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Aim: To compare efficacy and safety of cardioselective beta-adrenoblockers nebivolol and metoprolol in patients with hypertension and ischemic heart disease (IHD) combined with type 2 diabetes., Material and Methods: Patients with IHD, class II-III angina and moderately severe compensated or subcompensated type II diabetes (n=35, 29 with grade 1-2 hypertension according to WHO 1999 classification) were divided into 2 groups with similar clinical and laboratory characteristics. Patients of group 1 received metoprolol (50-100 mg/day), of group 2--nebivolol (5-7.5 mg/day) for 8 weeks. Data of physical investigation, exercise tests, 24-hour blood pressure and heart rate monitoring, analysis of lipid spectrum and glycemic profile were used for assessment of treatment efficacy., Results: Decrease of number of anginal attacks and nitroglycerine requirement was more pronounced in nebivolol treated patients. The use of both drugs was associated with lowering of blood pressure and heart rate. There were no unfavorable changes of parameters of carbohydrate and lipid metabolism. Pronounced (by 19.2%) lowering of triglycerides was observed in nebivolol treated patients. Both drugs were well tolerated., Conclusion: Nebivolol and metoprolol are effective and safe antianginal agents in patients with IHD and hypertension combined with type 2 diabetes. However in doses used nebivolol produced more favorable metabolic and hemodynamic effects.

Background: Partial fatty acid oxidation inhibitors have raised great interest since they are expected to counteract a dysregulated gene expression of hypertrophied cardiocytes. Some of these compounds have been developed for treating non-insulin-dependent diabetes mellitus and stable angina pectoris. A shift from fatty acid oxidation to glucose oxidation leads to a reduced gluconeogenesis and improved economy of cardiac work. An increased glucose oxidation can be achieved with the following enzyme inhibitors: etomoxir, oxfenicine, methyl palmoxirate, S-15176, metoprolol, amiodarone, perhexiline (carnitine palmitoyltransferase-1); aminocarnitine, perhexiline (carnitine palmitoyltransferase-2); hydrazonopropionic acid (carnitine-acylcarnitine translocase); MET-88 (gamma-butyrobetaine hydroxylase); 4-bromocrotonic acid, trimetazidine, possibly ranolazine (thiolases); hypoglycin (butyryl-CoA dehydrogenase); dichloroacetate (pyruvate dehydrogenase kinase). CLINICAL TRIALS with trimetazidine and ranolazine showed that this shift in substrate oxidation has an antianginal action. Etomoxir and MET-88 improved the function of overloaded hearts by increasing the density of the Ca(2+) pump of sarcoplasmic reticulum (SERCA2). The promoters of SERCA2 and alpha-myosin heavy-chain exhibit sequences which are expected to respond to transcription factors responsive to glucose metabolites and/or peroxisome proliferator-responsive element (PPAR) agonists. Further progress in elucidating novel compounds which upregulate SERCA2 expression is closely linked to the characterization of regulatory sequences of the SERCA2 promoter.

Unlabelled: Although various noninvasive methods have been used to detect vasospasm, none of them are sensitive enough for patients with sporadic attacks. Because abnormal fatty acid metabolism and cardiac adrenergic neuronal damage are observed in ischemic myocardium, (123)I-15-(p-iodophenyl)-3-R,S-methyl pentadecanoic acid (BMIPP) and (123)I-metaiodobenzylguanidine (MIBG) have recently been proposed as useful tracers for detection of myocardial damage. This study investigated the relationships among the coronary vasospastic regions, abnormal left ventricular regional wall motion, fatty acid metabolism, and sympathetic nerve functions and their changes during treatment in patients with vasospastic angina., Methods: We evaluated 50 patients with vasospastic angina (25 with clinically documented vasospasm [group A] and 25 with vasospasm induced by ergonovine provocation [group B]) and 25 control subjects who had chest pain but had normal coronary arteries without ergonovine provocation of spasm. Sixteen patients in group A were reevaluated 6 mo after medical treatment. The territorial regions of the vasospasm-induced coronary artery, wall motion determined by left ventriculography, and BMIPP and MIBG uptake were compared., Results: Regions exhibiting a positive reaction to the ergonovine provocation were observed in the right coronary artery in 41 patients, the left anterior descending artery in 33, and the left circumflex artery in 21. Provocation occurred in multiple vessels in 29 patients (58%). Reduction of wall motion was observed in 19 patients (38%). Sensitivity and specificity for the identification of vasospastic angina were 86% (43/50 patients) and 88% (22/25 control subjects), respectively, for BMIPP scintigraphy and 100% (50/50 patients) and 56% (14/25 control subjects), respectively, for MIBG scintigraphy. In the region exhibiting a reduction in left ventricular wall motion, BMIPP or MIBG uptake was decreased. The sensitivity and specificity of determination of vasospasm-induced coronary arteries were 71% (67/95 arteries) and 95% (71/75 arteries), respectively, for BMIPP scintigraphy and 96% (91/95 arteries) and 55% (41/75 arteries), respectively, for MIBG scintigraphy. After 6 mo, during treatment, vasospasm was reinduced by ergonovine provocation in 6 patients (group I) and was not reinduced in 10 patients (group II). Improvements of decreased BMIPP and MIBG uptake were lower in group I (25% +/- 4% and 16% +/- 4%, respectively) than in group II (69% +/- 4% and 50% +/- 3%, respectively; both P < 0.01). The regions in which vasospasm was reinduced exhibited decreased BMIPP and MIBG uptake., Conclusion: Abnormal fatty acid metabolism and cardiac sympathetic denervation were observed more frequently than were wall motion abnormalities in the vasospastic region in patients with vasospastic angina. BMIPP and MIBG scintigraphy are highly accurate and noninvasive techniques for determining the presence and location of vasospasm.

Background: Acute administration of mitochondrial adenosine triphosphate-dependent potassium channel openers preconditions the heart, but whether their long-term administration induces a permanent state of protection is unknown. These studies investigate the effect of long-term treatment with the mitochondrial adenosine triphosphate-dependent potassium channel opener nicorandil on the response of the human myocardium to ischemia and preconditioning., Methods: Right atrial tissue obtained from patients regularly treated with or without nicorandil (mean of 20 mg/d for 18.6 +/- 2.5 months) and undergoing cardiac surgery was sliced and equilibrated for 30 minutes and then subjected to 90 minutes of simulated ischemia, followed by 120 minutes of reoxygenation. In study 1 the following groups were studied to investigate the effect of nicorandil on the susceptibility of the myocardium to ischemia and on the protective effect of ischemic and pharmacologic preconditioning: (1) aerobic control; (2) simulated ischemia and reoxygenation alone; (3) ischemic preconditioning with 5 minutes of simulated ischemia and 5 minutes of reoxygenation; and (4) phenylephrine (0.1 micromol/L) for 5 minutes and 5 minutes' washout before simulated ischemia and reoxygenation. In study 2 the following groups were studied to investigate the effect of nicorandil on the responsiveness of mitochondrial adenosine triphosphate-dependent potassium channels: (1) aerobic control; (2) simulated ischemia and reoxygenation; (3) ischemic preconditioning; (4) diazoxide (100 micromol/L) for 10 minutes before simulated ischemia and reoxygenation, and (5) 5-hydroxydecanoate (1 mmol/L) for 10 minutes before simulated ischemia and reoxygenation. In study 3 the following groups were included to investigate the effect of the long-term administration of nicorandil on the kinase pathway involved in preconditioning: (1) aerobic control; (2) simulated ischemia and reoxygenation alone; (3) ischemic preconditioning; (4) phorbol 12-myristate 13-acetate (1 micromol/L), a protein kinase C activator, for 10 minutes before simulated ischemia and reoxygenation; and (5) anisomycin (1 nmol/L), a p38 mitogen-activated protein kinase activator, for 10 minutes before simulated ischemia and reoxygenation. At the end of each protocol, the leakage of creatine kinase (in units per gram wet weight) and the reduction of 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide into insoluble formazan dye (in millimoles per gram wet weight) were measured., Results: In study 1 the leakage of creatine kinase and the reduction of 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide induced by simulated ischemia and reoxygenation were similar in the groups with or without nicorandil (creatine kinase, 3.4 +/- 0.1 and 3.5 +/- 0.2, respectively; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, 74.6 +/- 3.9 and 67.9 +/- 7.3, respectively; P >.2 in each instance). Ischemic preconditioning and pharmacologic preconditioning protected the myocardium from patients without nicorandil (creatine kinase, 2.3 +/- 0.1 and 2.4 +/- 0.1, respectively; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, 131.4 +/- 4.9 and 128.4 +/- 5.6, respectively; P < 0.001 vs simulated ischemia and reoxygenation alone in each instance) but not the myocardium from patients receiving nicorandil (creatine kinase, 3.3 +/- 0.1 and 3.3 +/- 0.2, respectively; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, 89.7 +/- 6.5 and 86.4 +/- 5.2, respectively; P >.2 vs simulated ischemia and reoxygenation alone in each instance). In study 2 the administration of diazoxide had identical protection to that of ischemic preconditioning in the myocardium of patients not receiving nicorandil (creatine kinase, 2.1 +/- 0.2 and 2.3 +/- 0.1, respectively; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, 141.4 +/- 7.4 and 131.4 +/- 4.9, respectively; P < 0.001 vs simulated ischemia and reoxygenation alone in each instance) but failed to precondition the myocardium from patients treated with nicorandil (creatine kinase, 3.3 +/- 0.2 and 3.4 +/- 0.1, respectively; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, 90.1 +/- 7.2 and 86.4 +/- 5.2, respectively; P > 0.2 vs simulated ischemia and reoxygenation alone in each instance). In study 3 phorbol 12-myristate 13-acetate or anisomycin given for 10 minutes before simulated ischemia and reoxygenation afforded similar protection to that of ischemic preconditioning in the myocardium from patients with (creatine kinase, 1.5 +/- 0.3 and 1.4 +/- 0.1, respectively; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, 147.0 +/- 4.9 and 160.0 +/- 16.1, respectively; P < 0.001 vs simulated ischemia and reoxygenation alone in each instance) and without nicorandil (creatine kinase, 1.7 +/- 0.4 and 1.4 +/- 0.2, respectively; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, 160.3 +/- 13.6 and 158.3 +/- 11.8, respectively; P <.001 vs simulated ischemia and reoxygenation alone in each instance)., Conclusion: The myocardium of patients chronically treated with nicorandil cannot be preconditioned either by ischemia or pharmacologically, and this is because of unresponsive mitochondrial adenosine triphosphate-dependent potassium channels. However, protection can be obtained by protein kinase C and p38 mitogen-activated protein kinase activation, which are downstream of mitochondrial adenosine triphosphate-dependent potassium channels in the signaling transduction pathway of preconditioning.

Nitric oxide (NO) plays an important role in the control of vascular tone as well as structure. This study examined the possibility that the extent of restenosis 3 months after percutaneous transluminal coronary angioplasty (PTCA) might be correlated with the magnitude of NO production at the PTCA sites on the day following PTCA. In 23 consecutive patients who underwent PTCA, we examined the coronary artery diameter response to intracoronary administration of L-arginine (1 microg/kg) and isosorbide dinitrate (ISDN, 40 microg/kg) at the sites of PTCA (n = 25) and at untreated sites distal to the PTCA sites approximately 18 h after PTCA. The coronary artery diameter at the PTCA site was determined 3 months after PTCA in all patients. Normalized vasodilator responses to L-arginine (responses to L-arginine/those to ISDN) were greater at the PTCA sites than at the untreated sites (P = 0.05), whereas vasodilator responses to ISDN did not differ between the PTCA and untreated sites. These results suggest a greater production of NO at the PTCA sites despite presumable loss of the endothelium due to the PTCA. Furthermore, the magnitude of normalized vasodilator responses to L-arginine examined at 18 h after PTCA correlated with the coronary artery diameter 3 months after PTCA (r = 0.592, P = 0.002). These results suggest that augmented NO production after PTCA may protect against the development of coronary restenosis. Treatment that enhances local NO production may be clinically useful in preventing restenosis after PTCA.

Background: Among patients with suspected acute coronary syndromes, cardiac troponin T levels have prognostic value. However, there is concern that renal dysfunction may impair the prognostic value, because cardiac troponin T may be cleared by the kidney., Methods: We analyzed the outcomes in 7033 patients enrolled in the Global Use of Strategies to Open Occluded Coronary Arteries IV trial who had complete base-line data on troponin T levels and creatinine clearance rates. The troponin T level was considered abnormal if it was 0.1 ng per milliliter or higher, and creatinine clearance was assessed in quartiles. The primary end point was a composite of death or myocardial infarction within 30 days., Results: Death or myocardial infarction occurred in 581 patients. Among patients with a creatinine clearance above the 25th percentile value of 58.4 ml per minute, an abnormally elevated troponin T level was predictive of an increased risk of myocardial infarction or death (7 percent vs. 5 percent; adjusted odds ratio, 1.7; 95 percent confidence interval, 1.3 to 2.2; P<0.001). Among patients with a creatinine clearance in the lowest quartile, an elevated troponin T level was similarly predictive of increased risk (20 percent vs. 9 percent; adjusted odds ratio, 2.5; 95 percent confidence interval, 1.8 to 3.3; P<0.001). When the creatinine clearance rate was considered as a continuous variable and age, sex, ST-segment depression, heart failure, previous revascularization, diabetes mellitus, and other confounders had been accounted for, elevation of the troponin T level was independently predictive of risk across the entire spectrum of renal function., Conclusions: Cardiac troponin T levels predict short-term prognosis in patients with acute coronary syndromes regardless of their level of creatinine clearance.

Partial fatty acid oxidation inhibition is effective therapy for the treatment of chronic stable angina and is particularly useful in patients with persistent angina despite optimal traditional therapy. The heart derives most of its energy from the oxidation of fatty acids. Fatty acid oxidation strongly inhibits pyruvate oxidation in the mitochondria and the uptake and oxidation of glucose. The primary effect of demand-induced ischaemia is impaired aerobic formation of ATP in the mitochondria, resulting in activation of non-oxidative glycolysis and lactate production, despite a relatively high residual myocardial oxygen consumption and continued reliance on fatty acid oxidation. Traditional drugs for chronic stable angina act by reducing the use of ATP through suppression of heart rate and blood pressure or by increasing aerobic formation of ATP by increasing coronary blood flow. Partial inhibition of fatty acid oxidation increases glucose and pyruvate oxidation and decreases lactate production, resulting in higher pH and improved contractile function during ischaemia. These agents do not affect heart rate, coronary blood flow or arterial blood pressure. Clinical trials with ranolazine or trimetazidine, either alone or in combination with a Ca2+ channel antagonist or a beta-adrenergic receptor antagonist, have demonstrated reduced symptoms of exercise-induced angina.

Background: C-reactive protein (CRP) level is a sensitive marker of inflammation and a probable predictor of cardiovascular risk. The aim of this study was to assess the relationship between the presence and the extent of coronary atherosclerosis and CRP level in patients referred for coronary angiography for stable angina pectoris or a pathological exercise test., Patients and Methods: A group of 200 patients were prospectively analyzed for the relationship between the presence and extent of coronary atherosclerosis and high-sensitivity CRP. Patients with stable angina pectoris or a pathological exercise test were included., Results: For the whole group the CRP geometric mean was 2.92 mg/l and the median 3.0 mg/l. There was no difference between groups of patients with different extents of coronary lesions (P = 0.320, one-way analysis of variance). In patients without significant coronary disease the CRP geometric mean was 3.1 (2.28-4.21) mg/l with a variation coefficient of 118.4%; in patients with coronary artery disease the geometric mean was 2.83 (2.34-3.43) mg/l with a variation coefficient of 104.0%. The difference in CRP between both groups was not significant (P = 0.601). There was also no significant difference in CRP levels between groups of patients with and without a history of myocardial infarction (2.65 (2.08-3.36) mg/l and 3.18 (2.54-3.98) mg/l, P = 0.266) respectively. There was no correlation between the classification of angina pectoris and the logarithm of CRP level (P = 0.331). This relationship was not confirmed even in the group of patients with significant coronary artery disease (P = 0.693)., Conclusions: CRP level is not related to the extent or the presence of coronary atherosclerosis assessed by coronary angiography, history of myocardial infarction or class of stable angina pectoris in patients referred for coronary angiography for stable angina pectoris or a pathological exercise test.

Background: This study presents a systematic analysis of atherothrombotic lesions taken by percutaneous atherectomy and post mortem examination from coronary arteries, in order to identify: a) the topographic occurrence of fibrinogen and smooth muscle cells (SMCs), b) their independent expression in stable and unstable plaques, and c) their co-expression, which can provide a better understanding of the involvement of fibrinogen and SMCs in the development and progression of atherosclerotic plaques., Material/methods: 120 specimens from atherosclerotic lesions were collected, using directional coronary atherectomy; 40 additional specimens were collected from postmortem examinations. All specimens were stained by immunohistochemical methods with monoclonal and polyclonal antibodies (DAKO) for fibrinogen and SMCs., Results: Fibrinogen appeared to be a component of all stable and unstable coronary atherosclerotic plaques, with a significant predominance in unstable angina. No significant difference was observed between SMC-stained areas in stable and unstable angina; however, a significant difference exists in co-expression of SMCs and fibrinogen between unstable and stable angina. Interestingly, the total number of SMCs at the first stages of formation of unstable plaques is less than in stable plaques. However, in a number of advanced coronary atherosclerotic plaques associated with unstable angina, we observed an increasingly progressive inflammatory cell activity, in which SMC areas were significantly increased., Conclusions: This distribution of fibrinogen and SMCs suggests the possibility of a link between SMC migration and proliferation, intensifying the increased fibrinogen concentration in atherosclerotic plaques.

Ranolazine is a novel drug that has shown promise in the treatment of cardiovascular disease. Ranolazine exerts its effect by shifting myocardial energy metabolism away from free fatty acids and toward glucose as the substrate for production of adenosine triphosphate. Preclinical data have confirmed that ranolazine reduces myocardial ischaemic injury in various animal models. Researchers are continuing to gather clinical data but findings to date support the conclusion that ranolazine has anti-ischaemic effects without inducing the typical reduction in blood pressure and heart rate associated with the use of traditional anti-ischaemic agents. Given the absence of haemodynamic effects associated with ranolazine, it has great promise as a drug that could be added to existing therapy without concern for hypotensive or bradycardic side effects. Ranolazine has been shown to improve exercise-induced myocardial ischaemia and to lessen the severity of angina in the setting of chronic ischaemic heart disease. Early preclinical observations also suggest positive effects of ranolazine in the management of congestive heart failure; however, trials in this area are ongoing. Several recently completed Phase III clinical studies in patients with chronic ischaemic heart disease have confirmed the findings of smaller trials and should satisfy regulatory concerns necessary to place ranolazine on the commercial market in the US. The maker of ranolazine, CV Therapeutics (Palo Alto, California), will file a New Drug Application (NDA) with the US FDA for the approval of ranolazine as an anti-anginal in the near future.

A study of 48 patients with angina pectoris carried out, in which the structural lipids of the hair were analyzed and correlated with the manifestations of angina and the potential incidence of dyslipidemia. It was noted that the excesses of hair lipids associated with deficiencies of some unsaturated fatty acids raised the frequency of angina attacks in the group studied by 2.7 times. The normalization of the lipid levels diminished the levels of angina. Data were obtained on the influence over a long time (weeks, months) of the hypolipidemic treatment. The analysis of the hair has been shown to be also useful in detecting latent dyslipidemia associated with angina pectoris. Also, through the analysis of hair, large scale epidemiologic studies can be carried out on the association between dyslipidemia and angina pectoris.

Aims: To study the dose-ranging population pharmacokinetics of controlled release verapamil in healthy subjects and patients with angina or hypertension. To characterize the pharmacodynamics of controlled-release verapamil in patients with hypertension., Methods: Dose-ranging studies were conducted in healthy volunteers and patients with hypertension and angina. Subjects received doses of 120, 180, 360, or 540 mg racemic verapamil as an osmotic controlled-release formulation. A population pharmacokinetic model involving zero-order release of verapamil into the gastrointestinal tract with first-order absorption and elimination was used to describe the steady-state plasma concentration profile for R- and S-verapamil. A population sigmoid E(max) pharmacodynamic model was used to describe the effect of R- and S-verapamil on mean arterial blood pressure., Results: S-verapamil had an approximate 4-fold greater apparent clearance than R-verapamil in both healthy volunteers and patients. The apparent plasma clearance of R- and S-verapamil in healthy volunteers decreased over the dose range of 120-540 mg. A similar dose-dependent decrease in apparent plasma clearance was also noted in patients. None of the patient demographic variables examined (age, total body weight, lean body weight, body mass index, and height) explained the variability in verapamil pharmacokinetics. The pharmacodynamic model describing the relationship between verapamil plasma concentration and mean arterial blood pressure indicated that the S-verapamil had a 3.6-fold lower estimated EC(50) compared to R-verapamil., Conclusions: The results from this dose-ranging pharmacokinetic investigation in healthy volunteers and patients are consistent with previous reports in healthy subjects. S-verapamil is cleared more rapidly than R-verapamil and the estimated EC(50) for S-verapamil was 3.6-fold lower than for R-verapamil. Estimated EC(50) values for R- and S-verapamil decreased with increasing age and decreasing weight., (Copyright 2002 John Wiley & Sons, Ltd.)

Background: Although increased tissue factor expression is known in vulnerable plaques, there is no reported study to compare plaque fibrinolysis in stable and unstable plaques. This study investigates the extent of plasminogen activator inhibitor-1 (PAI-1) and apolipoprotein (a) [apo(a)] in the plaques of different types of coronary artery disease as well as the correlation between these molecules and infiltration of macrophages to plaques., Methods: Using immunohistochemical staining, we examined PAI-1 expression and apo(a) deposition in coronary atherosclerotic specimens obtained by directional coronary atherectomy from 19 patients with acute myocardial infarction (AMI), 12 with unstable angina pectoris (UAP), and 13 with stable angina pectoris (SAP). The percentages of the total areas of specimens stained with PAI-1 or apo(a) were estimated by an NIH image program. The proportion of macrophages as a percentage of all cells in plaques was calculated as the macrophage density., Results: We found significantly higher percentages of total areas of specimens stained with PAI-1 in AMI (25.5 +/- 8.6%, P < 0.001) and UAP (22.2 +/- 10.4%, P < 0.005) than in SAP (9.5 +/- 5.0%), as well as with apo(a) (AMI; 11.7 +/- 7.1%, P < 0.005, UAP; 11.1 +/- 5.5%, P < 0.01 versus SAP; 3.9 +/- 1.5%). Linear regression analysis of all the samples showed a correlation between PAI-1 or apo(a) and macrophage density (PAI-1: r = 0.75, P < 0.001 and apo(a): r = 0.56, P < 0.001)., Conclusions: Our results suggest a possible contribution of increased PAI-1 and apo(a) in plaques to the pathogenesis of acute coronary syndromes including impaired fibrinolysis.

This paper aims to demonstrate that there is currently sufficient evidence to suggest that endothelin-1 (ET-1) may play a role in angina and be associated with myocardial ischaemia. In order to demonstrate the potential role of ET-1 in angina, this paper examines three main factors: (i) that endothelin-1 can cause the pathophysiological states associated with myocardial ischaemia and angina; (ii) that ET-1 is over-expressed in humans and in animal models of myocardial ischaemia, which is associated with angina; and (iii) that modification of the ET-1 system is associated with an improvement in myocardial ischaemia and angina.

Purpose: We studied the effect of myocardial ischemia and diabetes mellitus (DM) on the myocardial fatty acid metabolism using 123I-BMIPP myocardial scintigraphy., Methods: We performed 123I-BMIPP myocardial scintigraphy in 50 patients with myocardial ischemia and without DM (AP), in 30 patients with myocardial ischemia and DM (AP + DM), 12 patients with DM and without myocardial ischemia (DM), and in 10 normal subjects (N). Myocardial uptake rate of 123I-BMIPP was obtained using the time activity curve. Myocardial washout rate of 123I-BMIPP was calculated using the polar images of early and delayed SPECT images., Results: Myocardial uptake rate of 123I-BMIPP (%) were AP: 4.9 +/- 0.6, AP + DM: 5.5 +/- 0.5, DM 5.7 +/- 0.5 and N: 5.0 +/- 0.4. 123I-BMIPP myocardial uptake rate was increased in AP + DM and DM. 123I-BMIPP myocardial washout rate (%) were AP: 30.2 +/- 4.3, AP + DM: 24.5 +/- 3.9, DM: 16.1 +/- 2.8 and N: 19.4 +/- 3.2. 123I-BMIPP myocardial washout rate was increased in AP and AP + DM. 123I-BMIPP myocardial washout rate was increased particularly in patients with multi-vessels disease. 123I-BMIPP myocardial washout rate was decreased in DM., Conclusion: The present study suggested that diabetes mellitus increased myocardial fatty acid uptake and decreased myocardial fatty acid washout, and that myocardial ischemia increased myocardial fatty acid washout.

Objectives: The study investigated the effects of physical activity on preinfarction angina, a clinical equivalent of ischemic preconditioning (PC), in adult and elderly patients with acute myocardial infarction (AMI)., Background: Preinfarction angina seems to confer protection against in-hospital mortality in adult but not in elderly patients. However, it has been experimentally demonstrated that exercise training restores the protective effect of PC in the aging heart., Methods: We retrospectively verified whether physical activity preserved the protective effect of preinfarction angina against in-hospital mortality in 557 elderly patients with AMI. Physical activity was quantified according to the Physical Activity Scale for the Elderly (PASE)., Results: In-hospital mortality was 22.2% in elderly patients with preinfarction angina and 27.2% in those without (p = 0.20). When the PASE score was stratified in quartiles (0 to 40, 41 to 56, 57 to 90, >90), a high score was strongly associated with reduced in-hospital mortality (30.8%, 32.2%, 17.2% and 15.3%, respectively, p < 0.001 for trend). Interestingly, a high level of physical activity reduced in-hospital mortality in elderly patients with preinfarction angina (35.7%, 35.4%, 12.3% and 4.23%, respectively, p < 0.001 for trend) but not in those without (23.0%, 27.2%, 26.0% and 35.0%, respectively, p = 0.35 for trend). Accordingly, the protective role of preinfarction angina on in-hospital mortality was present only in elderly patients showing a high level of physical activity (adjusted odds ratio, 0.09; 95% confidence interval, 0.01 to 0.57; p < 0.05)., Conclusions: Physical activity and not preinfarction angina protects against in-hospital mortality in elderly patients with myocardial infarction. Nevertheless, the protective effect of preinfarction angina is preserved in elderly patients with a high level of physical activity.

Angina, the prototypic vasoocclusive pain, is a radiating chest pain that occurs when heart muscle gets insufficient blood because of coronary artery disease. Other examples of vasoocclusive pain include the acute pain of heart attack and the intermittent pains that accompany sickle cell anemia and peripheral artery disease. All these conditions cause ischemia - insufficient oxygen delivery for local metabolic demand - and this releases lactic acid as cells switch to anaerobic metabolism. Recent discoveries demonstrate that sensory neurons innervating the heart are richly endowed with an ion channel that is opened by, and perfectly tuned for, the lactic acid released by muscle ischemia.

Objective: To study the relationship between ischemic preconditioning (IP) and lactate production and their impact on coronary artery bypass graft surgery patients., Design: Prospective, randomized, controlled study., Setting: University hospital., Participants: Eighty 3-vessel disease coronary artery bypass graft surgery patients with stable and unstable angina pectoris., Interventions: The IP patients were preconditioned with 2 periods of 2-minute ischemia followed by 3-minute reperfusion before aortic cross-clamping., Measurements and Main Results: The cardiac index (CI) after surgery was significantly higher in the IP group than in controls among stable patients (p = 0.013). IP was not effective in CI recovery in unstable patients. The baseline values of lactate production were 11.6%, 20.3%, -7.0%, and -2.9% in stable IP, stable control, unstable IP, and unstable control patients. Compared with baseline, lactate production increased significantly after the IP protocol (39.0% and 47.5% in the stable and unstable patients), and operation (47.5%, 31.7%, 35.4%, and 35.6% in stable IP, stable control, unstable IP, and unstable control patients) but not after 10 minutes of cardiopulmonary bypass (29.7% and 19.0% in the stable and unstable patients). There were no differences among the groups in lactate production after the operation. Lactate production after the IP protocol was negatively associated with CI recovery after surgery in the IP patients (p = 0.026)., Conclusion: The IP effects do not include modulation of lactate production. IP induces lactate production, but it seems not to be involved in the triggering process., (Copyright 2001 by W.B. Saunders Company.)

Objectives: The study examined possible clinical determinants of platelet resistance to nitric oxide (NO) donors in patients with stable angina pectoris (SAP) and acute coronary syndromes (ACS), relative to nonischemic patients and normal subjects., Background: We have shown previously that platelets from patients with SAP are resistant to the antiaggregating effects of nitroglycerin (NTG) and sodium nitroprusside (SNP)., Methods: Extent of adenosine diphosphate (1 micromol/liter)-induced platelet aggregation (impedance aggregometry in whole blood) and inhibition of aggregation by NTG (100 micromol/liter) and SNP (10 micromol/liter) were compared in normal subjects (n = 43), nonischemic patients (those with chest pain but no fixed coronary disease, (n = 35) and patients with SAP (n = 82) or ACS (n = 153). Association of NO resistance with coronary risk factors, coronary artery disease (CAD), intensity of angina and current medication was examined by univariate and multivariate analyses., Results: In patients with SAP and ACS as distinct from nonischemic patients and normal subjects, platelet aggregability was increased (both p < 0.01), and inhibition of aggregation by NTG and SNP was decreased (both p < 0.01). Multivariate analysis revealed that NO resistance occurred significantly more frequently with ACS than with SAP (odds ratio [OR] 2.3:1), and was less common among patients treated with perhexiline (OR 0.3:1) or statins (OR 0.45:1). Therapy with other antianginal drugs, extent of CAD, intensity of angina and coronary risk factors were not associated with variability in platelet responsiveness to NO donor., Conclusions: Patients with symptomatic ischemic heart disease, especially ACS, exhibit increased platelet aggregability and decreased platelet responsiveness to the antiaggregatory effects of NO donors. The extent of NO resistance in platelets is not correlated with coronary risk factors. Pharmacotherapy with perhexiline and/or statins may improve platelet responsiveness to NO.

Ischemic preconditioning (IPC, i.e. increase in the organ resistance to a prolonged ischemia which occurs after a brief ischemic challenge) seems to be one of the most powerful endogenous cardioprotective mechanisms known to date. Current data regarding molecular mechanisms of early (classic) IPC as well as the second window of protection are reviewed in the context of the concept of sequential three-staged development of protective effect. Based on original and published data, possible mechanisms of remote IPC are considered. The review comprises current ideas of existence of the IPC clinical correlates and its use in clinic.

Background: Oxidative stress is present in cardiovascular diseases (CVDs), and hyperhomocysteinemia, an independent risk factor for these diseases, may play a role by inducing production of oxygen free radicals., Methods: To evaluate the possible role of homocysteine (Hcy) in inducing oxidative stress in coronary artery disease (CAD), plasma Hcy was measured in 68 consecutive cardiovascular patients, and plasma malondialdehyde (MDA), both free and total (free + bound), was measured in 40 patients with CAD (18 with chronic stable angina and 22 with unstable angina). As controls, we tested 70 healthy volunteers. Hcy was measured by an immunoenzymatic method and MDA, an index of lipid peroxidation, by gas chromatography-mass spectrometry., Results: Plasma Hcy concentrations were significantly higher in cardiovascular patients than in controls (10.2 vs 8.9 micromol/L; P <0.0002), with no significant difference between values in the stable and unstable angina subgroups. Similarly, total MDA was significantly higher in the CAD group than in the controls (2.6 vs 1.3 micromol/L; P <0.00001), again with no significant difference between stable and unstable angina patients. By contrast, free MDA, which was significantly higher in the CAD patients than the controls (0.4 vs 0.2 micromol/L; P < 0.00001), was also significantly higher in the unstable than in the stable angina group (0.5 vs 0.3 micromol/L; P <0.03). However, no correlation was observed among Hcy and free and total MDA., Conclusions: Our findings show that a moderate increase of Hcy is associated with CVD but that Hcy at the detected values cannot be considered completely responsible for oxidative damage. That lipid peroxidation is involved in CAD is shown by our observation of significantly increased plasma free and total MDA concentrations compared with controls. Moreover, free MDA values discriminated between unstable and chronic stable angina, and could thus represent a new diagnostic tool.

Diabetic alterations of myocardial metabolism result mainly from malfunctions of acetyl-coenzyme A carboxylase, carnitine-palmitoyl-transferase-I and pyruvate-dehydrogenase inducing an overshoot of fatty acid oxidation that inhibits glucose oxidation. Gene expression of pyruvate-dehydrogenase and glucose transporters and depression of the third step of the mitochondrial respiratory chain also contribute to the diabetic alterations of myocardial metabolism. Ischaemic cardiovascular alterations are common and treatment is rarely successful in cases of diabetes since fatty acid oxidation is the costliest metabolic pathway for oxygen. Thus, in diabetes, aerobic glycolysis gradually shifts to anaerobic glycolysis under ischaemia, with accumulation of lactate and acid metabolites that in turn induce myocardial deterioration, Animal experiments have demonstrated that elective depression of activity of carnitine-palmitoyl-transferase-I enzyme-activity promotes glucose oxidation and early rapid recovery of myocardial contractility, especially under diabetic conditions. To reduce diabetic alterations of myocardial metabolism, anti-diabetic treatment must be switched to insulin during the acute ischaemic and post-ischaemic period of coronary diseases. Trimetazidine optimizes energy metabolism by selectively inhibiting action of the 3-ketoacyl-coenzyme A thiolase enzyme involved in beta-oxidation and inhibiting the overshoot of fatty oxidation. Trimetazidine, as the first 3-ketoacyl-coenzyme A thiolase inhibitor, therefore provides permanent myocardial cytoprotection in stable angina pectoris. However, in our experience, this beneficial anti-anginal effect is only observed in well-controlled situations.

Background: Cardioplegia and reperfusion may induce an inflammatory reaction, which may contribute to postoperative morbidity and mortality., Methods: Gene expression of cytokines, adhesion molecules, and vasoactive substances was evaluated in left ventricular biopsies taken before cardioplegia (lasting approximately 70 minutes) and after reperfusion (approximately 40 minutes) from 19 patients (5 with valvular or combined disease, 7 with stable angina pectoris, 7 with unstable angina). mRNA was extracted and amplified with a semiquantitative reverse transcription polymerase chain reaction., Results: Cardioplegia-reperfusion increased mRNA for E-selectin by a factor of 17 +/- 5 (p < 0.002) (mean +/- SEM), interleukin-1beta, with 9 +/- 3 (p < 0.007), tumor necrosis factor-alpha with 6 +/- 3 (p < 0.05), interleukin-2 receptor alpha chain CD25 with 2 +/- 0.6 (p < 0.04), and intercellular adhesion molecule-1 with 2 +/- 0.4 (p < 0.005). Before cardioplegia, mRNA for endothelial nitric oxide synthase was predominantly detected in unstable angina patients, and increased by a factor of 11 +/- 6 (p < 0.02) during reperfusion. mRNA for endothelin-1 decreased by a factor of 0.5 +/- 0.1 (p < 0.0005). The changes were more pronounced in unstable patients. The transcription factor nuclear factor kappa B (NFkappaB), which regulates expression of inflammatory mediators, was activated during reperfusion (n = 10, p < 0.0001)., Conclusions: Open heart surgery induces an inflammatory response in the human heart, which is more pronounced in patients with unstable angina. It involves NFkappaB activation and expression of several NFkappaB-regulated genes.

Background: Platelet-activating factor (PAF), the lipid mediator of inflammation and potent platelet agonist, can be hydrolysed and inactivated by PAF-acetylhydrolase (PAF-AH). We investigated the PAF-AH activity in relation to PAF formation in platelets from patients with stable angina undergoing elective percutaneous transluminal coronary angioplasty (PTCA)., Design: Twenty-seven patients with stable angina, undergoing PTCA, and 30 age- and sex-matched controls were studied. The platelet-associated and secreted PAF-AH activity was measured, before PTCA, as well as at 4 h, 48 h and 6 months afterwards. PAF formation by thrombin-stimulated platelets and the platelet aggregation responses to PAF and ADP were also determined., Results: The PAF-AH activity secreted by thrombin-stimulated platelets before PTCA (in pmol/10(9) cells/h) was significantly higher compared to controls (892 +/- 222 vs. 624 +/- 144, P < 0.001). The enzyme activity was not altered at 4 h after PTCA, but was significantly increased at 48 h (1284 +/- 312, P < 0.005) to return to the levels observed in the control group 6 months afterwards. Detectable levels of PAF in thrombin-stimulated platelets were found only at 6 months after PTCA. Furthermore, the cell-associated enzyme activity in resting platelets before PTCA was significantly lower compared with controls. Unlike in controls, the platelet-associated enzyme activity in the patient group was not increased after stimulation with thrombin and it was associated by a platelet hyperaggregability to PAF. Both the intact cell-associated activity and the platelet hyper-reactivity to PAF were restored at 6 months after PTCA., Conclusions: Alterations in the platelet PAF-AH activity, which affect the PAF formation in thrombin-stimulated platelets and are associated by an increased aggregatory response to PAF, are observed in patients with stable angina and are completely restored after PTCA.

Aim: To elucidate the relations between angina severity, stability, concomitant arterial hypertension, diabetes mellitus, plasma oxidation., Material and Methods: The study included 152 patients with stable angina of effort (functional class II-III). Of them, 67 had concomitant arterial hypertension (AH), 20 AH and compensated diabetes mellitus type II, 14 patients with anginal functional class III were admitted to hospital for unstable angina, 11 patients with IHD with unstable angina and 28 healthy donors. The study was made of dynamic features of lipid oxidation using copper-induced plasma oxidation. Lipids were measured with enzyme assays., Results: The degree of LP oxidation increases with aggravation of angina. IHD risk factors activate atherogenic modification of lipids in patients with stable angina. There was no differences between the groups in content of low density lipoproteins cholesterol., Conclusion: Plasma resistance to oxidation may serve an additional criterion for assessment of severity and stability of various IHD forms.

The aim of this study was to examine whether detection of coronary calcium and the autoimmune response associated with atherosclerosis, either solely or in combination, are different in patients with typical and atypical chest pain. Coronary calcium as detected by spiral computerized tomography and levels of antibodies against cardiolipin (CL), oxidized low-density lipoprotein (ox-LDL), and beta2-glycoprotein-I (beta2-GPI) were studied in patients with typical chest pain (n = 52), atypical chest pain (n = 19), or without chest pain (n = 21). Patients with typical chest pain had higher mean levels of coronary calcium (expressed as natural transformation of total coronary calcium score) compared with patients with atypical chest pain and controls (5.04 vs 3.21 and 2.75, respectively; p < 0.001). The levels of anti-CL were (mean +/- SD of optical density multiplied by 1,000): 262 +/- 140, 170 +/- 82, and 230 +/- 115 for patients with typical chest pain, atypical chest pain, and controls, respectively (p = 0.016). No significant difference was found between groups regarding anti-ox-LDL and anti-beta2-GPI autoantibody levels. In the typical chest pain group, there was a higher prevalence of high total coronary calcium scores (p = 0.03) and high anti-CL levels (p = 0.01) than in the atypical chest pain group. Eighteen of 52 patients with typical chest pain (35%) had both high calcium scores and high antibody levels, whereas none of the 19 patients (0%) who had atypical chest pain had high levels of both (p = 0.003). A combination of both coronary calcium and anti-CL was associated with higher area under the receiver operator characteristic curves than for each separately. High coronary calcium scores or high anti-CL levels are found more often in typical than in atypical chest pain patients, but a combination of high levels of both can better differentiate typical from atypical chest pain patients.

Studies in healthy subjects showed that blood coagulation factor VII (FVII) is activated postprandially after consumption of high-fat meals, but accompanying thrombin formation has not been demonstrated. In patients with coronary atherosclerosis, the arterial intima is supposed to present more tissue factor, the cofactor of FVII, to circulating blood; therefore, thrombin formation in response to FVII activation is more likely to occur in such patients. This hypothesis was tested in a randomized crossover study of 30 patients (aged 43 to 70 years) with stable angina pectoris and angiographically verified coronary atherosclerosis. They were served a low-fat (5% of energy from fat) breakfast and lunch and a high-fat (40% of energy from fat) breakfast and lunch on 2 different days. Venous blood samples were collected at 8:15 AM (fasting), 12:30 PM, 2:00 PM, 3:30 PM, and 4:45 PM and analyzed for triglycerides, activated FVII (FVIIa), FVII protein concentration (FVII:Ag), prothrombin fragment 1+2 (F1+2), and soluble fibrin. Triglyceride levels increased from fasting levels on both diets, but they increased most markedly on the high-fat diet. FVIIa and FVIIa/FVII:Ag increased with the high-fat diet and decreased with the low-fat diet. For both diets, FVII:Ag and F1+2 decreased slightly. No postprandial changes were observed for soluble fibrin. Postprandial mean values of triglycerides, FVIIa, FVII:Ag, and FVIIa/FVII:Ag were significantly higher for the high-fat diet than for the low-fat diet. Our findings confirm that high-fat meals cause immediate activation of FVII. The clinical implication is debatable because FVII activation was not accompanied by an increase in plasma F1+2 concentrations in patients with severe atherosclerosis. However, a local thrombin generation on the plaque surface cannot be excluded.

A number of cardiac interventional procedures are available for the treatment of angina, including percutaneous transluminal coronary angioplasty (PTCA), stent insertion and rotational atherectomy (RA). Variable degrees of myocardial cell injury during PTCA and stent insertion have been observed, based on rises in creatine kinase MB isoenzyme (CK-MB) and cardiac troponin T (cTnT) 6-24 h post-procedure. As there are many variations in technique within each procedure it would be helpful to be able to determine objectively the degree of myocardial damage in order to optimize technique. We measured CK-MB, cTnT and cardiac troponin I (cTnI) to ascertain which is the most sensitive marker for minor myocardial damage in this setting. Blood samples were taken both before and 6, 14 and 24h after the procedure in 109 patients (77 men) with angina, 42 of whom had unstable angina. Of the 109 patients, 86 had a stent inserted (21 as a primary stent), nine had PTCA, eight had RA and six intracoronary brachytherapy. Using the manufacturers' recommended cut-offs--CK-MB 4 microg/L, cTnI and cTnT 0.1 microg/L--five patients were excluded from further analysis as all three markers were raised pre-procedure. Post procedure all three markers were in agreement for 68 patients (44 all normal, 24 all raised). Overall, CK-MB was raised in 28 patients, cTnT in 38 and cTnI in 58. In 19 patients CK-MB and cTnT were normal, but cTnI was raised (15 between 0.11 and 0.30 microg/L). cTnI was the most sensitive indicator of minor myocardial damage, but at the recommended cut-off of 0.1 microg/L may be overly sensitive. We await the results of our follow-up study to determine the clinical implications of these small rises in cTnI.

Background: Raised triglyceride-rich lipoproteins significantly increase the risk for cardiovascular disease. Variation in the activity of the enzyme lipoprotein lipase (LPL), which is crucial in the removal of these lipoproteins, may therefore modulate this risk., Methods and Results: Postheparin levels of LPL activity and mass were measured in a large cohort of male coronary artery disease patients participating in the Regression Growth Evaluation Statin Study (REGRESS), a lipid-lowering regression trial. In addition, the relationships between LPL activity and mass and severity of angina pectoris according to the NYHA classification and silent ischemia on 24-hour ambulatory ECG monitoring were assessed. Patients in different LPL activity quartiles and mass had different severities of angina; a total of 47% of patients in the lowest LPL quartile reported class III or IV angina. In contrast, only 29% in the highest activity quartile (P:=0.002) had severe angina. These parameters were supported by ambulatory ECG results, for which the total ischemic burden in the lowest LPL activity quartile was 36. 5+/-104.1 mm x min compared with 14.8+/-38.8 mm x min in the highest quartile of LPL activity (P:=0.001). LPL activity levels were strongly correlated with LPL mass (r=0.70, P:<0.0001). A significant association between the LPL protein mass and NYHA class (P:=0.012) was also demonstrated., Conclusions: We have demonstrated a significant relationship between LPL mass and activity and severity of ischemia as defined by angina class and ambulatory ECG. These results suggest that LPL influences risk for coronary artery disease by both catalytic and noncatalytic mechanisms.

Aims: To study the pharmacokinetics of trinitroglycerin (GTN) and its four metabolites in angina patients during their transient use of transdermal GTN tape following intravenous administration of GTN., Methods: Four patients received a GTN tape following intravenous administration of 0.1 microg kg-1 min-1 GTN, and the other four patients received two GTN tapes following intravenous administration of 0.2 microg kg-1 min-1 GTN., Results: Plasma concentrations of GTN in both groups during tape application showed a slight decrease for the hour after the application of the tape and then were con- stant for 24 h. In contrast, the concentrations of dinitroglycerins (GDNs) and mononitroglycerins (GMNs) depended on the duration of previous intravenous administration of GTN. Neither significant cardiovascular changes nor undesirable complications were observed during the study., Conclusions: The results suggest that appropriate replacement of intravenous GTN administration with transdermal tape application could maintain a therapeutic GTN level.

Association of ischemic heart disease (IHD) with vascular affections of the brain is the cardiocerebrovascular syndrome having common pathogenetic mechanisms of formation in the structure of cardiovascular pathology. Some specificities were studied of the clinical course of IHD concomitant with hypertensive dyscirculatory encephalopathy (HDE) in 35 patients (main group), with 25 IHD controls free from manifestations of neurological symptomatology. In IHD HDE patients the anginous syndrome is characterized by a lesser dependency on time in each period of 24 hours and physical load and greater dependency on arterial pressure, meteofactors, it is often accompanied by cephalgia appearing with the intake of antianginal drugs, dizziness, memory, sleep disturbances. The main group patients demonstrated elevated levels of LPO products, those of lipid metabolism, and the AO system tension.

In patients with unstable angina, intravenous heparin reduces thrombin activity but does not influence thrombin generation. Recombinant hirudin, a direct thrombin inhibitor, may be more effective in inhibiting both thrombin generation and activity. We measured the plasma levels of prothrombin fragment 1+2 (a marker of thrombin generation) and fibrinopeptide A (a marker of thrombin activity) in 67 patients with unstable angina enrolled in the GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) IIb trial who were receiving either recombinant hirudin (31 patients) or heparin (36 patients). Blood samples were obtained at baseline (before any treatment), after 3 to 5 days of study drug infusion (immediately before discontinuation), and 1 month later. In the patients receiving recombinant hirudin, the prothrombin fragment 1+2 levels measured immediately before drug discontinuation were significantly lower than at baseline (P:=0.0014), whereas they had not changed in the patients receiving heparin; at this time point, the difference between patients receiving hirudin and those receiving heparin was statistically significant (P:=0.032). One month later, the prothrombin fragment 1+2 levels in both groups were similarly persistently high and did not differ from baseline. Fibrinopeptide A plasma levels at the end of infusion were significantly lower than at baseline in both treatment groups (P:=0. 0005 for hirudin and P:=0.042 for heparin) and remained lower after 1 month (P:=0.0001 for both hirudin and heparin). The fibrinopeptide A plasma levels were not different between patients treated with hirudin versus heparin at baseline, at the end of infusion, and after 1 month. Thus, in patients with unstable angina, in vivo thrombin generation and activity are reduced during intravenous infusion of recombinant hirudin. However, the inhibition of thrombin generation is not sustained, and after 1 month, the majority of patients have biochemical signs of increased thrombin generation.

Background and Aim of the Study: Transmyocardial laser revascularization (TMR) has demonstrated significant relief in patients presenting with refractory angina. However, the mechanism by which TMR improves clinical symptoms is unclear. This study analyzes the early immunohistochemical and ultrastructural features of the human myocardium following TMR., Methods: Specimens of myocardium that contained laser channels were removed in toto at autopsy from three male patients, ages 41, 57, and 65 (mean age 55.8) who had died 1 to 11 days (mean 6.8) following laser revascularization. Consecutive parallel sections of specimens were stained with cell-type specific antibodies to CD3 (to identify T-lymphocytes), CD68 (macrophages), Factor VIII (endothelial cells), and myosin (myocytes). Additionally, adjacent areas of myocardium that contained laser channels were processed and analyzed by transmission electron microscopy., Results: The internal lining surface of laser channels was composed of vacuolized and condensed myocardial debris. No obvious connections were noted between laser channels and the ventricular cavity. No endothelialization of channels was observed, whereas the adjacent noninjured myocardium demonstrated microvessels lined by well-preserved endothelial cells. The laser channels were surrounded by zones of necrotic cardiomyocytes., Conclusions: Our observations suggest that laser channels are not lined by endothelial cells during the early stages following TMR. Mechanisms other than direct myocardial perfusion from the ventricular cavity by patent endothelialized channels may explain the immediate relief from angina provided by TMR.

Background: The rapid utilization of fibrinolytics following Q-wave myocardial infarction has clearly modified the evolution of this disease. However, it is still not known whether the immediate inhibition of platelet aggregation (PA) during the coronary event improves outcomes., Hypothesis: The present study was designed to test, in patients with known coronary artery disease (chronic stable angina), whether the particular kinetic pattern of lysine acetylsalicylate (LA) compared with aspirin may affect the time to onset of inhibition of platelet aggregation., Methods: Ten patients suffering from chronic stable angina participated in this study to compare the efficacy and speed of the inhibition of PA with 320 mg of LA versus 320 mg of aspirin. All patients discontinued the use of aspirin and any other anti-inflammatory agents for 15 days prior to the beginning of the study. They were randomly assigned to LA or aspirin. Blood specimens were obtained to measure the PA at admission, and 5, 10, 20, 30, and 60 min after ingestion. Patients continued to take the assigned drug once a day for the following 4 days. On Day 5, a new blood sample was taken. After this, patients underwent a 15-day wash-out period, and then crossed over to the opposite drug. The samples were analyzed immediately using platelet-rich plasma stimulated with adenosine diphosphate (ADP) 2 mumol/l, collagen 1 microgram/ml, epinephrine 20 mumol/l, and sodium arachidonate acid 0.75 mm/l., Results: The same level of PA inhibition after 30 and 60 min of aspirin administration can be obtained with LA 5 min following ingestion (sodium arachidonate acid: LA: 16.3 +/- 25.9 vs. aspirin 57.6 +/- 8.2; p = 0.00014; collagen: LA 18.9 +/- 20.1 vs. aspirin 47.2 +/- 10.5; p = 0.00092; ADP: LA 27.3 +/- 18.4 vs. aspirin 39.7 +/- 21.8, p = 0.18; epinephrine: LA 22.0 +/- 9.9 vs. aspirin 55.4 +/- 10.9, p = 0.00002., Conclusions: Platelet aggregation inhibition immediately following LA may have significant clinical implications for the treatment of coronary syndromes.

Background: Oxidized lipoproteins may play an important role in the pathogenesis of atherosclerosis, and it has been shown that antioxidants have a protective effect against the progression of atherosclerosis., Hypothesis: The aim of this study was to investigate the oxidative susceptibility of apolipoprotein B-containing lipoproteins and antioxidant status in patients with acute coronary syndromes and chronic stable angina pectoris., Methods: The study population included 70 patients with acute coronary syndromes (14 with recent acute myocardial infarction and 56 with unstable angina pectoris), 105 patients with stable angina pectoris, and 75 control subjects. In addition to conventional lipid and lipoprotein analysis, the susceptibility of apolipoprotein B-containing lipoproteins to in vitro oxidation (lag phase) and plasma vitamin E and total carotene levels was measured., Results: The lag phase was significantly shorter in patients with acute coronary syndromes (45 +/- 12 min) than in patients with stable angina pectoris (51 +/- 10 min) and in control subjects (58 +/- 9 min) (p < 0.0001). Both plasma vitamin E and total carotene levels were lowest in patients with acute coronary syndromes (1.11 +/- 0.32 mg/dl and 119 +/- 32 micrograms/dl, respectively), followed by patients with stable angina pectoris (1.25 +/- 0.37 mg/dl and 132 +/- 37 micrograms/dl) and then controls (1.52 +/- 0.31 mg/dl and 167 +/- 41 micrograms/dl)., Conclusions: These data suggest that there is an intense oxidative process and a lower antioxidant status in acute coronary syndromes. This may lead to plaque instability due to the activation of the inflammatory response in coronary atherosclerotic lesions.

Recent studies showed that coronary artery spasm may be due to disturbances of secretory and excretory endothelial activity in atherosclerotic coronary artery. However, this theory does not explain the reasons of coronary artery spasm when endothelium is not damaged. There must be other patomechanisms of coronary artery spasm. The aim of our study was examination of calcium efflux through the lymphocytic cell membrane and determination of endothelin-1 plasma levels in patients with variant angina in order to define the participation of these factors in pathogenesis of coronary artery spasm. The survey was made in 76 patients with ischaemic heart disease. All patients were divided into 2 groups. The first group consisted of 48 patients with variant angina (d.b.s.), the other consisted of 28 patients with stable angina (d.b.w.). The control group (g.k.) was composed of 25 healthy people. Patients were administered 100 ml of trometamol (TRIS, pH = 10.5) intravenously for 5 minutes. After stopping the infusion the examined patient was breathing deeply for 5 minutes at a rate of 40/min. The endothelin-1 (ET-1) plasma levels and transmembrane calcium transport in lymphocytes were determined before and just after the hyperventilation test, as well as 10 minutes after the test. ET-1 plasma concentrations were estimated with a radioimmunologic assay. The method of estimation of transmembrane calcium transport was elaborated in Laboratory of Department of Cardiology of Medical University of Wrocław. We showed that ET-1 plasma levels and transmembrane calcium transport in patients with d.b.s. before the test were normal. There was an increase in transmembrane calcium efflux in patients with d.b.s. during coronary artery spasm that had been caused by ET-1. ET-1 plasma levels were still high 10 min. after the coronary artery spasm. Disturbances of transmembrane calcium transport and increased endothelin-1 plasma level may be the primary factors responsible for coronary artery spasm.

Background: Does transmyocardial laser revascularization (TMLR), a new surgical technique for treating patients with otherwise intractable angina pectoris, improve myocardial perfusion, metabolism, and, consequently, function?, Methods: Patients referred for TMLR, alone or with coronary artery bypass grafting (CABG), were preoperatively evaluated clinically and by treadmill stress testing, echocardiography, ventriculography, radionuclide assessment of perfusion and metabolism, and hemodynamic assessment. Intraoperatively it was decided that some patients only required CABG. Follow-up evaluations were repeated after 6 (n = 40) and 12 months (n = 23) and compared with preoperative values., Results: CABG only was performed in 35 cases, TMLR + CABG in 17, TMLR only in 45. 1-year mortality was 11% in the TMLR, zero in the TMLR + CABG, and 11% in the CABG groups. In all groups a significantly improved CCS angina- and NYHA class was observed immediately after operation and after 6 and 12 months. In all study groups treadmill tolerance (p<0.05) improved, but regional and global function, perfusion at rest, and metabolism were not significantly changed at 6 and 12-months follow-ups. Perfusion studies under stress demonstrated an improvement only in the CABG group after 12 months (p<0.05), whereas in both TMLR groups the lasered ischemic segments remained unchanged., Conclusions: TMLR significantly improves long-term clinical status and treadmill stress tolerance, but appears to have little if any effect upon regional and global function, perfusion, and metabolism.

Objectives: The purpose of the study was to evaluate clinical effects, exercise performance and effect on maximal oxygen consumption (MVO2) of transmyocardial revascularization with CO2-laser (TMR) in patients with refractory angina pectoris., Background: Transmyocardial laser revascularization is a new method to treat patients with refractory angina pectoris not eligible for conventional revascularization. Few randomized studies comparing TMR with conventional treatment have been published., Methods: One hundred patients with refractory angina not eligible for conventional revascularization were block-randomized in a 1:1 ratio to receive continued optimal medical treatment (MT) or TMR in addition to MT. The patients were evaluated at baseline and at three and 12 months with end points to symptoms, exercise capacity and MVO2., Results: Transmyocardial laser revascularization resulted in significant relief in angina symptoms after three and 12 months compared to baseline. Time to chest pain during exercise increased from baseline by 78 s after three months (p = NS) and 66 s (p < 0.01) after 12 months in the TMR group, whereas total exercise time and MVO2 were unchanged. No significant changes were observed in the MT group. Perioperative mortality was 4%. One year mortality was 12% in the TMR group and 8% in the MT group (p = NS.), Conclusions: Transmyocardial laser revascularization was performed with low perioperative mortality and caused significant symptomatic improvement, but no improvement in exercise capacity.

Trimetazidine is a clinically effective antianginal agent that has no negative inotropic or vasodilator properties. Although it is thought to have direct cytoprotective actions on the myocardium, the mechanism(s) by which this occurs is as yet undefined. In this study, we determined what effects trimetazidine has on both fatty acid and glucose metabolism in isolated working rat hearts and on the activities of various enzymes involved in fatty acid oxidation. Hearts were perfused with Krebs-Henseleit solution containing 100 microU/mL insulin, 3% albumin, 5 mmol/L glucose, and fatty acids of different chain lengths. Both glucose and fatty acids were appropriately radiolabeled with either (3)H or (14)C for measurement of glycolysis, glucose oxidation, and fatty acid oxidation. Trimetazidine had no effect on myocardial oxygen consumption or cardiac work under any aerobic perfusion condition used. In hearts perfused with 5 mmol/L glucose and 0.4 mmol/L palmitate, trimetazidine decreased the rate of palmitate oxidation from 488+/-24 to 408+/-15 nmol x g dry weight(-1) x minute(-1) (P<0.05), whereas it increased rates of glucose oxidation from 1889+/-119 to 2378+/-166 nmol x g dry weight(-1) x minute(-1) (P<0.05). In hearts subjected to low-flow ischemia, trimetazidine resulted in a 210% increase in glucose oxidation rates. In both aerobic and ischemic hearts, glycolytic rates were unaltered by trimetazidine. The effects of trimetazidine on glucose oxidation were accompanied by a 37% increase in the active form of pyruvate dehydrogenase, the rate-limiting enzyme for glucose oxidation. No effect of trimetazidine was observed on glycolysis, glucose oxidation, fatty acid oxidation, or active pyruvate dehydrogenase when palmitate was substituted with 0.8 mmol/L octanoate or 1.6 mmol/L butyrate, suggesting that trimetazidine directly inhibits long-chain fatty acid oxidation. This reduction in fatty acid oxidation was accompanied by a significant decrease in the activity of the long-chain isoform of the last enzyme involved in fatty acid beta-oxidation, 3-ketoacyl coenzyme A (CoA) thiolase activity (IC(50) of 75 nmol/L). In contrast, concentrations of trimetazidine in excess of 10 and 100 micromol/L were needed to inhibit the medium- and short-chain forms of 3-ketoacyl CoA thiolase, respectively. Previous studies have shown that inhibition of fatty acid oxidation and stimulation of glucose oxidation can protect the ischemic heart. Therefore, our data suggest that the antianginal effects of trimetazidine may occur because of an inhibition of long-chain 3-ketoacyl CoA thiolase activity, which results in a reduction in fatty acid oxidation and a stimulation of glucose oxidation.

Correction of the metabolic link of the natural course of ischemic heart disease (IHD) was found out to be a real reserve of enhancement of therapy efficiency in treating this condition. A total of 137 IHD patients were examined, presenting with functional class II-III exertional angina, their age ranging between 67 to 86 years. Kinds of metabolic complexes to be used in IHD treatment included amino acids, antioxidants, cofactors, energy-providing compounds that enhance efficiency of basic methods of IHD therapy. A positive therapeutic effect of metabolic correction treatments was evidenced by earlier dispelling of electrocardiographic signs of myocardial ischemia, higher tolerance to physical load, improvement in parameters characterizing cardio-hemodynamics.

In 70 patients (94% were a consecutive series) with angina pectoris and normal coronary angiograms, we measured cardiac exchange of lactate, glucose, free fatty acids (FFAs), glutamate, alanine, citrate, and oxygen together with coronary sinus blood flow and blood pressure in response to pacing (150 beats/min). Twelve patients had an abnormal exercise stress test; 26 developed ST depression and 46 had chest pain in response to pacing. Sixteen patients had no ST changes (exercise/ pacing) and no pain during pacing. Pacing induced an increase in cardiac carbohydrate extraction and a decrease in FFA extraction in the entire group of patients. Less than 3% of patients had significant cardiac lactate release in response to pacing, and there were no consistent differences in the cardiac metabolic or hemodynamic responses between patient groups. The pacing-induced shift from FFA to carbohydrate extraction probably reflects the cardiac response to an acute workload. A definite sign of cardiac ischemia (lactate production) was a rare finding in these patients and not confined to the demonstration of electrocardiographic signs of ischemia.

Patients with ischemic heart disease (angina pectoris of functional class II and III) whose mean age was 67.4 +/- 1.67 years were divided into 3 randomized groups. 15 control patients received standard treatment. 30 and 15 patients of group 1 and 2, respectively, received standard treatment plus amino acid composition (100 mg 3 times a day sublingually) or preductal (20 mg 3 times a day)--groups 1 and 2, respectively. The treatment lasted 21 days. Before the treatment and on its day 1, 7 and 21 measurements were made of glutathione level, activity of glutathion-dependent enzymes, catalase, Cu, Zn-superoxide dismutase and malonic dialdehyde in red cells. The amino acid composition was found to raise the level of antioxidant system and suppress lipid peroxidation. Preductal raised the activity of Cu, Zn-superoxide dismutase and had an unbalanced effect on the antioxidant system.

Administration of N(G)-monomethyl-L-arginine (LNMMA), an inhibitor of nitric oxide synthase, causes a reduction in epicardial coronary artery and stenosis diameter in patients with coronary artery disease, indicating that these diseased vessels produce nitric oxide. Elevations of low density lipoprotein cholesterol impair human endothelium-dependent relaxation. The relationship between serum lipid level and nitric oxide production by normal and atheromatous human epicardial coronary arteries in vivo is unknown. The effects of an intracoronary infusion of LNMMA (8 and 16 micromol/min) followed by intracoronary administration of 250 mcg nitroglycerin on non-stenotic proximal and distal coronary segments and coronary stenoses were studied in 11 patients with coronary artery disease and in 19 patients with 'normal arteriograms'. Coronary luminal diameter was measured by computerized quantitative angiography. In patients with cholesterol level> or = 220 mg/dl, no significant response to LNMMA was observed in the proximal segments in either those with 'normal angiograms' or those with coronary disease. In patients with cholesterol <220 mg/dl significant constriction (P<0.01) was observed in the proximal segments of patients with 'normal coronary angiograms' at both 8 and 16 micromol doses, but occurred only at the 16 micromol/min dose (P<0.01) in those with coronary disease. In conclusion the difference in vasomotor response to LNMMA in relation to cholesterol level is localised to the proximal coronary segments, and the response does not correlate with cholesterol or triglyceride level. This is therefore more likely to be an indirect effect of elevated cholesterol, e.g. undetected atheroma, than a direct effect on nitric oxide synthesis.

Patients with chest pain represent an inhomogeneous group with greatly varying severity of coronary artery disease and cardiac risk. The proper selection of different treatment strategies in these patients requires reliable risk assessment. Patients with definitive myocardial infarction: in patients with ST-segment elevation on ECG, a positive troponin T (cTnT) on admission identifies a group of patients having a threefold higher mortality rate than patients with a negative cTnT test. The differences in risk based on cTnT are found for patients treated with thrombolytic as well as mechanical recanalization therapy. These differences in mortality based on admission cTnT may be explained by more severe coronary artery disease, worse left ventricular function, and less efficient microvascular reperfusion in the cTnT-positive patients. Patients with rest angina: in patients with angina at rest, a positive cTnT value on admission identifies a subgroup having a threefold higher cardiac event rate than cTnT-negative patients. The cTnT-positive patients seem to benefit from treatment with low molecular weight heparin and fibrinogen receptor antagonists, while cTnT-negative patients do not. The differences in risk and response to therapy may be due to more severe coronary artery disease, more critical coronary artery stenoses, and a higher rate of intracoronary thrombus formation in the cTnT-positive versus negative patients. Low risk chest pain patients: in low risk chest pain patients, (i.e. no rest angina, no ECG-changes) cTnT-positive patients on admission have a twofold higher cardiac event rate than cTnT-negative patients. The proper treatment strategy for the low risk cTnT-positive patients remains to be determined. Troponin T versus troponin 1: many of the findings on cTnT also relate to troponin I. However, there is a high interassay variability of troponin I assays, which has to be taken into consideration.

The treatment of stable angina should aim to relieve symptoms and in at-risk cases prolong life. Medical therapy, PTCA and CABG should be seen as complementary, not competitive, strategies. Optimal utilization of all three treatment modalities either alone or in combination can provide substantial and sustained symptomatic relief for angina patients. Metabolic agents such as Trimetazidine by acting at the cellular level and not influencing heart rate or blood pressure have a useful and unique role to play in addition to conventional haemodynamic agents such as the betablockers or calcium antagonists. This review looks at the role of trimetazidine as part of the overall management of the stable angina patient.