[Effect of Xinling Wan in treatment of stable angina pectoris: a randomized, double-blinded, placebo parallel-controlled, multicenter trial].

To evaluate the effectiveness and safety of Xinling Wan on patients with stable angina pectoris, a randomized, double-blinded, placebo parallel-controlled, multicenter clinical trial was conducted. A total of 232 subjects were enrolled and randomly divided into experiment group and placebo group. The experiment group was treated with Xinling Wan (two pills each time, three times daily) for 4 weeks, and the placebo group was treated with placebo. The effectiveness evaluation showed that Xinling Wan could significantly increase the total duration of treadmill exercise among patients with stable angina pectoris. FAS analysis showed that the difference value of the total exercise duration was between experiment group (72.11±139.32) s and placebo group (31.25±108.32) s. Xinling Wan could remarkably increase the total effective rate of angina pectoris symptom score, and the analysis showed that the total effective rate was 78.95% in experiment group and 42.61% in placebo group. The reduction of nitroglycerin dose was (2.45±2.41) tablets in experiment group and (0.50±2.24) tablets in placebo group on the basis of FAS analysis. The decrease of symptom integral was (4.68±3.49) in experiment group and (3.19±3.31) in placebo group based on FAS analysis. Besides, Xinling Wan could decrease the weekly attack time and the duration of angina pectoris. PPS analysis results were similar to those of FAS analysis. In conclusion, Xinling Wan has an obvious therapeutic effect in treating stable angina pectoris, with a good safety and a low incidence of adverse event and adverse reaction in experiment group.

Vitamin E ameliorates ox-LDL-induced foam cells formation through modulating the activities of oxidative stress-induced NF-κB pathway.

The role of antioxidant supplementation with vitamin E in the prevention of atherosclerosis has been a topic of considerable recent interest. The relevance of vitamin E for macrophage-derived foam cell formation, a hallmark of atherosclerosis, however, has not been unequivocally resolved. Here, we investigated the effect of oxidized LDL (ox-LDL) and vitamin E on lipid accumulation and total cholesterol content in U937 macrophages, reactive oxygen species generation and expression of nuclear factor-κB (NF-κB) signaling pathway. The results showed that the mRNA expression and protein levels of P-selectin were evident in U937 macrophages treated with ox-LDL and vitamin E, which indicating that expression of P-selectin is important in macrophage-derived foam cell formation. Moreover, P-selectin changes in ox-LDL-induced foam cell formation can be mediated by vitamin E through activities of nuclear NF-κB activated by serine phosphorylation of NF-κB inhibitor α, suggesting that activation of NF-κB pathway by macrophages may occur. Taken together, these data suggested that vitamin E can prevent ox-LDL-induced foam cell macrophages formation through modulating the activities of oxidative stress-induced NF-κB pathway.

Effects of mid-myocardial pacing on transmural dispersion of repolarization and arrhythmogenesis.

INTRODUCTION: Epicardial (Epi) activation of the left ventricular (LV) wall increases transmural dispersion of repolarization (TDR), which creates a substrate for the development of ventricular arrhythmia. We hypothesize that pacing from the LV mid-myocardium may decrease the TDR and occurrence of arrhythmias. METHODS AND RESULTS: A transmural electrocardiogram and transmembrane action potentials were simultaneously recorded from Epi, mid-myocardial (M), and endocardial (Endo) layers of the arterially perfused canine LV wedge preparations (n= 8). Transmural dispersion of repolarization varied when the preparations were paced at each layer, respectively (Endo pacing, 35.6 ± 6.6 ms; M pacing, 34.9 ± 7.3 ms; Epi pacing, 72.4 ± 4.9 ms; P< 0.001). A significant difference was noted in TDR between M pacing and Epi pacing (P< 0.001), but not between M pacing and Endo pacing (P= 0.831). This result was reproducible in the presence of ischaemia-reperfusion experiments (n= 8). Transmural dispersion of repolarization was amplified as compared with non-ischaemic experiments and differed when preparations were paced at each layer (Endo pacing, 62.8 ± 13.8 ms; M pacing, 63.3 ± 13.3 ms; Epi pacing, 111.1 ± 17.7 ms; P< 0.001). There was again no significant difference between Endo pacing and M pacing (P= 0.948). However, as pacing was shifted from M to Epi, there was a significant increase in TDR (P< 0.001). Ventricular arrhythmias were induced in two of eight ischaemic preparations during Epi pacing, but did not occur in either M or Endo pacing. CONCLUSION: Mid-myocardial pacing can significantly decrease the TDR and prevent the occurrence of ventricular arrhythmias as compared with Epi pacing.

Catheter ablation of cardiac fat pads attenuates Bezold-Jarisch reflex in dogs.

BACKGROUND: Bezold-Jarisch reflex (BJR) plays an important role in the pathophysiology of several cardiovascular disorders. Radiofrequency catheter ablation (RFCA) of the vagal ganglia in cardiac fat pads (FPs) may attenuate BJR. The purpose of this study was to examine the effects of RFCA of the cardiac FPs on veratridine-induced BJR in dogs. METHODS AND RESULTS: This study was performed in 30 pentobarbital-anesthetized and open-chest dogs: control group received no ablation (n = 15); and ablation group (n = 15) received epicardial ablation of the 3 FPs located near the right pulmonary vein, the inferior vena cava, and the aortic root. The BJR was induced by injection of veratridine (15 µg/kg) into the left ventricle. Before injection of veratridine, there were no significant differences in heart rate (HR), systolic arterial pressure (SAP), diastolic arterial pressure (DAP), mean arterial pressure (MAP), left ventricular systolic pressure (LVSP), left ventricle end-diastolic pressure (LVEDP), left ventricular peak systolic and diastolic velocity (±dp/dt(max)) between these 2 groups (P > 0.05). However, the veratridine-induced decrease of HR in ablation group was significantly lower than that in control group (22.9 ± 8.5 bpm vs 93.3 ± 18.4 bpm, P < 0.01). There were no differences in the reduction of SAP, DAP, MAP, LVSP, LVEDP and dp/dt(max) between both groups (P > 0.05). CONCLUSIONS: RFCA of the cardiac FPs significantly attenuated veratridine-induced cardio-vagal component but not the vasodepressor component of the BJR. This might have therapeutic implications in BJR-related disorders such as cardio-inhibitory vasovagal syncope.

Network pharmacology for the identification of phytochemicals in traditional Chinese medicine for COVID-19 that may regulate interleukin-6.

OBJECTIVE: ´Three formulas and three medicines,' namely, Jinhua Qinggan Granule, Lianhua Qingwen Capsule, Xuebijing Injection, Qingfei Paidu Decoction, HuaShi BaiDu Formula, and XuanFei BaiDu Granule, were proven to be effective for coronavirus disease 2019 (COVID-19) treatment. The present study aimed to identify the active chemical constituents of this traditional Chinese medicine (TCM) and investigate their mechanisms through interleukin-6 (IL-6) integrating network pharmacological approaches. METHODS: We collected the compounds from all herbal ingredients of the previously mentioned TCM, but those that could down-regulate IL-6 were screened through the network pharmacology approach. Then, we modeled molecular docking to evaluate the binding affinity between compounds and IL-6. Furthermore, we analyzed the biological processes and pathways of compounds. Finally, we screened out the core genes of compounds through the construction of the protein-protein interaction network and the excavation of gene clusters of compounds. RESULTS: The network pharmacology research showed that TCM could decrease IL-6 using several compounds, such as quercetin, ursolic acid, luteolin, and rutin. Molecular docking results showed that the molecular binding affinity with IL-6 of all compounds except γ-aminobutyric acid was < -5.0 kJ/mol, indicating the potential of numerous active compounds in TCM to directly interact with IL-6, leading to an anti-inflammation effect. Finally, Cytoscape 3.7.2 was used to topologize the biological processes and pathways of compounds, revealing potential mechanisms for COVID-19 treatment. CONCLUSION: These results indicated the positive effect of TCM on the prevention and rehabilitation of COVID-19 in at-risk people. Quercetin, ursolic acid, luteolin, and rutin could inhibit COVID-19 by down-regulating IL-6.

Vicious cycle composed of gut flora and visceral fat: a novel explanation of the initiation and progression of atherosclerosis.

Microorganisms infection was thought to be associated with atherosclerosis (AS), but the results of trials investigating antibiotic therapy in patients with coronary artery disease were controversial. Recently, a series of studies explored the relationship between gut flora and obesity, which showed that western-style diet (high fat) could induce imbalanced ratio of the Firmicutes versus the Bacteroidetes in the gut of germ-free mice and human beings, and gut flora could promote obesity through several novel pathways, such as inhibition of fasting-induced adipocyte factor. Meanwhile, data from some studies confirm that some link exists between the abdominal obesity and satiety centers (hindbrain and hypothalamus) with neurotransmitters and hormones. All of the above showed some connection between western-style diet, gut flora, visceral fat, and satiety centers, but until now, no study has shown us the exact mechanism about it. It is proposed that the vicious cycle composed of gut flora and visceral fat may initiate and promote AS. Attempts to confirm this hypothesis may lead to new directions in the study of the pathogenesis of AS and the development of novel strategies for the treatment of AS.

Dysfunction of AQP7 in the periadventitial fat: A novel trigger of atherosclerosis.

Vascular adventitial lesion as a new etiological factor of atherosclerosis (AS) has been confirmed by the results of several different animal models, and some evidence supports adventitial inflammation as the main cause, but the exact mechanism is still elusive. The data from some studies confirm that some link exists between the adventitial inflammation (which also might happen in the periadventitial fat) and atherosclerotic lesions. Aquaporin7 (AQP7) as an aquaglyceroporin, which regulates the permeation of glycerol through the cell membrane and located in the adipose tissue, shows some relationship with obesity. The result of the studies about AQP7-knockout mice and different expression of AQP7 in the cutaneous abdominal adipose tissue among people with different body types proved this phenomenon. Meanwhile, some degree of dysfunction of AQP7 has been proved in the obese. Until now, no study has shown us the data on the correlation of the expression of AQP7 in the periadventitial fat with the severity of atherosclerotic lesions. It is proposed that dysfunction of AQP7 in the periadventitial fat may trigger the adventitial inflammation. Attempts to confirm this hypothesis may lead to new directions in the study of the pathogenesis of AS and the development of a novel agent for this disorder.

[Evaluation on cardio-ankle vascular index derived from ultrasound].

OBJECTIVE: The cardio-ankle vascular index (CAVI) could be obtained by measuring pulse wave velocity (PWV) and blood pressure (BP). This method is associated with various technical drawbacks. We evaluated the accuracy and usefulness of CAVI measured by ultrasound via detecting the aortic and ankle flow directly by ultrasonic probe. METHODS: CAVI was determined in 96 subjects [64 male, mean age (41.2 +/- 8.9) years] who took part in the annual check up program in our department by means of the professional equipment (BP-203RPEII, VP-1000, Japan, CAVIp), the M-mode (CAVIm) and color Doppler flow imaging (CAVId). Measurement reproducibility on was obtained by repeat the measurements in 20 subjects choose randomly from the 96 subjects. Carotid ultrasound (CU) was performed to obtain intima-media thickness (IMT) and beta index in all subjects. RESULTS: CAVI obtained by various methods were similar and comparable (CAVIm 7.74 +/- 1.62, CAVId 7.77 +/- 1.59, CAVIp 8.74 +/- 1.57, all P > 0.05). Inter-group and inter-observer variance was negligible (r1 = 0.98, r2 = 0.97). There were also significant correlations between CAVIm and IMT, CAVIm and beta (r1 = 0.824, r2 = 0.812, all P < 0.01), and between CAVId and IMT, CAVId and beta (r1 = 0.815, r2 = 0.813, all P < 0.01). CONCLUSIONS: CAVI could be correctly measured by ultrasound technique.

[Efficacy and safety of olmesartan medoxomil versus losartan potassium in Chinese patients with mild to moderate essential hypertension].

OBJECTIVE: To evaluate the efficacy and safety of olmesartan medoxomil compared with losartan potassium in patients with mild to moderate essential hypertension. METHOD: This is a randomized, double-blind, double-dummy, active-controlled, parallel, multi-center study. After a 2-week placebo run-in period, a total of 287 eligible subjects were randomized at 1:1 ratio to receive olmesartan medoxomil 20 mg or losartan potassium 50 mg, once daily for 8 weeks. The blood pressure was assessed after 4 weeks treatment. If the subject's seating diastolic blood pressure (SeDBP) was still >or=90 mm Hg, the dosage was doubled for another 4 weeks; for those subjects whose SeDBP was <90 mm Hg after 4-week treatment, the initial dosage remained unchanged and the treatment continued until completion of the study. RESULTS: (1) The mean trough reduction in SeDBP from baseline in olmesartan group was significantly greater than that in losartan group after 4 weeks (11.72 mm Hg vs 9.23 mm Hg, P=0.004) and 8 weeks treatment (12.94 mm Hg vs 11.01 mm Hg, P=0.035). (2) The number and percentage of responders in olmesartan group (81, 65.3%) were statistically higher than those (68, 52.7%) in losartan group (P=0.028) after 4 weeks treatment and were similar between the two groups after 8 weeks treatment (P>0.05). (3) Individual and overall trough/peak ratios of DBP and SBP in 24-hour ambulatory blood pressure monitoring were higher in olmesartan group than losartan group. The hypotensive effect of olmesartan was more durable than losartan at 24 hour interval. (4) The incidence of study drug-related adverse events (AEs) in olmesartan group (10.5%) was similar as that in losartan group (13.9%, P>0.05). Most of these AEs were mild and transient. CONCLUSION: This study shows that olmesartan medoxomil, at oral dose of 20 mg-40 mg once daily was effective and safe for hypertension treatment and the hypotensive effect was superior to losartan potassium (50 mg-100 mg once daily).

[Effects of antidepressant therapy in patients with suspected "angina pectoris" and negative coronary angiogram complicating comorbid depression].

OBJECTIVE: We observed the therapeutic effectiveness and safety of different antidepressants as well as the correlation between symptomatic improvement of depression and improvement of chest pain in patients with susceptible "angina pectoris" and negative coronary angiogram complicating comorbid depression. METHODS: In this double-blinded randomized study, a total of 123 eligible patients were allocated into three groups: (1) Group F: fluoxetine 20 mg QN (n = 41); (2) Group P: Placebo 1 tablet QN (n = 40); (3) Group F + O: fluoxetine 20 mg + olanzapine 2.5 mg QN for the former 2 weeks and only fluoxetine 20 mg QN for the latter 2 weeks (n = 42). The total therapy duration was 4 weeks. HAMD, HAMA and self-evaluation table of chest pain were obtained before therapy, at the end of 1 and 2 weeks after therapy. RESULTS: Baseline HAMD and HAMA scores and self-evaluation score of chest pain were similar among 3 groups and all scores were significantly improved post various therapies in the order of group F + O > group F > group P. The rate of score decrease were seen after 1 week treatment in group F + O and after 2 week treatment in group F. There was a significant positive correlation between the rates of self-evaluation chest pain score decrease and HAMD (r = 0.867, P < 0.001) and HAMA (r = 0.854, P < 0.001) score decreases after 4 weeks therapies (P < 0.05). During the whole course of treatment, no serious adverse reaction was found in all patients. CONCLUSION: In patients with suspected "angina pectoris" and negative coronary angiogram complicating comorbid depression, the antidepressants were safe and significantly improved the symptoms of depression and anxiety and chest pain. Low dose fluoxetine plus short term olanzapine regimen was superior to fluoxetine alone regimen in terms of stronger and quicker symptom improvement.

Increased levels of CD40-CD40 ligand system in patients with essential hypertension.

BACKGROUND: Although it has been hypothesized that hypertension is in part an inflammatory disorder, clinical data linking inflammation with incident hypertension are scarce. There is evidence that have shown that CD40-CD40L interaction plays a pathogenic role in inflammatory disorders. We assessed whether CD40 system expressions were altered in patients including 30 with hypertension grade 1, 80 with hypertension grade 2 and 40 with hypertension grade 3. METHODS: Twenty normal controls and 150 patients with essential hypertension were investigated. The expression of CD40 and CD40L on platelet was analyzed by indirect-immunofluorescence flow cytometry and soluble CD40L level was determined by a commercially available ELISA. C-reactive protein was also measured by ELISA. RESULTS: All patients with hypertension showed a significant increase of CD40 (67.1+/-9.6 Mean Fluorescence Intensity, MFI) and CD40L (15.3+/-5.0 MFI) coexpression on platelets as well as sCD40L levels (12.8+/-3.9 ng/ml ) compared with controls (p<0.0001). We found that CRP levels related to CD40-CD40L system. We also observed a slight correlation between sCD40L level and blood pressure. During 3 months follow-up, patients with enhanced levels of sCD40L (>15 ng/ml) indicated a tough control of blood pressure. CONCLUSION: Patients with essential hypertension show increased coexpression of CD40 system, which suggests that hypertension is in part an inflammatory disorder.

Cholesterol-lowering effect of a theaflavin-enriched green tea extract: a randomized controlled trial.

BACKGROUND: Tea consumption has been associated with decreased cardiovascular risk, but potential mechanisms of benefit are ill-defined. While epidemiologic studies suggest that drinking multiple cups of tea per day lowers low-density lipoprotein cholesterol (LDL-C), previous trials of tea drinking and administration of green tea extract have failed to show any impact on lipids and lipoproteins in humans. Our objective was to study the impact of a theaflavin-enriched green tea extract on the lipids and lipoproteins of subjects with mild to moderate hypercholesterolemia. METHODS: Double-blind, randomized, placebo-controlled, parallel-group trial set in outpatient clinics in 6 urban hospitals in China. A total of 240 men and women 18 years or older on a low-fat diet with mild to moderate hypercholesterolemia were randomly assigned to receive a daily capsule containing theaflavin-enriched green tea extract (375 mg) or placebo for 12 weeks. Main outcome measures were mean percentage changes in total cholesterol, LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglyceride levels compared with baseline. RESULTS: After 12 weeks, the mean +/- SEM changes from baseline in total cholesterol, LDL-C, HDL-C, and triglyceride levels were -11.3% +/- 0.9% (P =.01), -16.4% +/- 1.1% (P =.01), 2.3% +/- 2.1% (P =.27), and 2.6% +/- 3.5% (P =.47), respectively, in the tea extract group. The mean levels of total cholesterol, LDL-C, HDL-C, and triglycerides did not change significantly in the placebo group. No significant adverse events were observed. CONCLUSION: The theaflavin-enriched green tea extract we studied is an effective adjunct to a low-saturated-fat diet to reduce LDL-C in hypercholesterolemic adults and is well tolerated.

[Efficacy and safety of azosemide in patients with edema and ascites].

OBJECTIVE: To assess the efficacy and safety of azosemide in patients with edema and ascites. METHODS: A multicentral, randomized, double-blind, controlled clinical trial was applied. All 223 patients (cardiac edema 92, hepatogenic edema 63, renal edema 68) were randomized to azoesmide and furosemide group, and all patients were treated for 2 weeks. Patients with cardiac or renal edema took azosemide (30 mg/d) or furosemide (20 mg/d); patients with hepatogenic edema took azosemide (60 mg/d) or furosemide (40 mg/d). The dosage were adjusted to azosemide 60 mg/d (cardiac, renal edema), 90 mg (hepatogeic edema); or furosemide 40 mg/d (cardiac, renal edema), 60 mg (hepatogeic edema), if diuretic effects were not obtained at the end of third day. RESULTS: At the end of the study, the weight changes were (2.87+/-3.10) kg and (2.81 +/-2.84) kg; the total effective rate of edema lessen was 89.19% and 89.81%; the total effective rate of heart function improvement was 64.44% and 66.66%; the 24 h urine output increased (321.85 +/-669.52) ml and (273.80 +/-645.72) ml for azosemide and furosemide, respectively. The total effective rate of ascites lessen (tested by B-ultrasound) was 89.28% and 86.66%; abdominal girth decreased (5.20 +/-3.58) cm and (5.03 +/-3.74) cm for azosemide and furosemide, respectively. The adverse event rate was 23.01% in azosemide group and 21.01% in furosemide group; the main adverse effects were hypokalemia, hyperuricemia, hypertriglyceridemia and thirsty. CONCLUSION: Azosemide could effectively lessen edema, improve heart function and decrease ascitesûit is well tolerated and is particularly useful for the diuretic treatment.

[Effects of pravastatin, fosinopril and their combination on myocardium TNF-alpha expression and ventricular remodeling after myocardial infarction in rats].

OBJECTIVE: To investigate the effects of pravastatin, fosinopril and their combination on ventricular remodeling, cardiac function, tumor necrosis factor-alpha (TNF-alpha) mRNA expression, and matrix metalloproteinases (MMPs) activities after myocardial infarction (MI) in rats. METHODS: Acute myocardial infarction (AMI) was established by ligation of the anterior descending coronary artery in male Sprague-Dawly (SD) rats. Twenty-four hours after the procedure, the 48 surviving rats were grouped randomly as AMI control, fosinopril (10 mg.kg(-1).d(-1)), pravastatin (20 mg.kg(-1).d(-1)) and a combined use of the 2 drugs. Sham-operated group (n = 8) was taken randomly as non-infarction control. Six weeks after treatment with the drugs by gastric gavage, heart function and left ventricular remodeling were assessed. Left ventricular weight (LVW)/body weight (BW) ratio was determined. The relative expression of myocardium TNF-alpha mRNA was assessed by reverse transcription-polymerase chain reaction. Left ventricular myocardium MMPs activities were assessed by Zymography. RESULTS: There were no significant differences among the four AMI groups in infarction size (P > 0.05). In comparison with the AMI group, left ventricular end-diastolic pressure, left ventricular end-diastolic diameter, LVW/BW all decreased significantly (P < 0.05 - 0.01); while dp/dtmax, dp/dtmin, fractional shortening (FS) and ejection fraction (EF) increased significantly in all three drug-treated groups (P < 0.05 - 0.01); increments of FS, LVEF and dp/dtmax were more evident in the combination group than either the fosinopril or pravastatin group (P < 0.05). The levels of TNF-alpha mRNA in AMI rats treated with fosinopril, pravastatin and their combination reduced 29%, 26% and 33%, respectively (P < 0.01); MMP-2 activity reduced 25%, 30% and 35%, respectively (P < 0.01); MMP-9 activity reduced 20%, 18% and 24%, respectively (P < 0.01). There were no significant differences in other variables among the 3 treatment groups (P > 0.05). CONCLUSION: Pravastatin, fosinopril and their combination showed favorable effects on left ventricular remodeling after AMI in rats and demonstrated improved cardiac function. The combined treatment group yielded better results in the context of improving left ventricular systolic function. These effects could be relevant to the attenuation of increased MMP-2 and MMP-9 activities and left ventricular expression of TNF-alpha.

Impact of losartan and angiotensin II on the expression of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in rat vascular smooth muscle cells.

The present study aimed to investigate the impact of losartan and angiotensin II (AngII) on the expression of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1), secreted by rat vascular smooth muscle cells (VSMCs). Rat VSMCs were isolated and cultured in different concentrations of AngII and losartan for 24 h and western blot analysis and quantitative polymerase chain reaction were performed to observe the subsequent impact on the gene and protein expression of MMP-9 and TIMP-1. AngII was shown to promote the protein and gene expression of MMP-9 in VSMCs in a concentration-dependent manner. No effect was observed on the expression of TIMP-1, therefore, an increase in the MMP-9/TIMP-1 ratio was observed. Losartan was shown to be able to inhibit MMP-9 protein and gene expression in a concentration-dependent manner, whilst promoting an increase in TIMP-1 expression, thus decreasing the ratio of MMP-9/TIMP-1. The combined action of losartan and AngII resulted in the same directional changes in MMP-9 and TIMP-1 expression as observed for losartan alone. The comparison of AngII, losartan and the combinatory effect on the expression of MMP-9 and TIMP-1 in VSMCs indicated that losartan inhibited the effects of AngII, therefore reducing the MMP-9/TIMP-1 ratio, which may contribute to the molecular mechanism of losartan in preventing atherosclerosis. In atherosclerosis, the development of the extracellular matrix of plaque is closely correlated with the evolution of AS. The balance between MMPs and TIMPs is important in maintaining the dynamic equilibrium between the ECM, and the renin-angiotensin-aldosterone system, which is involved in the pathologenesis of AS, and in which AngII has a central role.

Association of blood pressure and coronary collateralization in type 2 diabetic and nondiabetic patients with stable angina and chronic total occlusion.

OBJECTIVE: We investigated whether and to what extent blood pressure (BP) affects coronary collateralization in type 2 diabetic and nondiabetic patients with stable angina and chronic total occlusion. METHODS: Brachial BP was measured using an inflatable cuff manometer in 431 diabetic and 287 nondiabetic patients with stable angina and angiographic total occlusion of at least one major coronary artery. They were classified according to the SBP (<100, 100-119, 120-139, 140-159, 160-179, and ≥180 mmHg), DBP (<60, 60-69, 70-79, 80-89, 90-99, and ≥100 mmHg), and pulse (<40, 40-49, 50-59, 60-69, 70-79, and ≥80 mmHg) BP ranges. The degree of coronary collaterals supplying the distal aspect of a total occlusion from the contralateral vessel was graded as poor (Rentrop score of 0 or 1) or good collateralization (Rentrop score of 2 or 3). RESULTS: In diabetic patients, the incidence of poor collateralization was related to the DBP in a U-shaped pattern, with the lowest risk at 80-89 mmHg. In nondiabetic patients, an optimal DBP range was 90-99 mmHg for good collaterals, but no U-shaped relation between DBP and coronary collateralization was observed. After adjusting for the baseline characteristics in the logistic regression models, the increased risk of poor collateralization persisted for low or high DBP ranges in diabetic [odds ratio (OR) 2.02-7.29, P ≤ 0.04] and nondiabetic patients (OR 3.62-5.98, P ≤ 0.02). No such relations were observed between collateral grades and SBP and pulse BP. CONCLUSION: This study demonstrates that 80-89 and 90-99 mmHg are the optimal ranges for DBP in diabetic and nondiabetic patients with stable angina and chronic total occlusion, within which the risk of poor collateralization is low.

Effect of CD40--CD40 ligand interaction on diacylglycerol-protein kinase C and inositol trisphosphate-Ca(2+) signal transduction pathway in human umbilical vein endothelial cells.

BACKGROUND: Increasing evidence shows that CD40-CD40L interaction plays a crucial role in the pathogenesis of atherosclerosis and coronary artery disease. The mechanism of CD40-CD40L interaction might be related to signal transduction via receptor. The transduction pathway of the CD40 receptor may involve the activation of phospholipase C (PLC) which induces the production of inositol trisphosphate (IP(3)) leading to the increase of the intracellular free calcium on one hand, and of diacylglycerol (DAG) which stimulates the translocation to the membrane of protein kinase C (PKC). METHODS: Endothelial cells were isolated from human umbilical vein and incubated with indicated concentrations of CD40 ligand (CD40L) for various periods. The DAG levels in HUVEC were studied with radioenzymatic assay. Quantitative measurements of 32P phosphatidic acid were performed by thin-layer chromatography and autoradiography. IP(3) was quantitatively measured by the radioreceptor binding assay. The activity of PKC and [Ca(2+)]i induced by CD40L were measured by its ability to transfer phosphate from [gamma-32P]ATP to lysine-rich histone and flow cytometric analysis loading with the Ca(2+) dye fluo3/Am, respectively. RESULTS: The DAG levels were raised by CD40L in a dose-dependent, biphasic manner. The early phase was rapid and transient, peaking at 20 s; and the late phase reached the maximal level at 10 min and then decayed slowly. CD40L increased the PKC total activity in a dose-dependent manner with phase peaking at 12 min, then decreased slowly and maintained for at least 20 min. The results also showed that CD40L induced PKC activity translocation from the cytosolic to membrane. Similarly, the CD40L-induced transient IP(3) formation was coincident with the first peak of DAG formation. Moreover, CD40L also induced biphasic [Ca(2+)]i responses including the rapid initial transient phase and the sustained phase. Anti-CD40 monoclonal antibody can significantly suppress CD40L-induced DAG-PKC and IP(3)-[Ca(2+)]i signal pathway activation in HUVEC. CONCLUSIONS: CD40-CD40 ligand interaction can induce a robust stimulation of the DAG-PKC and inositol trisphosphate-Ca(2+) signal transduction pathway in HUVEC.

The effect of elevated serum soluble CD40 ligand on the prognostic value in patients with acute coronary syndromes.

BACKGROUND: Increasing evidence shows that high expression of CD40L plays an important role in the pathogenesis of atherosclerosis and coronary artery disease. We evaluated the clinical predictive value of increased serum soluble CD40 ligand (CD40L) in patients with acute coronary syndromes (ACS) and acute chest pain. METHODS: Serum levels of soluble CD40 ligand were measured by ELISA in 128 patients with ACS and in 68 patients with acute chest pain. Platelet activation was assessed by flow cytometry. RESULTS: The levels of soluble CD40 ligand were increased in 57.8% patients with ACS (>8.0 ng/ml) and in 35 patients with acute chest pain (>8.0 ng/ml), respectively. The level of soluble CD40 ligand was slightly correlated with measured levels of troponin T (r=0.21, p<0.05), and the increased soluble CD40L levels (>8.0 ng/ml) were associated with higher risk for AMI, sudden death and recurrent angina. Patients with elevated serum levels of sCD40L and cTnT showed a significantly increased risk of major adverse cardiovascular events (including AMI, sudden death and recurrent angina) in the two groups during 30 days and 6 months of follow-up. CONCLUSION: In patients with unstable coronary artery disease, elevation of serum soluble CD40L levels indicated an independent increased risk of major adverse cardiovascular events.