Jieming Mao

Homocysteine impairs coronary artery endothelial function by inhibiting tetrahydrobiopterin in patients with hyperhomocysteinemia

Hyperhomocysteinemia (HHcy) has been associated with impaired vascular endothelial function. Our previous study demonstrated significantly higher secretion of the chemokine monocyte chemoattractant protein-1 from monocytes in response to lipopolysaccharide in patients with HHcy. In the present study, we investigated whether coronary endothelial function was damaged in patients with chronic HHcy (plasma level of homocysteine >15 μmol/l) and, if so, whether this impaired endothelial function is induced by the uncoupling of endothelial nitric oxide synthase (eNOS). When tetrahydrobiopterin levels are inadequate, eNOS is no longer coupled to l-arginine oxidation, which results in reactive oxygen species rather than nitric oxide production, thereby inducing vascular endothelial dysfunction. The 71 participants were divided into two groups, control (n = 50) and HHcy (n = 21). Quantification of coronary flow velocity reserve (CFVR) was after rest and after adenosine administration done by noninvasive Doppler echocardiography. Plasma levels of nitric oxide and tetrahydrobiopterin were significantly lower in patients with HHcy than in controls (99.54 ± 32.23 vs. 119.50 ± 37.68 μmol/l and 1.43 ± 0.46 vs. 1.73 ± 0.56 pmol/ml, all P < 0.05). Furthermore, CFVR was significantly lower in the HHcy than the control group (2.76 ± 0.49 vs. 3.09 ± 0.52, P < 0.05). In addition, plasma level of homocysteine was negatively correlated with CFVR. Chronic HHcy may contribute to coronary artery disease by inducing dysfunction of the coronary artery endothelium. The uncoupling of eNOS induced by HHcy in patients with chronic HHcy may explain this adverse effect in part.

Low density lipoprotein cholesterol level inversely correlated with coronary flow velocity reserve in patients with Type 2 diabetes

Objectives To evaluate the association of coronary artery endothelial function and plasma levels of low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C) in patients with Type 2 Diabetes Mellitus (DM). Methods We investigated 90 participants from our institution between October 2007 to March 2010: non-DM (n = 60) and DM (n = 30). As an indicator of coronary endothelial dysfunction, we used non-invasive Doppler echocardiography to quantify coronary flow velocity reserve (CFVR) in the distal part of the left descending artery after rest and after intravenous adenosine administration. Results Plasma level of LDL-C was significantly higher in patients with DM than in non-DM (3.21 ± 0.64 vs. 2.86 ± 0.72 mmo/L, P < 0.05), but HDL-C level did not differ between the groups (1.01 ± 0.17 vs. 1.05 ± 0.19 mmo/L). Furthermore, the CFVR value was lower in DM patients than non-diabetics (2.45 ± 0.62 vs. 2.98 ± 0.68, P < 0.001). Plasma levels of LDL-C were negatively correlated with CFVR in all subjects (r = −0.35, P < 0.001; 95% confidence interval (CI): −0.52 – −0.15) and in the non-DM (r = −0.29, P < 0.05; 95% CI: −0.51– −0.05), with an even stronger negative correlation in the DM group (r = −0.42, P < 0.05; 95% CI: −0.68 – −0.06). Age (β = −0.019, s = 0.007, sβ = −0.435, 95% CI: −0.033 – −0.005, P = 0.008), LDL-C (β = −0.217, s = 0.105, sβ = −0.282, 95% CI: −0.428 – −0.005, P = 0.045) remained independently correlated with CFVR in the DM group. However, we found no correlation between HDL-C level and CFVR in any group. Conclusions Diabetes may contribute to coronary artery disease (CAD) by inducing dysfunction of the coronary artery endothelium. Increased LDL-C level may adversely impair coronary endothelial function in DM. HDL-C may lose its endothelial-protective effects, in part as a result of pathological conditions, especially under abnormal glucose metabolism.

Coronary flow velocity reserve is improved by PPAR-α agonist fenofibrate in patients with hypertriglyceridemia.

INTRODUCTION Fenofibrate, an agonist of peroxisome proliferator-activated receptor-α (PPAR-α), has a vascular protective effect. AIMS We investigated the effect of the PPAR-α agonist on coronary artery endothelial function in patients with hypertriglyceridemia. METHODS Fifty-eight patients with hypertriglyceridemia were divided into two groups: control (no treatment; n = 23) and fenofibrate treatment (n = 35), 200 mg/d, for 6 months. The patients had undergone rest and adenosine treatment to induce hyperemia for quantification of coronary flow velocity reserve (CFVR) by noninvasive Doppler echocardiography before treatment and at 6-month follow-up. Pulse wave velocity (PWV) was measured before treatment and at 6-month follow-up. RESULTS CFVR was significantly improved with fenofibrate treatment as compared with baseline level and control group (3.14 ± 0.36 vs. 2.80 ± 0.58 and 2.79 ± 0.65, P < 0.01 and 0.05, respectively), with no difference between baseline levels and untreated controls. In addition, at 6 months, plasma level of homocysteine was significantly increased with fenofibrate treatment as compared with at baseline and control group (median 18.13 [range 14.46-22.02]μmol/L vs. 14.09 [12.01-18.81] and 13.34 [9.69-17.06]μmol/L, P < 0.001 and 0.01, respectively). Furthermore, at 6 months, PWV was significantly decreased with fenofibrate treatment as compared with control group (1446 ± 136 cm/s vs. 1570 ± 203 cm/s, P < 0.05). CONCLUSIONS Treatment with PPAR-α agonist fenofibrate significantly improved CFVR and arterial stiffness in patients with hypertriglyceridemia. This endothelial protective effect may be reduced in part by the side effect of increasing homocysteine.

Antidiabetic Rosiglitazone Reduces Soluble Intercellular Adhesion Molecule-1 Level in Type 2 Diabetic Patients with Coronary Artery Disease

Background. We investigated the level of soluble adhesion molecules in diabetic patients and the effect of the peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist rosiglitazone on plasma levels of adhesion molecules and an inflammation marker in type 2 diabetic patients with coronary artery disease (CAD) after percutaneous coronary intervention (PCI). Methods. A total of 116 diabetic patients with CAD who had undergone PCI were randomized to receive rosiglitazone (4 mg/d) or not for 6 months. Plasma levels of soluble intercellular adhesion molecules (sICAM-1) and P-selectin (sP-selectin) were measured on ELISA. Results. After 6-month rosiglitazone treatment, plasma levels of sICAM-1 were lower than baseline and control group levels (370.4 (332.4–421.9) pg/mL versus 423.5 (327.4–500.3) pg/mL and 404.6 (345.2–483.4) pg/mL, P < .001). In addition, plasma levels of C-reactive protein were significantly reduced from baseline levels. However, plasma level of sP-selectin was not significantly lowered with rosiglitazone treatment than with control treatment after 6-month follow-up. Conclusions. Rosiglitazone reduces chronic inflammatory responses and improves levels of markers of endothelial dysfunction in patients with diabetes and CAD. PPAR-γ agonist may have a beneficial effect on the vascular endothelium through its anti-inflammatory mechanism and may be useful as therapy in patients undergoing PCI.