotor tone is regulated in part directly by smooth muscle cells and indirectly through the endothelium. To study the mechanisms underlying vasoconstriction, the effect of angioplasty and endothelial denudation on endothelium-dependent and -independent relaxation was examined in 15 mongrel dogs. Percutaneous transluminal angioplasty and endothelial denudation of the right femoral artery were performed. Endothelial injury was assessed by adhesion of indium-111-labeled platelets. Endothelium-dependent and -independent relaxation were assessed using acetylcholine and nitroglycerin, respectively. Vessels precontracted with potassium chloride and exposed to acetylcholine showed impaired relaxation in both the angioplasty and denuded groups (angioplasty = 14 +/- 5%, denuded = 0 +/- 0%, normal = 73 +/- 12%; P less than 0.05 for both angioplasty and denuded compared to normal). Precontraction with phenylephrine yielded similar results (angioplasty = 16 +/- 8%, denuded = 4 +/- 2%, normal = 39 +/- 10%; P less than 0.05 only for denuded segment compared to normal). Segments precontracted with phenylephrine and exposed to nitroglycerin did not demonstrate impaired relaxation (angioplasty = 73 +/- 9%, denuded = 68 +/- 9%, normal = 71 +/- 7%, P = ns). Mean indium-111 counts were similar in both the angioplasty and denuded segments (2820 +/- 1481 and 2963 +/- 1228 counts/min/g, respectively) compared to a lower count in the normal segment (1514 +/- 956 counts/min/g). Thus, angioplasty produces significant vascular injury and impairment of vasodilator function, comparable to that caused by endothelial denudation alone. This implies that vasoconstriction seen following coronary angioplasty may be due to endothelial injury and the resultant loss of control of vasomotor tone.     

Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension

BACKGROUND. Endothelium regulates vascular tone by influencing the contractile activity of vascular smooth muscle. This regulatory effect of the endothelium on blood vessels has been shown to be impaired in atherosclerotic arteries in humans and animals and in animal models of hypertension. METHODS. To determine whether patients with essential hypertension have an endothelium-dependent abnormality in vascular relaxation, we studied the response of the forearm vasculature to acetylcholine (an endothelium-dependent vasodilator) and sodium nitroprusside (a direct dilator of smooth muscle) in 18 hypertensive patients (mean age [+/- SD], 50.7 +/- 10 years; 10 men and 8 women) two weeks after the withdrawal of antihypertensive medications and in 18 normal controls (mean age, 49.9 +/- 9; 9 men and 9 women). The drugs were infused at increasing concentrations into the brachial artery, and the response in forearm blood flow was measured by strain-gauge plethysmography. RESULTS. The basal forearm blood flow was similar in the patients and controls (mean +/- SD, 3.4 +/- 1.3 and 3.7 +/- 0.8 ml per minute per 100 ml of forearm tissue, respectively; P not significant). The responses of blood flow and vascular resistance to acetylcholine were significantly reduced in the hypertensive patients (P less than 0.0001); maximal forearm flow was 9.1 +/- 5 ml per minute per 100 ml in the patients and 20.0 +/- 8 ml per minute per 100 ml in the controls (P less than 0.0002). However, there were no significant differences between groups in the responses of blood flow and vascular resistance to sodium nitroprusside. Because the vasodilator effect of acetylcholine might also be due to presynaptic inhibition of the release of norepinephrine by adrenergic nerve terminals, the effect of acetylcholine was assessed during phentolamine-induced alpha-adrenergic blockade. Under these conditions, it was also evident that the responses to acetylcholine were significantly blunted in the hypertensive patients (P less than 0.03). CONCLUSIONS. Endothelium-mediated vasodilation is impaired in patients with essential hypertension. This defect may play an important part in the functional abnormalities of resistance vessels that are observed in hypertensive patients.     

Exercise stress testing in angina patients with positive response to hyperventilation testing: influence of the coronary artery tone

We studied the exercise stress test and the coronary artery tone in two groups of angina patients with comparable coronary atherosclerosis. Group I (20 males and 5 females, mean age 53.5 years) with a positive, and group II (22 males and 3 females, mean age 52.5 years) with a negative response to the hyperventilation test (HVT). A positive exercise stress test (ST depression greater than or equal to 1 mm) was found in 24 patients in group I vs. 15 in group II (p less than 0.01), despite a lower maximal rate pressure product (198 +/- 11.2 vs. 236 +/- 10.1, p less than 0.05) and maximal work load (110 W +/- 7.1 vs. 136 +/- 7.4 W, p less than 0.02) in group I. A high coronary artery tone (dilatation (DIL%) of the coronary arteries after nitroglycerin greater than or equal to 10%) was found in 18 patients in group I and in 4 in group II (p less than 0.01). DIL% was 22.6 +/- 3.8 vs. 5.8 +/- 1.4 in groups I and II, respectively (p less than 0.005). DIL% was significantly related to persistence of ST depression after exercise (r = 0.36, p less than 0.05), and 21 of 22 patients with high tone had a positive exercise stress test vs. 18 of 28 with low tone (p less than 0.05). These findings suggest that the coronary artery tone influences the response to exercise in some patients with angina. Since the patients in group I were identified by HVT, our results underline the clinical relevance of this test.     

The degree of neointimal formation after stent placement in atherosclerotic rabbit iliac arteries is dependent on the underlying plaque.

The purpose of this study was to determine the effects of stent placement on the underlying arterial morphology and the relations of stent-vessel wall interactions with subsequent neointimal formation in an atherosclerotic artery. Seven New Zealand White rabbits with experimentally induced atherosclerosis underwent balloon angioplasty (n = 7) and stent placement after balloon angioplasty (n = 7) in the iliac arteries. Histologic analysis of the treated arteries was performed at 28 days to assess device interactions with the artery and the pattern of the neointimal response. The area within the external elastic lamina of the stented vessels was 66% greater than the arteries with balloon angioplasty alone (p = 0.001) which contributed to a significantly greater late lumen area (3.33 +/- 0.51 mm2 versus 1.33 +/- 0.20 mm2, p = 0.0028). Neointimal thickness was measured at 220 stent wire sites from 21 sections of stented arteries of which 139 (63%) had underlying plaque and 81 (37%) were adjacent to normal media. Rupture of the internal elastic lamina (IEL) occurred at only 9 (11%) of the 81 stent wire sites over normal media. The mean neointimal thickness was 0.16 +/- 0.01 mm lor all stent wire sites. The neointimal thickness was greater at the stent wire sites with underlying plaque (0.23 +/- 0.01 min) than at the stent wire sites adjacent to normal media (0.08 +/- 0.01 mm) or at sites with rupture of the internal elastic lamina (0.16 +/- 0.02 mm, p = 0.0001). The degree of neointimal formation within the stents strongly correlated with the area of the underlying atherosclerotic plaque (r = 0.76, p = 0.0007) and the extent of plaque or medial compression by the struts (r = 0.90, p = 0.006). The present study characterizes stent interactions in a model commonly employed to evaluate novel therapies for the prevention of restenosis. The neointimal response was influenced by the local arterial morphology and correlated with the extent of plaque or medial compression by the stent. These data may be useful for future studies in this model and understanding the mechanism of in-stent restenosis.     

Myocardial ischemia caused by distal coronary-artery constriction in stable angina pectoris

BACKGROUND. In patients with stable coronary artery disease, the ischemic threshold for the production of effort-related angina is often quite variable. Although this feature is commonly attributed to changes in the caliber of coronary arteries at the site of stenosis, it could also be caused by the constriction of distal vessels, collateral vessels, or both. METHODS. In order to test this hypothesis, we studied 11 patients with stable angina, total occlusion of a single coronary artery that was supplied by collateral vessels, normal ventricular function, no evidence of coronary-artery spasm, and no other coronary stenoses. These conditions precluded the modulation of coronary flow by vasomotion at the site of the coronary stenosis. RESULTS. The ischemic threshold--assessed by multiplying the heart rate by the systolic blood pressure at a 1-mm depression of the ST segment during exercise testing--increased by 19 percent after the administration of nitroglycerin (P less than 0.05) and decreased by 18 percent after the administration of ergonovine (P less than 0.01). Ambulatory electrocardiographic monitoring of the patients when not receiving treatment detected 73 ischemic episodes that, in keeping with the history, showed variations of 25 to 52 beats per minute in the heart rate at a 1-mm depression of the ST segment; 12 episodes of sinus tachycardia exceeded the lowest ischemic heart rate by a mean (+/- SD) of 22 +/- 13 beats per minute without ST-segment depression. Furthermore, 21 ischemic episodes occurred at a heart rate more than 25 beats per minute below that at a 1-mm depression of the ST segment during exercise testing. Delayed and reduced filling of collateral and collateralized vessels associated with depression of the ST segment similar to that observed during ambulatory monitoring was detected on angiographic evaluation after the intracoronary administration of ergonovine in three patients. CONCLUSIONS. We propose that the constriction of distal coronary arteries, collateral vessels, or both may cause myocardial ischemia in patients with chronic stable angina.     

Effect of exercise on coronary endothelial function in patients with coronary artery disease

BACKGROUND: Studies of the cardioprotective effects of exercise training in patients with coronary artery disease have yielded contradictory results. Exercise training has been associated with improvement in myocardial perfusion even in patients who have progression of coronary atherosclerosis. We therefore conducted a prospective study of the effect of exercise training on endothelial function in patients with coronary artery disease. METHODS: We randomly assigned 19 patients with coronary endothelial dysfunction, indicated by abnormal acetylcholine-induced vasoconstriction, to an exercise-training group (10 patients) or a control group (9 patients). To reduce confounding, patients with coronary risk factors that could be influenced by exercise training (such as diabetes, hypertension, hypercholesterolemia, and smoking) were excluded. In an initial study and after four weeks, the changes in vascular diameter in response to the intracoronary infusion of increasing doses of acetylcholine (0.072, 0.72, and 7.2 microg per minute) were assessed. The mean peak flow velocity was measured by Doppler velocimetry, and the diameter of epicardial coronary vessels was measured by quantitative coronary angiography. RESULTS: In the initial study, the two groups had similar vasoconstrictive responses to acetylcholine. After four weeks of exercise training, coronary-artery constriction in response to acetylcholine at a dose of 7.2 microg per minute was reduced by 54 percent (from a mean [+/-SE] decrease in the luminal diameter of 0.41+/-0.05 mm in the initial study to a decrease of 0.19+/-0.07 mm at four weeks; P<0.05 for the comparison with the change in the control group). In the exercise-training group, the increases in mean peak flow velocity in response to 0.072, 0.72, and 7.2 microg of acetylcholine per minute were 12+/-7, 36+/-11, and 78+/-16 percent, respectively, in the initial study. After four weeks of exercise, the increases in response to acetylcholine were 27+/-7, 73+/-19, and 142+/-28 percent (P<0.01 for the comparison with the control group). Coronary blood-flow reserve (the ratio of the mean peak flow velocity after adenosine infusion to the resting velocity) increased by 29 percent after four weeks of exercise (from 2.8+/-0.2 in the initial study to 3.6+/-0.2 after four weeks; P<0.01 for the comparison with the control group). CONCLUSIONS: Exercise training improves endothelium-dependent vasodilatation both in epicardial coronary vessels and in resistance vessels in patients with coronary artery disease.     

Susceptibility to atherosclerosis in aortas and coronary arteries of swine with von Willebrand's disease.

The development of coronary and aortic atherosclerosis was determined after balloon catheter injury of coronary arteries and administration of an atherogenic diet in normal pigs and pigs that were homozygous and heterozygous for von Willebrand's disease. Coronary atherosclerosis developed to a similar degree in all three phenotypic groups. The mean intimal thickness at the site of maximal thickness in ballooned vessels was .51 mm in the normal pigs, .67 mm in carrier pigs, and .55 mm in bleeder pigs. The intimal thickness of non-ballooned vessels was .28 mm in normal pigs, .28 mm in carrier pigs, and .35 mm in bleeder pigs. Fibrous lesions of atherosclerosis covered an average of 3.88% of the aorta in normal pigs, 2.83% in carrier pigs, and 2.37% in bleeder pigs. The difference between the aortic lesions of normal animals and bleeders was significant (P less than .05). Absence of von Willebrand factor was associated with limited resistance to atherosclerosis in the aortas of experimental pigs but did not affect the development of atherosclerosis in either ballooned or nonballooned coronary arteries. These findings suggest, first, that von Willebrand factor function is not essential to the development of the atherosclerotic lesion in this model and, second, that the role of the von Willebrand factor in the development of atherosclerosis is complicated and appears to involve interaction with variables not yet defined.     

The utility of multi-detector row spiral CT for detection of coronary artery stenoses

Contrast-enhanced multi-detector row spiral computed tomography (MDCT) was introduced as a promising noninvasive method for vascular imaging. This study examined the accuracy of this technique for detecting significant coronary artery stenoses. Both MDCT(Sensation 16, Siemens, Germany, 12x0.75 mm collimation and 0.42 sec rotation speed, 120 kV, 500 effective mA, and 2.7 mm/rotation table-feed) and invasive coronary angiography (CAG) were performed on 61 patients (mean age 59.2+/-10, 44 men) who were suspected of having coronary artery disease. All patients were treated with atenolol (25-50 mg) prior to imaging and the heart rate was maintained below 65 beats per minutes during image acquisition. The images were reconstructed in the diastole around TI-400 ms with a 0.5 mm increment and a 1.0 mm thickness. All coronary arteries with a diameter of 2.0 mm or more were assessed for the presence of a stenosis (>50% luminal narrowing). Two independent radiologists who were unaware of the results of the invasive CAG evaluated the MDCT data, and the results were compared with those from the invasive CAG (interval 1-27, mean 11 days). An evaluation of the CT coronary angiogram (CTCA) was possible in 58 of the 61 patients (95%). Image acquisition of the major coronary arteries including the left main trunk was available in 229 out of 244 arteries. Invasive CAG showed that 35 out of 58 patients had significant coronary artery stenoses by. patient analysis of those who could be evaluated showed that CT coronary angiography correctly classified 30 out of 35 patients as having at least 1 coronary stenosis (sensitivity 85.7%, specificity 91.3%, positive predictive value 93.8%, negative predictive value 80.8%). By analyzing each coronary artery, CAG found 62 stenotic coronary arteries in the 229 coronary arteries that could be evaluated. MDCT correctly detected 50 out of 62 stenotic coronary arteries and an absence of stenosis was correctly identified in 156 out of 167 normal coronary arteries (sensitivity 80.6%, specificity 93.4%, positive predictive value 81.9%, negative predictive value 92.8%). The non-invasive technique of MDCT for examining the coronary artery appears to be a useful method for detecting coronary artery stenoses with a high accuracy particularly with the proximal portion and large arteries.     

Vasoreactivity in isolated perfused atherosclerotic human coronary arteries

Atherosclerosis may be important in the modulation of arterial vasoreactivity and coronary artery flow. Since the endothelium is reduced or absent in atherosclerosis, drug effects are enhanced or modulated. To examine this hypothesis, vasoreactivity induced by serotonin (5-HT) was studied in isolated, perfused, and pharmacologically responsive normal and atherosclerotic human coronary arteries obtained within five hours post mortem. In this model, flow was maintained through the vessels and the effects of vasospasm and vasorelaxation on decreasing and increasing flow respectively were measured. Vessels 3 cm long and approximately 1.5 mm in internal diameter were dissected free and perfused at constant pressure (30 mm Hg) with oxygenated Krebs bicarbonate solution. 5-HT was introduced in the perfusate at 10(-5) M final concentration as a pulse of 100 ml followed by a 1-l washout with drug-free solution. Flow rate and total flow were measured. Normal and atherosclerotic coronary arteries showed peak reductions in flow rate of 22% and 92% respectively, while the times to peak reduction of flow averaged 6 and 4 min and the times to 50% relaxation averaged 13 and 24 min. Ultrasound imaging showed that heavily atherosclerotic regions with extensive focal plaque maintained the induced spasm for a longer period than regions with less disease within the same vessel. Silver nitrate staining showed that these heavily atherosclerotic regions were devoid of endothelium. Thus, atherosclerotic human coronary arteries show a larger magnitude of spasm which persists for a longer period of time as compared to normal coronaries.(ABSTRACT TRUNCATED AT 250 WORDS)     

Impaired flow-mediated vasodilation of epicardial coronary artery in vasospastic angina.

To evaluate whether the flow-mediated vasodilation and coronary flow reserve are impaired or not in patients with vasospastic angina (VA), we measured the changes of epicardial coronary artery diameter and flow reserve in spasm related-left anterior descending coronary artery (LAD). The flow mediated-response of epicardial coronary arteries in 15 VA were compared with 15 controls. Using quantitative coronary angiography, we measured the diameter of proximal (pLAD) and middle segment (mid-LAD) of LAD under baseline conditions, during increased blood flow after distal adenosine injection and after proximal administration of nitroglycerin. An increased fraction of average peak velocity after injection of adenosine was similar in both groups [control 340 (mean)+/-24 (SEM)%; VA 330+/-19%]. Flow-mediated vasodilation was preserved in all controls (pLAD 13.1+/-1.4%; mid-LAD 15.8+/-2.5%) but it was significantly impaired in patients with VA (pLAD -1.0+/-1.8%; mid-LAD 0.1+/-3.5%). The vasodilator response to nitroglycerin was comparable in controls (pLAD 25.8+/-2.8%; mid-LAD 27.2+/-2.8%) and VA (pLAD 26.2+/-5.2%; mid-LAD 26.7+/-3.5%). Coronary flow reserve is preserved in patients with VA. However, the flow-mediated response of spasm related-epicardial coronary artery is impaired. This may play an important role in the pathogenesis of coronary artery spasm.     

Impairment of endothelium-dependent pulmonary-artery relaxation in chronic obstructive lung disease

BACKGROUND. Endothelial cells release endothelium-derived relaxing factor (EDRF) in a variety of vascular beds, including the pulmonary circulation. However, the role of EDRF-mediated pulmonary-artery relaxation in chronic hypoxic lung disease is unknown. METHODS. We studied endothelium-dependent relaxation mediated by EDRF in vitro in pulmonary arteries that had been obtained from 22 patients undergoing heart-lung transplantation for end-stage chronic obstructive lung disease. Control pulmonary arteries were obtained from 15 patients undergoing lobectomy for lung carcinoma who did not have evidence of other chronic lung disease. The responses of all vascular rings (external diameter, 1.2 to 3.4 mm) to the endothelium-dependent vasodilators acetylcholine and adenosine diphosphate were studied immediately after lung excision. RESULTS. Pulmonary arterial rings from the patients with chronic lung disease developed a greater tension (2.19 +/- 0.16 g) in response to phenylephrine (10(-6) M) than the rings from control patients (1.28 +/- 0.18 g, P less than 0.05). Inhibition of EDRF synthesis by treatment with NG-monomethyl-L-arginine (10(-4) M) eliminated this difference, increasing the tension in the rings from the controls (P less than 0.01) but not in those from the patients with chronic lung disease. Rings from control patients relaxed in response to cumulative doses (10(-10) to 10(-5) M) of acetylcholine (maximal relaxation, 81.3 +/- 3.9 percent) and adenosine diphosphate (maximal relaxation, 85.3 +/- 2.6 percent). By contrast, rings from patients with chronic obstructive lung disease achieved only 41.3 +/- 4.8 percent of maximal relaxation in response to acetylcholine (n = 32) and 49.4 +/- 5.5 percent in response to adenosine diphosphate (n = 24) (P less than 0.001, as compared with control rings). Rings from both the controls and the patients with chronic lung disease relaxed similarly in response to the endothelium-independent vasodilator sodium nitroprusside (10(-4) M). There was an inverse correlation between the degree of intimal thickening and the level of maximal relaxation of the rings from the patients with chronic lung disease (r = -0.60, P less than 0.001). Maximal relaxation was also related directly to the partial pressure of arterial oxygen before transplantation (r = 0.68, P less than 0.01) and inversely to the partial pressure of arterial carbon dioxide before transplantation (r = -0.55, P less than 0.01), but not to the forced expiratory volume in one second (r = 0.19, P not significant). CONCLUSIONS. Endothelium-dependent pulmonary-artery relaxation in vitro is impaired in arteries from patients with end-stage chronic obstructive lung disease. Such impairment may contribute to the development of pulmonary hypertension in chronic hypoxic lung disease.     

In vivo induction and reversal of nitroglycerin tolerance in human coronary arteries

The mechanism by which tolerance to the clinical effects of organic nitrates develops has not been elucidated. This study was done to determine whether an intravenous infusion of nitroglycerin induces tolerance in the coronary vascular bed and whether such tolerance is reversed by the sulfhydryl-group donor N-acetylcysteine. We studied 19 subjects--17 with coronary artery disease and 2 without it--who had a mean age (+/- SD) of 54 +/- 9 years. Coronary sinus blood flow, which approximates blood flow to the left ventricle, was measured before and during intracoronary injections of nitroglycerin (10, 25, 50, and 100 micrograms). The patients then received a 24-hour intravenous infusion of saline (n = 7) or of nitroglycerin, 45 +/- 13 micrograms per minute (n = 12), after which the responses of coronary sinus flow to the same doses of intracoronary nitroglycerin used earlier were measured. In the seven patients given saline, the four doses of intracoronary nitroglycerin caused similar percentage increases in coronary sinus flow before and after the saline infusion. In the 12 patients given intravenous nitroglycerin, the four intracoronary doses caused percentage increases in coronary flow before the infusion of 30 +/- 9, 35 +/- 14, 41 +/- 12, and 52 +/- 15, respectively. After the infusion, the same doses of nitroglycerin caused smaller (P less than 0.05) percentage increases (16 +/- 6, 21 +/- 11, 23 +/- 12, and 27 +/- 11, respectively), indicating the development of partial tolerance. Subsequently, 7 of the 12 patients received N-acetylcysteine, after which intracoronary nitroglycerin caused percentage increases in coronary sinus flow similar to the values measured before the intravenous nitroglycerin was given (34 +/- 13, 32 +/- 8, 38 +/- 11, and 44 +/- 16, respectively). We conclude that the coronary vasodilator effect of nitroglycerin is attenuated by an intravenous infusion of nitroglycerin (that is, partial tolerance develops) and that tolerance to the agent can be reversed by administration of the sulfhydryl-group donor N-acetylcysteine. The mechanism by which N-acetylcysteine reverses tolerance will require further investigation.     

Divergent effects of serotonin on coronary-artery dimensions and blood flow in patients with coronary atherosclerosis and control patients

BACKGROUND. Studies in animals have shown that serotonin constricts coronary arteries if the endothelium is damaged, but in vitro studies have revealed a vasodilating effect on isolated coronary segments with an intact endothelium. To investigate the effect of serotonin in humans, we studied coronary-artery cross-sectional area and blood flow before and after the infusion of serotonin in seven patients with angiographically normal coronary arteries and in seven with coronary artery disease. METHODS. We measured the cross-sectional area of the coronary artery by quantitative angiography and coronary blood flow with an intracoronary Doppler catheter. Measurements were obtained at base line and during intracoronary infusions of serotonin (0.1, 1, and 10 micrograms per kilogram of body weight per minute, for two minutes). We repeated the measurements after an infusion of ketanserin, an antagonist of serotonin receptors that is thought to block the effect of serotonin on receptors in the arterial wall but not in the endothelium. RESULTS. In patients with normal coronary arteries, the highest dose of serotonin increased cross-sectional area by 52 percent (P less than 0.001) and blood flow by 58 percent (P less than 0.01). The effect was significantly potentiated by administration of ketanserin. In patients with coronary-artery atherosclerosis, serotonin reduced cross-sectional area by 64 percent (P less than 0.001) and blood flow by 59 percent (P less than 0.001). Ketanserin prevented this effect. CONCLUSIONS. Serotonin has a vasodilating effect on normal human coronary arteries; when the endothelium is damaged, as in coronary artery disease, serotonin has a direct, unopposed vasoconstricting effect. When considered with other evidence, these data suggest that platelet-derived factors such as serotonin may have a role in certain acute coronary ischemic syndromes.     

Accelerated progression of atherosclerosis in coronary vessels with minimal lesions that are bypassed

Accelerated progression of atherosclerosis is known to occur in surgically bypassed coronary arteries in which the preoperative stenosis was greater than 50 per cent. To assess the effect of coronary bypass on vessels with lesser degrees of stenosis, we studied 85 men who had undergone coronary bypass surgery. In this group we identified bypass grafts placed in 37 arteries with minimal atherosclerosis, which was defined as less than 50 per cent stenosis of the vessel diameter. In the same 85 men there were 93 coronary vessels with minimal atherosclerosis for which a bypass graft had not been placed. Progression of atherosclerosis, defined as further loss of at least 25 per cent of the lumen, during an average follow-up period of 37 months was more than 10 times as frequent (38 per cent vs. 3 per cent) in bypassed arteries with minimal atherosclerosis as in comparable arteries that were not bypassed. These findings support the view that minimally diseased coronary arteries should not be bypassed.     

Delineation of the extent of coronary atherosclerosis by high-frequency epicardial echocardiography

Postmortem studies suggest that coronary angiography does not always accurately delineate the extent of coronary-artery disease. We examined this problem in living human hearts by performing high-frequency epicardial echocardiography at the time of cardiac surgery. The ratio of the diameter of the lumen of the coronary artery to the thickness of its wall was used to quantify the severity of coronary lesions. In 11 patients with no angiographic evidence of coronary disease anywhere in the coronary tree, the mean (+/- SEM) ratio was 5.9 +/- 0.3. In 21 patients with angiographic disease at the site evaluated by echocardiography, the mean ratio was lower (2.3 +/- 0.2, P less than 0.05), reflecting encroachment into the arterial lumen by atherosclerotic plaque. In 15 patients with arterial segments that were angiographically normal but with arterial stenoses elsewhere in the coronary tree, the mean ratio was 4.1 +/- 0.3, with marked overlap with the values in the patients who had angiographic disease at the site of the echocardiographic evaluation. These results demonstrate, in living human hearts, that diffuse coronary atherosclerosis is often present when coronary angiography reveals only discrete stenoses. This finding suggests that coronary angiography may underestimate the severity and extent of coronary disease.     

Reactivity of intrarenal arteries to vasoconstrictor and vasorelaxant polypeptides in adult stroke-prone spontaneously hypertensive rats.

The reactivity of intrarenal arteries to vasoconstrictor and vasodilator polypeptides was examined in adult stroke-prone spontaneously hypertensive rats (SHRSP). The contraction response to endothelin-1 (ET-1) was greater in SHRSP than in age-matched Wistar-Kyoto rats (WKY), and so was the pD2 estimate (8.05+/-0.03 in SHRSP, and 7.73+/-0.06 in WKY; n=5, P < 0.05). The contraction response to, and the pD2 estimate of, vasopressin were comparable in SHRSP and WKY. Neuropeptide Y did not contract the intrarenal arteries. In norepinephrine-precontracted arteries with intact endothelium, substance P and neurokinin A did not relax the arteries of either SHRSP or WKY, while calcitonin gene-related peptide (CGRP) induced a profound relaxation response. Relaxation response to CGRP was significantly greater in SHRSP than in WKY. Atrial, brain, and C-type natriuretic peptides (ANP, BNP, CNP), vasoactive intestinal polypeptide (VIP), and peptide histidine isoleucine (PHI) all caused relaxation responses, with a greater extent of relaxation to ANP, BNP, and VIP and a less extent to CNP and PHI. However, there were no significant differences in these relaxation responses between SHRSP and WKY. The current results revealed the character of heterogeneity of rat intrarenal arteries in response to vasoconstrictor and vasodilator peptides, and showed an enhanced reactivity to ET-1 and to CGRP in SHRSP.     

Difference between endothelium-dependent relaxation in arterial and in venous coronary bypass grafts

Both the internal mammary artery and the saphenous vein are used to construct coronary-artery bypass grafts. We hypothesized that the release or production of endothelium-derived relaxing factor, which regulates blood flow and inhibits platelet function, may differ in venous and arterial grafts. We therefore studied endothelium-dependent relaxation in internal mammary arteries, internal mammary veins, and saphenous veins obtained from 58 patients undergoing coronary bypass surgery. Vascular rings with and without endothelium were suspended in organ chambers, and isometric tension was recorded. Acetylcholine (10(-8) to 10(-4) M), thrombin (1 U per milliliter), and adenosine diphosphate (10(-7) to 10(-4) M) evoked potent endothelium-dependent relaxation in the mammary artery but weak response in the saphenous vein (P less than 0.005; n = 6 to 27). In the mammary artery, relaxation was greatest in response to acetylcholine (86 +/- 4 percent reduction in norepinephrine-induced tension), followed by thrombin (44 +/- 7 percent) and adenosine diphosphate (39 +/- 8 percent). In the saphenous and mammary veins, relaxation was less than 25 percent. Relaxation was unaffected by indomethacin but was inhibited by methylene blue and hemoglobin (P less than 0.005 and 0.01, respectively), which suggests that endothelium-derived relaxing factor was the mediator. Endothelium-independent relaxation in response to sodium nitroprusside was similar in arteries and veins. We conclude that endothelium-dependent relaxation is greater in the mammary artery than in the saphenous vein. The possibility that this contributes to the higher patency rate among arterial grafts than among venous grafts will require further study.     

Monocyte adhesion and changes in endothelial cell number, morphology, and F-actin distribution elicited by low shear stress in vivo.

Left common carotid arteries of New Zealand white rabbits were ligated rostral to origin of the thyroid artery to reduce flow in the carotid upstream of this branch, and the vessels were examined 5 days later. Estimates of mean shear stress in the upstream carotid artery indicated a decrease of 73% (from 12.1 +/- 1.6 dynes/cm2 to 3.26 +/- 0.58 dynes/cm2). The contralateral common carotid artery carried collateral flow and experienced a 170% increase in shear stress (from 11.3 +/- 1.6 dynes/cm2 to 30.5 +/- 4.6 dynes/cm2). There was an adaptive reduction in the diameter in the left common carotid artery (low shear) from 2.07 +/- 0.06 mm to 1.75 +/- 0.12 mm, but the diameter of the right carotid was unchanged. Fluorescence microscopy and scanning electron microscopy of endothelium exposed to low shear revealed attachment of leukocytes (5.02 +/- 1.59 cells/mm2, mean +/- SE) that were identified as monocytes using the monoclonal antibody HAM 56. Laser confocal microscopy demonstrated that they were migrating across the endothelial cell monolayer. Fluorescence microscopy and scanning electron microscopy of left common carotid artery (low shear) also revealed cell morphology suggestive of endothelial cell desquamation. Endothelial cell loss was confirmed by morphometric determination of cell number (1.29 +/- 0.13 x 10(4) cells/mm length in experimental animals versus 1.71 +/- 0.08 x 10(4) cells/mm length in sham-operated animals). This endothelial cell loss may be an adaptation to a narrowing of carotid arteries exposed to low shear, which reduces luminal surface area of the vessel. Staining of F-actin with rhodamine phalloidin showed that endothelial cells exposed to low shear were less elongated and had fewer stress fibers than normal cells. By contrast, increasing shear stress by two- to threefold caused an increase in the number of stress fibers and a reduction in peripheral actin staining. Distal carotid ligation provided a consistent and well-defined in vivo technique for manipulating shear stresses imposed on a large population of endothelial cells.     

体外反搏对高胆固醇血症猪动脉粥样硬化病理形态及核因子κB表达的影响

目的探讨使用增强型体外反搏器(EECP)提高血流剪切应力对高胆固醇血症实验猪血管病理形态、血管内皮形态与功能及核因子κB(NFκB)表达的影响。方法健康雄性家猪随机分为普通饲料组、高脂对照组、高脂反搏组。后两组同量持续高胆固醇饲料喂养建立高胆固醇血症及早期动脉粥样硬化动物模型。高脂反搏组在高胆固醇喂养2个月后进行体外反搏。15周后取出冠状动脉、胸主动脉和腹主动脉行病理形态学观察和NFκB免疫荧光激光共聚焦扫描。结果高脂对照组及高脂反搏组血脂水平较普通饲料组显著升高(P<0.01),而高脂对照组与高脂反搏组之间血脂水平差异无统计学意义(P>0.05)。主动脉大体苏丹Ⅲ染色示高胆固醇血症猪斑块形成较普通饲料组增多;而高脂反搏组斑块/内膜面积比[(3.33±2.40)%]显著少于高脂对照组[(12.03±7.12)%](P<0.05)。扫描电镜示高脂对照组内皮细胞排列紊乱,大量破坏脱落,有较多血小板黏附;高脂反搏组内皮细胞较完整,沿血流方向梭形排列,血小板黏附较少。透射电镜示高脂对照组内皮细胞变性凋亡脱落显著,内皮下大量泡沫细胞积聚,平滑肌细胞呈合成型改变,大量增生并向内膜移行;而高脂反搏组上述改变明显减轻。冠状动脉HE染色及弹力纤维染色示高脂对照组弹力纤维紊乱断裂,内膜较普通饲料组增厚[(24.36±9.72)μm比(9.97±4.02)μm,P<0.05];而高脂反搏组的内膜增厚比高脂对照组明显减少[(11.87±5.95)μm比(24.36±9.72)μm;P<0.05]。免疫荧光激光共聚焦扫描示高胆固醇血症猪冠脉内皮细胞及平滑肌细胞的细胞核NFκB荧光强度较普通饲料组增高,但高脂反搏组荧光强度较高脂对照组减少(P<0.05)。结论通过体外反搏提高血流剪切应力可改善血管内皮细胞形态与功能,减轻内膜增生和血管重塑,从而抑制高胆固醇血症猪早期动脉粥样硬化的形成和进展。其机制可能与下调NFκB的活性表达有关。