Reflex increase in blood pressure during the intracoronary administration of adenosine in man.

Infusion of adenosine (0.022-2.2 mg/min) into the left anterior descending (LAD) coronary artery of 26 patients produced a dose-dependent increase in blood pressure without a change in heart rate. At adenosine 2.2 mg/min, systolic pressure rose by 21.0 +/- 2.2 mmHg from 134 +/- 4.3 mmHg (P less than 0.001) and diastolic pressure increased by 10.4 +/- 1.1 mmHg from 76 +/- 1.9 mmHg (P less than 0.001). The rise in arterial pressure was associated with a 22 +/- 3.4% increase in systemic vascular resistance (P less than 0.01) and no change in cardiac output (-2.8 +/- 4.3%, P = NS). Plasma norepinephrine levels rose by 40 +/- 14% from 105 +/- 9 pg/ml (P less than 0.05) and epinephrine levels by 119 +/- 31% from 37 +/- 9 pg/ml (P less than 0.01). Right atrial infusion of adenosine produced insignificant hemodynamic effects, suggesting that systemic spillover of adenosine was not responsible for the observed effects. In 20 cardiac transplant patients with denervated hearts, LAD infusion of adenosine (2.2 mg/min) produced no change in systolic pressure (-0.1 +/- 1.6 mmHg from 139 +/- 3.4 mmHg, P = NS) and a decrement in diastolic pressure (-4.7 +/- 1.2 mmHg from 98 +/- 2.5 mmHg, P less than 0.01). Thus, infusion of adenosine into the LAD coronary artery causes a reflex increase in arterial pressure due to a rise in systemic vascular resistance, probably as a result of increased sympathetic discharge. This reflex pathway may be of importance in disease states such as myocardial ischemia, in which myocardial adenosine levels are elevated.

Responses of coronary arteries of cardiac transplant patients to acetylcholine.

Accelerated coronary atherosclerosis is a major cause of graft failure after heart transplantation. Graft atherosclerosis is typically diffuse and difficult to detect even with coronary arteriography. Recently, acetylcholine was shown to dilate blood vessels by releasing a vasorelaxant substance from the endothelium (endothelium-derived relaxing factor). We have demonstrated paradoxical vasoconstriction induced by acetylcholine both early and late in the course of coronary atherosclerosis in patients, suggesting an association of endothelial dysfunction and atherosclerosis. In this report, we tested the hypothesis that coronary arteries of heart transplant patients can show endothelial dysfunction before or in the early stages of angiographically evident coronary atherosclerosis. Acetylcholine was infused into the left anterior descending artery of 13 heart transplant patients at 12 (n = 9) and 24 (n = 4) mo after transplantation. Vascular responses were evaluated by quantitative angiography. Among patients with angiographically smooth coronary arteries, relatively few (6/25) arterial segments had preserved vasodilator responses, while the majority failed to dilate (10/25) or paradoxically constricted (9/25). Angiographically irregular coronary arteries were present in three patients, in whom 8/10 segments showed marked paradoxical constriction and the remaining 2/10 failed to dilate. Only 1 of 13 patients retained appropriate dilation to acetylcholine in all segments. Nitroglycerin, which acts directly on vascular smooth muscle, dilated nearly all segments. No clinical features of the patients, including myocardial rejection appeared to correlate with the impaired functional response of vessels. Thus impaired response to acetylcholine is a common early finding in heart transplant patients and emphasizes the potential importance of endothelial dysfunction in the development of atherosclerosis.

Atherosclerosis influences the vasomotor response of epicardial coronary arteries to exercise.

We studied the vasomotion of epicardial coronary arteries during exercise and tested the hypotheses that abnormal vasoconstriction is related to the presence of atherosclerosis and may be related to endothelial dilator dysfunction. During cardiac catheterization quantitative coronary angiography was performed in 21 patients during supine bicycle exercise. 21 of 28 smooth, angiographically normal vessel segments dilated (14.0 +/- 1.8%) during exercise; four smooth segments did not change whereas only three constricted. In contrast, 15 of 16 vessel segments with irregularities constricted in response to exercise (17.0 +/- 0.1%) with only one segment dilating. All 10 stenotic segments constricted to exercise (23 +/- 4%). Six patients also received intracoronary acetylcholine before exercise to test endothelium-dependent dilator function. In five of six patients all nine vessel segments showed the same directional response to acetylcholine and exercise. Three irregular and two stenotic segments constricted with acetylcholine (51 +/- 21%) and exercise (9.0 +/- 0.6%). In contrast, four smooth segments dilated to acetylcholine (19 +/- 6%) and exercise (9 +/- 1%). Both exercise and acetylcholine generally dilated smooth but constricted irregular and stenosed coronary segments. It appears likely that atherosclerosis plays an important role in the abnormal vasomotion of diseased coronary arteries during exercise and the pattern of abnormality suggests impairment of vasodilator function.

Plasma alpha-tocopherol and coronary endothelium-dependent vasodilator function.

BACKGROUND: In the presence of atherosclerosis, the coronary endothelial vasomotor response to acetylcholine is frequently abnormal but is variable between patients. We tested the hypothesis that the plasma concentration of alpha-tocopherol is associated with the preservation of nitric oxide-mediated endothelium-dependent vasomotion. METHODS AND RESULTS: We studied 15 men and 6 women (mean age 61+/-10 years) at coronary angiography who were not taking vitamin supplements. Coronary endothelium-dependent and -independent vasomotion was assessed by intracoronary infusions of acetylcholine and nitroglycerin. The vasomotor responses were compared with the plasma concentration of alpha-tocopherol and the plasma alpha-tocopherol concentration relative to total lipid (total cholesterol plus triglycerides). The mean plasma alpha-tocopherol was 25.6+/-6.1 micromol/L, total cholesterol 193+/-27 mg/dL, triglycerides 115+/-66 mg/dL, and alpha-tocopherol to total lipid 4. 2+/-0.9 micromol. L(-1). (mmol/L)(-1). The mean vasomotor response to acetylcholine was -1% (range -33% to 28%) and to nitroglycerin 22% (range 0% to 54%). Plasma alpha-tocopherol was significantly correlated with the acetylcholine response (r=0.49, P<0.05) but not the nitroglycerin response (r=0.13, P>0.05). The acetylcholine response remained significant after adjustment for other potential sources of oxidant stress (total cholesterol, diabetes mellitus, smoking, angina class) (P<0.01). The relative concentration of alpha-tocopherol to total lipid was not related to endothelial function (r=0.24, P=0.3, n=20). CONCLUSIONS: alpha-Tocopherol may preserve endothelial vasomotor function in patients with coronary atherosclerosis. This effect may be related primarily to the action of alpha-tocopherol in the vascular wall. Further studies that assess the impact of alpha-tocopherol supplementation as therapy of endothelial dysfunction are justified.

Role of endothelin-1 in the active constriction of human atherosclerotic coronary arteries.

BACKGROUND: Atherosclerotic coronary arteries are prone to constriction but the underlying causes are incompletely understood. We tested the hypothesis that endothelin-1 (ET-1), a potent vasoconstrictor, contributes to the heightened tone of atherosclerotic human coronary arteries. METHODS AND RESULTS: In 8 patients with coronary artery disease (CAD) and 8 patients with angiographically smooth coronary arteries (normal), we infused BQ-123, an antagonist of the ET(A) receptor, into a major coronary artery (infused artery) at 40 nmol/min for 60 minutes. The infused artery in the CAD patients contained a >50% stenosis. Using quantitative angiography, we compared the dilation of the infused artery with another, noninfused coronary artery. To estimate the magnitude of the contribution of ET-1 to coronary tone, we compared the dilation to BQ-123 with that elicited by intracoronary nitroglycerin (200 microgram). BQ-123 induced significant dilation in the normal arteries (7.3% at 60 minutes, P<0.001 versus noninfused arteries) and a greater dilation in the CAD arteries (16.3% at 60 minutes, P<0.001 versus infused normal arteries). The dilation at stenoses was particularly pronounced (21.6% at 60 minutes, P<0.001 versus infused CAD arteries). Compared with the dilation from nitroglycerin, ET-1 contributed to 39% of the coronary tone in normal arteries, 74% of tone in CAD arteries, and 106% of tone at stenoses (P<0.01). CONCLUSIONS: ET-1 accounts for nearly all the resting tone in atherosclerotic coronary arteries, especially at stenoses. Inhibitors of ET-1, by relieving constriction, may significantly lessen the hemodynamic significance of coronary stenoses and thereby reduce myocardial ischemia.

Large coronary arteries in humans are responsive to changing blood flow: an endothelium-dependent mechanism that fails in patients with atherosclerosis.

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)

Transcatheter closure of a calcified patent ductus arteriosus in an elderly man.

Successful transcatheter closure of a calcified patent ductus arteriosus was performed in a symptomatic 78 year old man. Cardiac catheterization revealed a left to right shunt across the patent ductus arteriosus with a pulmonary to systemic flow ratio of 2.8:1. Calcification of the ductus and severe lung disease increased the risk of surgical patent ductus arteriosus closure. A 17 mm Rashkind double umbrella was positioned in the ductus percutaneously by way of the femoral vein. After closure of the ductus there was marked hemodynamic improvement and the patient was discharged with improved exercise tolerance. Transcatheter closure of patent ductus arteriosus may be a viable option for the elderly patient too sick to withstand cardiovascular surgery.

Nitric oxide and nitrovasodilators: similarities, differences and potential interactions.

Many similarities exist between the exogenous nitrates and endothelium-derived relaxing factor, which is nitric oxide or a thiol derivative. Both act by way of guanylate cyclase, which increases intracellular concentrations of cyclic guanosine monophosphate, resulting in smooth muscle cell relaxation and antiplatelet effects. Thiols may be important in the biotransformation of exogenous nitrates and other intracellular processes involving nitric oxide. As such, important interactions might be expected between nitrates and endothelium-dependent processes that involve nitric oxide. This review explores the mechanisms of action, biologic effects and potential interactions between nitrates and endothelium-derived relaxing factor.

Control of shear stress in the epicardial coronary arteries of humans: impairment by atherosclerosis.

Altered arterial wall shear stress may adversely affect vascular endothelium and contribute to atherogenesis. This study examined the hypothesis that, in humans, dilation of normal coronary arteries with increased flow limits increases in shear stress and that loss of flow-mediated dilation in atherosclerosis results in failure to control shear stress. Coronary blood flow was increased by infusing adenosine (0.022 to 2.2 mg/min) through a 2.5F Doppler flow catheter positioned in the middle segment of the left anterior descending coronary artery in 8 patients with mild atherosclerosis but no flow-limiting stenosis and in 10 patients with entirely smooth coronary arteries. Quantitative angiography and coronary flow velocity were used to estimate shear stress in a proximal segment of the left anterior descending artery exposed to increased flow, but not to adenosine. The peak increase in blood flow was the same in smooth (371 +/- 65%) and irregular (377 +/- 50%) arteries. However, at peak flow, dilation was greater in smooth segments (16.3 +/- 2.7%) than in irregular segments (2.0 +/- 1.5%) (p less than 0.001). In each patient, smooth segments dilated with increasing shear stress (slope 7.4 +/- 0.9%), whereas irregular segments dilated less (slope 0.9 +/- 0.6%) and showed greater increases in shear stress (p less than 0.01). The peak increase in shear stress was less in smooth (189 +/- 23%) than in irregular (365 +/- 52%) segments (p less than 0.01). These results suggest a control mechanism in normal coronary arteries whereby increases in shear stress stimulate vasodilation and thus limit further increases in this force at the endothelial surface.(ABSTRACT TRUNCATED AT 250 WORDS)

Detection of pacing-induced myocardial ischemia by endocardial electrograms recorded during cardiac catheterization.

Rapid atrial pacing confirms myocardial ischemia in patients with coronary artery disease when angina is provoked, and is accompanied by an increase in left ventricular end-diastolic pressure. In such cases, abnormalities in the surface electrocardiogram (ECG) are often not apparent. To enhance detection of subendocardial ischemia during rapid atrial pacing, local unipolar electrograms were recorded from the tip of a 0.025 in. (0.064 cm) diameter guidewire positioned against the endocardial surface of potentially ischemic regions. Endocardial electrograms, left ventricular end-diastolic pressure and multiple surface ECG leads were recorded during rapid atrial pacing in 21 patients with coronary artery disease. Before pacing, endocardial electrograms in all 21 patients were free of ST elevation. Marked ST elevation was apparent in 17 of the 21 patients after rapid atrial pacing and could be abolished by nitroglycerin. Moreover, in several patients, endocardial ST elevation after rapid atrial pacing was abolished after successful percutaneous transluminal coronary angioplasty of the critically stenosed artery supplying the ischemic region of myocardium. It is concluded that ST elevation in the endocardial electrogram after rapid atrial pacing is a reflection of myocardial ischemia and may be a sensitive marker of pacing-induced ischemia appearing earlier than angina, postpacing increase in left ventricular end-diastolic pressure or ST depression in the surface ECG.

Nitroglycerin-induced coronary vasodilation is not enhanced in patients with impaired endothelium-dependent dilation.

OBJECTIVES: This study was designed to determine whether enhanced sensitivity to exogenous nitrovasodilators is present in the coronary arteries of patients with impaired endothelium-dependent dilation. BACKGROUND: Animal studies have demonstrated that the dilator response to exogenous nitrovasodilators is exaggerated in the setting of endothelial dysfunction (diminished nitric oxide activity). Whether such relative hyperresponsiveness to exogenous nitrates occurs and is important in humans is unknown. METHODS: We assessed coronary vasomotion in 110 patients (mean [+/- SD] age 56 +/- 10 years) by serial intracoronary infusions of acetylcholine (10(-8) to 10(-6) mol/liter) to test endogenous nitric oxide and nitroglycerin (40 micrograms) to test responses to exogenous nitrovasodilators. RESULTS: The vasomotor response to 10(-6) mol/liter of acetylcholine differed between patients with (n = 95) and those without (n = 15) normal endothelial dysfunction (-21 +/- 14% vs. 12 +/- 8%, respectively, p < 0.001). However, neither the dilator response to nitroglycerin (21 +/- 14% vs. 18 +/- 13%) nor the baseline diameter differed between those with endothelial dysfunction and normal function, respectively. There was no correlation between the magnitude of the dilator response to nitroglycerin and acetylcholine. The response to nitroglycerin was decreased with increasing age (r = -0.21, p = 0.03) but was not related to any other demographic factors or to the angiographic appearance of the vessel. CONCLUSIONS: The coronary vasodilator response to nitroglycerin is not significantly enhanced in patients with impaired endothelium-dependent dilation but decreases with increasing age. This finding provides indirect evidence that basal coronary tone is not increased in patients with endothelial dysfunction and that supersensitivity to exogenous nitrates is not clinically important in humans.

Peak left ventricular pressure during percutaneous aortic balloon valvuloplasty: clinical and echocardiographic correlations.

Peak left ventricular pressure during balloon inflation was measured in 20 patients who underwent balloon valvuloplasty for severe aortic stenosis to define the determinants of ventricular pressure development in response to increased loading conditions. The peak left ventricular pressure ranged from 150 +/- 5 to 386 +/- 22 mm Hg (mean +/- SD), was reproducible in each patient with each balloon inflation (mean coefficient of variation 7.8%) and correlated with concurrent echocardiographic measurements of ejection fraction (r = 0.89, p = 0.0001) and mass/volume ratio in systole (r = 0.91, p = 0.0001) or diastole (r = 0.88, p = 0.0001). Thirteen patients with class II or more severe congestive heart failure had lower values for peak left ventricular pressure than did those without failure (225 +/- 46 versus 305 +/- 45 mm Hg, p = 0.002), whereas no difference in rest left ventricular systolic pressure was seen between the two groups. The measurement of peak left ventricular pressure was inversely related to rest mean circumferential end-systolic wall stress (r = 0.52, p = 0.046). Thus, peak left ventricular systolic pressure measured during aortic valvuloplasty in humans correlates closely with traditional measures of left ventricular function. This measurement, which previously has been obtained only in experimental animal studies, is a simple and reproducible hemodynamic index that may provide new insights in studies of ventricular function and congestive heart failure in aortic stenosis.

Thrombolytic therapy of acute pulmonary embolism: current status and future potential.

Recombinant human tissue-type plasminogen activator (rt-PA), a relatively clot-specific fibrinolytic agent, represents a novel and promising approach to thrombolytic therapy of pulmonary embolism. Therefore, the efficacy and safety of peripheral intravenous rt-PA therapy were assessed in 47 patients with angiographically documented pulmonary embolism. The drug regimen was 50 mg over 2 hours followed by repeat angiography and, if necessary, an additional 40 mg over 4 hours. By 6 hours, 44 of the 47 patients had angiographic evidence of clot lysis that was slight (n = 5), moderate (n = 12) or marked (n = 27). Among the 34 patients with pulmonary hypertension before treatment (mean pulmonary artery pressure exceeding 17 mm Hg), the pressure decreased from 43/17 (mean 27) to 31/13 (mean 19) mm Hg (p less than 0.0001). Fibrinogen decreased 33% from baseline at 2 hours and 42% from baseline at 6 hours. There were two major complications that required surgical control of bleeding: hemorrhage from a pelvic tumor and mediastinal tamponade in a patient 8 days after coronary artery bypass surgery. The initial results demonstrate that, among selected patients, peripheral intravenous rt-PA can rapidly and, for the most part, safely lyse pulmonary embolism within 6 hours.

Praecordial mapping of Q waves and RS ratio changes in acute myocardial infarction.

The theory related to the loss of R waves and appearance of Q waves in acute myocardial infarction is discussed. A method of praecordial mapping of RS ratio changes and the appearance of Q waves that occur in acute myocardial infarction is described. The serial changes in these electrocardiographic signs in 17 patients during acute infarction are recorded. The potential value of these serial measurements in delineating the extent of myocardial injury in patients with acute infarction, and evaluating the effects of any treatment aimed at limiting infarct size is discussed.

Plasma lysosomal enzyme activity in acute myocardial infarction.

N-acetyl-beta-glucosaminidase (EC 3.2.1.30, recommended name beta-N-Acetylglucosaminidase) was found to be a constituent of human cardiac lysosomes. beta-glucuronidase was also found in this tissue, while lysozyme, an enzyme present in leucocyte lysosomes, was not detectable in the heart. The activities of both N-acetyl-beta-glucosaminidase and beta-glucuronidase were elevated in plasma during the first 24 h after the onset of chest pain in patients with acute myocardial infarction and the peak levels of N-acetyl-beta-glucosaminidase correlated well with those of creatine kinase. N-acetyl-beta-glucosaminidase showed a further rise in plasma activity which gave a peak at 72 h after the onset of chest pain and this was accompanied by a rise in lysozyme activity. It is suggested that lysosome disruption caused by myocardial cell necrosis was responsible for the initial rise in plasma lysosomal enzyme activity and that the subsequent inflammatory reaction gave rise to the second peak.

Continuous imaging of regional myocardial blood flow in dogs using krypton-81m.

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.

Character and causes of transient myocardial ischemia during daily life. Implications for treatment of patients with coronary disease.

Measures of the severity of angina pectoris, coronary anatomy, and left ventricular function are widely used to assess prognosis and determine management in patients with ischemic heart disease. However, recent evidence suggests that myocardial ischemia, with or without angina, is also a reliable prognostic sign. Studies using ambulatory ST-segment monitoring of patients with chronic stable angina out of the hospital have shown that the majority of episodes of transient myocardial ischemia are silent and surprisingly prolonged. Most episodes occur without the increase in heart rate noted during physical exertion. Characteristic abnormalities of regional myocardial perfusion have been observed using positron tomography during both painful and painless episodes of ischemia. Among these abnormalities is an absolute reduction in the perfusion to the poststenotic ischemic segment of myocardium. Episodes of ischemia can be induced in the hospital by a number of ordinary daily activities, including mental stress, cold, and cigarette smoking, and they often resemble episodes recorded from patients out of the hospital. These observations suggest that both an increased myocardial demand and a reduction in coronary blood flow may be important in the genesis of ischemia out of the hospital. If prospective studies confirm that myocardial ischemia is damaging, even in the absence of angina, investigation and treatment policies may need to be reevaluated. Results of ongoing clinical studies will show whether control of the total ischemic burden can prevent myocardial damage and improve the prognosis.

Current concepts in cardiovascular pathology: the role of LDL cholesterol in plaque rupture and stabilization.

Emerging evidence is redefining traditional concepts of coronary atherosclerosis. Recent data indicate that severe stenoses, the traditional focus of attention, do not cause most coronary events. Rather, interest has increased in the often less stenotic but more vulnerable lesions that are characterized by thin fibrous caps, large lipid accumulations, large numbers of macrophages, and depletion of smooth muscle cells. Such lesions appear prone to rupture, which allows the blood to come into contact with the highly thrombogenic material in the lipid core of the plaque, thereby precipitating thrombosis. The fibrous cap may become weakened through decreased synthesis of the extracellular matrix or increased degradation of the matrix. The cytokine interferon-gamma, produced by T-lymphocytes, inhibits the ability of smooth muscle cells to synthesize collagen, a structurally important component of the fibrous cap. A family of enzymes known as matrix metalloproteinases can degrade all major constituents of the vascular extracellular matrix: collagen, elastin, and proteoglycans. Additional studies on the biochemical mechanisms of atherosclerosis may provide a fuller understanding of the ways in which lipid-lowering therapy can confer clinical benefit.

Clinical evaluation of transient myocardial ischemia during daily life.

Ambulatory ST-segment monitoring has been introduced in an attempt to obtain an objective measure of transient myocardial ischemia during daily life. Serial observations conducted out of the hospital have produced a picture of the nature and activity of ischemic heart disease that differs markedly from that obtained by conventional assessment. Episodes of transient ischemia appear to be more frequent and prolonged than is suggested by the occurrence of chest pain. Furthermore, only a minority of episodes are associated with tachycardia, and most occur at heart rates well below those achieved during exercise testing. This suggests that mechanisms other than an excessive increase in myocardial oxygen demand may be responsible for the many episodes occurring outside the hospital. Accurate interpretation of this new information depends on the reliability of transient ST-segment depression as a marker of ischemia. In 100 normal volunteers, episodes of significant ST-segment depression similar to that observed in patients with angina were rare (2 percent). Positron emission tomography with rubidium-82 was used to study regional myocardial perfusion during transient ST-segment depression with and without pain in patients with angina and coronary disease. All episodes of painless ST-segment depression and 97 percent of episodes with angina were accompanied by tomographic evidence of ischemia. This much broader view of ischemic heart disease, revealed by studies performed out of the hospital during patients' ordinary daily activities, has important implications for the objective assessment of symptoms, the relief of ischemia, and the prevention of myocardial damage.

Clinical problems in coronary disease are caused by wide variety of ischemic episodes that affect patients out of hospital.

Transient ischemia arising from proximal events in epicardial coronary arteries causes important symptoms, such as angina pectoris, and is usually studied in the hospital with provocative tests. However, Holter monitoring of ST-segment disturbances in patients out of the hospital has shown frequent asymptomatic evidence of ischemia that is surprisingly prolonged and that is not associated with the obvious tachycardia of exercise or stress. Positron emission tomography has been developed to measure the regional myocardial uptake of a cation (rubidium-82) in order to assess repeatedly the directional changes in regional coronary blood flow during these events. This method has been used to show that both symptomatic and asymptomatic episodes of ST depression are reliably associated with disturbances in regional myocardial perfusion. The daily activities of patients have been analyzed and reproduced in the hospital to assess the effects of cold stimulation, mental arithmetic, cigarette smoking, and exercise. Physical exercise was associated with angina, ST-segment change, and regional abnormalities of myocardial perfusion, including decreased perfusion in poststenotic segments. The other tests caused the same disturbances in myocardial perfusion; these perfusion disturbances were mostly asymptomatic and surprisingly prolonged, with periods of recovery that were two to five times longer than the ST-segment disturbance and the pain. Current studies using a structured diary indicate that the episodes of transient ischemia occurring out of the hospital are more frequently associated with different levels of mental arousal than with any other activity. Physical exercise is a relatively infrequent cause of transient ischemia. The examination of coronary blood flow using provocative tests derived from the patients' own activities out of the hospital have confirmed that, irrespective of the pattern of angina, patients have frequent episodes of asymptomatic transient ischemia that are surprisingly prolonged and that these episodes occur in response to previously unsuspected ordinary daily activities. The disturbances in coronary blood flow usually include a regional decrease in myocardial perfusion that can only be explained by pathophysiologic events in the proximal epicardial coronary arteries.