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The identification of potential triggers of acute coronary syndromes (ACS) represented by unstable angina (UA), myocardial infarction (MI) (preceded or not by UA), and sudden coronary death (SCD) is a rapidly growing area of research. Coronary plaque disruption and subsequent thrombosis is the major recognized pathogenetic component of “unstable plaques,” which characterize the transition from stable coronary artery disease (CAD) to ACS. However, in the presence of unstable or even stable plaques, a thrombogenic state or “high-risk blood” may contribute, at least in some cases, to the development of ACS.1 Furthermore, thrombosis is also an integral component of the chronic atherothrombotic progression of atherosclerosis. Although the observation that plaque disruption leads to ACS goes back a number of decades, the notion of “vulnerable plaques” was first developed a little over a decade ago on the basis of post-mortem observations in patients with ACS.2 At the site of culprit coronary lesions, a rupture was often found at the shoulder of atheromatous plaques with a large pultaceous lipid core and a thin fibrous cap. Such rupture was originally thought to be the result of localized mechanical shear stress forces.3 However, on the basis of emerging evidence of a prevalent inflammatory component in ACS, inflammatory mechanisms of plaque instability began to receive considerable attention.4 The acquisition of knowledge does not necessarily makes things more comprehensible, but rather often adds novel complexities. Yet, when confronted with a pressing issue, such as predicting major future adverse events, there is a natural inclination to accept generalizations not yet justified by available data. The intriguing concept of a vulnerable plaque, as a potential short-term precursor of unstable plaques, derives from the theoretical possibility of identifying those coronary atherosclerotic plaques that might become unstable and thus trigger ACS. The notion of vulnerable plaques is …

Background— Platelet reactivity is increased by exercise in patients with obstructive coronary artery disease (CAD) but not in patients with syndrome X. In this study, we prospectively investigated whether the platelet response to exercise might help distinguish, among patients with angina, those with obstructive CAD from those with normal coronary arteries (NCAs). Methods and Results— Venous blood samples were collected before and 5 minutes after exercise from 194 consecutive patients with stable angina. Platelet reactivity was measured by the platelet function analyzer (PFA)-100 system as the time for flowing whole blood to occlude a collagen-adenosine diphosphate ring (closure time). Coronary angiography showed CAD in 163 patients (84%) and NCA in 31 patients (16%). Baseline closure time was shorter in NCA patients (78.0±16 versus 95.5±23 seconds, P P P =0.0004). An increase in closure time with exercise ≥10 seconds had 100% specificity and positive predictive value for NCAs. Similarly, a decrease ≥10 seconds had 100% specificity and positive predictive value for CAD. A closure time change (increase or decrease) ≥10 seconds allowed a correct classification of 55% of all patients. Conclusions— Among patients with stable angina, the response of platelet reactivity to exercise was predictive of normal or stenosed coronary arteries at angiography. Specifically, an increase in closure time with exercise ≥10 seconds was invariably associated with the presence of NCA.

Atherosclerosis, formerly considered a bland lipid storage disease, actually involves an ongoing inflammatory response. Recent advances in basic science have established a fundamental role for inflammation in mediating all stages of this disease from initiation through progression and, ultimately, the thrombotic complications of atherosclerosis. These new findings provide important links between risk factors and the mechanisms of atherogenesis. Clinical studies have shown that this emerging biology of inflammation in atherosclerosis applies directly to human patients. Elevation in markers of inflammation predicts outcomes of patients with acute coronary syndromes, independently of myocardial damage. In addition, low-grade chronic inflammation, as indicated by levels of the inflammatory marker C-reactive protein, prospectively defines risk of atherosclerotic complications, thus adding to prognostic information provided by traditional risk factors. Moreover, certain treatments that reduce coronary risk also limit inflammation. In the case of lipid lowering with statins, this anti-inflammatory effect does not appear to correlate with reduction in low-density lipoprotein levels. These new insights into inflammation in atherosclerosis not only increase our understanding of this disease, but also have practical clinical applications in risk stratification and targeting of therapy for this scourge of growing worldwide importance.

Background— Patients undergoing revascularization procedures for peripheral vascular disease (PVD) have a greatly increased risk for coronary artery disease (CAD) that is predicted only partly by clinical data and cardiovascular risk factors. We investigated whether the prognostic assessment in PVD patients could be improved by preoperative measurements of C-reactive protein (CRP). Methods and Results— We assessed clinical and risk factors profiles, Eagle clinical scores, and preoperative CRP serum levels in 51 patients with PVD at Fontaine-Leriche stages II to IV without severe rest ventricular dysfunction or ischemia. During 24 months of follow-up, 17 patients (34%) had fatal (11) or nonfatal (6) myocardial infarction (MI). With univariate logistic regression analysis, only previous history of CAD, Eagle score, and CRP were independently related to MI. At multivariate logistic regression analysis, only CRP values in the upper tertile (P Conclusions— The high incidence of MI in patients with PVD severe enough to require revascularization is strongly predicted by preprocedural measurements of serum CRP, independent of previous CAD, Eagle score index, and traditional cardiovascular risk factors. These patients may benefit from therapy modulating the inflammatory response.

Background —C-reactive protein (CRP) plasma levels have been associated with short- and long-term occurrence of coronary events. We investigated whether circulating inflammatory cell responsiveness to low-grade stimuli could contribute to the reported association between CRP and coronary events. Methods and Results —We studied 32 patients with unstable angina who were followed for 24 months and were free of symptoms for 6 months (group 1): 19 patients had persistently high CRP levels (>0.3 mg/dL) (group 1A); 13 patients had normal CRP levels (group 1B). During the follow-up, 12 (63%) group 1A but no group 1B patients developed an infarction or recurrence of unstable angina ( P P r =0.42, P =0.005). Conclusions —Mononuclear cells of patients with recurrent phases of instability exhibit an enhanced production of IL-6 in response to low-dose of LPS, correlated with baseline CRP levels, 6 months after the last acute event. This persisting enhanced acute-phase responsiveness may help explain the association between CRP and acute coronary events.

Background —Enhanced coronary vasomotion may contribute to acute coronary occlusion during the acute phase of myocardial infarction (AMI). Japanese have a higher incidence of variant angina than Caucasian patients, but racial differences in vasomotor reactivity early after AMI are controversial. Methods and Results —The same team studied 15 Japanese and 19 Caucasian patients within 14 days of AMI by acetylcholine injection into non–infarct-related (NIRA) and infarct-related (IRA) coronary arteries followed by nitroglycerin. Incidence of vasodilation, vasoconstriction, spasm, and basal tone were assessed in proximal, middle, and distal segments after each drug bolus by quantitative angiography. Japanese patients had much lower cholesterol levels than Caucasians (183±59 versus 247±53 mg/dL, P P P P Conclusions —Soon after AMI, Japanese patients exhibited a 3-fold-greater incidence of spasm and greater vasoconstriction of nonspastic segments after acetylcholine than Caucasians. The causes of such differences warrant further investigation because they may have relevant pathophysiological and therapeutic implications.

Background —A growing body of evidence suggests a role for inflammation in acute coronary syndromes. The aim of this study was to assess the role of proinflammatory cytokines, their time course, and their association with prognosis in unstable angina. Methods and Results —We studied 43 patients aged 62±8 years admitted to our coronary care unit for Braunwald class IIIB unstable angina. In each patient, serum levels of interleukin-1 receptor antagonist (IL-1Ra), interleukin-6 (IL-6) (which represent sensitive markers of biologically active IL-1β and tumor necrosis factor-α levels, respectively), and troponin T were measured at entry and 48 hours after admission. Troponin T–positive patients were excluded. Patients were divided a posteriori into 2 groups according to their in-hospital outcome: group 1 comprised 17 patients with an uneventful course, and group 2 comprised 26 patients with a complicated in-hospital course. In group 1, mean IL-1Ra decreased at 48 hours by 12%, and IL-6 diminished at 48 hours by 13%. In group 2, IL-1Ra and IL-6 entry levels were higher than in group 1 and increased respectively by 37% and 57% at 48 hours ( P Conclusions —These findings indicate that although they receive the same medical therapy as patients who do not experience an in-hospital event, patients with unstable angina and with complicated in-hospital courses have higher cytokine levels on admission. A fall in IL-1Ra and IL-6 48 hours after admission was associated with an uneventful course and their increase with a complicated hospital course. These findings may suggest novel therapeutic approaches to patients with unstable angina.

A64-year-old man with type 2 diabetes mellitus wasadmitted to our emergency department for a 12-hourhistory of waxing and waning chest pain.Contrast echocardiography,performed to improve the definition of thrombus morphology.

Pessi et al1 showed in 101 cases of ST-segment elevation myocardial infarction that bacterial DNA typical for endodontic infection was 16 times higher in thrombi than that found in patients’ blood samples. Oral viridans streptococci was measured in 78% of thrombi and periodontal pathogens in 35%.1 Furthermore, there was a significant association between the presence of periapical abscess and endodontic bacteria in the thrombus aspirates (odds ratio, 7.71) in 30 patients with available dental panoramic tomography. This is an exciting finding that begs the question of how the presence of a chronic oral infection can mediate an acute transition to plaque thrombosis. First, it underscores …

Background In experimental models, ischemic preconditioning of the heart protects against ischemic damage and ventricular arrhythmias during subsequent coronary occlusion. In this study, we investigated whether protection against ischemic suffering and ischemia-induced arrhythmias may occur after spontaneous transmural ischemia in humans. Methods and Results We performed 24-hour Holter monitoring in 10 patients with variant angina who developed complex ventricular arrhythmias (CVAs, more than five premature ventricular beats per minute or repetitive ventricular arrhythmias) during episodes of ST-segment elevation. A total of 150 episodes of ST-segment elevation were detected on Holter monitoring, 21 (14%) of which showed CVAs. Episodes separated from the previous one by a time interval of ≤30 minutes or by a time interval of >30 minutes did not differ in either magnitude or duration of ST-segment elevation, but CVAs occurred more frequently in the second group (3% versus 29%, P P P =.009) episode of the clusters, while ST-segment elevations were similar (2.1±1.6 versus 2.2±1.1 mm) and ischemia durations shorter in the first than in the last episode (3.9±3.6 versus 6.1±1.7 minutes, P =.03). Conclusions Our data indicate that preconditioning by transient ischemia induces a significant protection against ischemia-induced CVAs in patients with variant angina. This beneficial effect was not related to a reduction in either severity or duration of ischemia, suggesting that arrhythmic protection was a direct consequence of preconditioning rather than an epiphenomenon of ischemic protection.

Background The purpose of this study was to validate a novel method for noninvasive quantification of regional myocardial oxygen consumption (MMR o 2 , mL·min −1 ·100 g −1 ) and oxygen extraction fraction (OEF) by use of positron emission tomography (PET) and inhalation of 15 O-labeled molecular oxygen gas ( 15 O 2 ). Methods and Results Twenty-four measurements were performed in eight closed-chest anesthetized greyhounds at baseline and during infusions of adenosine (100 to 200 μg·kg −1 ·min −1 ), isoproterenol (1 to 10 μg/min), and propranolol (5 mg bolus+0.2 to 1 mg/min) with morphine (5 mg slow infusion+0.2 to 0.5 mg/min) to obtain a wide range of oxidative metabolism. The PET imaging protocol consisted of 15 O 2 emission (OEF and MMR o 2 ), transmission, [ 15 O]CO emission (blood pool), and [ 15 O]CO 2 emission (myocardial blood flow: MBF pet , mL·min −1 ·g −1 ) scans. OEF was calculated from the PET data (OEF pet ) by three different analytical techniques: steady-state, 5-minute, and 8-minute autoradiographic analyses. Reference measurements of MBF (MBF ref ) and OEF (OEF ref ) were obtained during 15 O 2 inhalation with radiolabeled microspheres and paired arterial and coronary sinus blood sampling, respectively. MMR o 2 was calculated from the PET (MMR o 2pet ) and the reference (MMR o 2ref ) data as follows: MMR o 2 =OEF×MBF×(O 2 content of arterial blood). OEF measured by the steady-state PET method was well correlated with the reference data over the range 0.16 to 0.73 (OEF pet =1.03 OEF ref −0.01, r =.97), as was MMR o 2 over the range 2.4 to 27.5 mL·min −1 ·100 g −1 (MMR o 2pet =0.98 MMR o 2ref +0.91, r =.94). OEF pet calculated by use of the 5-minute and 8-minute autoradiographic analyses were equally well correlated with the reference measurements ( r =.95 and r =.97, respectively). There were no significant differences between values of MMR o 2pet calculated by use of the steady-state, 5-minute, and 8-minute autoradiographic analyses ( P =NS by ANOVA). Regional values of MBF pet , OEF pet , and MMR o 2pet were homogeneously distributed and similar to the whole-heart values both at baseline and during the various pharmacological interventions. Conclusions Accurate quantification of OEF and MMR o 2 is feasible with 15 O 2 inhalation and PET imaging using both the steady-state and autoradiographic analytical approaches. These studies suggest the applicability of this method for quantitative assessments of regional cardiac oxidative metabolism in clinical studies.

The WISE workshop was convened to review results from the Women’s Ischemic Syndrome Evaluation (WISE) study and other studies of ischemic heart disease to examine the nature and scope of gender differences in both chronic and acute cardiac ischemia, in terms of clinical manifestations, detection, and treatment. The purpose of the workshop was to provide recommendations to National Heart, Lung and Blood Institute that (1) address the need for improved diagnosis of ischemia and coronary artery disease (CAD) in women; (2) explore strategies for improved translation of promising research results into clinical practice; and (3) assess opportunities for effective educational strategies, including further refinement of the key messages for women with regard to risk factors and heart attack symptoms. CAD in women continues to be a major public health problem that represents a leading cause of death and disability.1–3 Among US women, more than a quarter of a million deaths per year are attributed to CAD, and this figure is expected to increase in the first decades of the 21st century as our population ages. The increased prevalence of obesity and diabetes in women is also expected to contribute to this increase in CAD. Women have a higher frequency of angina/chest pain than men; however, women have a lower prevalence of obstructive CAD compared with men with similar symptoms.4–6 Nevertheless, young women with obstructive CAD experience a significantly worse outcome compared with men with regard to prognosis after myocardial infarction,7 and older women with obstructive CAD often have …

Background Unstable angina is most frequently caused by coronary thrombosis, with or without plaque fissure, but the mechanisms underlying these events are still speculative. Since cytomegalovirus (CMV) antigens and DNA encoding CMV major immediate-early (MIE) gene have been detected in atherosclerotic arterial walls, the active replication of CMV may be responsible for plaque instability. Therefore the expression of CMV MIE gene mRNA, an early marker of viral replication, was assessed in coronary atherectomy specimens from patients with stable or unstable angina. Methods and Results Twenty patients with unstable angina (12 men and 8 women; mean age, 62 years; range, 44 to 89 years) and 20 patients with stable angina (16 men and 4 women; mean age, 62 years; range, 43 to 81 years) who underwent successful directional coronary atherectomy were enrolled in the study. The efficiency of mRNA extraction, transcription, and amplification from each coronary atherectomy specimen was assessed by performance of reverse transcription and thermal cycling amplification of a 548-bp human β-actin cDNA segment. After Southern blotting and hybridization with a specific probe, all specimens but one showed a positive hybridization signal. The negative sample was excluded from the study. Reverse transcription and thermal cycling amplification of a 145-bp CMV cDNA segment of the MIE gene were then carried out. After Southern blotting and hybridization with a specific probe, none of the specimens showed a positive hybridization signal. Plasmid pACYC 184 containing the Xba I–inserted MIE gene cDNA was used as a positive control: as few as 10 molecules of the plasmid per reaction were detectable after amplification. Conclusions Our results do not support the hypothesis that, in patients with unstable angina, replication of CMV in coronary atherosclerotic plaques is a major cause of plaque instability. These findings suggest that the research for the causes of unstable angina should be directed toward processes other than CMV replication.

A 70-year-old woman was referred to cardiac evaluation because of the detection of dilation of the main pulmonary artery by chest computed tomography performed before the removal of a thoracic lipoma. The computed tomography scan with contrast also excluded arterial thromboembolism of the main and distal pulmonary branches. The patient had a previous diagnosis of mild pulmonary stenosis with a right ventricle-pulmonary artery peak systolic pressure gradient of 24 mm Hg by right catheterization in 1978. Since then, the patient has been asymptomatic, and she has been conducting normal daily-life activities without undergoing further cardiovascular controls. In 2001, a previous computed tomography scan had already shown mild dilatation of the main pulmonary artery for which no investigation was later performed. On the first evaluation, the patient was asymptomatic, her heart rate was 83 bpm, and her blood pressure was 130/70 mm Hg. Cardiac examination revealed a regular rhythm, with a 3/6 systolic murmur at the upper right and left sternal border. Lung fields were normal; neither jugular venous distention nor hepatomegaly and peripheral edema were detected. The ECG showed sinus rhythm and normal atriventricular and intraventricular conduction, with slight ST-segment abnormalities in inferior leads. Transthoracic echocardiography (Figure 1 and Movie I in the online-only Data Supplement) confirmed the presence of significant dilation of the main pulmonary …

BACKGROUND Serotonin, released by aggregating platelets, may contribute to or cause myocardial ischemia by constricting epicardial vessels. Experimental studies suggest that this constriction is mediated by two distinct serotonin receptor subtypes: 5-hydroxytryptamine1-like (S1-like) and 5-hydroxytryptamine2 (S2). METHODS AND RESULTS To determine the relative contribution of S1-like and S2 receptors to the vasoconstrictor effects of serotonin, we studied the effect of ketanserin (0.75 mg, intracoronary), a selective S2 receptor antagonist, on the constrictor response of human coronary vessels to intracoronary infusions of serotonin. In control patients (n = 7), serotonin (10(-4) mol/l) caused significant (p less than 0.05) constriction only in distal segments, which was significantly (p less than 0.05) inhibited by ketanserin. In stable angina patients (n = 8), serotonin (10(-4) mol/l) caused significant constriction in proximal (p less than 0.01) and distal (p less than 0.01) segments, which was significantly inhibited by ketanserin in proximal (p less than 0.05) but not distal (p = 0.30) segments. In patients with variant angina (n = 3), epicardial occlusion at the site of preexisting stenoses in proximal locations occurred at infused concentrations of 10(-6) (one patient) or 10(-5) (two patients) mol/l. The infusion of the same concentration of serotonin after ketanserin again caused epicardial occlusion. CONCLUSIONS Our results suggest that functionally important S1-like receptors that mediate vasoconstriction exist in the epicardial vessels of patients with stable or variant angina. Their activation, either at hyperreactive sites in patients with variant angina or in the distal epicardial vessels of patients with chronic stable angina, may contribute to or cause myocardial ischemia when serotonin is released after the intracoronary activation of platelets.

BACKGROUND It has been suggested that recurring coronary artery spasm may lead to the development of fixed atherosclerotic coronary obstructions. METHODS AND RESULTS We studied 10 patients with typical Prinzmetal's variant angina in whom the disease remained active for years and in whom occlusive coronary spasm occurred reproducibly at the same arterial site during repeat coronary arteriography (25 +/- 12 months after initial angiography). At initial evaluation, four patients had significant (greater than or equal to 50% fixed coronary diameter reduction) one-vessel coronary artery disease, and six had nonsignificant disease. Spasm developed at stenotic sites (20-65% diameter reduction) in nine patients and at an angiographically normal site in one patient. Progression of coronary disease was assessed in 62 segments: 10 spastic (of which nine were stenotic) and 52 nonspastic (eight stenotic and 44 angiographically normal), using computerized arteriography. Mean diameters (millimeters) of spastic segments, nonspastic stenoses, and angiographically normal nonspastic segments were not significantly different at first and second arteriograms (1.52 +/- 0.14 versus 1.43 +/- 0.21, 1.32 +/- 0.17 versus 1.12 +/- 0.23, and 2.40 +/- 0.12 versus 2.42 +/- 0.12, respectively). Stenosis progression (from 65% diameter reduction to total occlusion) occurred in one patient at a spastic site and in two at nonspastic sites (from 34% to 65% and from 84% to 100%). Complicated stenoses suggestive of plaque fissuring were not observed during the study. CONCLUSIONS In patients with chronic Prinzmetal's variant angina without myocardial infarction, stenosis progression was not frequently observed at spastic sites despite the recurrence of focal coronary spasm over relatively long periods of time.

BACKGROUND Calcitonin gene-related peptide (CGRP) is a potent dilator of normal epicardial coronary vessels in humans, but its effects on myocardial blood flow and atheromatous coronary vessel diameter are unknown. METHODS AND RESULTS Seven patients were entered for study of the effects of CGRP on coronary blood flow and 13 for the comparison of its effects on normal and atheromatous coronary arteries. In the first seven patients, left anterior descending artery (LAD) diameter at an angiographically normal site, coronary sinus oxygen saturation (CSO2S), systemic blood pressure, and heart rate were measured during intracoronary infusion of increasing concentrations of CGRP (up to 200 ng/ml at 2 ml/min) followed by intracoronary adenosine (0.267 micrograms/ml at 2 ml/min) and finally intracoronary glyceryl trinitrate (GTN) (5 micrograms/ml at 2 ml/min). CGRP dilated the normal segment of the LAD by 22.6 +/- 8% (mean +/- 95% confidence interval), p less than 0.001, with only a small increase in CSO2S from 40.1 +/- 2.7% to 47.3 +/- 2.7%, p less than 0.001. Adenosine, a potent dilator of myocardial resistance vessels, caused no further increase in LAD diameter but caused a rise in CSO2S from 47.3 +/- 2.7% to 76.0 +/- 2.7%, p less than 0.001. GTN caused no further increase in LAD diameter. As heart rate-blood pressure product remained unchanged throughout the study, the increase of CSO2S indicated only a small increase in myocardial blood flow after CGRP infusion. In 13 patients with atheromatous coronary artery disease, the effects of intracoronary CGRP at angiographically normal sites, stenoses, angiographically normal sites immediately adjacent to stenoses, and sites of coronary artery wall irregularity were compared after intracoronary infusion of a single dose of CGRP (200 ng/ml at 2 ml/min) followed by intracoronary GTN (5 micrograms/ml at 2 ml/min). At these four sites, CGRP resulted in dilatation by 17.0 +/- 5.6%, 15.3 +/- 12.1% (NS), 7.6 +/- 5.4% (NS), and 15.9 +/- 7.8%, respectively. There was no significant further dilatation after GTN at any of the four sites. CONCLUSIONS These data indicate that CGRP has little effect in humans at rest on coronary resistance vessels in nonischemic myocardium but causes marked dilatation of normal arteries and variable dilatation of atheromatous epicardial arteries.

BACKGROUND The effects of the endothelium-dependent vasodilator substance P (SP) on atherosclerotic human coronary arteries was studied. METHODS AND RESULTS [125I]-SP binding to luminal cells was shown to be preserved in the atherosclerotic epicardial coronary arteries of four patients. No binding to medial smooth muscle cells was demonstrated. Intracoronary infusions of SP were undertaken in patients with coronary artery disease. SP was infused for 2-minute periods starting at a dose of 2.8 pmol/min rising by doubling increments to 22.4 pmol/min. Analysis of the epicardial coronary artery diameter, using a computerized analysis system (CAAS) of the angiograms, was performed at the end of each infusion. Analysis of seven smooth vessel segments from seven coronary vessels, which were stenosed at more proximal sites, was performed. Significant dose-dependent dilatation was seen (p = 0.04), which was maximal at 5.6 pmol/min SP. No additional dilatation was produced with 2 mg intracoronary isosorbide dinitrate (ISDN). Two of these seven patients showed no response to SP, and only one of these appeared to sustain dilatation with ISDN (2 mg intracoronary). In a second group of six patients with discrete coronary stenoses, analysis at the site of the stenosed segments appeared to reveal dilatation in response to SP in only one instance. One other stenotic segment dilated with isosorbide dinitrate but failed to dilate with SP; the remaining four were fixed. The segment immediately proximal to the stenosis preserved a dose-dependent vasodilator response. CONCLUSIONS These findings demonstrate that the endothelium-dependent vasodilator substance P can still produce epicardial vasodilatation in vivo in the presence of coronary atherosclerosis.

Background We recently found that patients who had had two myocardial infarctions in different myocardial regions frequently reported different locations of infarct pain, whereas patients who had had two infarcts at the same site had a similar distribution of pain. The aim of this study was to assess whether a different location of anginal pain may help identify patients with a new stenosis on an artery perfusing another myocardial region as opposed to those with restenosis after coronary angioplasty (PTCA). Methods and Results We studied 38 patients (59±11 years old) who underwent PTCA for single-vessel disease, with recurrence of symptoms requiring repeat coronary angiography during a 3-year follow-up. According to our inclusion criteria, angiography showed either a significant restenosis of the dilated lesion, with no evidence of lesions in the other vessels (n=26), or a new stenosis in either of the other coronary arteries, with no restenosis in the dilated vessel (n=12). Before each procedure, patients reported the location and radiation of anginal pain. There was no relation between location of pain and site of the coronary stenosis. However, none of the patients with restenosis reported a different location of pain after angioplasty, compared with 5 patients with new stenosis (0% versus 42%, P =.002). Radiation of pain involved different areas of the body in 1 patient with restenosis and in 6 with new stenosis (4% versus 50%, P =.002). Overall, location or radiation of pain in a different body area had a specificity of 96% and a sensitivity of 58% in detecting a stenosis on a new artery. Conclusions A different location of anginal pain may distinguish patients with a new coronary stenosis from those with restenosis after PTCA for single-vessel disease. These findings suggest that in individual patients, differences in the location of cardiac pain may be indicative of the occurrence of ischemia in different myocardial regions.

Background— The causal role of Epstein-Barr virus (EBV) in inflammatory cardiomyopathy (IC) is still unclear, because this virus is present in latently infected circulating B lymphocytes in 90% of adults. Laser capture microdissection (LCM) has been applied on endomyocardial biopsy samples from patients with IC to assess the presence of EBV genome in separately dissected lymphocytes and myocytes. Methods and Results— Among 142 patients with cardiac dilation and dysfunction and a histological and immunohistochemical diagnosis of myocarditis, 44 had a myocardial viral infection detected by polymerase chain reaction on frozen endomyocardial biopsy samples. In 9 of them, the virus detected was EBV. LCM was performed on 5-μm-thick paraffin sections of EBV-infected hearts. Lymphocytes and myocytes were microdissected and analyzed separately by polymerase chain reaction analysis on DNA extracted from the collected cells. Blood and myocardial samples from patients with positive and negative serology for EBV were used as controls. EBV genome was detected in myocytes but not in infiltrating lymphocytes of patients, nor in myocardial samples from controls. Despite full conventional antifailure therapy, a progressive cardiac dilation and dysfunction was documented in patients with EBV-related IC at a mean of 31±14 months of follow-up. Conclusions— Intramyocyte detection of EBV can be obtained by LCM in up to 6.3% of patients with IC. This supports a cytopathic EBV role and suggests the opportunity for an antiviral/immunomodulatory therapy.

he prognostic implications of the diagnosis of ischemiavary dramatically in different clinical ischemic syn-dromes. At one extreme end, in unstable angina, the detectionof ischemia indicates the persistence or recurrence of insta-bility and hence carries much more severe prognostic impli-cations than in chronic stable angina. At the other extreme, inpatients with microvascular angina, the detection of ischemiadoes not indicate an increased risk of infarction or suddencardiac death and becomes clinically relevant only if itscauses can be understood and effectively treated.A typical condition in which the diagnosis of myocardialischemia is difficult is the so-calledcardiac syndrome X. Thissyndrome, which includes 60% to 70% of women (about 60%postmenopausal and 40% premenopausal) but also 30% to40% of men, is characterized by angina pectoris and normalcoronary angiography. Its incidence may vary from 10% to50% of patients submitted to coronary arteriography.Such broad inclusion criteria confuse the issue because ofthe likely inclusion of heterogeneous patients with andwithout a cardiac origin of pain. The selection of patients whopresent with specific patterns of clinical symptoms and withtransient ischemic ECG changes during chest pain would leadto more homogeneous subgroups, inasmuch as the associationof anginal pain with transient ECG changes indicates acardiac, although not necessarily ischemic, origin of pain.Moreover, distinct patterns of clinical presentation mightcorrespond with different specific pathogenetic mechanisms.

Background— It has been suggested that inflammation can have a role in the development of atrial arrhythmias after cardiac surgery and that a genetic predisposition to develop postoperative complications exists. This study was conceived to verify if a potential genetic modulator of the systemic inflammatory reaction to cardiopulmonary bypass (the −174 G/C polymorphism of the promoter of the Interleukin-6 gene) has a role in the pathogenesis of postoperative atrial fibrillation (AF). Patients and Results— In 110 primary isolated coronary artery bypass patients the −174G/C Interleukin-6 promoter gene variant was determined. Interleukin-6, fibrinogen and C-reactive protein plasma levels were determined preoperatively, 24, 48, and 72 hours after surgery and at discharge. Heart rate and rhythm were continuously monitored for the first 36 to 48 hours; daily 12-lead electrocardiograms were performed thereafter until discharge. GG, CT, and CC genotypes were found in 62, 38, and 10 patients, respectively. Multivariate analysis (which included genotype, age, sex, and classical risk factors for AF) identified the GG genotype as the only independent predictor of postoperative AF. The latter occurred in 33.9% of GG versus 10.4% of non-GG patients (hazard ratio 3.25, 95%CI 1.23 to 8.62). AF patients had higher blood levels of Interleukin-6 and fibrinogen after surgery ( P Conclusion— The −174G/C Interleukin-6 promoter gene variant appears to modulate the inflammatory response to surgery and to influence the development of postoperative AF. These data suggest an inflammatory component of postoperative atrial arrhythmias and a genetic predisposition to this complication.

Background—Heat shock proteins (HSPs) are a family of proteins with immunogenic and proinflammatory properties. Human andChlamydia pneumoniae(Cp) HSP60 were found in patients with stable coronary disease.Methods and Results—We measured the levels of anti–Cp-HSP60 and anti-Cp immunoglobulin G (IgG) in 179 patients with unstable angina, 40 with acute myocardial infarction, and 40 with stable angina (SA), as well as 100 control subjects. Forty-one patients with acute coronary syndromes (ACS) were also studied at follow-up. We also measured plasma levels of high-sensitivity C-reactive protein (hs-CRP) and troponin T (TnT). Seropositivity to Cp-HSP60 was found in 99% of ACS patients but in only 20% of SA patients and none of the control subjects. Seropositivity to Cp was detected in 67% of ACS patients, 60% of SA patients, and 30% of the control subjects. No differences in Cp-HSP60 IgG and in Cp IgG were observed between patients with myocardial infarction and patients with unstable angina. No correlation was found between Cp-HSP60 IgG, TnT, and hs-CRP or between IgG against Cp and hs-CRP. In ACS patients at follow-up, Cp-HSP60 IgG decreased from 0.88±0.25 to 0.45±0.14 arbitrary units (P.Conclusions—Seropositivity for Cp-HSP60 appears to be a very sensitive and specific marker of ACS, unrelated to Cp IgG antibody titers or hs-CRP and TnT levels. Its causal involvement in instability and its diagnostic role in ACS deserve further study.

Background —Monocytes are constitutively activated in unstable angina (UA), resulting in the production of IL-6 and the upregulation of acute phase proteins. Underlying mechanisms are not understood. To explore whether the production of the potent monocyte activator IFN-γ is altered in UA, we compared cytokine production by T lymphocytes in patients with UA (Braunwald’s class IIIB) and with stable angina (SA). Methods and Results —Peripheral blood lymphocytes were collected at the time of hospitalization and after 2 and 12 weeks. Cytokine-producing CD4 + and CD8 + T cells were quantified by 3-color flow cytometry after stimulation with phorbol myristate acetate and ionomycin. UA was associated with an increased number of CD4 + and CD8 + T cells producing IFN-γ, whereas patients with SA had higher frequencies of IL-2 + and IL-4 + CD4 + T cells. Expansion of the IFN-γ + T-cell population in UA persisted for at least 3 months. Increased production of IFN-γ in UA could be attributed to the expansion of an unusual subset of T cells, CD4 + CD28 null T cells. Conclusions —Patients with UA are characterized by a perturbation of the functional T-cell repertoire with a bias toward IFN-γ production, suggesting that monocyte activation and acute phase responses are consequences of T-cell activation. IFN-γ is produced by CD4 + CD28 null T cells, which are expanded in UA and distinctly low in SA and controls. The emergence of CD4 + CD28 null T cells may result from persistent antigenic stimulation.

Background —The causal role of asymptomatic critical coronary artery obstruction in patients presenting with severe global biventricular dysfunction but no evidence of myocardial infarction is uncertain. Methods and Results —Among 291 patients aged >40 years undergoing a noninvasive (2-dimensional echocardiography) and invasive (catheterization, coronary angiography, and biventricular endomyocardial biopsy, 6 to 8 samples/patient) cardiac study because of progressive heart failure (New York Heart Association functional class III or IV) with global biventricular dysfunction and no history of myocardial ischemic events, 7 patients (2.4%; 7 men; mean age, 49±6.9 years) had severe coronary artery disease (3 vessels in 4 patients; 2 vessels in 1 patient, proximal occlusion of left anterior descending coronary artery in 2 patients). Left ventricular end-diastolic diameter and ejection fraction by 2-dimensional echocardiography were 73±10.5 mm and 23±6.5%, respectively, and right ventricular end-diastolic diameter and ejection fraction were 39±7 mm and 29±7.2%, respectively. Biopsy specimens showed extensive lymphocytic infiltrates with focal myocytolysis meeting the Dallas criteria for myocarditis in all patients (in 5 patients with and 2 patients without fibrosis). Cardiac autoantibodies were detected with indirect immunofluorescence in the serum of 2 patients with active myocarditis. The 2 patients with active inflammation received prednisone (1 mg · kg −1 · d −1 for 4 weeks followed by 0.33 mg · kg −1 · d −1 for 5 months) and azathioprine (2 mg · kg −1 · d −1 for 5 months) in addition to conventional drug therapy for heart failure. At 8-month overall follow-up, cardiac volume and function improved considerably in immunosuppressed patients but remained unchanged in conventionally treated patients, of whom 1 died. Conclusions —Global biventricular dysfunction in patients with severe asymptomatic coronary artery disease and no evidence of previous myocardial infarction may be caused by myocarditis. Histologic findings may influence the treatment.

Background Previous studies have suggested that an abnormal cardiac adrenergic tone may have a pathophysiological role in syndrome X (effort angina, positive exercise testing, angiographically normal coronary arteries). Methods and Results To evaluate cardiac adrenergic nerve function, we performed [ 123 I]metaiodobenzylguanidine (MIBG) myocardial scintigraphy in 12 patients with syndrome X and 10 control subjects. Cardiac MIBG uptake was assessed by the heart/mediastinum (H/M) ratio and by an MIBG uptake defect score (higher values=lower uptake). In syndrome X patients, we also correlated MIBG scintigraphic findings with stress myocardial perfusion as assessed by 201 Tl scintigraphy. An inferior MIBG defect was observed in only 1 control subject, whereas 9 patients ( P P =.03) and MIBG uptake defect score higher (35±31 versus 4±2, P =.003) in syndrome X patients. Reversible stress thallium perfusion defects were found in 62% of patients with MIBG defects but in no patient with normal MIBG uptake. MIBG defects persisted unchanged in 7 patients at a 5±3-month follow-up study. Conclusions In this study, obvious defects in global and/or regional cardiac MIBG uptake, indicating an abnormal cardiac adrenergic nerve function, were detected in 75% of patients with syndrome X. These findings strongly support the cardiac origin of chest pain in syndrome X, although the mechanisms and the pathophysiological meaning of the abnormal cardiac MIBG uptake in these patients deserve further investigation.

Background Thrombotic occlusion of the infarct-related coronary artery is often intermittent in the early, evolving phase of acute myocardial infarction. To assess their relationship to this pattern of coronary occlusion, serum or plasma concentrations of cholesterol, triglyceride, lipoprotein(a), and coagulation and fibrinolytic factors were measured in venous blood before the initiation of thrombolytic therapy. Methods and Results Thirty-two patients (23 men, 9 women; age, 30 to 70 years) with acute myocardial infarction received intravenous recombinant tissue plasminogen activator (20 to 60 megaunits) within 6 hours of the onset of symptoms. Continuous ECG ST-segment recording demonstrated intermittent occlusion of the infarct-related coronary artery in 12 patients (group 1) before the start of thrombolytic treatment and persistent occlusion in 20 patients (group 2). Groups 1 and 2 were similar in age, sex, race, duration of symptoms, blood sample collection time, location of the infarct-related coronary artery, and extent of coronary artery disease. The serum level (median [interquartile range]) of lipoprotein(a) was 34 (13 to 47) mg/dL versus 11.5 (5 to 27) mg/dL ( P =.02), and the plasma level (median [interquartile range]) of thrombin–antithrombin III complex was 10.85 (6.4 to 21.5) versus 6.8 (4.2 to 8.7) μg/L −1 ( P Conclusions The phenomenon of spontaneous intermittent closure and reopening of coronary arteries early during acute myocardial infarction in humans is associated with a higher level of lipoprotein(a) and of a marker of thrombin generation, suggesting that lipoprotein(a) and thrombin are closely related to coronary patency in these patients.

Background Although a major role of coronary thrombosis in the pathogenesis of unstable angina has been demonstrated, the results of a series of studies have suggested that activation of the hemostatic system may not be confined to ischemic episodes. The purpose of this study was to investigate the temporal relation between ischemic episodes and activation of the coagulation system in unstable angina. Methods and Results Thrombin–antithrombin III (TAT) and prothrombin fragment 1+2 (F 1+2 ) levels were measured in 13 patients during spontaneous ischemic episodes (time 0, 5, and 15 minutes and 1 hour) to evaluate the time course of the activation of the coagulation system associated with the development of ischemia (protocol A). TAT and F 1+2 levels were also measured in 28 patients with unstable angina on admission to hospital (every 6 hours for 24 hours and daily for 3 days) to assess their temporal relation with ischemic episodes (protocol B). In protocol A, TAT and F 1+2 levels were elevated in 10 of 13 patients (77%) in at least 1 sample. The median value of TAT showed a peak at 5 minutes and returned to baseline within 15 minutes ( P 1+2 showed no significant changes, possibly because of its longer half-life, which tends to dampen sudden bursts of thrombin production. In protocol B, activation of the clotting system was found in 10 of 33 samples (30%) temporally related to ischemia and also in 23 of 150 (15%, P =.07) of those not temporally related to ischemia. Conclusions Our study demonstrates that patients with active unstable angina develop frequent bursts of thrombin production not necessarily associated with ischemic episodes and that, conversely, some ischemic episodes are not associated with evidence of thrombin activation.

BACKGROUND Sublingual nitrates are much more effective in relieving angina pectoris in patients with coronary artery disease than in patients with syndrome X, but it is not known whether their effect on exercise tolerance is also different in these two groups of patients. METHODS AND RESULTS Treadmill exercise testing was performed before and after administration of sublingual isosorbide dinitrate (ISDN, 5 mg) in 18 patients with syndrome X (effort angina and normal coronaries, group X) and in 33 patients with documented coronary artery disease (group C). As a selection criterion, all patients had ST-segment depression > or = 1 mm on the control exercise test. Compared with the control test, the main differences in the two groups observed during the exercise test after administration of ISDN were (1) heart rate at 1-mm ST-segment depression was higher (126 +/- 25 versus 104 +/- 15 beats per minute [bpm], P < .01) in group C, whereas it was not different (125 +/- 15 versus 126 +/- 16 beats per minute) in group X; (2) the rate-pressure product at 1-mm ST-segment depression, the time to 1-mm ST-segment depression, and the exercise duration were significantly improved in group C (P < .01 for all) but were worsened in group X (18,047 +/- 4159 versus 20,535 +/- 4507 bpm . mm Hg, P = .014; 268 +/- 312 versus 429 +/- 214 seconds, P < .01; 494 +/- 279 versus 622 +/- 194 seconds, P = .013, respectively); (3) a normalization of the ECG (no ST-segment depression) was obtained in 10 patients (30%) of group C but in only 1 (5%) of group X (P < .01); (4) angina was prevented in 10 of 19 patients of group C but in no patient of group X (P < .01). CONCLUSIONS In patients presenting with anginal chest pain, the effects of sublingual nitrates on exercise testing appear to be clinically useful to distinguish patients with coronary artery stenoses from patients with syndrome X. Indeed, worsening of exercise tolerance is highly predictive of normal coronary arteries. Furthermore, the failure of nitrates to improve exercise tolerance in patients with syndrome X suggests that a deficiency in coronary prearteriolar nitric oxide production is unlikely to play a key role in the pathophysiology of the syndrome.

BACKGROUND Previous experimental studies have shown that the effect of serotonin on a coronary stenosis depends on whether that stenosis is compliant or fixed. However, the relation between coronary stenosis morphology and the response to serotonin in patients with angina is not known. METHODS AND RESULTS Using computerized quantitative coronary angiography, we studied the effects of intracoronary infusion of serotonin on 38 coronary stenoses of different morphologies (concentric, eccentric, complicated) in 11 patients with stable angina and 4 with variant angina. In response to the maximum infused concentration of serotonin, 100% of complicated stenoses and 50% of concentric stenoses constricted by > or = 20% (P < .05). The magnitude of constriction was greater at eccentric stenoses (32.08 +/- 4.1%) than concentric stenoses (15.68 +/- 2.8%, P < .05) and greater in complicated stenoses (57.69 +/- 7.6%, P < .05) than eccentric stenoses. At complicated stenoses, the constriction was greater (0.85 +/- 0.16 mm, P < .05) than at the adjacent reference segments (0.42 +/- 0.12 mm). It was similar to the reference segment for both concentric and eccentric stenoses. The constriction at the stenosis was greater for irregular (complicated) lesions than for smooth (concentric and eccentric) lesions in both patients with stable (51.8 +/- 7.3% versus 22.5 +/- 4.1%, P < .001) and those with variant (77 +/- 17% versus 28.2 +/- 8.1%, P < .05) angina. There was a weak correlation (r = .39) of magnitude of constriction with stenosis length but not with baseline stenosis severity (minimum diameter). CONCLUSIONS In these patients, the magnitude of the vasoconstrictor response to serotonin at the site of an atheromatous coronary plaque depends on the morphological characteristics of the plaque and is more closely related to irregular contour than stenosis severity or length. This relation suggests that variations in receptor type or density or in the smooth muscle cell response to stimulation may determine the response to locally released serotonin in patients with coronary disease.

BACKGROUND NG-Monomethyl-L-arginine (L-NMMA), a specific inhibitor of nitric oxide synthesis, was used to determine the effects of inhibition of nitric oxide synthesis in the human coronary circulation. METHODS AND RESULTS Twelve patients (mean age, 52 +/- 2 years) with normal epicardial coronary arteries were studied. The surface ECG, systemic blood pressure, and coronary venous oxygen saturation (coronary SvO2), an index of coronary blood flow, were monitored continuously. Coronary artery diameter was measured by quantitative arteriography. L-NMMA was given as intracoronary infusions at 2 mL/min via the diagnostic arteriography catheter. In two patients, low doses (0.01 to 5 mumol/min) of L-NMMA were infused into the nondominant right coronary artery. There was no evidence of ischemia in these patients, who were not included in the final analysis. In 10 patients, higher doses of L-NMMA (4, 10, and 25 mumol/min, each for 5 minutes) were infused into the left coronary artery. In six patients, incremental doses of acetylcholine were infused (1, 10, and 100 nmol/min, each for 3 minutes) before and after the L-NMMA infusion. Finally, in all patients, sodium nitroprusside, a nitric oxide donor, was infused. No patient developed myocardial ischemia. The heart rate and systemic blood pressure remained unchanged throughout the infusions. L-NMMA (25 mumol/min), compared with the control saline infusion, caused a significant reduction in distal (-5.9 +/- 2.1%, P = 0.021) but not proximal left anterior descending coronary artery (LAD) diameter and a fall in coronary SvO2 from 37.5 +/- 2.8% to 34.3 +/- 2.8% (P = 0.019). Sodium nitroprusside dilated the proximal (17.8 +/- 6.9%, P = 0.033) and distal (24.5 +/- 6.5%, P = 0.006) LAD and increased the coronary SvO2 to 61.6 +/- 5.0% (P = 0.0002). Acetylcholine caused significant dilatation of the distal (13.8 +/- 5.4%, P = 0.049) but not proximal LAD and a significant increase in coronary SvO2 from 36.5 +/- 3.5% to 59.2 +/- 2.8% (P < 0.0001). After L-NMMA, acetylcholine-induced dilatation of the distal LAD was abolished, but the rise in coronary SvO2 was unchanged. CONCLUSIONS Inhibition of nitric oxide synthesis in the human coronary circulation caused a decrease in basal distal LAD diameter and basal coronary blood flow assessed by coronary SvO2, indicating that there is a small basal release of nitric oxide in the distal epicardial coronary arteries and resistive vessels. Distal epicardial coronary artery dilatation in response to acetylcholine is nitric oxide dependent, but coronary resistive vessel dilatation is not.

BACKGROUND Previous assessments of myocardial viability using positron emission tomography (PET) relied on demonstration of glucose metabolism in hypoperfused asynergic segments using the glucose analogue [18F]2-fluoro-2-deoxyglucose (FDG). Recently, it was shown that myocardial viability could be assessed by calculating the water-perfusable tissue index (PTI) for the asynergic region. PTI represents the proportion of the myocardium that is capable of rapid transsarcolemmal exchange of water and thus perfusable by water. The aim of the present study was to assess myocardial viability by PET using PTI in patients undergoing coronary revascularization. METHODS AND RESULTS Twelve patients with chronic coronary artery disease and previous myocardial infarction were studied. Analysis of transmission (tissue density) and 15O-labeled carbon monoxide (blood pool), and 15O-labeled water (myocardial blood flow [MBF]) emission PET data enabled the simultaneous quantification of MBF (ml.min-1.g perfusable tissue-1) and PTI (gram of perfusable tissue per gram of total anatomic tissue). In addition, PET imaging with FDG after 75-g oral glucose load was performed in eight patients. Preoperative echocardiography identified 33 hypocontractile and 26 control segments. Follow-up echocardiography performed 3 to 5 months later demonstrated 26 of 33 segments with improved wall motion (recovery) and seven of 33 segments without improvement (nonrecovery). MBF in the control segments (0.97 +/- 0.22 ml.min-1.g perfusable tissue-1) was significantly higher (p < 0.001) than in both the recovery (0.73 +/- 0.18 ml.min-1.g perfusable tissue-1) and the nonrecovery (0.45 +/- 0.11 ml.min-1.g perfusable tissue-1) segments. PTI in the recovery regions (0.99 +/- 0.15) was > or = 0.7 in all cases and slightly less than in control regions (1.10 +/- 0.15, p < 0.02). FDG uptake in these regions was 92 +/- 17% (n = 13) of the uptake in control segments with normal wall motion. In the nonrecovery group, PTI was 0.62 +/- 0.06 (p < 0.02 versus control and recovery) and always < 0.7. In the one patient in whom a comparison with metabolic imaging was made, FDG uptake was 46% of the uptake in a reference region with normal wall motion. CONCLUSIONS These data showed that contractile recovery occurred only in segments where PTI was > or = 0.7, suggesting that > or = 70% of myocardial tissue in a given asynergic segment should be perfusable by water to enable contractile recovery. There was good agreement between the PTI and FDG methods for predicting improvements in regional wall motion after revascularization. Although further studies should be performed in a larger patient group, the preliminary results are promising and suggest that PTI may be a good predictor of contractile recovery after coronary revascularization.

BACKGROUND The mechanism responsible for exercise-induced myocardial ischemia early after successful coronary angioplasty (PTCA) is poorly understood. METHODS AND RESULTS Twelve patients who underwent one-vessel PTCA were studied. Exercise testing was performed before and on day 7 after PTCA, which was repeated after 10 mg sublingual isosorbide dinitrate if the test was positive. Quantitative coronary arteriography was also performed on day 8 after PTCA in the basal state, after intracoronary infusion of 0.9% saline, 1, 5, 10, and 20 micrograms ergonovine, and after 300 micrograms nitroglycerin. All patients had a positive exercise test before PTCA but on day 7, six patients had a positive exercise test (group 1) and six patients (group 2) had a negative exercise test. In group 1, all positive exercise tests on day 7 became negative when repeated after isosorbide dinitrate. Intracoronary ergonovine was associated with a dose-dependent constriction of the PTCA segment, a segment distal to it, and a control segment, with no significant difference in the magnitude of the response between the two groups; maximum constriction for group 1 was 19 +/- 3%, 23 +/- 2%, and 16 +/- 3% (p less than 0.001 versus basal), and in group 2 was 20 +/- 4%, 18 +/- 4%, and 9 +/- 2% (p less than 0.01 versus basal). No angina, ischemic ST segment changes, occlusive, or subocclusive spasm occurred in any patient of either group. CONCLUSIONS We could find no evidence that exercise-induced myocardial ischemia early after PTCA is related to the presence of fixed angiographic restenosis or to dynamic constriction of any epicardial coronary segment. Therefore, inappropriate small coronary vessel constriction responsive to nitrates should be considered as a possible alternative explanation.

BACKGROUND To study the impact of percutaneous transluminal coronary angioplasty (PTCA) on coronary vasomotion, we prospectively analyzed spontaneous changes in coronary diameter and the response to the cold pressor test and intracoronary nitroglycerin in 11 patients subjected to successful single-vessel PTCA. METHODS AND RESULTS All antianginal medications were stopped 48 hours before each study. The minimum diameter of the PTCA segment and the diameter of a distal segment in the angioplastied vessel and of a segment in a control vessel not manipulated by the balloon catheter or guide wire were measured by computerized edge detection immediately before PTCA and 5 minutes after, 4 hours after, and 8 days after PTCA. At 4 hours, PTCA and distal segments were constricted by 38 +/- 9% and 16 +/- 5%, respectively, compared with the values at 5 minutes (p less than 0.01). Before angioplasty, the cold pressor test caused vasoconstriction of PTCA and distal segments by 23 +/- 6% (p less than 0.0001) and 15 +/- 4% (p less than 0.008), respectively, but no constrictor response was elicited at 5 minutes or 4 hours after angioplasty. Eight days after PTCA, the basal coronary diameters were similar to those observed 5 minutes after PTCA and the response to the cold pressor test was similar to that observed before PTCA. All segments dilated significantly with nitroglycerin at all times, and no vasoconstriction changes were found in the control segments. CONCLUSIONS Four hours after PTCA, transient spontaneous vasoconstriction of the PTCA and distal segments occurs, which is so intense that the cold pressor test does not cause any further constriction. These abnormalities resolve within 8 days of PTCA.

BACKGROUND Oxygen-15-labeled water is a diffusible, metabolically inert myocardial blood flow tracer with a short half-life (2 minutes) that can be used quantitatively with positron emission tomography (PET). The purpose of this study was to validate a new technique to quantify myocardial blood flow (MBF) in animals and to assess its application in patients. METHODS AND RESULTS The technique involves the administration of 15O-labeled carbon dioxide (C15O2) and rapid dynamic scanning. Arterial and myocardial time activity curves were fitted to a single tissue compartment tracer kinetic model to estimate MBF in each myocardial region. Validation studies consisted of 52 simultaneous measurements of MBF with PET and gamma-labeled microspheres in nine closed-chest dogs over a flow range of 0.5-6.1 ml/g/min. A good correlation between the two methods was obtained (y = 0.36 + 1.0x, r = 0.91). Human studies consisted of 11 normal volunteers and eight patients with chronic stable angina and single-vessel disease, before and after intravenous dipyridamole infusion. In the normal group, MBF was homogeneous throughout the left ventricle both at rest and after administration of dipyridamole (0.88 +/- 0.08 ml/g/min and 3.52 +/- 1.12 ml/g/min, respectively; p less than or equal to 0.001). In patients, resting MBF was similar in the distribution of the normal and stenotic arteries (1.03 +/- 0.23 and 0.93 +/- 0.21 ml/g/min, respectively). After dipyridamole infusion, MBF in normally perfused areas increased to 2.86 +/- 0.83 ml/g/min, whereas in the regions supplied by stenotic arteries it increased to only 1.32 +/- 0.27 ml/g/min (p less than or equal to 0.001). CONCLUSIONS PET with C15O2 inhalation provides an accurate noninvasive quantitative method for measuring regional myocardial blood flow in patients.

BACKGROUND There is increasing evidence that neuropeptide Y (NPY) contributes to the autonomic control of the circulation. NPY coexists with noradrenaline in perivascular nerve terminals, may be released during sympathetic stimulation, and is a potent constrictor of the human coronary circulation and other vascular beds. In vitro studies show that NPY can act either directly on vascular smooth muscle or indirectly by modulation of the presynaptic release or the postsynaptic actions of noradrenaline. It is unclear to what extent these mechanisms operate in vivo. METHODS AND RESULTS The effect on forearm blood flow of intra-arterial NPY was studied in six volunteers during coinfusion of noradrenaline and during reflex sympathetic stimulation induced by lower-body negative pressure. NPY alone induced a dose-dependent reduction of forearm blood flow in all subjects studied, to a maximum of 49 +/- 6.1%. The reduction of flow during infusion of noradrenaline alone was 42 +/- 8%. The response to noradrenaline was unaffected by coinfusion of a threshold constrictor dose of NPY (50 pmol/min). Furthermore, the reflex sympathetic vasoconstrictor response to 20 cm H2O of lower-body negative pressure was similar in both the infused and control arms during the infusion of 50 pmol/min NPY. The response to noradrenaline was abolished by alpha-blockade with phentolamine, but the flow reduction induced by NPY was unaffected by alpha-blockade. CONCLUSIONS NPY is a potent constrictor of human forearm resistance vessels and has a direct effect independent of alpha-receptors. NPY has no detectable modulating effect in vivo on the action of endogenous or infused noradrenaline.