Tetrahydrobiopterin improves endothelial dysfunction in coronary microcirculation in patients without epicardial coronary artery disease

OBJECTIVES: We aimed to determine whether intracoronary supplementation with nitric oxide (NO) synthase co-factor tetrahydrobiopterin (BH4) improves NO-dependent coronary microvascular dilation in patients with coronary risk factors but no significant organic stenosis. BACKGROUND: Impaired coronary microvascular dilator reserve attributable to endothelial dysfunction plays an important role in the regulation of coronary blood flow (CBF). METHODS: Fifteen patients were measured for CBF (Doppler-wire and quantitative coronary angiography). Stimulated release of NO in the coronary microcirculation was evaluated by percent increase in CBF (%ACBF) at graded doses of intracoronary acetylcholine (1, 3, 10 and 30 microg/min). Measurements were repeated after intracoronary co-infusion of BH4 (4 mg/min) and acetylcholine. RESULTS: The patients were divided into two groups on the basis of CBF responses to acetylcholine: those with "diminished" (%deltaCBF <300%, n = 8) and "normal" (%deltaCBF >300%, n = 7) flow responses. Tetrahydrobiopterin significantly (p < 0.0001) improved acetylcholine-induced increases in CBF in patients with diminished flow responses, but exerted no effect in those with normal flow responses. Among the 15 studied patients, the magnitude of flow improvement by BH4 was inversely correlated with baseline flow responses (p < 0.02). Microvascular dilator response to direct NO donor (isosorbide dinitrate) was not affected by BH4. CONCLUSIONS: We demonstrated for the first time that intracoronary BH4 improved acetylcholine-induced microvascular dilator responses in patients with endothelial dysfunction in vivo. Thus, supplementation with BH4 may be a novel therapeutic means to increase NO availability for patients with coronary microvascular disease.     

AT1-receptor antagonism improves endothelial function in coronary artery disease by a bradykinin/B2-receptor-dependent mechanism

Impaired flow-dependent, endothelium-mediated vasodilation is an early finding in patients with coronary artery disease (CAD). Experimental and some clinical studies observed that angiotensin type-1 receptor antagonists (AT1A) enhance endothelium-dependent relaxation in CAD. The present study was designed to determine whether AT1A improves flow-dependent dilation (FDD) in patients with CAD and, if so, whether bradykinin and NO are involved. High-resolution ultrasound was used to measure radial artery diameter at rest and during reactive hyperemia, causing endothelium-mediated vasodilation. Twenty patients with CAD were randomly assigned to receive intrabrachial infusion of candesartan (800 microg/min) with and without icatibant, a bradykinin B2-receptor antagonist (90 microg/min; group A) or N-monomethyl-l-arginine (L-NMMA), an NO-synthase inhibitor (7 micromol/min; group B). The AT1A candesartan improved FDD by >40%, an effect that was inhibited by icatibant (group A: control, 7.3+/-0.9; candesartan, 10.3+/-1.1; candesartan+icatibant, 5.0+/-0.5%). Similarly, L-NMMA blunted the beneficial effect of candesartan (group B: control, 6.3+/-0.6; candesartan, 8.9+/-0.6; candesartan+L-NMMA: 4.7+/-0.5%; each P<0.01). The angiotensin type-1 receptor antagonist candesartan improves flow-dependent, endothelium-mediated vasodilation in patients with CAD. This effect is inhibited by either icatibant and or L-NMMA, suggesting that both bradykinin and NO contribute to the vascular effects of AT1-receptor antagonists in this patient population.     

Effect of tirofiban on percutaneous coronary intervention-induced endothelial dysfunction in patients with stable coronary artery disease

Recent studies demonstrated that glycoprotein (GP) IIb/IIIa receptor antagonists improve endothelial dysfunction of forearm resistance vessels in patients with stable coronary artery disease. However, it remains unclear whether these findings can be extended to the conductance vessel level. In this study, we aimed to evaluate the acute effect of tirofiban on endothelial function of arterial conductance vessels in patients undergoing percutaneous coronary intervention (PCI). Endothelial function was examined by ultrasonographic measurement of flow-mediated vasodilation (FMD) of the brachial artery. Endothelium-independent vasodilation was determined in response to nitroglycerin. Sixty-six patients who underwent PCI were included in the study. Thirty-three patients received a bolus of 10 microg/kg body weight of tirofiban, whereas 33 patients who did not receive tirofiban served as the control group. FMD was measured in all patients before and 30 minutes after PCI. Tirofiban significantly improved FMD (6.0 +/- 0.4% before vs 7.8 +/- 0.5% after PCI, p <0.0001), whereas FMD deteriorated in patients in the control group (6.1 +/- 0.6% before vs 4.7 +/- 0.7% after PCI, p = 0.006). Nitroglycerin-induced dilation remained unaltered in response to PCI. In another group of 11 patients with coronary artery disease, FMD did not change after coronary angiography without coronary intervention. In conclusion, PCI induces endothelial dysfunction in forearm conductance vessels that can be reversed with tirofiban.     

Exercise training but not rosiglitazone improves endothelial function in prediabetic patients with coronary disease

BACKGROUND: Impaired glucose tolerance (IGT) is associated with endothelial dysfunction and upregulation of inflammatory markers, which is potentially reversible by adequate treatment. It was our aim to compare the impact of exercise training with that of rosiglitazone on endothelial function and inflammatory markers in patients with IGT and coronary artery disease (CAD). METHODS: Patients with IGT and CAD were randomly assigned to either exercise training (n=13), rosiglitazone (8 mg; n=11), or a control group (n=10). During the first week, exercise training consisted of 6 x 15 min/d followed by three weeks of 30 min/d submaximal ergometer exercise. In addition, group exercise training of 1 h was performed twice per week. RESULTS: After 4 weeks, triglycerides and uric acid were significantly lower in the exercise group whereas fasting glucose, HbA1c, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, C-reactive protein, fibrinogen, and body mass index did not differ between groups. In the exercise group, exercise capacity (123+/-33 vs. 144+/-31 W; P=0.006) and endothelium-dependent, flow-mediated vasodilatation (P<0.01) increased significantly, whereas in the rosiglitazone group and in the control group (P=n.s.) no changes were seen. CONCLUSION: In patients with IGT and CAD, 4 weeks of exercise training exert significant and superior improvement of endothelium-dependent vasodilatation as compared with rosiglitazone therapy or usual care. This finding should be seen as an even further encouragement to recommend and, where available, prescribe exercise training to our patients.     

Comparison of peripheral endothelial dysfunction and intimal media thickness in patients with suspected coronary artery disease

Objective—Flow associated dilatation (FAD%) and intimal media thickness are established markers of early atherosclerosis. This study aimed to compare the ability of the non-invasive measurements FAD% and intimal media thickness to predict coronary artery disease.
Methods—FAD% and intimal media thickness were determined using high resolution ultrasound in 122 patients with clinically suspected coronary artery disease before coronary angiography. Results are given as mean (SD).
Results—Patients with coronary artery disease had reduced FAD% compared with those with angiographically normal coronary vessels (3.7 (4.1) v 7.0 (3.5)%, p < 0.001), whereas intimal media thickness tended to be increased in patients with coronary artery disease (0.58 (0.35) v 0.47 (0.11)mm, p = 0.054). There was a negative correlation between FAD% and intimal media thickness (R = −0.317, p = 0.0004). Receiver operating characteristic analysis showed that FAD%  4.5% predicted coronary artery disease with a sensitivity of 0.71 (95% confidence interval 0.61 to 0.80) and a specificity of 0.81 (0.58 to 0.95). In contrast, intimal media thickness showed a positive correlation with the extent of coronary artery disease (number of vessels with a lesion  50%) (R = 0.324, p = 0.0003), without a clear cut off point.
Conclusions—In patients with clinically suspected coronary artery disease, FAD% discriminates between the presence or absence of coronary artery disease, whereas intimal media thickness is associated more with the extent of coronary artery disease.

Keywords: coronary artery disease;  endothelial dysfunction;  intimal media thickness;  flow associated dilatation     

Soluble VCAM-1 and E-selectin, but not ICAM-1 discriminate endothelial injury in patients with documented coronary artery disease

It has been shown that endothelial cell adhesion molecules play an important role in the development of coronary atherosclerosis and inflammatory disease. We sought to test whether soluble vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and E-selectin are increased in patients with documented coronary artery disease (CAD). Plasma levels of VCAM-1, ICAM-1 and E-selectin were measured in 40 patients with documented CAD, 20 subjects with angiographically documented normal coronary arteries, and 14 healthy volunteers. Patients with documented CAD exhibited significant elevation of VCAM-1 (535 +/- 227.1 ng/ml, p = 0.0001), E-selectin (69.4 +/- 29.4 ng/ml, p = 0.006), but not ICAM-1 (320.5 +/- 65.1 ng/ml, p = 0.9) concentrations as compared to subjects with normal coronary arteries (252.3 +/- 79.8, 49.7 +/- 22.0 and 311.4 +/- 40.2 ng/ml), and healthy controls (110.0 +/- 17.7, 29.0 +/- 2.0 and 237.5 +/- 46.5 ng/ml), respectively. Soluble markers of endothelial injury are not uniformly increased in patients with documented CAD as compared to those with normal coronary arteries and healthy controls. However, VCAM-1 and E-selectin, but not ICAM-1 could identify endothelial injury in such patients.     

Enhanced external counterpulsation improves endothelial function in patients with symptomatic coronary artery disease

OBJECTIVES: The goal of this study was to examine the effect of enhanced external counterpulsation (EECP) on endothelial function. BACKGROUND: Enhanced external counterpulsation improves symptoms and exercise tolerance in patients with symptomatic coronary artery disease (CAD). However, the exact mechanisms by which this technique exerts its clinical benefit are unclear. METHODS: Reactive hyperemia-peripheral arterial tonometry (RH-PAT), a noninvasive method to assess peripheral endothelial function by measuring reactive hyperemic response in the finger, was performed in 23 patients with refractory angina undergoing a 35-h course of EECP. In each patient RH-PAT measurements were performed before and after the first, at midcourse, and the last EECP session. In addition, RH-PAT response was assessed one month after completion of EECP therapy; RH-PAT index, a measure of reactive hyperemia, was calculated as the ratio of the digital pulse volume during reactive hyperemia divided by that at rest. RESULTS: Enhanced external counterpulsation led to symptomatic improvement (>/=1 Canadian Cardiovascular Society class) in 17 (74%) patients; EECP was associated with a significant immediate increase in average RH-PAT index after each treatment (p < 0.05). In addition, average RH-PAT index at one-month follow-up was significantly higher than that before EECP therapy (p < 0.05). When patients were divided by their clinical response, RH-PAT index at one-month follow-up increased only in those patients who experienced clinical benefit. CONCLUSIONS: Enhanced external counterpulsation enhances peripheral endothelial function with beneficial effects persisting at one-month follow-up in patients with a positive clinical response. This suggests that improvement in endothelial function may contribute to the clinical benefit of EECP in patients with symptomatic CAD.     

Long-term treatment with probucol improves endothelial function in patients with coronary artery disease.

Recent studies have shown that endothelial function is impaired in patients with coronary artery disease (CAD). Probucol has been recognized to have antioxidant properties as well as lipid-lowering effects, and may improve endothelial function. The aim of this study was to evaluate the effects of probucol on endothelial function in patients with CAD. We evaluated endothelial function, based on flow-mediated vasodilation during reactive hyperemia (FMD), and the intima-media thickness (IMT) of the common carotid artery using high resolution ultrasonography in patients either with (CAD group, n=26) or without CAD (Control group, n=12). We measured the serum cholesterol concentration, including the low-density lipoprotein cholesterol (LDL-cholesterol) concentration, and the plasma concentrations of homocyst(e)ine and asymmetric dimethylarginine (ADMA). Measurements of FMD and serum cholesterol were repeated after 3 months of probucol (500 mg/day, n=9) or placebo (n=9) treatment in patients with CAD. The IMT was significantly greater (p < 0.001) and FMD was significantly lower (p < 0.001) in the CAD group than in the Control group. While the serum cholesterol concentration and plasma ADMA were similar in the two groups, the plasma homocyst(e)ine concentrations were higher in the CAD group than in the Control group (p < 0.01). After probucol therapy, FMD was significantly improved in the CAD group (p < 0.05). The serum LDL-cholesterol concentration did not significantly decrease after probucol treatment. Placebo treatment did not alter FMD or the serum cholesterol concentration. Our findings suggest that long-term treatment with probucol improves endothelial function in patients with CAD, an outcome independent of the LDL-cholesterol-lowering effects of probucol, and that homocyst(e)ine may be a better predictor of atherosclerosis than ADMA.     

The prevalence of endothelial dysfunction in patients with and without coronary artery disease

Background:

Endothelial dysfunction (ED) is frequently present in patients presenting with acute or stable coronary artery disease (CAD), but it is also found in patients presenting with chest pain without angiographic coronary lesions.

Hypothesis:

We hypothesized that even in patients without CAD, the presence of cardiovascular (CV) risk factors will correlate with the presence of ED.

Methods:

Our study included a total of 341 consecutive patients referred for coronary angiography. We used pulse wave analysis with a finger plethysmograph (peripheral arterial tonometry) to determine endothelial function. Hyperemia ratio was calculated as the ratio of the postischemic hyperemia response relative to baseline measurement.

Results:

The hyperemia ratio was significantly higher in patients without CAD (2.02 ± 0.52) compared with patients with chronic CAD (1.81 ± 0.44, P = 0.001) or acute CAD (1.74 ± 0.49, P < 0.001). Prevalence of ED was 33%, 46%, and 58%, respectively. In multivariate analysis, the presence of CAD, diabetes, and cigarette smoking, and the total number of CV risk factors, were strong predictors of ED. In 67% of the patients without CAD but with ≥3 CV risk factors, ED was present.

Conclusions:

Prevalence of ED in patients with chest pain depends on the presence of CAD and CV risk factors. Patients without CAD but with ≥3 risk factors frequently presented with ED. Such patients may be at increased risk for future CV events and may profit from intensified therapy to control CV risk factors. The authors have no funding, financial relationships, or conflicts of interest to disclose. This study was supported by the Swiss Heart Foundation, Bern, Switzerland, and the Kamillo Eisner Foundation, Hergiswil, Switzerland. Stefan Toggweiler was supported by a grant from the Swiss National Foundation. None of the granting institutions had any influence on the study design, data collection, analysis, or interpretation.     

Evidence of endothelial dysfunction in angiographically normal coronary arteries of patients with coronary artery disease

Acetylcholine causes endothelium-dependent dilation of normal arteries in most animal species. The effect of acetylcholine on normal human coronary arteries is controversial. Pathologic studies and epicardial echocardiography have shown that diffuse atherosclerosis is often present despite angiographic evidence of discrete coronary artery disease (CAD). Therefore, we postulated that acetylcholine would cause vasoconstriction of coronary arteries that are angiographically normal in patients with CAD. Coronary artery diameter, measured by automated quantification of digitized cineangiograms, was determined before and after the intracoronary infusion of 0.2 mM acetylcholine at 0.8-1.6 ml/min. The diameter of stenotic or irregular segments of six atherosclerotic coronary arteries decreased from 1.80 +/- 0.42 mm before acetylcholine to 1.26 +/- 0.46 mm after acetylcholine (p = 0.0025). Acetylcholine had a significantly different effect on the diameter of two groups of coronary arteries that are angiographically normal. Acetylcholine caused a 0.16 +/- 0.09-mm increase in the diameter of 14 normal coronary arteries in patients without CAD, whereas it caused a 0.26 +/- 0.12-mm decrease in the diameter of 14 normal coronary arteries in patients with CAD (p less than 0.01). Thus, the normal response to intracoronary acetylcholine is vasodilation, suggesting that endothelium-derived relaxing factor is released from normal human coronary endothelium. The vasoconstrictive effect of acetylcholine in the angiographically normal coronary arteries of patients with CAD suggests the presence of a diffuse abnormality of endothelial function.     

Roles of endothelial dysfunction in coronary artery disease

Endothelial dysfunction is an early and persistent vascular abnormality in the evolution of atherothrombotic disease. Risk factors for atherosclerosis promote an inflammatory oxidative environment in the vasculature that induces pathologic changes in endothelial function, including the support of enhanced smooth muscle tone, thrombosis, and smooth muscle proliferation. This article provides an overview of the molecular basis of endothelial dysfunction and of its diagnosis and treatment.     

培垛普利对冠心病患者经皮冠状动脉介入术后肱动脉内皮功能障碍的影响

目的探讨培垛普利对经皮冠状动脉介入（PCI）操作所诱发的肱动脉内皮功能不全的影响。方法实行PCI的冠心病患者62例,随机分为2组,培垛普利组31例,对照组31例,应用高频超声探头分别测量2组PCI术前及术后的肱动脉基础内径、反应性充血内径、含服硝酸甘油后内径,计算肱动脉血流介导的舒张反应（FMD）,并运用多普勒技术测定血流速度峰值,最后比较2组间及组内上述参数的差异。超声测量于PCI术前2h和术后30min内完成。结果培垛普利组的FMD明显改善[（5．9±0．3）％术前vs（7．7±0．4）％术后PCI,P〈0．0013,而对照组明显恶化[（6．0±0．5）％术前vs（4．8±0．6）％术后PCI,P〈0．0013。两组硝酸甘油介导的血管舒张反应及反应性充血血流速度峰值均无明显变化。结论培垛普利可改善PCI介导的肱动脉内皮功能不全。