Tao-Cheng Wu

Long-term angiotensin-converting enzyme inhibition reduces plasma asymmetric dimethylarginine and improves endothelial nitric oxide bioavailability and coronary microvascular function in patients with syndrome X

Angiotensin-converting enzyme (ACE) inhibition has been shown to improve clinical myocardial ischemia in patients with syndrome X (angina pectoris, positive treadmill exercise test, normal coronary angiograms, and no evidence of coronary spasm). This study was conducted to investigate the effects of long-term ACE inhibitors on endothelial nitric oxide (NO) metabolism and coronary microvascular function in patients with syndrome X. After a 2-week washout period, 20 patients with syndrome X were randomized to receive either enalapril, an ACE inhibitor, 5 mg twice daily (n = 10) or placebo (n = 10) in a double-blind design for 8 weeks. Another 6 age- and gender-matched subjects with negative treadmill exercise tests were also studied as controls. Compared with control subjects, patients with syndrome X had significantly reduced coronary flow reserve, reduced plasma levels of nitrate and nitrite (NOx), and a reduced plasma L-arginine to asymmetric dimethylarginine (ADMA) ratio (an index of systemic NO metabolism), as well as reduced endothelial function. These patients also had increased plasma levels of ADMA, which is an endogenous inhibitor of NO synthase and of von Willebrand factor, a marker of endothelial injury. Baseline characteristics including exercise performance and coronary flow reserve were similar between enalapril and placebo groups. After an 8-week treatment period, exercise duration (p = 0.001) and coronary flow reserve (p = 0.001) significantly improved with enalapril but not with placebo. Enalapril treatment, but not placebo, reduced plasma von Willebrand factor (p = 0.03) and ADMA levels (p = 0.01) and increased NOx levels (p = 0.01) and the ratio of L-arginine to ADMA (p <0.01). In patients with syndrome X, the plasma NOx level was positively and ADMA level inversely correlated with coronary flow reserve before and after the treatment. In conclusion, long-term ACE inhibitor treatment with enalapril improved coronary microvascular function as well as myocardial ischemia in patients with syndrome X. This may be related to the improvement of endothelial NO bioavailability with the reduction of plasma ADMA levels.

Vascular endothelial function and circulating endothelial progenitor cells in patients with cardiac syndrome X

Background: Endothelial dysfunction and microvascular abnormalities have been reported in patients with cardiac syndrome X (CSX), but the underlying mechanisms are unclear. Recent insights suggest that the injured endothelial monolayer is regenerated by circulating bone marrow-derived endothelial progenitor cells (EPCs). Aim: To test the hypothesis that the biology of altered EPCs might contribute to the pathophysiology of CSX. Methods: 34 subjects (mean (SD) age: 62 (7) years) were enrolled in the study, including 12 patients with CSX, 12 stable subjects with coronary artery disease (CAD) and 10 healthy controls. The number and adhesive function of EPCs were measured in peripheral-blood samples from these study participants. Results: The baseline characteristics in patients with CSX and CAD were enhanced Framingham risk scores, more hypertension and lower high-density lipoproteins than the controls. Patients with CSX and CAD had significantly decreased endothelium-dependent flow-mediated vasodilation (FMD) compared with normal controls (normal controls vs CSX vs CAD: 10.6% (3.5%) vs 6.1% (1.8%) vs 4.1% (1.9%), p<0.001), but the difference was not found in endothelium-independent nitroglycerine-mediated vasodilation (p = 0.159). Reduced numbers of colony-forming units (CFU) of EPCs were noted in patients with CSX and CAD (normal vs CSX vs CAD: 41 (9) vs 30 (7) vs 14 (7) CFU/well, p<0.001). Levels of EPCs were shown to be associated with FMD (r = 0.557, p = 0.001) and high-density lipoprotein (r = 0.339, p = 0.049). Also, attenuated fibronectin adhesion function of EPCs was found in patients with CSX and CaD compared with normal subjects (104 (12) vs 80 (20) vs 65 (13)/well, p<0.001). Conclusions: This study clearly showed for the first time that compared with normal subjects, patients with CSX have decreased levels and adhesive function of circulating EPCs. These findings may explain the underlying mechanisms which contribute to the endothelial dysfunction and microvascular abnormalities observed in patients with CSX.

Plasma matrix metalloproteinase-3 level is an independent prognostic factor in stable coronary artery disease

Background  Recent evidence suggests the important role of matrix metalloproteinases (MMPs) in the progression of atherosclerosis and development of clinical events. We assessed the prognostic value of different plasma MMPs in patients with stable coronary artery disease (CAD).

Comparison of endothelial vasodilator function, inflammatory markers, and N-terminal pro-brain natriuretic peptide in patients with or without chronotropic incompetence to exercise test

Objective: To investigate the role of endothelial function, inflammatory markers, and N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients with impaired chronotropic response during exercise test. Methods: 86 subjects were enrolled. Treadmill exercise test was conducted according to the modified Bruce protocols. Brachial ultrasound was used to measure endothelium dependent flow mediated vasodilatation (FMD). Chronotropic incompetence was defined as either failure to achieve 85% of the age predicted maximum heart rate or a low chronotropic index (< 0.8). Results: Of the 86 patients, 20 (23%) exhibited chronotropic incompetence. The patients were divided into three groups according to chronotropic index: group 1, < 0.8 (n  =  20); group 2, 0.8–1.0 (n  =  26); and group 3, > 1.0 (n  =  40). Patients with impaired chronotropic response had significantly lower FMD than those with higher chronotropic response (mean (SD) 2.8 (1.9)% v 5.0 (2.8)% v 5.3 (2.5)%, p  =  0.002, for groups 1, 2, and 3, respectively). Serum concentrations of high-sensitivity C reactive protein (hsCRP), monocyte chemoattractant protein-1 (MCP-1), and NT-proBNP were significantly higher in group 1 than in groups 2 and 3 (hsCRP: 19 (12) v 9 (6) v 9 (6) mg/l, p < 0.05; MCP-1: 140 (51) v 133 (60) v 108 (46) pg/ml, p  =  0.046; NT-proBNP: 4760 (1980) v 3710 (850) v 3910 (1060) mg/l, p  =  0.019, respectively). In addition, chronotropic index was significantly related to FMD (r  =  0.380, p  =  0.001) and inversely related to hsCRP (r  =  −0.267, p  =  0.013). By multivariate analysis, impaired chronotropic response was significantly related to endothelial dysfunction (p  =  0.012). Conclusion: Patients with impaired chronotropic response to graded exercise had endothelial dysfunction, enhanced systemic inflammation, and higher NT-proBNP concentrations. These findings may partly explain the mechanism of chronotropic incompetence as a predictor of cardiovascular risk and increased mortality.

Differential mononuclear cell activity and endothelial inflammation in coronary artery disease and cardiac syndrome X

BACKGROUND Circulating mononuclear cells could be activated with endothelial inflammation in patients with coronary artery disease (CAD). In some patients with normal coronary angiograms, myocardial ischemia could also present with coronary microvascular dysfunction (cardiac syndrome X). This study was undertaken to investigate whether mononuclear cell activation and endothelial inflammation can present in syndrome X patients. METHODS We evaluated the biochemical parameters, circulating soluble adhesion molecules, circulating superoxide free radicals, and mononuclear cell activity in 32 patients with syndrome X, 34 with angiographically documented CAD, and 17 age- and gender-matched healthy control subjects. RESULTS Compared to that in control subjects, plasma high-density lipoprotein was reduced (P<0.001) and insulin to glucose ratio increased (P=0.02) in CAD patients. Circulating level of soluble intracellular adhesion molecule-1 was significantly higher in both syndrome X and CAD patients than in control subjects (P<0.01), whereas the levels of soluble vascular cell adhesion molecule (P=0.02) and von Willebrand factor (P=0.01) were increased in CAD patients only. The peak (P<0.001) and total counts of superoxide free radicals in whole blood (P<0.001) was significantly higher in syndrome X patients than in the other two groups. However, phorbol-12-myristate-13-acetate-induced superoxide free radical generation of mononuclear cells was increased in CAD (10.5+/-4.6%, P=0.01) but not in syndrome X patients (8.7+/-2.0%) as compared with control subjects (7.7+/-0.5%). CONCLUSIONS The results indicated that the activity of mononuclear cells was increased with significant endothelial inflammation and injury in CAD patients. In syndrome X patients, though circulating superoxide free radicals were increased, there was minimal endothelial inflammation without mononuclear cell activation. The relatively preserved lipid and metabolic profiles might contribute to less vascular inflammation in syndrome X patients.

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.

Decreased Circulating Endothelial Progenitor Cell Levels and Function in Patients with Nonalcoholic Fatty Liver Disease

Objectives Nonalcoholic fatty liver disease (NAFLD) is associated with advanced atherosclerosis and a higher risk of cardiovascular disease. Increasing evidence suggests that injured endothelial monolayer is regenerated by circulating bone marrow derived-endothelial progenitor cells (EPCs), and levels of circulating EPCs reflect vascular repair capacity. However, the relation between NAFLD and EPC remains unclear. Here, we tested the hypothesis that patients with nonalcoholic fatty liver disease (NAFLD) might have decreased endothelial progenitor cell (EPC) levels and attenuated EPC function. Methods and Results A total of 312 consecutive patients undergoing elective coronary angiography because of suspected coronary artery disease were screened and received examinations of abdominal ultrasonography between July 2009 and November 2010. Finally, 34 patients with an ultrasonographic diagnosis of NAFLD, and 68 age- and sex-matched controls without NAFLD were enrolled. Flow cytometry with quantification of EPC markers (defined as CD34+, CD34+KDR+, and CD34+KDR+CD133+) in peripheral blood samples was used to assess circulating EPC numbers. The adhesive function, and migration, and tube formation capacities of EPCs were also determined in NAFLD patients and controls. Patients with NAFLD had a significantly higher incidence of metabolic syndrome, previous myocardial infarction, hyperuricemia, and higher waist circumference, body mass index, fasting glucose and triglyceride levels. In addition, patients with NAFLD had significantly decreased circulating EPC levels (all P<0.05), attenuated EPC functions, and enhanced systemic inflammation compared to controls. Multivariate logistic regression analysis showed that circulating EPC level (CD34+KDR+ [cells/105 events]) was an independent reverse predictor of NAFLD (Odds ratio: 0.78; 95% confidence interval: 0.69–0.89, P<0.001). Conclusions NAFLD patients have decreased circulating EPC numbers and functions than those without NAFLD, which may be one of the mechanisms to explain atherosclerotic disease progression and enhanced cardiovascular risk in patients with NAFLD.

Prognostic impact of body mass index in patients undergoing coronary artery bypass surgery

Background Obesity has numerous adverse effects on general, and especially, cardiovascular health. Plasma adiponectin, an adipokine, is inversely related to adipose tissue mass, and also the prognosis of heart failure and coronary artery disease (CAD). Coronary artery bypass grafting (CABG) surgery is usually the treatment of choice for patients with complex CAD. Objective To investigate the impact of body mass index (BMI) and the associated biomarkers on clinical outcomes after CABG. Methods Patients with CAD who underwent CABG by a single cardiac surgeon team were prospectively enrolled and followed for up to 5 years after CABG. Results Among the 234 consecutive patients (aged 70.4±10.5 years, BMI 24.68±3.27 kg/m2, 84.6% men), there were 76 mortalities during follow-up. BMI was negatively correlated with adiponectin (r=−0.203, p=0.003), high-sensitivity C-reactive protein (hsCRP; r=−0.176, p=0.009), and N-terminal pro-brain natriuretic peptide (NT-proBNP; r=−0.271, p<0.001). Patients of normal weight (BMI <25 kg/m2) had a decreased event free survival when compared with overweight or obese patients (BMI ≥25 kg/m2). After accounting for age, sex, manifest acute coronary syndrome, glomerular filtration rate, and left ventricular ejection fraction, BMI remained correlated with cardiovascular mortality in the study population. (HR and 95% CI per 1 kg/m2: 0.912 (0.833 to 0.998)). However, adiponectin, hsCRP, and NT-proBNP would abolish the prognostic impact of BMI. In addition, risk-stratified subgroup analysis showed that adiponectin, hsCRP and NT-proBNP predicted mortality in patients with normal weight, rather than in overweight or obese patients. Conclusions BMI was inversely associated with the prognosis of CABG. Such association may be linked to the baseline mechanisms related to metabolic disorder (adiponectin) and systemic inflammation (hsCRP). Future pathophysiological validation is indicated.

Serum bilirubin predicts long-term clinical outcomes in patients with cardiac syndrome X

Background Increased oxidative stress and vascular inflammation have been demonstrated in patients with cardiac syndrome X (CSX). Bilirubin, once considered simply the metabolic end product of haem degradation, has emerged as a potential endogenous inhibitor of atherosclerosis. This study was conducted to evaluate the prognostic role of serum bilirubin in disease progression and clinical outcome in patients with CSX. Methods A total of 108 consecutive CSX patients were enrolled. Serum bilirubin levels were examined from blood samples collected before coronary angiography. All patients were prospectively followed up for 5 years for the composite end point of total adverse events including death and non-fatal cardiovascular events (non-fatal myocardial infarction, ischaemic stroke, rehospitalisation for unstable angina, and coronary revascularisation). Results There were 20 adverse events, including five deaths, five ischaemic strokes and 10 rehospitalisations for unstable angina during follow-up. Patients with adverse events had lower baseline serum bilirubin levels (p<0.001). All patients were stratified into high-bilirubin, normal-bilirubin and low-bilirubin groups. The patients in the high-bilirubin group had the lowest incidence of total adverse events (p=0.008) and non-fatal cardiovascular events (p=0.008). In a multivariate Cox regression analysis, serum bilirubin, in addition to age and basal superoxide generation of circulating mononuclear cells, was also an independent predictor of total adverse events (HR 0.002; 95% CI 0.000 to 0.520; p=0.028). Conclusions In patients with CSX, baseline serum bilirubin level was associated with long-term outcomes. Serum bilirubin could be a predictive and protective biomarker for disease progression and the development of cardiovascular events in CSX patients.

Plasma levels of soluble receptor for advanced glycation end products are associated with endothelial function and predict cardiovascular events in nondiabetic patients.

ObjectivesWe sought to test the hypothesis that decreased plasma soluble receptor for advanced glycation end products (sRAGE) levels were associated with endothelial dysfunction in nondiabetic patients. BackgroundsRAGE, a C-truncated secretary isoform of the receptor protein, has been shown to neutralize vascular damage mediated by advanced glycation end products, and has been implicated in atherogenesis. However, the relation between plasma sRAGE level and endothelial function remains unclear. MethodsPlasma levels of sRAGE were examined in 180 nondiabetic participants with suspected coronary artery disease. Endothelial function was evaluated by endothelium-dependent flow-mediated vasodilation (FMD) of the brachial artery. The primary end point was the combined occurrence of major adverse cardiovascular events, including nonfatal myocardial infarction, revascularization with percutaneous coronary intervention or coronary artery bypass grafting, ischemic stroke, and cardiovascular death. ResultsAll participants were divided into three groups according to the magnitude of FMD: group 1 (FMD <3%), group 2 (FMD ≥3 and <6%), group 3 (FMD ≥6%). The plasma levels of sRAGE were significantly decreased in group 1 compared with groups 2 and 3 (676±270, 820±357, and 1140±451 pg/ml; P<0.001). By multivariate analysis, it was shown that the plasma sRAGE level was an independent predictor of endothelium-dependent FMD (R = 0.46; P<0.001). After a 48-month follow-up period, there were 23 events (26%) in the lower sRAGE group(≤median, 809 pg/ml) and 11 events (12%) in the higher sRAGE group (>809 pg/ml; P<0.05). By the Kaplan–Meier analysis, it was shown that enhanced plasma levels of sRAGE were associated with better major adverse cardiovascular event-free survival (P = 0.032). ConclusionThe results indicate that plasma sRAGE levels are positively associated with endothelial function and predict cardiovascular events in nondiabetic participants with suspected coronary artery disease, suggesting its pivotal role in atherothrombosis.