Clinical validation of intravascular ultrasound imaging for assessment of coronary stenosis severity: comparison with stress myocardial perfusion imaging.

OBJECTIVES: To validate intravascular ultrasound (IVUS) measurements for differentiating functionally significant from nonsignificant coronary stenosis. BACKGROUND: To date, there are no validated criteria for the definition of a flow-limiting coronary artery stenosis by IVUS. METHODS: Preinterventional IVUS imaging (30-MHz imaging catheter) of 70 de novo coronary lesions was performed. The lesion lumen area and three IVUS-derived stenosis indixes comparing lesion lumen area with the lesion external elastic lamina (EEL) area, the mean reference lumen area and the mean reference EEL area were compared with the results of stress myocardial perfusion imaging. RESULTS: The lesion lumen area and three IVUS-derived stenosis indexes showed sensitivities and specificities ranging between 80% and 90% using stress myocardial perfusion imaging as the gold standard. The lesion lumen area < or =4 mm2 is a simple and highly accurate criterion for significant coronary narrowing. CONCLUSIONS: Quantitative IVUS indices can be reliably used for identifying significant epicardial coronary artery stenoses.

Angioscopic coronary macromorphology after thrombolysis in acute myocardial infarction.

In addition to a disruption of yellow plaque, vasospasm may also play a role in thrombotic occlusions of coronary arteries in small cases of infarction. Macroscopic vascular injury and thrombus seemed to be unnecessary for vasospasm culminating in myocardial infarction.

Coronary remodeling of proximal and distal stenotic atherosclerotic plaques within the same artery by intravascular ultrasound study.

The aim of this intravascular ultrasound study was to compare the type and the degree of vessel remodeling in proximal and distal de novo lesions within the same coronary artery in patients with stable angina pectoris. Seventy-six de novo coronary artery lesions in 38 coronary arteries of 38 patients were imaged by intravascular ultrasound. The vessel area (VA) within the external elastic lamina and the lumen area (LA) were measured, and the wall area (VA-LA) was calculated at the lesion site, and the proximal and distal reference sites. The VA ratio was defined as (lesion VA/average of the proximal and distal reference VAs) to represent the degree of vessel remodeling. The proximal coronary segments showed compensatory enlargement more often (68% vs 29%, p < 0.01) than the distal segments, and the VA ratio at the lesion site was significantly larger (1.1 +/- 0.3 vs 1.0 +/- 0.2, p <0 .01) in proximal segments than in distal segments. The type of coronary remodeling was discordant in 61% and concordant in only 39% of coronary arteries between the proximal and distal segments. The type of coronary remodeling of proximal and distal coronary lesions was inhomogeneous, even within the same vessel. Proximal coronary segments showed more prominent compensatory enlargement than distal segments, which have a similar degree of luminal narrowings.

Angioscopy, coronary thrombi and acute coronary syndromes.

Coronary angioscopy is a new diagnostic imaging technique in which optic fibres are used to directly observe the intracoronary lumen. Angioscopy provides a full colour, high resolution, three-dimensional image of the intracoronary artery surface morphology. Studies using angioscopy revealed that the frequency of coronary thrombi in patients with acute coronary syndromes was higher than previous studies, based on arteriography, had reported. Arteriographic recognition of thrombus in unstable angina was from 1.3% to 52%. On the other hand, thrombi were observed in 88% by angioscopy in patients with rest angina in our study. Whereas ordinary arteriography provides only two-dimensional black and white images, angioscopy can distinguish between a thrombus and a plaque, even if the clot is very small. In a study of 17 unstable angina and 22 myocardial infarction patients, the frequencies of coronary thrombi in the two groups were essentially the same. Grayish-white thrombi were observed in most of the unstable angina patients but in none of the infarction patients. On the other hand, red or mixed red and white thrombi were observed in all infarction patients but in only a few unstable angina patients. This difference may account for the contrasting results of thrombolytic therapy.

Endothelial function and peripheral vasomotion in the brachial artery in neurally mediated syncope.

BACKGROUND: Paradoxical peripheral vasodilation is one of the suspected mechanisms of neurally mediated syncope. Parasympathetic stimulation following sympathetic activation during orthostatic stress mainly contributes to this vasodilation. HYPOTHESIS: Since endothelial function modulates peripheral vascular tone, this study aimed to determine whether endothelial function and inappropriate peripheral vasomotion has a significant role in the pathogenesis of neurally mediated syncope. METHODS: To investigate whether endothelial function is augmented or whether abnormal peripheral vasomotion exits, flow-mediated dilation (FMD, endothelium-dependent vasodilation) and sublingual glyceryl trinitrate-induced dilation (0.3 mg, GTN-D, endothelium-independent vasodilation) were measured in the brachial artery in 16 patients with neurally mediated syncope, aged 33 +/- 10 years, by using high-resolution ultrasound. All patients underwent positive head-up tilt testing. These measures were compared with those in 16 control subjects matched with the patients by age, gender, and coronary risk factors. For FMD, percent diameter changes were obtained from baseline to hyperemic conditions (1 min after 5 min occlusion of the forearm artery). There were five smokers in both the patient and the control groups, but there was no structural heart disease in either group. RESULTS: Baseline brachial artery diameters were comparable (3.8 +/- 0.6 vs. 3.8 +/- 0.7 mm, NS). Flow-mediated dilation in patients with neurally mediated syncope had a normal value of 9.8 +/- 5.0% despite the inclusion of five smokers. Flow-mediated dilation and GTN-D in patients with neurally mediated syncope were significantly greater than those in controls (9.0 +/- 5.0 vs. 3.0 +/- 3.5%, p<0.05; 18.4 +/- 5.5 vs. 14.1 +/- 4.4%, p<0.05). CONCLUSIONS: Augmented endothelial function and/or abnormal peripheral vasomotion in peripheral arteries are important in patients with neurally mediated syncope in selected populations.

Painless myocardial ischemia in elderly patients compared with middle-aged patients and its relation to treadmill testing and coronary hemodynamics.

We compared painless ST-segment depression (1 mm greater than or equal to 80 ms and lasting greater than or equal to 60 s) in elderly patients with coronary artery disease (greater than or equal to 65 years, mean 67 years; n = 22) and that of middle-aged patients (less than 60 years, mean 54 years; n = 20) by Holter monitoring for 24 hours to determine the relationship between episodes of painless myocardial ischemia, findings of treadmill testing, and coronary hemodynamics. Coronary arteriographic findings (Gensini score) and ejection fraction (EF) did not differ between the two groups. Painless ST-segment depression was found to be 77% in the older age group versus 45% in the middle-aged group (p less than 0.05). However, treadmill exercise score, ST-segment depression, and ST-segment integral achieved did not differ significantly between the two groups. Within 2 weeks after the above testing, coronary hemodynamic study was performed. The increment of coronary sinus flow in the older age group was 1.4 +/- 0.3 versus 1.8 +/- 0.3 in the middle-aged group (p less than 0.05), and the change of lactate extraction ratio from the basal condition in the older age group was -50 +/- 40% versus -2 +/- 15% in the middle-aged group (p less than 0.05). We conclude that episodes of painless myocardial ischemia in elderly patients with aging may be associated with the impairment of the coronary vascular reserve and easier anaerobic myocardial metabolism by pacing stress despite similar findings of coronary artery disease and EF in both groups.

Significance of circulatory epinephrine levels in exercise-induced neurally mediated syncope.

BACKGROUND AND HYPOTHESIS: Previous research has failed to document temporal changes in epinephrine levels in patients with neurally mediated syncope associated with exercise. The purpose of this study was to investigate the role of circulatory catecholamines in exercise-induced neurally mediated syncope, specifically focusing on epinephrine levels. METHODS: The present study deals with temporal changes of circulatory catecholamine levels during head-up tilt tests (40 min, 80 degree tilt) in 62 patients with syncope of unknown origin, 7 of whom had syncope associated with exercise (exercise-induced group, 19+/-3 years). Data were compared with 10 control subjects (control group, 45+/-23 years). Of the 55 patients with syncope not associated with exercise, 32 tested positive for the head-up tilt tests (positive group, 31+/-16 years) and 23 patients tested negative (negative group, 46+/-19 years). Blood samples for circulatory catecholamine assay were obtained from the antecubital vein in the baseline supine position 2 min after the tilt started, every 10 min during tilt, and at the time of the onset of symptoms or the end of tilt. Levels of norepinephrine and epinephrine were determined using the high-pressure liquid chromatography (HPLC) method (pg/ml). RESULTS: Plasma norepinephrine levels among the four groups were similar at the supine position and during tilt testing. In contrast, patients in the exercise-induced group had significantly higher maximum epinephrine levels during head-up tilt testing than the other three groups (288+/-191 vs. 148+/-117, 66+/-31, and 54+/-27 pg/ml, respectively, p < 0.05). Patients in the positive group had higher maximum epinephrine levels than those in the negative group (p <0.05). Also, patients in the exercise-induced group and those in the positive group had a significantly shorter tilt-testing time than patients in the negative and control groups. CONCLUSIONS: A marked increase of epinephrine was observed during head-up tilt testing in patients with neurally mediated syncope associated with exercise. The present findings further accelerate the identification of the role of epinephrine in the mechanisms behind neurally mediated syncope associated with exercise.

Autonomic responses to orthostatic stress in head-up tilt testing: relationship to test-induced prolonged asystole.

BACKGROUND: Prolonged asystole is sometimes an extreme manifestation of neurally mediated syncope. HYPOTHESIS: To investigate the mechanism of head-up tilt testing-induced prolonged (life-threatening) cardiac asystole, we measured temporal changes in frequency domain heart rate variability indices in 25 patients with syncope of undetermined etiology. METHODS: Head-up tilt testing (80 degrees) was performed in 25 patients for up to 40 min or until asystole or syncope occurred. Three patients (Group 1; 37 +/- 13 years, 1 man 2 women) had an episode of prolonged cardiac asystole (> or = 10 s) during testing, necessitating cardiopulmonary resuscitation. Syncope, but no asystole, was induced in 10 patients (Group 2; 48 +/- 31 years, 6 men, 4 women), and 12 patients (Group 3; 55 +/- 20 years, 5 men, 7 women) failed to show asystole or syncope during testing. Power spectra of low (0.04-0.15 Hz) and high (0.15-0.40 Hz) frequency, and total (0.01-1.00 Hz) frequency spectra were measured in consecutive 2 min segments throughout the test. RESULTS: Maximally changed values in heart rate, systolic blood pressure, and heart rate variability indices during testing were compared among the three groups (maximally changed values did not include the values during tilt-induced symptoms). High frequency spectra in Groups 2 and 3, but not in Group 1, decreased during the test. High frequency spectra, low frequency spectra, and total spectra in Group 1 were significantly higher than those in Groups 2 and 3 during testing. In Group 1 patients, findings at test-induced asystole were consistent with exaggerated sympathetic and concurrent persistent parasympathetic activity. CONCLUSION: Unusual autonomic responses to orthostatic stress can cause prolonged asystole, and this autonomic nerve dysregulation may relate to asystolic episodes associated with cardiovascular collapse.

Endothelial dysfunction and decreased exercise tolerance in interferon-alpha therapy in chronic hepatitis C: relation between exercise hyperemia and endothelial function.

BACKGROUND: We previously reported that reversible endothelial dysfunction is caused by interferon-alpha therapy (IFN) in patients with chronic hepatitis C. In experimental studies, limb blood flow during exercise is reported to be dependent on endothelium-derived nitric oxide. HYPOTHESIS: The purpose of this study was to confirm the effect of IFN on endothelial function and to investigate whether exercise hyperemia is dependent on endothelial function in humans. METHODS: We performed symptom-limited exercise treadmill testing and measured flow-mediated vasodilation (FMD, endothelium-dependent vasodilation) and sublingual glyceryl-trinitrate-induced dilation (GTN-D, 0.3 mg, endothelium-independent vasodilation) in the brachial artery by using high-resolution ultrasound in 10 patients with chronic active hepatitis C (age 53 +/- 11 years, 2 men, 8 women) before and immediately after administration of recombinant interferon 2b (10 million U/day) for 4 weeks. RESULTS: There were no significant abnormal findings in any patients in routine studies of 24-h ambulatory electrocardiogram monitoring, two-dimensional echocardiography, and exercise treadmill testing both before and after treatment. Leg fatigue and exhaustion were the reasons for termination of exercise treadmill testing in each patient. Pressure rate product was calculated at rest and peak exercise. Interferon-alpha therapy significantly (p<0.05) decreased FMD (6.8 +/- 3.1 vs. 1.9 +/- 2.6%), exercise treadmill testing tolerance time (437 +/- 89 vs. 395 +/- 62 s) and peak pressure rate product (283 +/- 41 vs. 241 +/- 47 mmHg x beats/min x 10(-2)), but not GTN-D (13.4 +/- 5.4 vs. 17.0 +/- 5.5%). The change of FMD due to IFN significantly and highly correlated with exercise treadmill testing tolerance time (r = 0.86, p<0.001), but not with change of peak pressure rate product, suggesting that FMD is more closely related to the condition of the peripheral circulation than is cardiac performance. CONCLUSION: These results suggest that IFN in patients with chronic hepatitis C impairs endothelial function and exercise tolerance, and that endothelial function might be at least partly involved in exercise hyperemia in humans.

How long can a coronary reperfusion catheter be placed in acute coronary occlusion following failed transluminal coronary angioplasty? A case report.

A coronary reperfusion catheter (CRC) is designed to preserve antegrade coronary flow when abrupt coronary closure occurs during percutaneous transluminal coronary angioplasty (PTCA). Insertion of the catheter to an occluded coronary artery for a few hours has been reported to be effective for myocardial salvage: however, it is unknown how long the catheter can be kept in place without causing extension of myocardial ischemia. The authors experienced a case in which the CRC was kept in place for twenty-four hours for anticoagulant therapy of an occluded coronary artery following failure of PTCA. This case suggests that adequate anticoagulant therapy can prolong the period during which a CRC can be kept in place if emergency coronary bypass surgery cannot be performed immediately after failure of coronary angioplasty.

A serial observation of coronary thrombi in vivo by a new percutaneous transluminal coronary angioscope.

This study was undertaken to observe coronary thrombus formation serially from an antegrade perspective by means of a new thin flexible angioscope that has an inflatable balloon at the distal tip and an angulation mechanism. To test its capabilities, thrombi were induced in the left anterior descending coronary artery of 11 dogs by copper coils, and the thrombi were then observed through this angioscope, which had been introduced into the coronary artery by a guide catheter. Five minutes after insertion of the copper coil, fibrin-like material and white components of the thrombi were seen massing around the copper coil. Then, thin, mixed thrombotic white and red components formed around the copper coil. At fifteen minutes after the copper coil insertion, the thrombi grew in size. Ten minutes later, the thrombi finally obstructed the coronary lumen in most dogs. The red and white appearance of these thrombi was confirmed macroscopically, and the microscopic findings of these occluding thrombi revealed a fibrinous network with platelet aggregates and blood cell coagulation. Though ordinary angiography cannot reveal the precise features of the various coronary thrombi, this new angioscope was able to discern them from the antegrade perspective. The capabilities of this angioscope, which enabled these findings, should prove helpful in evaluating the stages of human coronary thrombosis. Of additional benefit, this angioscope can be used clinically for cardiac catheterization.

The effect of intravenous infusion of urokinase on coronary artery thrombolysis in the dog.

The effect of intravenous administration of urokinase on the rate and time of thrombolysis was investigated in 22 dogs with an occlusive coronary artery thrombus induced by placement of a copper coil in the left anterior descending artery. One hour after angiographic confirmation of complete coronary artery occlusion, an intravenous bolus of urokinase was administered in a dose of either 1.2 X 10(6) units (Group 1, n = 7); 0.6 X 10(6) units (Group 2, n = 9) or 0.3 X 10(6) units (Group 3, n = 6). Reperfusion occurred in all 7 (100%) Group 1 dogs, in 7 of 9 (78%) group 2 dogs and in 3 of 6 (50%) group 3 dogs (p = 0.07 for Group 1 vs Group 3). There was no residual intra-arterial thrombus in any group 1 (high dose) dog but 4 of the 10 reperfused Group 2 or Group 3 (intermediate or low dose) dogs had small thrombus in the distal left anterior descending artery (3.5 +/- 4.0 mg) and all 5 non-reperfused dogs had thrombus in the coil (26.1 +/- 6.2 mg). The frequency of residual thrombus was significantly less in Group 1 compared to Group 2 and 3 (p less than 0.01). We conclude that intravenous administration of urokinase has a dose dependent efficacy for lysing intracoronary thrombus in the canine model.

In vivo and in vitro cell-mediated immune reactions to auto-chthonous tumor extracts in patients with gastric cancer.

Sixty patients with advanced gastric cancer were subjected to the macrophage electrophoretic mobility test and delayed hypersensitivity skin test to tumor and normal tissue (gastric mucosa) extracts. Tumor extract induced significant inhibition of macrophage mobility in 51% and positive skin reaction in 32% of examined cases. Close correlation was observed between macrophage inhibition and diameter of skin reaction to tumor extract. Incidence of positive reaction in both tests to normal tissue extract was 55% and 12%, respectively. Significant inhibition of macrophage to tumor extract was also observed in breast cancer, but not in superficial gastric cancer and healthy persons. Normal tissue extract did not induce significant inhibition of macrophage in gastric ulcer. These results suggest that macrophage electrophoretic mobility test indicates a certain aspect of tumor-associated (but not tumor-specific) immunity in cancer patients. Macrophage inhibition appeared to be related with macroscopic tumor types rather than to clinical stages. Positive skin reaction to tumor extract was observed in Stages II, III, and IV of gastric cancer.

Effects of new calcium channel blocker of niludipine on the coronary hemodynamics, diastolic properties, and metabolic responses to tachycardia stress in patients with coronary disease.

A new calcium channel blocker, niludipine, was administered intravenously to nine patients with coronary artery disease in order to investigate its effects on left ventricular systolic and diastolic function, coronary sinus blood flow, and myocardial lactate metabolism. Coronary sinus pacing was performed in all patients and produced angina in six patients. Niludipine increased the resting heart rate from 75+/-3 beats/min (mean+/-SEM) to 82+/-3 (NS) and decreased the left ventricular systolic pressure from 155+/-4.7 mm Hg to 134+/-2.8 (p less than 0.05). Coronary sinus blood flow increased by 9%(NS). During pacing after niludipine, clinical improvement occurred in the six patients who had initially experienced angina. The extent of ischemic ST segment depression was decreased (-1.56+/-0.27 mm to -0.78+/-0.38, p less than 0.02) and myocardial lactate metabolism was improved. When pacing was terminated, niludipine suppressed the elevation of left ventricular end-diastolic pressure compared to pretreatment values (16.2+/-2.5 mm Hg vs 8.5+/-0.9, p less than 0.05) and decreased the left ventricular time constant T(26.4+/-3.6 msec to 20.2+/-2.4 p less than 0.05). The results suggest that niludipine appears to be beneficial in reducing systolic and diastolic work of the left ventricle during pacing induced angina without a significant change in total coronary sinus blood flow. Niludipine appears to have less of a hypotensive and reflex tachycardic effect than nifedipine.

Different mechanisms of isoproterenol-induced and nitroglycerin-induced syncope during head-up tilt in patients with unexplained syncope: important role of epinephrine in nitroglycerin-induced syncope.

INTRODUCTION: A reduction in left ventricular volume and an increase in epinephrine levels have been reported in tilt-induced neurally mediated syncope. To compare the mechanisms of isoproterenol-induced and nitroglycerin-induced syncope during head-up tilt and to investigate the role of catecholamines, the temporal changes in plasma levels of norepinephrine and epinephrine and in left ventricular volume were measured. METHODS AND RESULTS: The first study population consisted of 90 patients with syncope of unknown etiology and 12 control subjects. The second study population consisted of 43 patients with unexplained syncope. In the first study, head-up tilt (80 degree angle) was conducted for 40 minutes, and norepinephrine and epinephrine levels were measured. In the second study, all patients were randomly allocated to either isoproterenol test (20 patients) or nitroglycerin test (23 patients) for 20-minute head-up tilt. Isoproterenol infusion was given at a rate of 1 to 3 microg/min. Intravenous infusion of nitroglycerin was started at 250 microg/hour with increasing dosages up to 1,500 microg/hour. Norepinephrine and epinephrine were measured in peripheral venous blood. Left ventricular volumes were measured by echocardiography with patients in the supine position and during head-up tilt every 1 minute. End-diastolic volume and end-systolic volume were calculated. In the first study, 61 patients demonstrated a positive response and 29 patients demonstrated a negative response. Plasma norepinephrine changes during head-up tilt were not significantly different, whereas epinephrine levels were significantly higher in the positive patients than in the negative and control subjects (148 +/- 118 pg/mL vs 66 +/- 31 pg/mL and 55 +/- 27 pg/mL). Thirteen of the 20 patients given isoproterenol and 15 of the 23 patients given nitroglycerin showed a positive head-up tilt (65.0% vs 65.2%; P = NS). During isoproterenol and nitroglycerin infusion head-up tilt, epinephrine in the positive group determined by the nitroglycerin test was significantly higher than that in the other three groups (103 +/- 38 pg/mL vs 60 +/- 33 pg/mL, 31 +/- 21 pg/mL, and 50 +/- 52 pg/mL). In contrast, end-systolic volume was significantly smaller in the positive group than in the other three groups based on findings of the isoproterenol test. CONCLUSION: The findings suggest that nitroglycerin triggers head-up tilt-induced syncope by increasing epinephrine levels, whereas isoproterenol induces syncope by decreasing left ventricular volume.

Angioscopy in variant angina: coronary artery spasm and intimal injury.

Studies in pigs and dogs show that intimal injury is related to coronary artery spasm; it is not known whether intimal injury is related to coronary artery spasm in human beings. We examined intima at the site of coronary artery spasm by percutaneous transluminal coronary angioscopy in 10 of 13 consecutive patients with variant angina. Coronary artery spasms occurred spontaneously or were induced by intracoronary acetylcholine (10-100 micrograms). Angioscopy showed intimal injuries (haemorrhage, flap, thrombus, or ulcer) in 4 of the 10. We suggest that intimal injury is related to coronary artery spasm in human beings.

[Effects of diltiazem on hemodynamics, plasma catecholamine and renin activity during exercise in hypertension].

The effects of diltiazem on hemodynamics, plasma catecholamine and plasma renin activity were studied during treadmill exercise test in 9 cases with moderate essential hypertension. Diltiazem of 120 mg/day was orally administered for 4 weeks. At maximum exercise, significant decrease in systolic blood pressure (-32 mmHg), heart rate (-16/min), pressure-rate product (-7,883 mmHg/min), plasma norepinephrine (-195 ng/L) and plasma epinephrine (-11 ng/L) were observed; while, diastolic blood pressure, ST depression and plasma renin activity showed no significant change. Also, a significant correlation between systolic blood pressure and plasma norepinephrine (r = 0.57, p < 0.001), especially after diltiazem therapy (r = 0.68, p < 0.001), was observed. These findings indicated that diltiazem can reduce the secretion of catecholamine from the sympathetic nerves during exercise in patients with essential hypertension.