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We examined the relation between B-type natriuretic peptide (BNP) levels and a history of stable angina pectoris and/or healed myocardial infarction in 1,240 patients who were evaluated in the emergency department for possible heart failure. In patients who had heart failure, there was no relation between BNP levels and previous stable angina pectoris and/or healed myocardial infarction. However, in patients who did not have heart failure, there was a relation between BNP levels and previous stable angina pectoris and/or healed myocardial infarction but no significant independent relation in multiple regression analysis.

Current pharmacological treatment for the symptoms of chronic angina consists of nitrates, beta-blockers and calcium antagonists, which were introduced for use in 1867 (England), 1973 (United States) and 1982 (United States), respectively. There has not been a new class of drugs approved for symptomatic relief of chronic angina in the past 22 years. In the present review, the author discusses several new pharmacological approaches currently being tested, each with potentially different mechanisms of action. The proposed mechanisms of action of some of the new experimental drug classes that have proven antianginal and/or anti-ischemic properties may evolve or even change as newer science that more clearly elucidates how specific drugs work becomes available. Indeed, the mechanism whereby nitroglycerin exerts its action took 130 years to fully understand. The experimental drugs discussed in the present review are currently not approved for use in North America.

Experimental studies have shown that adrenomedullin (AM) causes vasodilation, in part, mediated by endothelium-derived nitric oxide (NO). However, it remains to be clarified how NO is involved in AM-induced coronary vasoreactivity in humans. We examined whether NO contributes to the vasodilatory effects of adrenomedullin on human coronary arteries. In 10 patients with angiographically normal coronary arteries, adrenomedullin (low dose: 1 ng/kg/min; high dose: 10 ng/kg/min) was infused into the left coronary ostium before and after an infusion of N-monomethyl-L-arginine (L-NMMA, 40 micromol/min for 5 min), an NO synthase inhibitor. Coronary diameter and coronary blood flow (CBF) were evaluated by quantitative angiography and Doppler flow velocity measurements. Changes in these parameters in response to adrenomedullin were expressed as percent changes from baseline values. Adrenomedullin at a high dose dilated coronary arteries (3.7+/-0.5%, P<0.001). Adrenomedullin increased the coronary blood flow at both doses (low: 55.7+/-13.9%, P<0.01; high: 48.8+/-9.8%, P<0.001). After the infusion of L-NMMA, adrenomedullin-induced coronary vasodilation and increase in coronary blood flow were attenuated. These findings suggest that adrenomedullin dilates human coronary arteries through an increase in NO production, at least in part.

Background: Percutaneous myocardial laser (PML) reduces symptoms in patients with intractable angina. PML leads to a certain loss of viable myocardium, we therefore assessed if troponin or cardiac markers release may explain the clinical effect, and furthermore assessed the markers release during percutaneous sham procedures., Methods: Eighty-two patients with chronic refractory angina were randomized to either percutaneous myocardial laser or a true sham procedure. Cardiac markers were assessed before the procedure, and (1/2), 2, 4, 6, and 10-12 h postprocedure., Results: Troponin I increased to median peak levels (range) of 4 (0.6-43) microg/L in the laser group vs. 1.5 (0.1-5.9) microg/L, p=0.001, and creatine kinase MB to 14 (6-357) microg/L vs. 11 (3-40) microg/L, p<0.05, within and between-group comparison, the rise of CK-MB occurred significantly earlier in the sham group, 3.8 vs. 2.5 h. A time-dependent between-group difference was only detected for troponin. 88% of sham and 100% of laser patients had marker levels above reference limits. There was no correlation between the number of laser/sham created channels, biomarker levels postprocedure, and changes in left ventricular ejection fraction or angina improvement during 12 months of follow-up., Conclusions: The release of cardiac markers is not related to relief of angina after myocardial laser. The use of intracardiac catheters induces a considerable marker release, which is not caused by acute ischemia.

Objectives: The purpose of this study was to assess local release of C-reactive protein (CRP) from atherosclerotic plaques or the vessel wall injured by stenting., Background: Recent research has focused on the local production of CRP, especially in inflammatory atherosclerotic plaques., Methods: The study consisted of two separate protocols. In protocol 1, we measured serum high-sensitivity-CRP (hs-CRP) levels in coronary arterial blood sampled just distal and proximal to the culprit lesions in 36 patients with stable angina and 13 patients with unstable angina. In protocol 2, we measured serial serum hs-CRP levels and activated Mac-1 on the surface of neutrophils in both coronary sinus and peripheral blood in 20 patients undergoing coronary stenting., Results: In protocol 1, CRP was higher in distal blood than proximal blood in both stable (p < 0.05) and unstable angina (p < 0.01). The translesional CRP gradient (distal CRP minus proximal CRP, p < 0.05) as well as the proximal CRP (p < 0.05) and distal CRP (p < 0.05) was higher in unstable angina than in stable angina. In protocol 2, the transcardiac CRP gradient (coronary sinus minus peripheral blood) and activated Mac-1 increased gradually after stenting, reaching a maximum at 48 h (p < 0.001 vs. baseline for both). There was a positive correlation between the transcardiac CRP gradient and activated Mac-1 at 48 h (r = 0.45, p < 0.01)., Conclusions: C-reactive protein is an excellent marker for plaque instability or poststent inflammatory status, and its source might be the inflammation site of the plaque or the coronary arterial wall injured by stenting.

Objectives: We sought to determine whether different stages of coronary artery disease (CAD) are associated with distinct differentiation patterns of activated T cells., Background: Atherosclerosis is an inflammatory disease. However, little is known about specific inflammatory cell activation in atherosclerosis, for example, the T-helper (Th)1/Th2-balance., Methods: We studied 18 patients with stable angina (SA), 28 patients with acute coronary syndrome (ACS) (16 with unstable angina pectoris and 12 with ST-segment elevation myocardial infarction), 19 patients with unheralded myocardial infarction (UH), and 16 control patients. Cytokine patterns and transcription factor signaling pathways of circulating T cells were characterized using reverse transcription polymerase chain reaction and flow cytometry., Results: Although interferon (IFN)-gamma(+)/CD3(+) T cells were approximately 2-fold greater in patients with SA or UH than in control subjects, there was a massive expansion of Th1 cells in patients with ACS (p < 0.001). This increase was paralleled by significantly increased mRNA transcript levels for signal-transducer-and-activator-4 (ACS 1.17 +/- 0.14 relative units [RU]; control patients 0.44 +/- 0.09 RU; SA 0.67 +/- 0.12 RU; UH 0.61 +/- 0.17 RU), interleukin-2 (ACS 1.55 +/- 0.51 RU; control patients 0.21 +/- 0.09 RU; SA 0.54 +/- 0.18 RU; UH 0.45 +/- 0.16 RU), and IFN-gamma in ACS (1.27 +/- 0.39 RU; control patients 0.35 +/- 0.09 RU; SA 0.58 +/- 0.11 RU; UH 0.53 +/- 0.24 RU; p < 0.002). Th2 and Th0 cells were not different across patient subsets. The burden of CAD was identical between SA (1.4 +/- 0.2 diseased vessels, 68 +/- 13% diameter stenosis) and ACS (1.4 +/- 0.2 diseased vessels, 64 +/- 17% diameter stenosis) but significantly greater in patients with UH (2.5 +/- 0.5 diseased vessels, 95 +/- 7% diameter stenosis; p < 0.05)., Conclusions: Patients with UH have a greater burden of obstructive CAD than SA but no greater T-cell activation. Patients with ACS have the same extent of CAD than SA but significantly greater activation of Th1 cells that may contribute to the increasing instability. Differences in circulating Th1 cells might indicate different pathogenic components, leading to ACS and UH.

Oxidative stress impairs endothelial function and may play an important role in the pathogenesis of acute cardiovascular diseases. Advanced oxidation protein products (AOPP) were proposed as one of the possible markers of oxidative injury, which originates under oxidative and carbonyl stress and increase global inflammatory activity. The present study was undertaken to compare AOPP concentrations in a control group of healthy individuals without ICHS (I), patients with stable angina pectoris (II), patients with acute coronary syndrome over 48 hours without ST elevations (III), and patients with ST elevation myocardial infarction (IV). Coronaronary angiography, risk factors and anamnestic data were analyzed. We examined 73 probands with signs of myocardial ischemia, mean age of 61.5 years (64% males) subjected to coronarography and 21 healthy individuals. No significant difference was found between venous blood and coronary samples, or between infarction and non-infarction arteries in the group IV. AOPP concentrations in healthy individuals in the group I (82.9 +/- 29.3 mmol/l) did not differ significantly from patients in group II (89.6 +/- 26.7 mmol/l) and group III (112.3 +/- 54.6 mmol/l). A significant difference in AOPP values was found between the groups I and IV, and between the groups II and IV (82.9 +/- 29.3 mmol/l vs. 125.8 +/- 101 mmol/l, p = 0.02, and 89.6 +/- 26.7 mmol/l vs. 125.8 +/- 101 mmol/l, p = 0.02). No correlations were found between AOPP and body mass index (BMI), nicotinism, left ventricular ejection fraction, parameters of glucose and lipid metabolism. ROC analysis revealed that AOPP concentrations of 89 mmol/l had 64% sensitivity and 71% specificity for revealing an acute coronary syndrome (AUC 0.65, 95% CI 0.55-0.80). AOPP are significantly increased in patients with acute coronary syndromes with ST segment elevation, but also tend to increase in patients with non-ST elevation myocardial infarction. Our observations suggest that AOPP may be used as a marker of oxidative stress and as a prognostic factor for severe forms of cardiovascular disease. A cut-off value of 89 mmol/l can be used with 64% sensitivity and 71% specificity for revealing acute coronary syndrome.

The classical model of coronary physiology implies the presence of maximal microcirculatory vasodilation during myocardial ischemia. However, Doppler monitoring of coronary blood flow (CBF) documented severe microcirculatory vasoconstriction during pacing-induced ischemia in patients with coronary artery disease. This study investigates the mechanisms that underlie this paradoxical behavior in nine patients with stable angina and single-vessel coronary disease who were candidates for stenting. While transstenotic pressures were continuously monitored, input CBF (in ml/min) to the poststenotic myocardium was measured by Doppler catheter and angiographic cross-sectional area. Simultaneously, specific myocardial blood flow (MBF, in ml.min(-1).g(-1)) was measured by 133Xe washout. Perfused tissue mass was calculated as CBF/MBF. Measurements were obtained at baseline, during pacing-induced ischemia, and after stenting. CBF and distal coronary pressure values were also measured during pacing with intracoronary adenosine administration. During pacing, CBF decreased to 64 +/- 24% of baseline and increased to 265 +/- 100% of ischemic flow after adenosine administration. In contrast, pacing increased MBF to 184 +/- 66% of baseline, measured as a function of the increased rate-pressure product (r = 0.69; P < 0.05). Thus, during pacing, perfused myocardial mass drastically decreased from 30 +/- 23 to 12 +/- 11 g (P < 0.01). Distal coronary pressure remained stable during pacing but decreased after adenosine administration. Stenting increased perfused myocardial mass to 39 +/- 23 g (P < 0.05 vs. baseline) as a function of the increase in distal coronary pressure (r = 0.71; P < 0.02). In conclusion, the vasoconstrictor response to pacing-induced ischemia is heterogeneously distributed and excludes a tissue fraction from perfusion. Within perfused tissue, the metabolic demand still controls the vasomotor tone.

The role of oxidation injury as an important factor in the pathophysiology of cardiomyopathy (CMP) has recently gained increasing interest. Semiquantitative analysis for isoprostane, 8-epi-prostaglandin F(2alpha) (8-epi-PGF(2alpha)), and oxidised low-density lipoprotein (ox-LDL) of coronary vascular tissue samples derived from CMP patients revealed an increased extent and intensity of uptake as compared to the respective controls. To evaluate oxidative stress in vivo, we examined plasma, serum, salivary, and urinary 8-epi-PGF(2alpha) in patients with dilated CMP (n=20) and ischemic CMP (n=20) with decreased left ventricular ejection fraction (LVEF). Patients with coronary heart disease (CHD) (n=20) and 20 healthy, age-matched, and sex-matched controls were investigated in parallel. 8-Epi-PGF(2alpha) levels were correlated with the functional severity of heart failure [New York Heart Association (NYHA) classification] and LVEF. 8-Epi-PGF(2alpha) levels were matched according to risk factors (smoking and hypercholesterolemia) and were significantly higher in patients with CMP as compared to healthy controls and patients with CHD in all investigated compartments. A positive correlation between NYHA stages and 8-epi-PGF(2alpha), as well as a negative correlation to LVEF, could be demonstrated in a subgroup analysis. These findings reflect the enhanced oxidation injury in patients with CMP and, to a lesser extent, in CHD as compared to healthy controls, thus highly indicating the relevance of oxidative stress for the pathogenesis and progression of cardiovascular disease.

To determine whether the expression of CD39 in coronary atherosclerotic lesions is related to plaque instability and thrombus formation, we assessed directional coronary atherectomy (DCA) specimens from patients with stable and unstable angina pectoris. CD39 immunoreactivity was decreased in culprit lesions in patients with unstable angina pectoris compared with those with stable angina pectoris, and was reduced in DCA specimens with thrombus formation. These results suggest that CD39 expressed in atheromatous plaque plays an important role in preventing acute coronary syndromes.

Several lines of evidence indicate that increased inflammatory activity in peripheral blood is associated with the acute coronary syndrome. Systemic inflammation in clinically stable conditions of coronary artery disease has been less studied. We examined cytokine profiles in 20 patients who had acute coronary syndrome, 45 who had angiographically verified coronary artery disease and stable angina pectoris, and 45 healthy controls. Circulating levels of C-reactive protein, interleukin-1 receptor antagonist, interleukin-2 receptor, interleukin-6, interleukin-10, and interleukin-18 were determined. Subpopulations of peripheral immune cells, including neutrophil-platelet aggregates, were analyzed by 3-color flow cytometry using a panel of monoclonal antibodies. Patients who had acute coronary syndrome and stable angina pectoris had significantly higher levels of C-reactive protein, interleukin-6, and interleukin-1 receptor antagonist than did controls, whereas levels of interleukin-2 receptor, interleukin-10, and interleukin-18 were similar across groups. Patients had significantly more neutrophils, and the numbers of neutrophil-platelet aggregates were particularly large in patients who had stable angina pectoris. High levels of C-reactive protein, interleukin-6, and interleukin-1 receptor antagonist in patients were significantly related to numbers of neutrophils and neutrophil-platelet aggregates but not to other immune cell subpopulations. The data suggest that the interaction between neutrophils and platelets is an important component of proinflammatory activity seen in peripheral blood of stable and unstable forms of coronary artery disease.

Effect of carvedilol on lipid peroxidation was investigated in patients with stable angina. The study comprised 30 patients (20 men and 10 women), aged 38-55 years (mean 48.3 years) with stable angina. The patients were administered carvedilol in increasing every four weeks doses: 12.5 mg/day, 25 mg/day, 50 mg/day. The control group consisted of 12 healthy subjects aged 39-49 years (mean 45.7 years). Blood samples were collected before and 4,8 and 12 weeks after therapy in patients and once in control group. Our study has been approved by the local Ethics Committee. MDA concentration in plasma and erythrocytes, which is a recognised indicator of tissue injury caused by reactive oxygen species, was measured according to Placer et al. MDA concentration was significantly higher (p < 0.05) in patients with stable angina than in control group. After 4, 8 and 12 weeks of carvedilol therapy, decrease in MDA concentration was observed in comparison to the initial values. MDA concentration did not differ in patients from that observed in healthy subjects after 8 and 12 weeks of therapy The results of our study have shown that carvedilol inhibits lipid peroxidation in patients with stable angina.

Objective: In women, sex hormones cause increased morbidity and mortality in patients with coronary heart disease (CHD) and adversely affect the coagulation profile. We have studied the effect of physiological testosterone replacement therapy in men on coagulation factor expression, to determine if there is an increased risk of thrombosis., Methods: Double-blind, randomized, placebo-controlled trial of testosterone in 46 men with chronic stable angina. Measurements of free, total and bioavailable testosterone, luteinising hormone (LH) and follicle-stimulating hormone (FSH), estradiol, plasminogen activator inhibitor-1 (PAI-1), fibrinogen, tissue plasminogen activator (tPA) and full blood count were made at 0, 6 and 14 weeks., Results: Bioavailable testosterone levels were: 2.58 +/- 0.58 nmol/l at baseline, compared with 3.35 +/- 0.31 nmol/l at week 14 (P < 0.001) after treatment compared with 2.6 +/- 0.18 nmol/l and 2.44 +/- 0.18 nmol/l in the placebo group (P was not significant). There was no change in fibrinogen (3.03 +/- 0.18 g/l at baseline and 3.02 +/- 0.18 g/l at week 14, P = 0.24), tPA activity (26.77 +/- 4.9 Iu/ml and 25.67 +/- 4.4 Iu/ml, P = 0.88) or PAI-1 activity (0.49 +/- 0.85 Iu/ml and 0.36 +/- 0.06 Iu/ml, P = 0.16) with active treatment and no differences between the groups (at week 14, P value 0.98, 0.59 and 0.8 for fibrinogen, PAI-1 and tPA respectively). Haemoglobin concentration did not change over time, in the testosterone group (1.44 +/- 0.02 g/l and 1.45 +/- 0.02 g/l, P = 0.22)., Conclusion: Physiological testosterone replacement does not adversely affect blood coagulation status.

Background: Matrix gammacarboxyglutamate (Gla)-protein (MGP) is a strong inhibitor of soft tissue calcification and is mainly produced by chondrocytes and vascular smooth muscle cells (VSMCs). MGP-deficient mice have extensive calcifications of cartilage and arteries leading to osteopenia, fractures and blood vessel ruptures. Promotor polymorphisms resulting in decreased expression levels were found to be associated with an increased risk for cardiovascular disease in humans., Methods: Recently, an ELISA-based assay has become available with which MGP may be detected in the circulation. The principle of the test kit is that of a competitive immunoassay using a monoclonal antibody against MGP bound to the microtiter plate., Results: Here, we report on a critical evaluation of this assay and its potential diagnostic utility in diseases associated with the degeneration of the arterial vessel wall and cartilage. The biochemical performance of the kit is satisfactory, and significant differences were found between a number of patient cohorts and the reference population. Serum MGP concentrations were significantly decreased in patients with angina pectoris and in various cartilage diseases., Conclusions: The assay allows comparison of groups and may become a suitable marker for risk assessment or diagnosis in cardiovascular disease and osteoarthritis.

Endothelial progenitor cell (EPC) mobilization has been reported following tissue damage, whereas no data are available regarding the mobilization of hematopoietic progenitor cells (HPCs). We performed the phenotypic and functional analysis of circulating CD34+ progenitor cells in patients with acute myocardial infarction (AMI), assessed from admission up to 60 days, in patients with stable angina pectoris (SA), and in healthy controls (CTRLs). In patients with AMI at admission (T0), the number of circulating CD34+ cells was higher (P < .001) than in CTRLs and became comparable with CTRLs within 60 days. Both the number of CD34+ cells coexpressing CD33, CD38, or CD117 and the number of HPCs was higher (P < .02 for all) in patients with AMI at T0 than in CTRLs, as was the number of hematopoietic colonies (P < .03). Patients with AMI (T0) had a significantly increased number of CD34+ vascular endothelial growth factor receptor 2-positive (VEGFR-2+) cells (P < .002) with respect to CTRLs, including CD34(+) CD133(+)VEGFR-2+ and CD34+ CD117(+)VEGFR-2+ EPCs. The number of endothelial colonies was higher in patients with AMI (T0) than in CTRLs (P < .05). No significant difference was documented between patients with SA and CTRLs. Spontaneous mobilization of both HPCs and EPCs occurs within a few hours from the onset of AMI and is detectable until 2 months.

A fatty acid analogue, 123I-labelled beta-methyl iodophenyl pentadecanoic acid (BMIPP), has been used to identify ischaemic and metabolically impaired myocardium. However, the prognostic value of BMIPP imaging, particularly in relation to stress myocardial perfusion imaging, remains unclear. Data from 167 consecutive patients with angina pectoris but without prior myocardial infarction (MI) who had undergone both BMIPP and stress 201Tl (sTL) imaging were analysed. Tracer uptake was graded using a 13-segment, 4-point scoring model. Patients were followed up for 48 months with primary end points (cardiac death, non-fatal MI) as hard cardiac events and with secondary end points (late revascularisation, recurrent angina and heart failure) as soft events. For overall cardiac events (5 hard and 29 soft events), Kaplan-Meier analysis revealed significantly lower event rates in subgroups with normal BMIPP uptake, a summed difference score of sTL (SDS) of <3 or absence of diabetes mellitus when compared to each counterpart. Multivariate Cox's analysis revealed reduced BMIPP uptake, SDS > or =3, diabetes and reduced ejection fraction to be significant predictors. Negative predictive values of normal BMIPP and SDS <3 for all events were 91% and 84%, respectively. No hard event occurred in 66 patients with normal BMIPP uptake, whereas two patients with SDS <3 but impaired BMIPP uptake had hard events. In conclusion, normal BMIPP imaging is an excellent prognostic sign, independently of stress myocardial perfusion imaging, in patients with angina pectoris without prior MI.

Objectives: To assess the link between perfusion, metabolism, and function in viable myocardium before and early after surgical revascularisation., Design: Myocardial blood flow (MBF, thermodilution technique), metabolism (lactate, glucose, and free fatty acid extraction and fluxes), and function (transoesophageal echocardiography) were assessed in patients with critical stenosis of the left anterior descending coronary artery (LAD) before and 30 minutes after surgical revascularisation., Setting: Tertiary cardiac centre., Patients: 23 patients (mean (SEM) age 57 (1.7) years with LAD stenosis: 17 had dysfunctional viable myocardium in the LAD territory, as shown by thallium-201 rest redistribution and dobutamine stress echocardiography (group 1), and six had normally contracting myocardium (group 2)., Results: LAD MBF was lower in group 1 than in group 2 (58 (7) v 113 (21) ml/min, p < 0.001) before revascularisation and improved postoperatively in group 1 (129 (133) ml/min, p < 0.001) but not in group 2 (105 (20) ml/min, p = 0.26). Group 1 also had functional improvement in the LAD territory at intraoperative echocardiography (mean regional wall motion score from 2.6 (0.85) to 1.5 (0.98), p < 0.01). Oxidative metabolism, with lactate and free fatty acid extraction, was found preoperatively and postoperatively in both groups; however, lactate and free fatty acid uptake increased after revascularisation only in group 1., Conclusions: MBF is reduced and oxidative metabolism is preserved at rest in dysfunctional but viable myocardium. Surgical revascularisation yields immediate perfusion and functional improvement, and increases the uptake of lactate and free fatty acids.

Objective: To examine the expression and localisation of adrenomedullin in human coronary atherosclerotic lesions from patients with unstable angina (UAP) and stable angina (SAP), and to study the relation between adrenomedullin expression and plaque instability., Design: A retrospective observational study., Patients: Directional coronary atherectomy samples were obtained from 15 patients with UAP and 12 with SAP., Methods: The localisation of adrenomedullin was examined by immunohistochemistry, and adreno-medullin mRNA expression was measured by quantitative polymerase chain reaction., Results: Adrenomedullin immunoreactivity was preferentially localised in macrophages, intimal smooth muscle cells, and proliferated microvessels. The mean number of adrenomedullin positive cells in five high power fields (x 400) per specimen was higher in patients with UAP than in those with SAP (mean (SEM), 110 (13) v 76 (7); p < 0.05); and the ratio of adrenomedullin positive to total cells was higher in patients with UAP (43.0 (2.2)% v 34.2 (2.0)%; p < 0.01). More adrenomedullin mRNA was expressed in the plaque of patients with UAP than in those with SAP (60.4 (16.9)% v 9.7 (3.3)%; p < 0.01)., Conclusions: The findings suggest that adrenomedullin is involved in the development of atherosclerosis and plaque instability in human coronary arteries, in an autocrine or paracrine manner.

Background: Apoptosis in human atherosclerotic coronary plaques possibly causes plaque destabilization by contributing to the weakening and breaking down of the fibrous cap. We tested the hypothesis that apoptosis is quantitatively increased in unstable atherosclerotic plaques., Methods and Results: We analyzed the expression of apoptotic genes such as BAX, CASP1, FAS, FAS L, FOS, MDM2, NFkB2, P53, PCNA, TERT, and XRCC1 in coronary plaques collected with directional coronary atherectomy from 15 patients with stable angina and 15 with acute coronary syndromes without ST elevation (ACS). Total RNA was extracted and cDNA was amplified with a specific set of primers and TaqMan probes. Apoptosis was also revealed by DNA laddering. To clarify the source of mRNAs, we performed in situ reverse transcriptase-polymerase chain reaction coupled with immunocytochemistry and found a substantial overlap between the mRNAs of the above genes and vascular smooth muscle cells. Gene expression analysis showed that the proapoptotic genes (ie, BAX, CASP1, FAS, FAS L, FOS, NFkB2, P53, PCNA) were significantly more expressed (P<0.001) in ACS plaques, whereas the antiapoptotic genes (ie, MDM2, TERT, XRCC1) were more transcribed (P<0.001) in stable angina plaques. Total gDNA gel electrophoresis identified a laddering pattern in the ACS plaques as evidence of end-point apoptosis. Western blotting substantially confirmed the above data., Conclusions: Our findings support the idea that ACS plaques are committed to apoptosis through an established meshwork of gene activation and inactivation, whereas stable angina plaques retain active cell homeostasis and repair mechanisms.

We examined the involvement of endogenous vasopressin and platelet-activating factor (PAF) in the pathogenesis of two types of experimental angina in urethane-anaesthetised male Wistar rats. In the first model, epinephrine (10 microg kg(-1)) was injected into the tail vein, followed at the development of the maximum blood pressure response, i.e., 30 s later, by phentolamine (15 mg kg(-1)). In the second model, the vasopressin V1 receptor agonist ornithine-vasopressin (ornipressin; 0.5 IU kg(-1), i.v.) was administered. The heart rate, mean arterial blood pressure and surface electrocardiogram (ECG, standard lead II) were registered simultaneously. As a measure of myocardial ischaemia, at 1 min after phentolamine or ornipressin administration, we found significant ST-segment depression, lasting for more than 10 or 5 min, respectively. Pretreatment (15 min, s.c.) with the vasopressin V1 receptor antagonist Mca1,Tyr(Me)2AVP (the Manning peptide; 0.02-0.2 microg kg(-1)) or the platelet-activating factor receptor antagonist ginkgolide B (BN 52021; 0.25-2.5 mg kg(-1)) alone caused a dose-dependent reduction of the ST-segment depression. Concurrent administration of the two antagonists in their threshold doses (0.02 microg kg(-1) and 0.25 mg kg(-1)) also attenuated the ST-segment depression in both models. Neither antagonist affected the blood pressure or heart rate changes throughout the studies. Our results suggest that endogenous vasopressin and platelet-activating factor interact synergistically in provoking myocardial ischaemia in vivo in experimental angina in the rat.

Angiogenic gene therapy in angina pectoris has been disappointing so far. Reasons might be that the administered genes already are overexpressed in ischemic myocardium, or that atrial and brain natriuretic peptides (ANP and BNP) are overexpressed, as they have anti-angiogenic effects. Five stable angina pectoris patients without heart failure were studied. Left ventricular biopsies were taken during coronary by-pass surgery from a region with stress-inducible ischemia and from a normal region. Both ANP and BNP but not vascular endothelial growth factor (VEGF) and VEGF-receptor 1 and 2 were overexpressed in ischemic regions compared to non-ischemic regions as measured by real-time PCR. The expression of 15 other angiogenic genes measured by oligonucleotide arrays was not consistently increased in ischemic regions. The overexpression of ANP and BNP suggests an anti-angiogenic effect in ischemic heart disease. The lack of overexpression of angiogenic genes supports the concept of therapeutic overexpression of these genes.

Concentrations of the circulating hepatocyte growth factor (HGF) increase in the very early phase of acute myocardial infarction, and are a marker of arterial thrombosis. A recently developed, highly sensitive HGF assay can detect the early stages of arterial thrombosis in patients with unstable angina pectoris, acute aortic dissection and pulmonary thromboembolism. Heparin rapidly induces the release of HGF into the circulation, and HGF is a major factor involved in heparin-induced angiogenesis. Furthermore, the activation of mast cells by thrombus formation releases HGF into the circulation. This new pathway, thrombus formation-mast cell activation- degranulation-heparin-HGF-angiogenesis, may be both diagnostically useful and a therapeutic target.

Objectives: We sought to verify whether the intravascular metabolism of chylomicron-like emulsion may predict the clinical evolution of patients with coronary artery disease (CAD) undergoing secondary prevention therapy of CAD., Background: Case-control studies have suggested an association between impaired intravascular catabolism of triglyceride (TG)-rich lipoproteins and CAD. However, evidence is lacking with respect to the potential clinical relevance of this metabolic disorder in CAD patients., Methods: During a period of 4.5 +/- 0.9 years, we followed up 63 stable CAD patients (mean age 60 +/- 10 years) undergoing secondary prevention therapy (low-density lipoprotein cholesterol <100 mg/dl) in whom kinetic studies of the in vivo catabolism of chylomicron-like emulsions were performed. At enrollment into the study, fasting patients were injected intravenously with a chylomicron-like emulsion labeled with radioactive triglyceride (3H-TG) and cholesteryl esters (14C-CE) to evaluate the efficacy of intravascular TG lipolysis., Results: At baseline, CAD patients displayed a diminished fractional clearance rate (FCR) for 3H-TG (-26%; p = 0.027), for 14C-CE (-37%; p = 0.015), and for delipidation index (DI) (-26%; p = 0.02) as compared with 35 control subjects. During follow-up of secondary prevention therapy, 33% of CAD patients (n = 21) presented with clinically refractory angina and aggravated coronary angiographic severity. The FCR for 3H-TG (-44%; p = 0.005) and DI (-41%; p = 0.006) in those patients with refractory angina was significantly lower than that observed in those with stable evolution. Moreover, in a Cox multivariate regression analysis, the presence of a DI less than the median value was an independent predictor of an unfavorable clinical evolution (adjusted hazard ratio 3.32; 95% confidence interval 1.21 to 9.14; p = 0.020)., Conclusions: The current study establishes that delayed intravascular TG lipolysis is a strong and independent predictor of evolution to severe angina among patients undergoing secondary prevention therapy of CAD.

Background: Atherosclerotic lesions are mainly composed of macrophages and T lymphocytes. Specific T helper type 1 (Th1) cytokines and interferon gamma (IFN-gamma) inducible chemokines have been shown to be present in these lesions, modulating the local immunologic response. To explore whether this increase in Th1 activity could also be detected in circulating cells indicating a systemic activation, we studied the peripheral expression of Th1 cytokines and chemokines in patients with coronary artery disease and controls., Methods and Results: Fifty patients with coronary artery disease (25 with unstable angina and 25 with stable angina) and 10 controls were studied. Serum interleukin (IL)-12 and IFN-gamma and the expression of IFN-gamma inducible chemokines IP-10, Mig and their receptor CXCR3 in peripheral cells were analyzed. Serum IL-12 and intracellular expression of IFN-gamma were significantly elevated in patients with unstable angina. An enhanced expression of IFN-gamma chemokines IP-10, Mig and CXCR3 in patients with stable angina was also observed., Conclusions: This study demonstrates an increased systemic inflammatory activity in patients with coronary heart disease with a predominant Th1 response, particularly in patients with unstable angina, suggesting an important role played by this polarization in plaque formation and rupture., (Copyright 2004 Elsevier Ltd.)

Objectives: We compared outcomes in patients with non-ST-segment elevation acute coronary syndromes (ACS) according to the degree of cardiac troponin I (cTnI) elevation., Background: Controlled trials of high-risk patients have found that troponin elevations identify an even higher risk subset. It is unclear whether outcomes are similar among a lower risk, heterogeneous patient group. Also, few studies have reported outcomes other than myocardial infarction (MI) or death, based on the peak troponin value., Methods: Consecutively, admitted patients without ST-segment elevation on the initial electrocardiogram underwent serial marker sampling using creatine kinase (CK), CK-MB fraction, and cTnI. Patients were grouped according to peak cTnI: negative = no detectable cTnI; low = peak greater than the lower limit of detectability but less than the optimal diagnostic value; intermediate = peak greater than or equal to the optimal diagnostic value but less than the manufacturer's suggested upper reference limit (URL); and high = peak greater than or equal to the URL. Thirty-day outcomes included cardiac death, MI based on CK-MB, revascularization, significant disease, and a reversible defect on stress testing. Six-month mortality was also determined. Negative evaluations for ischemia included nonsignificant disease, no reversible stress defect, and negative rest perfusion imaging., Results: Of the 4,123 patients admitted, 893 (22%) had detectable cTnI values. Cardiac events and positive test results at 30 days and 6-month mortality increased significantly with increasing cTnI values. Negative evaluations for ischemia were significantly and inversely related to peak cTnI values. Although adverse events were significantly more common in patients with a low cTnI value than in those with negative cTnI, negative evaluations for ischemia were frequent., Conclusions: Increased cTnI values are associated with worse outcomes. Although low cTnI values are associated with adverse events, they do not have the same implication as higher cTnI values, and nonischemic evaluations are frequent.

Despite increasing pharmacological and mechanical treatment options, ischemic heart disease continues to be associated with considerable patient mortality and morbidity. The estimates of the direct and indirect costs associated with chronic stable angina amount to billions of dollars. Given the epidemiological and economic magnitude of the problem, the need for more effective therapies is self-evident. Based on current guidelines, the management of ischemic heart disease has progressively broadened to include risk factor modification, patient education, and pharmacological therapy. The latter includes i) classic antianginal agents such as beta-blockers, calcium antagonists, and nitrates, and ii) drugs for secondary prevention, such as aspirin, clopidogrel, statins, and angiotensin-converting enzyme inhibitors. Tailoring therapy to individual needs has become even more challenging because of the marked changes in the clinical profile of patients with chronic ischemic heart disease. Compared with the past, today's patients tend to be older, to have undergone revascularization procedures, and to frequently have associated illnesses, including heart failure and diabetes. Significant progress has been made in recent years in understanding the role of cardiac energy metabolism in the pathogenesis of myocardial ischemia. A better understanding of metabolic derangements associated with ischemia and reperfusion is translating into innovative therapeutic approaches. Optimization of cardiac energy metabolism is based on promoting cardiac glucose oxidation. This has been proved to enhance cardiac function and protect myocardial tissue against ischemia-reperfusion injury. A new class of metabolic agents, known as the 3-ketoacyl coenzyme A thiolase inhibitors (trimetazidine), is able to elicit an increase in glucose and lactate combustion secondary to partial inhibition of fatty acid oxidation, producing clinical benefits in patients with ischemic heart disease.

Background: Tenascin-C (TNC) is an extracellular matrix glycoprotein that increases after inflammation and injury. In cultured cells TNC has been reported to markedly induce the expression of matrix metalloproteinase-9, which stimulates collagen degradation in the fibrous cap of human atherosclerotic plaque., Methods and Results: Immunohistochemical techniques were used to analyze the expression of TNC protein in 51 coronary atherectomy specimens obtained from patients with stable angina pectoris (SAP, n=23) or acute coronary syndromes (ACS) (n=28; unstable angina pectoris, n=20, acute myocardial infarction, n=8). Immunostaining for alpha-smooth muscle actin, CD68, CD45, and CD31 was also performed in serial sections to identify the cell types that express TNC protein. The %TNC + area (percentage of the area of immunostaining for TNC protein in the total surface area of the plaque) was larger in coronary samples with the plaque characteristics of thrombus, angiogenesis, intraplaque hemorrhage, and macrophage (CD68(+)), and lymphocyte (CD45 (+)) clusters than in coronary samples without them (52+/-3.4 vs 39+/-4.8, p<0.05; 57+/-3.7 vs 36+/-3.7, p<0.01; 51+/-3.6 vs 39+/-4.8, p<0.05; 53+/-3.4 vs 33+/-4.5, p<0.01; 56+/-4.1 vs 37+/-3.6, p<0.01, respectively). The presence of other components, such as dense fibrous tissue, neointimal hyperplasia, atheromatous gruel and calcification, was not significantly correlated with the %TNC + area. The %TNC + area was larger in coronary samples from patients with ACS than in samples from patients with SAP (56+/-3.2% vs 34+/-4.3%, p<0.01)., Conclusions: The results suggest that TNC may have specific functions in coronary plaque formation and may be involved in the pathogenesis of coronary lesions in ACS.

Aim: To define inter- and intraday variability in plasma perhexiline concentrations, time-to-maximum plasma perhexiline concentration and variability in the ratio of hydroxyperhexiline to parent perhexiline concentrations over the course of the day in patients at steady state., Methods: Eight blood samples were taken over a 24-h period from 12 adult patients already taking perhexiline for the treatment of angina pectoris. These patients were assumed to be at steady state, having taken the same dose of perhexiline for more than 4 weeks and having no changes made to other drug therapy that might have affected plasma perhexiline concentrations (especially drugs that interfere with CYP2D6). Perhexiline was assayed by HPLC/FL. The percentage increase over baseline concentration was determined for each patient for both perhexiline and hydroxyperhexiline., Results: Trough plasma perhexiline concentrations from two patients were below the limit of quantification of the assay (0.05 mg l-1) and thus were excluded from the analysis. The greatest mean percentage increase in plasma perhexiline concentration over the day was 21% (95%CI 9%, 33%, range -19% to 45%) which occurred 6 h postdose. The greatest mean percentage increase in plasma hydroxyperhexiline concentration was 10.8% (95%CI -5.3%, 26.9%, range -13% to 60%) which occurred 4 h postdose. However individual patients demonstrated > 60% intraday variability in perhexiline concentrations which was not related to the concomitant use of drugs that affect CYP2D6 activity. Changes in random plasma perhexiline concentration which are attributed to changes in concomitant drug therapy should be supported by additional kinetic data. Inter-day variability in plasma perhexiline concentration as determined by the ratio of C24 : C0 was small (mean 0.90, 95%CI 0.77, 1.03) which supports C0 as the best sampling time for perhexiline concentration monitoring. The variability in C24 : C0 for hydroxyperhexiline concentrations was smaller (mean 0.96, 95%CI 0.81, 1.11). Variability in the ratio of plasma concentrations of hydroxyperhexiline to perhexiline over the day was also small. The ratio of plasma hydroxyperhexiline to perhexiline concentration over the day fell within a narrow range for all subjects with 95% confidence intervals being < 15% for eight patients and < 25% for the remaining patient. This suggests that formation of the metabolite occurs rapidly and may be presystemic. It also supports the calculation of the hydroxyperhexiline : perhexiline ratio (in patients at steady state) on blood samples taken at any time during the dosing interval., Conclusions: The within-day variability in plasma perhexiline concentrations was small. While C0 is probably the best time for therapeutic drug monitoring purposes, it is not unreasonable to use samples drawn at any time during the dosing interval. The therapeutic range used in this hospital (0.15-0.6 mg l-1) was devised from earlier work using 4 h postdose blood sampling which is close to the 'peak' concentration and a mean of 16% higher than C0 in this study. This increase is probably clinically insignificant and a different C0 range is therefore not warranted.

Enhanced external counterpulsation (EECP) is noninvasive, safe, and effective for stable angina. We have reported that the development of functional collateral vessels is one of the mechanisms of EECP therapy using ammonia positron emission tomography (PET). The efficacy of heparin treatment on collateral growth is shown in several clinical studies. We evaluated whether EECP combined with intravenous heparin injection is effective for exercise capacity and oxygen metabolism of ischemic myocardium in stable angina. Eleven patients with stable angina were treated with conventional EECP therapy (C group). Seven patients with stable angina were treated with EECP therapy with 5000 IU heparin pretreatment (H group). At baseline and after the completion of treatment H, 7 patients underwent [(11)C] acetate PET to examine the change in regional myocardial oxygen metabolism. Although the total treadmill exercise time was prolonged after treatment in both groups, the extent of the improvements was significantly greater in the H group compared with the C group. Although k mono, the index of regional myocardial oxygen metabolism, in the nonischemic region remained unchanged, k mono in the ischemic region increased significantly ( P << 0.05) from 0.038 +/- 0.004 to 0.053 +/- 0.007. In conclusion, EECP with heparin pretreatment appears to be a new treatment remedy for patients with stable angina.

Coronary spasm plays an important role in the pathogenesis of not only variant angina but also coronary heart disease in general including acute coronary syndromes. The incidence of coronary spasm in Japanese patients with angina pectoris was about 40%. The total number of patients with angina pectoris increases with old age. The patients' age distribution was relatively younger in the coronary spasm than in the stable effort angina. The vascular endothelium has been reported to be a multifunctional organ whose integrity is essential to normal vascular physiology, and whose dysfunction can be a critical factor in the pathogenesis of vascular disease. Acetylcholine and methacholine cause vasodilation by endothelium-derived relaxing factor when endothelium is functioning normal, whereas they cause vasoconstriction when endothelium is removed or damaged. Coronary spasm can be induced by acetylcholine and methacholine. The patients with coronary spasm may have a disturbance in the endothelial function of the coronary arteries.

We performed BMIPP myocardial SPECT and Tl myocardial SPECT in patients with unstable angina (UAP) and stable effort angina (SAP), and compared the results for the two groups. Our subjects were 30 patients with the UAP and 25 patients with the SAP. The early and delayed images of the BMIPP were obtained with patients at rest. The early image of the Tl alone was obtained with patients at rest. We calculated severity score (SS) using the polar map based on SPECT short-axis image on the both myocardial SPECT. And, we calculated % uptake of the responsible coronary lesion and regional washout rate (WR) on myocardial SPECT with BMIPP. On coronary angiogram, no difference in % diameter stenosis was seen between the two groups. On myocardial SPECT with Tl, no difference in the SS was seen between the two groups. However, on myocardial SPECT with BMIPP, the SS was significantly higher score in the UAP group than in the SAP group. And, on myocardial SPECT with BMIPP, the % uptake and the WR were significant lower values in the UAP group than in the SAP group. Even if the two groups have almost the same level of myocardial perfusion disorder, the UAP group may have severer myocardial fatty-acid metabolic disorder than the SAP group, because the defects in BMIPP were significantly severer in the UAP group.

Background: Vascular wall remodeling is a major factor contributing to restenosis after angioplasty that involves migration and proliferation of vascular smooth muscle cells. The release of matrix-degrading metalloproteinases, including metalloproteinase-2 and metalloproteinase-9, facilitates remodeling. Experimental data suggest that nitric oxide (NO) decreases the activity of metalloproteinases and this may attenuate arterial remodeling after balloon injury. We investigated whether metalloproteinase-2, metalloproteinase-9 and NO are released into the coronary sinus blood during angioplasty in coronary patients., Methods: In 10 patients with stable angina undergoing elective percutaneous transluminal coronary angioplasty of an isolated stenosis of the proximal left anterior descending coronary artery, blood was sampled from the coronary sinus at baseline, immediately and 1 min after each balloon deflation. Plasma release of metalloproteinase-2 and metalloproteinase-9 was assayed by their gelatinolytic activity using zymography, while the liberation of NO metabolites was measured by high-performance liquid chromatography., Results: Two consecutive balloon inflations each of 60 s duration, resulted in an immediate increase (P<0.05) of metalloproteinase-9, but not metalloproteinase-2 activity, followed by normalization of metalloproteinase-9 levels to the baseline within 1 min. Plasma levels of NO metabolites remained unchanged., Conclusions: Rapid release of metalloproteinase-9 after balloon inflation may both contribute to remodeling and protect the vascular wall from post-angioplasty thrombosis.

Objectives: Previous studies have suggested that abnormal levels of cortisol and testosterone might increase the risk of serious somatic diseases. To test this hypothesis, we conducted a 5-year follow-up study in middle-aged men., Methods: A population-based cohort study conducted in 1995 amongst 141 Swedish men born in 1944, in whom a clinical examination supplemented by medical history aimed to disclose the presence of cardiovascular disease (CVD) (myocardial infarction, angina pectoris, stroke), type 2 diabetes and hypertension were performed at baseline and at follow-up in the year 2000. In addition, salivary cortisol levels were measured repeatedly over the day. Serum testosterone concentrations were also determined. Using the baseline data, an algorithm was constructed, which classified the secretion pattern of cortisol and testosterone from each individual as being normal or abnormal., Results: By the end of follow-up, men with an abnormal hormone secretion pattern (n = 73) had elevated mean arterial pressure (P = 0.003), fasting insulin (P = 0.009) and insulin : glucose ratio (P = 0.005) compared with men with a normal secretion pattern (n = 68). Body mass index, waist circumference, and waist : hip ratio were significantly elevated in both groups. However, the 5-year incidence of CVD, type 2 diabetes, and hypertension were significantly higher (P < 0.001) in men with an abnormal neuroendocrine secretory pattern compared to men with a normal pattern., Conclusions: These data suggest that an abnormal neuroendocrine secretory pattern is prospectively associated with an increased incidence of cardiovascular-related events and type 2 diabetes.

Background: Reverse redistribution and rapid washout of 99mTc-sestamibi are observed in patients with acute myocardial infarction and may indicate viable myocardium. However, the clinical significance of this phenomenon has not been rigorously examined in other cardiac diseases. Thus, we investigated whether reverse redistribution and washout of 99mTc-sestamibi could be used in the diagnosis and follow-up of patients with coronary spastic angina., Methods: Thirty patients diagnosed as coronary spastic angina were examined. During coronary arteriography, spasm was induced by provocation test with ergonovine, and only total or subtotal occlusion was considered positive. Myocardial perfusion tomography was obtained 45 min (early) and 3 hr (delayed) after 99mTc-sestamibi injection. Segmental defect score was visually graded from 0 (normal) to 4 (defect), and a total defect score was determined as the sum of defect scores for all segments. Washout rate of 99mTc-sestamibi from the myocardium was calculated for each segment. After medical treatment with calcium antagonists and nitrates for 3 months, 99mTc-sestamibi imaging was repeated., Results: Out of 30 patients, on the early images 17 (57%) patients demonstrated decreased 99mTc-sestamibi uptake in spastic segments; on the other hand, 24 (80%) patients did decreased 99mTc-sestamibi uptake in spastic segments on delayed images. Total defect scores in delayed images were higher than those in early images (6.9 +/- 0.3 vs. 3.6 +/- 0.4, p < 0.01). Reverse redistribution of 99mTc-sestamibi was observed in 17 out of 30 patients (57%) with coronary spastic angina. Washout rate of 99mTc-sestamibi from spastic segments was higher than that from non-spastic segments (16 +/- 2% vs. 11 +/- 5%, p < 0.01). After medical treatment, washout rate from spastic segments was decreased to 10 +/- 4 (p < 0.01), and left ventricular ejection fraction was increased from 63 +/- 8% to 73 +/- 4% (p < 0.01)., Conclusion: Rapid washout of 99mTc-sestamibi was observed in patients with coronary spastic angina and might indicate that the ability of myocyte to retain the tracer was impaired due to repetitive brief ischemia by coronary spasm. The early and delayed 99mTc-sestamibi imaging provides useful information for the diagnosis and responses to the treatment in patients with coronary spastic angina.

Recently, off-pump coronary artery bypass grafting (off-pump CABG: OPCAB) has been considered a safe alternative to conventional CABG (CCAB) for myocardial revascularization, because OPCAB improves operative mortality and morbidity from the view of reduction of multi-organ complications, duration of hospital stay, risks of blood transfusion and operative costs. This study was performed to estimate the benefit of OPCAB by examining the change of myocardial oxygen metabolism during OPCAB. Twenty five patients who had undergone OPCAB including the internal thoracic artery (LITA) on the segment 8 of the left anterior descending coronary artery (LAD) were studied in this series, and divided in 2 groups [17 angina pectoris (AP) cases, 8 old myocardial infarction (OMI) cases]. With 3-wave length near infrared spectroscopy (TOS-96: TOSTEC, Tokyo, Japan), the tissue hemoglobin (Hb) volume in the myocardium [Hb index (HbI) = 10 x calibrated absorption at 801 nm/clinical absorption intensity at 801 nm] and the myocardial tissue oxygen saturation (rSo2) on the surface of the left ventricle surrounded by LAD and the 2nd diagonal branch were measured at 5 minutes before and after OPCAB to LAD, and myocardial oxygen metabolism (OM) was calculated [OM = (20-1.34 x systemic Hb x rSo2/100) x HbI]. During OPCAB, several hemodynamic data, systemic Hb and arterial gas findings were not changed. In both groups, the HbI and the OM were significantly increased [HbI: AP group; 1.04 +/- 0.23 to 1.57 +/- 0.41 (p < 0.0001), OMI group; 0.99 +/- 0.28 to 1.55 +/- 0.39 (p = 0.0051), OM: AP group; 11.6 +/- 3.1 to 17.5 +/- 6.0 (p = 0.0010), OMI group; 10.6 +/- 2.3 to 16.1 +/- 2.8 (p = 0.0007)]. The rSo2 was not changed and remained within normal limit during OPCAB. These findings suggested that the regional myocardial oxygen metabolism would be improved immediately just after OPCAB and this finding might be one of the reasons why OPCAB shows the good mortality and morbidity compared with CCAB.

Objective: Studies on the effects of ischemic preconditioning in the human heart have yielded conflicting results and therefore remain controversial. This study investigated whether ischemic preconditioning was able to protect against myocardial tissue damage in patients undergoing coronary artery surgery with cardiopulmonary bypass and on the beating heart., Methods: A total of 120 patients were studied and divided into 3 groups: group I: cardiopulmonary bypass with intermittent crossclamp fibrillation; group II: cardiopulmonary bypass with cardioplegic arrest using cold blood cardioplegia; group III: surgery on the beating heart. In each group (n = 40), patients were randomly subdivided (n = 20/subgroup) into control and preconditioning groups (1 cycle of 5 minutes of ischemia/5 minutes reperfusion before intervention). Ischemic preconditioning was induced by clamping the ascending aorta in groups I and II or by clamping the coronary artery in group III. Serial venous blood levels of troponin T were analyzed before surgery and at 1, 4, 8, 24, and 48 hours after termination of ischemia. In addition, in vitro studies using right atrial specimens obtained before the institution of cardiopulmonary bypass, and then again 10 minutes after initiation of bypass, were performed. The specimens were equilibrated for 30 minutes before being allocated to 1 of the following 2 groups (n = 6 per group): (1) ischemia alone (90 minutes of ischemia followed by 120 minutes of reoxygenation) or (2) preconditioning with 5 minutes of ischemia and 5 minutes of reoxygenation before the long ischemic insult. Creatine kinase leakage (U/g wet weight) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction (mmol/l per gram wet weight), an index of cell viability, were assessed at the end of the experiment., Results: There were no perioperative myocardial infarctions or deaths in any of the groups studied. The total release of troponin T was similar in groups I and II (patients undergoing surgery with cardiopulmonary bypass) and in the release profile; they were unaffected by ischemic preconditioning. In contrast, the total troponin T release for the first 48 hours was significantly reduced by ischemic preconditioning in group III (patients undergoing surgery without cardiopulmonary bypass) from 3.1 +/- 0.1 to 2.1 +/- 0.2 ng. h. mL. Furthermore, the release profile that peaked at 8 hours in the control group shifted to the left at 1 hour. In the in vitro studies, the atrial muscles obtained before cardiopulmonary bypass were protected by ischemic preconditioning (creatine kinase = 2.6 +/- 0.2 and 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide reduction = 152 +/- 24 vs creatine kinase = 5.4 +/- 0.6 and 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide reduction = 87 +/- 16 in controls; P <.05); however, the muscles obtained 10 minutes after initiation of cardiopulmonary bypass were already protected (creatine kinase = 0.8 +/- 0.1 and 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide reduction = 316 +/- 38), and ischemic preconditioning did not result in further improvements., Conclusions: Ischemic preconditioning is protective in patients undergoing coronary artery surgery on the beating heart without the use of cardiopulmonary bypass, but it offers no additional benefit when associated with bypass regardless of the mode of cardioprotection used, because cardiopulmonary bypass per se induces preconditioning.

A study concerning vitamins A, C, E content in the blood of 22 patients with stable exercise-induced angina and in those patients (n = 28) with postinfarction cardiosclerosis without circulation failure was carried out. In patients with stable exertional angina, the blood plasma content of vitamin C has been shown to be on the increase, those patients with postinfarction cardiosclerosis revealed a rise in vitamin A in erythrocytes and that in vitamin C in blood plasma. After successful antianginal therapy the content of vitamin C in the blood plasma and erythrocytes has gotten normalized, that of vitamin A in red cells has also returned to normal.

A different rate and timing of subacute stent thrombosis after percutaneous coronary intervention was reported with various peri-interventional antithrombotic regimens. Next to platelet activation, coagulation triggered by tissue factor (TF) may play a key role in this process. Thirty-one consecutive patients with stable and unstable angina undergoing coronary stenting were randomly assigned to adjunct oral anticoagulation/anti-platelet therapy (coumadin, dipyridamole, aspirin and heparin; n = 16) or adjunct anti-platelet therapy with thienopyridin (ticlopidine, aspirin and heparin; n = 15). Antigen levels of plasma TF, total tissue factor pathway inhibitor (TFPI) and TFPI/ activated factor X (TFPI/FXa) complex were determined before and for up to 6 days after intervention by immunoassay. At baseline, significantly higher levels of plasma TF and TFPI/FXa were found in patients with unstable angina [TF, 161 pg/ml (126-191 pg/ml); TFPI/FXa, 7.8 ng/ml (6.1-9.6 ng/ml)] compared with stable angina [TF, 62 pg/ml (46-82 pg/ml), P < 0.0001; TFPI/FXa, 4.5 ng/ml (3-7.6 ng/ml), P= 0.003]. One hour after intervention, an increase of plasma TF and TFPI/FXa was seen in both treatment groups. In unstable angina patients, plasma levels of TF, TFPI and TFPI/FXa were more efficiently reduced by adjunct ticlopidine therapy compared with adjunct coumadin/dipyridamole. These data suggest reduced release of circulating TF by combined anti-platelet therapy with ticlopidine and aspirin after coronary artery stenting, which may-contribute to the lower incidence of subacute stent thrombosis previously observed.

Background: Increased oxidative stress has been implicated in the pathogenesis of coronary vasospasm. Thioredoxin (TRX) is a redox-active protein that is known to be induced by oxidative stress., Hypothesis: The serum TRX level may be high in patients with coronary vasospasm., Methods: The serum TRX level was determined using an enzyme-linked immunosorbent assay in 21 patients with the active stage of coronary spastic angina (CSA), in 18 patients with the inactive stage of CSA (iCSA), in 24 control subjects without coronary artery disease (Control), and in 20 patients with stable effort angina (SEA)., Results: Serum TRX levels (mean +/- standard deviation ng/ml) were significantly higher in CSA (64 +/- 44) than in iCSA (28 +/- 26), in Control (34 +/- 15), and in SEA (36 +/- 16). In contrast, serum alpha-tocopherol levels (mg/g lipids) were significantly lower in CSA (2.8 +/- 0.7) than in Control (4.0 +/- 1.2) and in SEA (3.2 +/- 0.4). Current smoking was significantly more prevalent in CSA (76%) than in any of the other groups. No significant correlation was found between the serum level of TRX and alpha-tocopherol in the study subjects. In nine patients with CSA, the serum TRX level decreased (93 +/- 41 --> 41 +/- 35 ng/ml) and the alpha-tocopherol level increased (2.7 +/- 0.6 --> 3.2 +/- 0.7 mg/g lipids) significantly under medication with calcium entry blockers after an at least 3-month angina-free period., Conclusions: Patients with coronary spastic angina had a higher serum TRX level associated with a lower serum level of antioxidant vitamin E, with redox equilibrium appearing to be related to the disease activity of coronary vasospasm in these patients. Oxidative stress may be related to the genesis of coronary vasospasm.

There is little information on the processes affecting selective tissue ACE inhibition and the implications in human subjects. We compared intravenously administered ACE inhibitors, perindoprilat and enalaprilat, for myocardial drug uptake and effects on angiotensin and bradykinin peptides versus hemodynamic effects in 25 patients with stable angina and well-preserved left ventricular systolic function. Myocardial uptake was rapid and more efficient for perindoprilat than for enalaprilat (peak content at 26+/-3 and 30+/-4 seconds, 0.58+/-0.12% and 0.27+/-0.07% of the administered dose for perindoprilat and enalaprilat, respectively, P=0.04 for difference). Both drugs caused a decrease in angiotensin (Ang) II level, an increase in Ang I level, and reduction in Ang II/Ang I ratio in arterial and coronary sinus blood. Bradykinin (BK)-(1-9) and BK-(1-8) levels increased in arterial blood and BK-(1-8) levels increased in coronary sinus blood after drug administration. Perindoprilat and enalaprilat caused a small decrease in mean arterial pressure (-3+/-1%, P<0.05; and -4+/-1%, P<0.01, respectively) and LV+dP/dt (-5.8+/-1.7%, P<0.01 and -4.2+/-2.8%, P<0.05, respectively), whereas systemic vascular resistance index was unchanged. Despite relatively cardioselective uptake of perindoprilat, both drugs had similar effects on the cardiac metabolism of angiotensin and bradykinin and on cardiac function. Under resting conditions, both drugs exerted small negative inotropic effects.

We investigated whether positive immunohistochemical staining of C-reactive protein (CRP) in initial culprit lesions is related to coronary plaque instability and whether it could affect the outcome of directional coronary atherectomy (DCA). The plasma level of CRP is a reliable marker of the risk of coronary events and restenosis after percutaneous coronary intervention. However, the influence of tissue CRP in atheromatous plaque on plaque vulnerability and restenosis remains unknown. Samples of DCA obtained from 12 patients with stable angina pectoris and 15 patients with unstable angina pectoris were immunohistochemically stained with a monoclonal antibody against CRP. We performed follow-up coronary angiography on 22 of 27 patients to evaluate the presence of restenosis after DCA. Immunoreactivity to CRP was localized to macrophages, smooth muscle cells, and necrotic areas. The ratio of CRP positive cells to total cells was significantly higher in DCA samples from patients with unstable (17.9 +/- 2.0%) than with stable angina (11.0 +/- 2.5%) (p <0.05). Follow-up coronary angiography showed that 12 of 22 patients developed restenosis after DCA. The ratio was also significantly higher in DCA specimens from patients with restenosis (19.3 +/- 2.8%) compared with those without restenosis (11.0 +/- 2.0%) (p <0.05). In addition, the ratio significantly correlated with late luminal loss (r = 0.428, p <0.05) and loss index (r = 0.636, p = 0.0011) after DCA. Immunoreactivity to CRP in coronary atheromatous plaque increases in culprit lesions of unstable angina, and it affects restenosis after DCA. These findings suggest that CRP in atheromatous plaque plays an important role in the pathogenesis of unstable angina and restenosis after coronary intervention.

The present study compared classical ADP-induced platelet aggregation vs. PFA-100 closure times using collagen/ADP membrane cartridges to monitor the degree of platelet-inhibiting effect of three drug regimens: ticlopidin, abciximab/ticlopidin and loading dose clopidogrel, each on top of aspirin (acetylsalicylic acid, ASA) during and after elective stent placement (intervention) in a total of 31 patients with acute coronary syndrome. Ticlopidin was started directly after stent implantation, abciximab was started before coronary intervention and given intravenously for 12 h, and a clopidogrel loading dose was given before intervention. The 10 patients treated with ticlopidin (500 mg daily) showed no significant prolongation of PFA closure times and a slight increase of ADP-induced platelet aggregation shortly after intervention. In 11 patients treated with abciximab/ticlopidin, the PFA closure times were significantly prolonged, and ADP-induced platelet aggregation was reduced by more than 80% during the 12-h abciximab infusion after intervention. The 10 patients pretreated with loading dose clopidogrel (450 mg followed by 75 mg daily) showed an intermediate but significant prolongation of PFA closure times and reduction of ADP-induced platelet aggregation at levels between the ticlopidin/aspirin- and the abciximab/ticlopidin/aspirin-treated groups. At 20 h after intervention, a similar degree of PFA closure time prolongation and inhibition of ADP-induced aggregation was observed in the abciximab/ticlopidin/aspirin- and the clopidogrel/aspirin-treated patient groups. Both measurement of PFA-100 closure times and inhibition of ADP-induced platelet aggregation showed a similar degree of platelet inhibition, but had rather broad SD ranges, which limit their precision for the follow-up of individual patients. In conclusion, abciximab on top of ticlopidin/aspirin showed a stronger antiplatelet effect for only less than 20 h, as compared to loading dose clopidogrel/aspirin in acute coronary syndrome patients undergoing stent implantation. Whether such a short-term superiority of abciximab, as compared to loading dose clopidogrel, translates into an overall clinical benefit of thombotic and bleeding complications remains to be established in a randomized clinical trial.