Impaired forearm reactive hyperemia is related to late restenosis after coronary stenting.

To investigate whether systemic endothelial function on forearm resistance vessels is related to angiographic restenosis after coronary stenting, 47 men who underwent elective coronary stenting were divided into 2 groups according to the presence (n = 20) or absence (n = 27) of in-stent restenosis 6 months after the procedure. Another 19 risk factor-matched men with normal coronary angiograms served as the control group. Forearm blood flow was assessed by venous occlusive plethysmography. Basal forearm blood flow was similar between restenosis, nonrestenosis, and control groups (2.63 +/- 0.19, 2.58 +/- 0.14, and 3.23 +/- 0.13 ml/100 ml forearm tissue per minute, respectively). In all 3 groups, forearm blood flow increased significantly during reactive hyperemia (5.75 +/- 0.7, 11. 32 +/- 1.23, and 14.52 +/- 1.36 ml/100 ml forearm tissue per minute, p <0.05, respectively) and remained unchanged after sublingual administration of nitroglycerin. The percentage change of forearm blood flow during reactive hyperemia was significantly lower in the restenosis group (117.3 +/- 18.3%) than in the nonrestenosis group (354.2 +/- 46.5%, p <0.01). This difference was still present after sublingual nitroglycerin (37.6 +/- 21.2% vs 226.4 +/- 40.5%, p <0. 01). In contrast, percentage change of hyperemic forearm blood flow was significantly lower in patients with angina (117.5 +/- 49.5%) than in those without angina (290.1 +/- 37.4%, p <0.05) at follow-up. In all patients, the angiographic loss index was correlated negatively to the percentage change of hyperemic forearm blood flow (r = -0.33, p <0.01) and positively to the percentage change of forearm vascular resistance during reactive hyperemia (r = 0.33, p <0.01). In patients with angiographic restenosis after coronary stenting, forearm reactive hyperemia was more impaired compared with those without angiographic restenosis. Systemic endothelial dysfunction might be either a marker or one of the confounding factors in the development of late restenosis after coronary stenting.

Differential coronary calcification on electron-beam CT between syndrome X and coronary artery disease in patients with chronic stable angina pectoris.

STUDY OBJECTIVES: The differential diagnosis of syndrome X and coronary artery disease (CAD) in patients with evidence of myocardial ischemia may be difficult. The possible difference in coronary calcium detected by electron-beam CT (EBCT) between syndrome X and CAD is rarely evaluated, especially in aged patients with chronic, stable angina. DESIGN AND SETTINGS: Prospective, controlled study at a tertiary referral medical center. PATIENTS AND MEASUREMENTS: Forty patients with syndrome X (85% male) and 53 patients with CAD (89% male) were enrolled. Ten control subjects (90% male) with negative exercise treadmill test results and normal coronary angiographic findings served as control subjects. EBCT determined the coronary calcium scores (CCSs), and standard cardiovascular risk factors of all study subjects were analyzed. RESULTS: The 93 study patients had CCSs that ranged from 0 to 1,857. Coronary calcification was seen in 2 of the 10 control subjects (20%), 21 of the 40 syndrome X patients (52.5%), and 51 of the 53 CAD patients (96.2%) [p < 0.01]. The CCS (median [range]) was significantly lower in syndrome X patients than in CAD patients: 1 (0 to 117) vs 202 (0 to 1,857) [p < 0.001]. Receiver operating characteristic curve analyses also demonstrated that coronary calcification differentiated syndrome X from CAD (area under curve, 0.891; 95% confidence interval, 0.806 to 0.947). Of the CAD patients whose CCSs were < 117 and overlapped with CCSs of syndrome X, multivariate analyses determined CCS > 5 (odds ratio, 13.1; 95% confidence interval, 2.86 to 59.7), hypertension (odds ratio, 6.4; 95% confidence interval, 1.5 to 27.4), and hypercholesterolemia (odds ratio, 6.7; 95% confidence interval, 1.5 to 30.5) to be independent discriminators to differentiate CAD from syndrome X. Patients with CAD had more frequent hypertension than patients with syndrome X. CONCLUSIONS: The coronary calcium detected noninvasively by EBCT was different, though with some overlapping, between patients with syndrome X and CAD. In addition to standard cardiovascular risk factors, CCS determined by EBCT (especially > 117 or = 0) could differentiate between syndrome X and CAD in patients with chronic, stable angina with evidence of myocardial ischemia. Larger trials would be useful to validate CCS on EBCT as a predictor of clinical outcome in these patients.

Pharmacokinetics of fosinoprilat in Chinese and whites after intravenous administration.

The pharmacokinetics of fosinoprilat was studied in 12 healthy Chinese men after a 7.5 mg intravenous dose of fosinoprilat. The data were compared with those from an earlier study using the same protocol in nine healthy white men. Blood and urine samples were obtained before and at various time intervals after fosinoprilat administration up to 24 hours and 48 hours, respectively. Pharmacokinetic parameters were calculated by fitting the plasma or serum concentrations to a three-compartment model. The total clearance (Clt), renal clearance (ClT), and nonrenal clearance (ClNR) were significantly lower in Chinese (16.29 +/- 6.92, 6.85 +/- 2.97, and 9.44 +/- 5.08 mL.hr-1.kg-1) than those obtained in whites (29.88 +/- 6.36, 13.55 +/- 3.45, and 16.33 +/- 5.07 mL.hr-1.kg-1). The Chinese subjects had a significantly lower volume of distribution (Vc [volume of distribution of central compartment] and Vdss [volume of distribution at steady state]) (29.38 +/- 21.12 and 73.67 +/- 40.20 mL/kg) than white men (58.14 +/- 15.01 and 152.49 +/- 24.89 mL/kg). The Chinese men also had a shorter elimination half-life than whites, although not statistically significant. The respective half-lives in Chinese and whites were 5.51 +/- 1.53 and 8.24 +/- 1.99 hours. The significant differences in ClNR and ClR may be related to lower liver elimination function and lower kidney excretory function, respectively. Plasma protein binding may contribute to part of the difference in the volume of distribution. Chinese men have smaller volume of distribution and clearances of fosinoprilat after intravenous administration compared with white men. The cumulative urine excretion of fosinoprilat was not different between Chinese and whites. Chinese may require a lower fosinoprilat dosage to obtain plasma concentrations similar to whites after intravenous administration. However, since a relatively high variation was found in fosinopril oral absorption, the oral dosage of fosinopril for Chinese and whites may not be different. Further study is obviously needed to elucidate whether the pharmacodynamic effect may be different between Chinese and whites.

Fosinopril: pharmacokinetics and pharmacodynamics in Chinese subjects.

This study examined thepharmacokinetics and pharmacodynamics of fosinopril (IVand oral) in Chinese subjects to determine whether they were different from a group of somewhat heavier and older Western control subjects previously published using the same methods. It was an open-label, randomized, balanced, two-way crossover study comparing oral and IV pharmacokinetics in 12 healthy Chinese subjects in a clinic in Taiwan. Each subject received 10 mg of oral fosinopril or 7.5 mg of IV fosinoprilatin a randomized sequence with sampling for fosinoprilat concentrations over 48 hours. Standard pharmacokinetics, including AUC, Cmax Tmax, T 1/2, Vss, bioavailability, total clearance, and renal and nonrenal clearance, were determined as well as pharmacodynamic effects on angiotensin-converting enzyme (ACE) activity. Following oral administration of 10 mg fosinopril, AUC0-T and AUCinf were 1,556 +/- 586 ng x hr/mL and 1,636 +/- 620 ng x hr/mL, respectively; T 1/2 was 17.4 +/- 11.4 hr; Cmax was 183.4 +/- 59.4 ng/mL; and median Tmax was 4.0 hr, with > 99% protein binding. Following IV administration of 7.5 mg fosinoprilat, AUC0-T and AUCinf were 7,727 +/- 2,638 ng x hr/mL and 7,816 +/- 2,693 ng x hr/mL, respectively; T 1/2 was 13.0 +/- 5.2 hr; and median Tmax was 4.0 hr, with 99.5% +/- 0.22% protein binding and a Vss of 5,850 +/- 2,780 mL. Bioavailability was 22.3% +/- 7.9%. Percent urinary excretion was 7.6% +/- 2.6% after oral dosing and 42.6% +/- 6.1% after IV dosing. After IV, dosing total clearance was 1,088 +/- 439 mL/hr, renal clearance was 472 +/- 213 mL/hr, and nonrenal clearance was 617 +/- 246 mL/hr. ACE inhibition was essentially complete through 12 hours and markedly reduced through 24 hours. Compared to a somewhat heavier and older previously reported control group, pharmacokinetic values were similar except for a slightly lower AUC and total clearance in Chinese and a statistically significantly lower nonrenal clearance. Pharmacodynamic effects on ACE activity were essentially identical. There is no reason to expect significant differences in fosinopril dosing or effect in a Chinese population compared to a Western population.

Does Chinese ethnicity affect the pharmacokinetics and pharmacodynamics of angiotensin-converting enzyme inhibitors?

Information from clinical and pharmacokinetic studies of angiotensin-converting enzyme inhibitors (ACEIs) has come from subjects who are mostly male and Caucasian, but the use of ACEIs extends to populations worldwide. Significant differences between Chinese in general and male Caucasians have been demonstrated in the pharmacokinetics/dynamics of other drug classes that could have implications for the use of ACEIs in the Chinese population. These include: significant Chinese/Caucasian genetic variation in the renin-angiotensin system based on an insertion/deletion (O/D) polymorphism of the ACE gene; the genetic determination of plasma ACE activity in the Chinese population; and genetic factors involving the disease substrate which may also influence the response to treatment. Oral and IV pharmacokinetic data from various studies of Chinese and Caucasian subjects are available for cilazapril, fosinopril, and perindopril, and pharmacodynamic data are available for eight different ACEIs. Based on these data, there are few differences among the pharmacokinetics of ACEIs between Chinese and Caucasians. Most ACEIs showed good blood pressure lowering efficacy in Chinese (benazepril, enalapril, fosinopril and spirapril), with perhaps less blood pressure lowering with cilazapril or a relatively shorter-term effect with cilazapril or perindopril compared to Caucasions. Chinese experience more cough from ACEIs (captopril and enalapril) than Caucasians. Data suggest that fosinopril may not induce cough in as many subjects as other ACEIs, and this seems to be true of Chinese as well. The mechanism, currently unknown, could involve fosinopril's dual elimination pathway (hepatic and renal). Pharmacokinetic data also support the use of fosinopril in congestive heart failure where elimination pathways may be impaired. In conclusion, ethnic differences between Chinese and Caucasians with respect to ACE and AGT gene polymorphism, which might be expected to differentially affect the action of ACEIs in these two ethnic groups, do not, in fact, have such an effect. Rather, differences among the ACEIs appear to be more important. Journal of Human Hypertension (2000) 14, 163-170.

Evidence for inhibition of low density lipoprotein oxidation and cholesterol accumulation by apolipoprotein H (beta2-glycoprotein I).

Low density lipoprotein (LDL) oxidation and lipid accumulation are thought to enhance the progression of atherosclerosis. Apolipoprotein H (apoH) has been implicated in the development of human atherosclerosis. However, the roles of apoH in the oxidative modification of LDL and cellular accumulation of lipid constituents remained uncharacterized. In this study, the level of plasma apoH was found to be significantly associated with the oxidative susceptibility of LDL in human subjects. Plasma levels of apoH were positively correlated with the lag time but negatively correlated with LDL oxidation rate in conjugated diene formation. By using a J774 A.1 macrophage culture system, we found that apoH could not only inhibit the formation of conjugated diene and thiobarbituric acid-reactive substances, but also reduce the electrophoretic mobility of oxidized LDL. Furthermore, apoH decreased cellular accumulation of cholesterol via a reduction in cholesterol influx and an increase in cholesterol efflux. This is the first demonstration that apoH appears to have "antioxidant"-like effects on LDL oxidation. The results also suggest that apoH can inhibit the translocation of cholesterol from extracellular pools to macrophages, suggesting that apoH may play an important role in the prevention of atherosclerosis.

Apical hypertrophic cardiomyopathy mimicking acute myocardial infarction.

Thrombolytic therapy was given to a 77-year-old man with typical ischemic chest pain and unequivocal electrocardiographic ST-segment elevations at the emergency department. The diagnosis of acute myocardial infarction was excluded during hospitalization and the patient was found to have apical hypertrophic cardiomyopathy with apical aneurysm formation and mid-ventricular obstruction.

Differential coronary artery calcification detected by electron beam computed tomography as an indicator of coronary stenosis among patients with stable angina pectoris.

BACKGROUND: The detection of coronary artery calcification by electron beam computed tomography (EBCT) has been suggested as an indicator of atherosclerosis and coronary artery disease (CAD). There is no consensus on the correlation between coronary calcification and angiographically significant stenosis on an artery-by-artery basis. OBJECTIVE: To examine the relationship between coronary calcification score (CCS) and the presence of significant CAD on an artery-by-artery basis in patients with stable angina pectoris. METHODS AND RESULTS: EBCT and coronary angiogram (CAG) were evaluated in 71 patients with stable angina and in nine control subjects. The CCSs of each of the four major coronary arteries were highest in patients with significant CAD (n=43), followed by patients with insignificant CAD (n=5), patients with syndrome X (n=23) and control subjects, respectively. Calcification scores of the four major coronary arteries appeared to have different predictive power for significant stenosis on the same vessel. For left main (LM) and left anterior descending (LAD) coronary arteries, CCSs of vessels with significant stenoses were not different from those without significant stenoses (values expressed as medians: LM 0 versus 1; LAD 98.5 versus 70; not significant). Calcification scores of left circumflex (LCX) and right coronary arteries (RCA) were significantly higher in vessels with significant stenosis (LCX 49.5 versus 0; RCA 53 versus 1; P<0.05). CCSs appeared to be moderately useful to predict significant stenoses in these two vessels (areas under receiver operating characteristic curves: LCX 0.68+/-0.08, 95% CI 0.52 to 0.81; RCA 0.71+/-0.08, 95% CI 0.55 to 0.84). CONCLUSIONS: The CCSs of RCA and LCX arteries, but not those of LM and LAD arteries, may predict significant angiographic stenosis on an artery-by-artery basis among patients with stable angina pectoris.

Synthesis of tetrasaccharides as possible metastatic inhibitors.

The synthesis is reported of the possible metastatic inhibitors-methyl beta-D-galactopyranosyl-(1-->4) -(2-acetamido-2-deoxy-alpha-D-glucopyranosyl)-(1-->6) -beta-D-galactopyranosyl-(1-->4)-beta-D-glucopyranoside (11) and methyl beta-D-galactopyranosyl- (1-->4)-(2-acetamido-2-deoxy-beta-D-glucopyranosyl)- (1-->6)-beta-D-galactopyranosyl-(1-->4)-beta-D-glucopyranoside (14)-by procedures for regio- and stereo-selective coupling, reduction of azido groups, N-acetylation, and O-deacetylation.

Increased arterial wave reflection may predispose syncopal attacks.

BACKGROUND: The incidence of syncope increases with age, while aging is also associated with increased arterial wave reflection. HYPOTHESIS: The study was undertaken to determine whether increased arterial wave reflection is a predisposing factor of syncope. METHODS: We recruited 38 patients (28 men and 10 women, mean age 57.2 +/- 20.3 years, range 17-87 years) with a history of syncope within 6 months of entry. The etiology of syncope was documented for each patient by a complete assessment of vasomotor function and cerebral flow. All patients received a comprehensive echocardiographic evaluation of cardiac structure and function. Carotid augmentation index (AI) was estimated noninvasively with the tonometry technique. The results were compared with those from 54 age- and gender-matched controls. RESULTS: The most frequent diagnoses of syncope were postural hypotension (13 patients) and cerebrovascular dysautoregulation (10 patients), and the cause could not be determined in 9 patients. Compared with the control group, the syncope group had a greater AI (20 +/- 21 vs. 10 +/- 15%, p = 0.013). Subgroup analysis of 20 patients aged > 50 years and with the aforementioned diagnoses showed even more striking results: AI, 29 +/- 10 vs. 11 +/- 15%, p < 0.001. The enhanced augmentation in the patients remained when age, systolic blood pressure, height, and heart rate were accounted for. Analysis of the carotid pulse wave suggested that both the timing and intensity of wave reflection were enhanced in patients with a history of syncope compared with controls. CONCLUSIONS: Our results support the hypothesis that enhanced arterial wave reflection is associated with the occurrence of syncope, especially in the elderly.

A double-blind ambulatory blood pressure monitoring study of the efficacy and tolerability of once-daily telmisartan 40 mg in comparison with losartan 50 mg in the treatment of mild-to-moderate hypertension in Taiwanese patients.

Ambulatory blood pressure monitoring (ABPM) was used to compare the efficacy and tolerability of once-daily telmisartan 40 mg and once-daily losartan 50 mg in Taiwanese patients with mild-to-moderate essential hypertension in a randomised, double-blind, double-dummy, parallel-group study. The initial 2-week placebo run-in phase was followed by randomisation to treatment with telmisartan 40 mg (n = 31) or losartan 50 mg (n = 30) for 6 weeks. The reduction in 18- to 24-h mean (SE) ambulatory diastolic blood pressure (DBP) from baseline was significantly greater with telmisartan 40 mg (-12.1 +/- 1.6 mmHg, p = 0.036) than with losartan 50 mg (-7.0 +/- 1.8 mmHg). The reduction in 18- to 24-h mean (SE) ambulatory systolic blood pressure (SBP) from baseline was also greater with telmisartan 40 mg (-16.0 +/- 2.4 mmHg) than with losartan 50 mg (-11.8 +/- 2.7 mmHg), but did not achieve statistical significance. Telmisartan was well tolerated; no serious adverse events occurred.

[Studies on synthesis and pharmacological activities of cimicifugamide from Cimicifuga dahurica, and its analogues].

The total synthesis of cimicifugamide, a new natural compound isolated from the roots of Cimicifuga dahurica, was accomplished by a reaction sequence of seven steps in an overall yield of 31%. Trifluoroacetoxy was used as leaving group at the anomeric carbon. The target product was characterized by IR, MS, 1HNMR, 13CNMR and elemental analysis. In addition, seven analogues were synthesized and their preliminary pharmacological activities were tested.

Anti-ischemic and anti-anginal effects of controlled-release and conventional isosorbide-5-mononitrate in stable angina pectoris.

BACKGROUND: A controlled-release formulation of isosorbide-5-mononitrate (5-ISMN) can be administered once daily to lower the peak plasma concentration of 5-ISMN to avoid peak-related side-effects, prolong duration of action and produce predictable and reproducible plasma concentrations of 5-ISMN. This study was undertaken to compare the anti-anginal and anti-ischemic efficacy of controlled-release 5-ISMN 60 mg administered once daily and conventional 5-ISMN 20 mg given twice daily in patients with stable angina pectoris. METHODS: In 44 patients with stable angina pectoris, controlled-release 5-ISMN and the conventional formulation of 5-ISMN were tested in an open, randomized, cross-over study. The study started with a one-week run-in period, during which nitrates were withdrawn. Patients were then randomly allocated to two-week treatment with controlled-release 5-ISMN 60 mg each morning followed by a one-week placebo washout and then a two-week treatment with the conventional formulation of 5-ISMN 20 mg twice daily, or vice versa. Treadmill exercise testing was performed at the end of the placebo run-in and washout periods and at the end of both active treatment periods. RESULTS: Thirty-nine patients completed the study and were included in the statistical evaluation. Total exercise duration and time to appearance of 1-mm ST depression increased significantly after two weeks of treatment with both drugs compared with placebo. However, the time to onset of chest pain increased significantly only after therapy with controlled-release 5-ISMN. Moreover, controlled-release 5-ISMN produced a more pronounced improvement in total exercise duration than the conventional formulation of 5-ISMN after two weeks of therapy. Adverse events were reported by five (13%) patients receiving controlled-release 5-ISMN and by the same percentage of patients receiving conventional 5-ISMN therapy; most of these events were headache and/or dizziness. CONCLUSIONS: Treatment with 5-ISMN in the controlled-release formulation of 60 mg administered once daily appears more effective in improving total exercise duration and increasing the time to onset of chest pain than the conventional formulation of 5-ISMN in patients with stable angina pectoris. Once-daily administration of controlled-release 5-ISMN is well tolerated and convenient.

Diffuse multiple coronary arteries to left ventricular fistulas.

Coronary artery to left ventricular fistula is an unusual anatomic anomaly consisting of a communication between one of the coronary arteries and the left ventricle. Only sporadic cases have been published in the literature. Diffuse multiple fistulas involving both left and right coronary arteries are even rarer. This report describes a 60-year-old woman with diffuse multiple fistulas communicating between both coronary arteries and the left ventricle. The patient manifested clinically with exertional angina and myocardial ischemia, as evidenced by a positive stress exercise test, which represents the coronary "steal" phenomenon.

Analysis of lipids in non-diabetic patients with acute myocardial infarction.

BACKGROUND: The incidence of postinfarct cardiac events can be reduced through secondary prevention by lipid regulation. The relationship between early-detected lipids and prognosis was investigated prospectively in 97 non-diabetic patients with acute myocardial infarction (AMI). METHODS: Blood samples were analyzed in five evolving stages of AMI: 1) immediately after admission (< 24 hours after the onset of symptoms); 2) on the second day after admission (< 48 hours after the onset of symptoms); 3) on the seventh day after admission; 4) two weeks after the AMI; and 5) three months after the AMI. Cardiac events, including congestive heart failure, reinfarction, unstable angina, ventricular tachyarrhythmia and sudden cardiac death were evaluated at a mean follow-up of 26 months. RESULTS: Serial measurements in 75 cases with complete follow-up showed that all lipids except lipoprotein(a) had a decline in plasma level after patients were admitted to hospital. The concentrations of lipids three months postinfarct approached the admission values. Age, body mass index, vessel number, severity of vessel disease and the initial values of lipids on admission had no influence on postinfarct cardiac events in these patients. CONCLUSIONS: The results indicate that the plasma levels of lipids detected within 24 hours after AMI can be used as the baseline lipid levels. Nevertheless, the impact of these lipids on the adverse outcomes in non-diabetic AMI patients should be further studied in a large-scale study.

Development of a coronary artery aneurysm three months after stent implantation: a case report.

Coronary artery stents have been used widely to prevent acute closure as a bailout procedure, or to decrease restenosis after balloon angioplasty. Stent use has increased substantially in recent years due to the ease and simplicity with which stents provide a predictable angiographic result. However, few data exist on the long-term safety of stents. This case report describes a 63-year-old male patient who developed intimal dissection after balloon angioplasty and who underwent coronary stent placement of a sheathed stent (half Palmaz-Schatz stent, 3.5 mm in diameter and 7 mm in length) as a bailout procedure. Postdilatation with a 3.5-mm balloon was performed at the maximum pressure of 14 atmospheres with a satisfactory angiographic result. However, an aneurysmal dilatation at the stent site was noted three months later. High-pressure stent use without immediately visible vascular dissection by angiography may not be effective for prevention of coronary aneurysm development in a case such as this. Aneurysmal dilatation may be a late complication in cases of coronary artery stent placement.

Safety and efficacy of the platelet glycoprotein IIb/IIIa inhibitor abciximab in Chinese patients undergoing high-risk angioplasty.

BACKGROUND: Platelets are believed to play a role in the ischemic complications of coronary angioplasty, such as abrupt closure of coronary vessels during or soon after the procedure. Accordingly, we evaluated the effect of a chimeric monoclonal antibody abciximab, directed against the platelet glycoprotein IIb/IIIa receptor, in patients undergoing angioplasty who were at high risk for ischemic complications. This receptor is the final common pathway for platelet aggregation. METHODS: In a prospective, double-blind trial, we randomly assigned 42 patients to receive a bolus and an infusion of placebo or a bolus and an infusion of abciximab. Low-dose, weight-adjusted heparin (initial dose of 70 U/kg of body weight) was used in both groups. Patients underwent coronary angioplasty for high-risk clinical situations involving unstable angina or high-risk coronary morphologic characteristics. The primary study end-point consisted of any of the following: death, nonfatal myocardial infarction, unplanned surgical revascularization, unplanned repeat percutaneous procedure, unplanned implantation of a coronary stent, or insertion of an intra-aortic balloon pump for refractory ischemia within 30 days of randomization. RESULTS: Compared with placebo, the abciximab resulted in a trend toward reduction in periprocedural myocardial infarction from 15% to 0%, although the differences were not statistically significant (p = 0.099). There were no significant differences between the two groups in the risk of major and minor bleeding and the need for blood transfusion. CONCLUSIONS: Inhibition of platelet glycoprotein IIb/IIIa receptor with abciximab, together with low-dose, weight-adjusted heparin, had a favorable trend toward the reduction of periprocedural myocardial infarction in patients undergoing high-risk angioplasty, without increasing the risk of hemorrhage.