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Objective: Laminar flow becomes disturbed at high velocities, reducing shear stress and augmenting vascular inflammation and proliferation, processes that are pivotal in restenosis and atherogenesis. We hypothesized that disturbed blood flow after coronary angioplasty is associated with adverse long-term clinical outcome., Methods and Results: The cineangiograms from 97 patients undergoing laser-assisted coronary angioplasty were analyzed. Coronary blood flow velocity, the residual lesion dimensions, and the Reynolds number (an index of disturbed flow) were measured by using a frame-counting technique and quantitative coronary angiography. Cox proportional hazards were used to assess the relative risk of adverse events (target-vessel revascularization, myocardial infarction, or death) over a mean 2.5 years after the index procedure. There were 41 adverse events during 245 patient years of follow-up (17% per year of follow-up). The risk of an adverse event was increased for patients with a high flow velocity (>250 mm/s; relative risk 2.5, 95% CI 1.3 to 4.7) or a high Reynolds number (>200) at the stenosis inlet (relative risk 2.1, 95% CI 1.1 to 4.1) at the end of the procedure. Adjustment for other factors did not alter these results., Conclusions: High Reynolds numbers, indicating disturbed blood flow after coronary angioplasty, increase the risk of adverse clinical events, potentially through shear-stress-related molecular mechanisms that promote restenosis and atherogenesis.

Background: The coronary arteries of transplanted hearts frequently develop accelerated diffuse arteriosclerosis. The effects of this disease on resistance vessel function are unknown., Methods and Results: To investigate the integrity of endothelium-dependent small-vessel vasodilation in transplanted hearts, coronary blood flow (CBF) responses to the endothelium-dependent dilator acetylcholine (10(-8) to 10(-6) M) and the essentially endothelium-independent dilator adenosine (10(-6) to 10(-4) M) were assessed in 40 studies of 29 transplant patients 1-3 years after transplantation and in seven nontransplanted controls. CBF was measured at constant arterial pressure with a Doppler catheter in the left anterior descending coronary artery. Controls, year 1 transplant patients, and year 2 transplant patients had similar increases in CBF in response to acetylcholine (232 +/- 40%, 200 +/- 41%, and 201 +/- 54%, respectively; p = NS), whereas year 3 transplant patients had increased CBF of only 100 +/- 39% (p less than 0.05 versus controls). An index of the proportion of CBF reserve attributable to endothelium-dependent dilation was obtained by normalizing each patient's peak acetylcholine flow response by the peak adenosine flow response. In patients receiving both acetylcholine and adenosine, endothelium-dependent flow responses declined over time [57 +/- 9% in controls, 56 +/- 10% for year 1, 47 +/- 12% for year 2, and 29 +/- 9% for year 3 (p less than 0.05 versus controls)]. An increased mean cyclosporine level (range, 99-261 ng/ml) (r = 0.67, p = 0.004) and increased transplant recipient age (range, 20-63 years) (r = 0.51, p = 0.004) predicted a preserved endothelium-dependent microvascular response., Conclusions: Thus, microvascular endothelium-dependent dilation deteriorates over time in the transplanted heart, which may reflect underlying graft arteriosclerosis and contribute to ischemic damage of the myocardium.

Changes in blood flow can alter vasomotion of conduit arteries. This study examined vasomotor responses to incremental blood flow induced by papaverine in the epicardial arteries of 10 patients with angiographically normal coronary arteries (group 1) and in 14 patients with arterial irregularities (group 2) using quantitative angiography and Doppler ultrasound flow velocity measurements. An increase in coronary blood flow of 384.3 +/- 32.8% (p less than 0.001) in group 1 patients was associated with dilation of the proximal coronary artery segment and a 23.2 +/- 4.6% increase in cross-sectional area (p less than 0.001). In contrast, in group 2 patients a similar increase in coronary blood flow of 339.3 +/- 18.7% (p less than 0.001) was associated with mixed responses and a modest net constriction in cross-sectional area of -7.4 +/- 2.8% (p less than 0.05). The dilation response to nitroglycerin was intact in group 1 (31.7 +/- 4.2%, p less than 0.001) and in group 2 (26.4 +/- 3.2%, p less than 0.001). In five patients from group 1 acetylcholine, an endothelium-dependent dilator, produced an increase in cross-sectional area of 20.7 +/- 4.6% (p less than 0.05) that paralleled the response to an increase in flow in the same segment (a 24.3 +/- 6.1% increase in cross-sectional area, p less than 0.05). Five group 2 patients demonstrated a vasoconstrictor response to acetylcholine (a -22.8 +/- 3.4% decrease in cross-sectional area, p less than 0.05) together with an impaired dilation response to incremental flow (a -6.4 +/- 3.2% decrease in cross-sectional area).(ABSTRACT TRUNCATED AT 250 WORDS)

Dilator reserve of the coronary microvasculature is diminished in patients with dilated cardiomyopathy. Although increased extravascular compressive forces, tachycardia, and increased myocardial mass can explain some impairment, recent evidence suggests the possibility of intrinsic microvascular disease. We tested the hypothesis that impairment of endothelium-dependent dilation of the microvasculature could be a contributing mechanism. We infused the endothelium-dependent dilator acetylcholine (Ach) (10(-8) to 10(-6) M) and the smooth muscle vasodilator adenosine (AD) (10(-6) to 10(-4) M) into the left anterior descending coronary artery in eight patients with dilated cardiomyopathy (mean ejection fraction, 28%) and seven controls (atypical chest pain). Small vessel resistance was assessed by measuring coronary blood flow (CBF) at constant arterial pressure with a Doppler velocity catheter (corrected for cross-sectional area by angiography). With Ach, control patients increased CBF 232 +/- 40% (mean +/- SEM), whereas CBF did not significantly change in cardiomyopathy patients (41 +/- 24%) (p less than 0.0001, control vs. cardiomyopathy). With AD, control patients increased CBF 422 +/- 56% and cardiomyopathy patients increased CBF 268 +/- 43% (p = 0.13). An index of the proportion of coronary flow reserve attributable to endothelium-dependent vasodilation was obtained by standardizing each patient's Ach dose response to his maximal AD flow response. In seven control patients receiving both Ach and AD, 56 +/- 9% of the maximal AD flow response was attained with the endothelium-dependent vasodilator Ach, whereas in seven cardiomyopathy patients receiving both Ach and AD, only 23 +/- 14% of the maximal AD response was attained (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

The physical and biological properties of 201thallium (Tl) have been investigated and are discussed in this review. A new technique using the ultra-short lived 81mkrypton (81mKr) as a continuous infusion into the aortic root in dogs and man is described. This provides a dynamic assessment of changes in regional myocardial perfusion. Experiments using 201Tl and 81mKr in dogs have shown that regional decreases in myocardial perfusion alone cannot be detected in images of the heart using 201Tl. The effects of perfusion and a variety of factors on the energy dependent cellular uptake of 201Tl are discussed as being of primary importance in changing the regional myocardial distribution of this tracer. The constant infusion of 81mKr in patients with anginal chest pain provides continuous measurement of regional myocardial perfusion in high spatial resolution images. This dynamic method provides a physiological assessment of stenosed coronary arteries at rest and during stress.

We studied 25 anesthetized and thoracotamized dogs before and during 5 hours of acute regional myocardial ischemia. Krypton-81m (81mKr) was infused constantly into the aortic sinuses. The myocardial equilibrium of this tracer was used to image and assess the distribution of regional myocardial perfusion using a gamma camera and digital computer. The epicardial ECG was recorded, S-T segment elevation and the loss of R and appearance of Q waves were measured, and the plasma activity of creatine kinase (CK) was determined in aortic and coronary venous blood throughout these experiments. Ten dogs underwent left anterior descending coronary artery (LAD) narrowing for 5 hours and received no drugs. Five dogs received nifedipine 13 microgram/kg, and another five received 1.0 microgram/kg intravenously 30 minutes after LAD narrowing. Those dogs receiving nifedipine, 13 microgram/kg, showed a 30% fall in aortic pressure, a 12% rise in heart rate, and an extension of regional ischemia. The ECG showed an extension of infarct size, and CK release into the coronary vein appeared earlier than in the controls. Dogs receiving nifedipine, 1 microgram/kg, showed a 12% fall in blood pressure, no rise in heart rate, an improvement in regional perfusion, and ECG signs that suggested limitation of infarct size. There also was delayed release of coronary venous CK. The effects of nifedipine on the natural history of regional myocardial perfusion, the electrocardiogram, and enzyme release from the heart were dose related and cannot be generalized. These observations warrant further clinical investigation to improve the use of this agent in man.

Studies in animals have suggested that increases in blood flow result in dilation of large arteries by an endothelium-dependent mechanism. Atherosclerosis can impair endothelium-dependent vasodilation to vasoactive agents. The purpose of this study was to determine whether or not large coronary arteries in humans exhibit dilation with increases in blood flow and to test the hypothesis that this response is impaired in the presence of atherosclerosis. Graded concentrations of adenosine were infused into the distal left anterior descending (LAD) coronary artery to test the dilator response of the proximal LAD to increases in blood flow. The proximal LAD was thereby exposed to changes in blood flow, but not directly to adenosine. Ten patients with angiographically smooth proximal LAD segments (group 1) and seven patients with irregularities in the proximal LAD consistent with mild atherosclerosis (group 2) were studied. Infusions of adenosine throughout the range of 0.022 to 2.2 mg/min into the LAD produced a dose-dependent increase in estimated coronary blood flow and a mean increase of 305 +/- 27% at 2.2 mg/min adenosine. At 2.2 mg/min adenosine, a striking difference (p less than 0.001) occurred between the significant flow-mediated dilation of the proximal LAD observed in group 1 (+13.2 +/- 1.3% from 2.63 +/- 0.16 mm, p less than 0.001), and the lack of dilation in group 2 (+1.8 +/- 1.5% from 3.20 +/- 0.17 mm, p = NS), despite a greater increase in coronary blood flow in group 2 (+387 +/- 29%) than in group 1 (+230 +/- 36%).(ABSTRACT TRUNCATED AT 250 WORDS)

Experiments were undertaken using rubidium-82 and position tomography to examine the relation between myocardial perfusion and cation uptake during acute ischemia. Rubidium-82 was repeatedly eluted from a strontium-82-rubidium-82 generator. In six dogs emission tomograms were used to measure the delivered arterial and myocardial concentrations at rest and after coronary stenosis, stress and ischemia. There was a poor overall relation between regional myocardial uptake and flow measured by microspheres and a large individual variability. Extraction of rubidium-82 was inversely related to flow. Significant regional reduction of cation uptake was detected in the tomograms when regional flow decreased by more than 35 percent. This reduction was significantly greater when ischemia was present. A small but significantly greater when ischemia was present. A small but significant decrease (33.0 +/- 9.1 percent, mean +/- standard deviation) in the myocardial uptake of rubidium-82 was detected only when flow was increased by more than 120 percent in relation to a control area after administration of dypiridamole. The technique using rubidum-82 and tomography was applied in five volunteers and five patients with angina pectoris and coronary artery disease. Myocardial tomograms recorded at rest and after exercise in the volunteers showed homogeneous uptake of cation in reproducible and repeatable scans. In contrast, the patients with coronary artery disease showed an absolute mean decrease of 36 +/- 14 percent in regional myocardial uptake of rubidium-82 after exercise. These abnormalities persisted in serial tomograms for more than 20 minutes after the symptoms and electrocardiographic signs of ischemia.

Use of radiolabeled microspheres is a standard method to measure regional myocardial perfusion in animals. Human albumin microspheres have been given safely to patients, but positron-emitting 68Ga-labeled human albumin microspheres are characterized by an unstable radiolabel. A new labeling procedure that covalently binds 11C (t1/2 = 20.3 min) to human albumin microspheres via 11CH3I was developed. Seven open-chest and two closed-chest dogs were studied. Reference and 11C-labeled human albumin microspheres (2 to 25 mCi) were both injected into the left atrium. Positron tomographic images were obtained of the myocardial distribution of the 11C-labeled microspheres. Timed arterial withdrawal was used for both reference gamma-labeled microspheres and 11C-labeled human albumin microspheres. Myocardial tissue samples matched to tomographic slices were well-counted for calculation of reference values of regional myocardial perfusion. Serial venous blood samples for residual 11C activity of 30 and 60 min after injection were less than 1% of the myocardial 11C concentration demonstrating a stable 11C bond to the human albumin microspheres. Regional myocardial perfusion calculated by this technique correlated well with values obtained with reference microspheres (r = .97) over a range of 0.2 to 3.5 ml/min/g. Correction for wall thickness improved the slope of the regression equation from y = 0.71 x -0.03 to y = 0.88 X -0.05. Thus, 11C human albumin microspheres are stable radiochemically and can be used as a quantitative measure of regional myocardial perfusion.

The unique physical properties of the freely diffusible gas krypton-81 m allowed continuous imaging of regional myocardial blood flow in dogs when infused into the aortic root. Regional changes in myocardial perfusion related to transient coronary artery occlusion were demonstrated both as high resolution gamma camera images and as a quantitative strip chart record.

Cigarette smoking is strongly associated with ischemic heart disease and acute coronary events. The effect of smoking a single cigarette on regional myocardial perfusion was studied in 13 chronic smokers with typical stable angina pectoris using positron emission tomography and rubidium-82 (82Rb). Findings were compared with the effects of physical exercise. After exercise, 8 patients (61%) had angina, ST depression and abnormal regional myocardial perfusion. Uptake of 82Rb increased from 49 +/- 8 to 60 +/- 7 in remote myocardium, but decreased from 46 +/- 3 to 37 +/- 5 in an ischemic area. The remaining 5 patients (39%) had homogeneous increases in 82Rb uptake without angina or ST depression. After smoking, 6 of the 8 patients with positive exercise test responses had a decrease in 82Rb uptake, from 47 +/- 3 to 35 +/- 6 in the same segment of myocardium affected during exercise. However, in contrast to exercise, the events during smoking were largely silent. The absolute decreases in regional 82Rb uptake after smoking occurred at significantly lower levels of myocardial oxygen demand than after exercise. This suggests that an impairment of coronary blood supply is responsible. Thus, in smokers with coronary artery disease, each cigarette can cause profound silent disturbances of regional myocardial perfusion that are likely to occur frequently during daily life. Such repeated insults may represent an important mechanism linking smoking with coronary events.

Ambulatory electrocardiographic (ECG) monitoring of patients with chronic stable angina has demonstrated frequent and prolonged episodes of ischemic ST segment depression, but its clinical use requires an understanding of the components and extent of variability. Therefore, variations in the frequency and duration of episodes of ST segment depression were evaluated with ambulatory ECG recording at daily, weekly, and monthly intervals in 42 patients with chronic stable angina and known coronary artery disease. Data were analyzed with a nested analysis of variance design that yields estimates of variance components. From the estimates of variance components, power calculations and minimum significant percent reductions in frequency and duration of ischemia were derived. During 4,656 hours of ambulatory ECG monitoring, 1,262 episodes of ischemic ST segment depression were detected. The frequency of episodes was 6.3 +/- 0.45/24 hr (mean +/- SEM), and the duration of episodes was 18.3 +/- 2.8/24 hr. Because of variability over time, the ability to detect significant changes was dependent upon the number of subjects, length of monitoring period, and intervals between monitoring periods. In a clinical trial, for example, a sample size of 25 patients monitored for 48 hours with 1 week between control and test conditions would require a 65% reduction in frequency, whereas a sample size of 50 patients monitored under similar conditions would require a 46% reduction in frequency, to attribute the change with 90% power to a therapeutic intervention rather than to a spontaneous variation. When monitoring a single patient for 48 hours with 1 week or 1 month between control and repeat monitoring sessions, episodes of ischemic ST depression must be eliminated to detect significant therapeutic changes in ischemic activity at the 95% confidence level.(ABSTRACT TRUNCATED AT 250 WORDS)