Togo Yamagata

Tetrahydrobiopterin restores endothelial function of coronary arteries in patients with hypercholesterolaemia

Objective: To examine the effect of tetrahydrobiopterin (BH4), an essential cofactor for nitric oxide synthase, on coronary artery endothelial function in hypercholesterolaemic patients. Design: Quantitative coronary angiography and Doppler flowmetry were used to examine the effects of intracoronary infusion of BH4 on vascular response to acetylcholine (ACh). Setting: Tertiary cardiology centre. Patients: 18 patients with angiographically normal coronary arteries, of whom nine had hypercholesterolaemia and nine had noromocholesterolaemia. Interventions: ACh (3 and 30 μg/min) was infused for two minutes into the left coronary ostium. ACh was then simultaneously infused with BH4 (1 mg/min) before and after infusion of L-NG-monomethyl-L-arginine (L-NMMA) (40 μmol/min for five minutes). Main outcome measures: Diameter of the epicardial coronary arteries and coronary blood flow. Results: In hypercholesterolaemic patients, BH4 attenuated the ACh induced decrease in coronary diameter (p < 0.05) and restored the ACh induced increase in coronary blood flow (p < 0.05). In normocholesterolaemic patients, BH4 did not affect the ACh induced changes in coronary diameter or coronary blood flow. In both groups, L-NMMA decreased the baseline coronary diameter (p < 0.05) and baseline coronary blood flow (p < 0.05). In hypercholesterolaemic patients, L-NMMA inhibited both the BH4 mediated attenuation of the ACh induced decrease in coronary diameter (p < 0.05) and the BH4 mediated enhancement of the ACh induced increase in coronary blood flow (p < 0.01). Conclusions: Intracoronary infusion of BH4 restores coronary endothelial function by improving the bioavailability of endothelium derived nitric oxide in hypercholesterolaemic patients.

Flow-mediated vasodilation of human epicardial coronary arteries: effect of inhibition of nitric oxide synthesis

OBJECTIVES This study sought to investigate the role of nitric oxide, an endothelium-derived relaxing factor, in flow-mediated vasodilation in human epicardial coronary arteries. BACKGROUND Endothelium-derived relaxing factors may be released from the coronary artery endothelium in response to increases in blood flow. METHODS We studied the effect of the nitric oxide synthesis inhibitor NG-monomethyl-L-arginine (L-NMMA) on the flow-mediated vasodilation of epicardial coronary arteries in 12 patients, using quantitative angiographic and Doppler flow velocity measurements. Adenosine at 100 micrograms/min was infused into the left anterior descending coronary artery to test the dilator response of the proximal artery to increases in blood flow. Acetylcholine at 3 and 30 micrograms/min was infused into the left coronary ostium to determine endothelium-dependent vasodilation of the proximal left anterior descending artery. Adenosine and acetylcholine were infused before and after the intracoronary infusion of L-NMMA (25 mumol/min for 5 min). RESULTS Infusion of L-NMMA caused a significant decrease in the baseline diameter of the proximal left anterior descending artery (from 2.90 +/- 0.14 to 2.74 +/- 0.13 mm [mean +/- SEM], p < 0.01). Adenosine increased coronary blood flow before and after L-NMMA (+399.5 +/- 27.5% and +511.9 +/- 33.3%, respectively). Flow-mediated vasodilation was observed in the proximal left anterior descending artery before and after L-NMMA (+9.2 +/- 1.5%, p < 0.01 and +8.6 +/- 2.1%, p < 0.01, respectively). A dose of 3 micrograms/min of acetylcholine significantly dilated the proximal left anterior descending artery before L-NMMA (+7.6 +/- 1.0%, p < 0.01), but acetylcholine-induced vasodilation was attenuated after L-NMMA (-1.8 +/- 1.0%). CONCLUSIONS Our data suggest that nitric oxide modulates basal coronary artery tone but that mediators other than nitric oxide may be responsible for the flow-mediated vasodilation of human epicardial coronary arteries.

Usefulness of flow-mediated dilation of the brachial artery and/or the intima-media thickness of the carotid artery in predicting coronary narrowing in patients suspected of having coronary artery disease.

It has been reported that flow-mediated dilation (FMD) of the brachial artery and the carotid intima-media thickness (IMT), markers of atherosclerosis, are altered in patients with coronary artery disease (CAD), but it is still not known if the presence of CAD can be detected using these markers. We examined whether the presence of CAD can be detected by FMD of the brachial artery and/or IMT. Eighty-one patients who underwent coronary angiography for the first time were enrolled. In each patient, brachial artery diameter responses to FMD and the administration of nitroglycerin spray, and carotid IMT were measured using high-resolution ultrasound (10 MHz) before coronary angiography. CAD was defined as >50% stenosis of a major coronary artery. Fifty-six patients had CAD. FMD was lower and IMT was greater in patients with CAD (FMD, 2.9 +/- 0.2% vs 9.4 +/- 0.5%; IMT, 1.09 +/- 0.05 vs 0.79 +/- 0.04 mm, both p <0.0001). Nitroglycerin-induced dilation did not differ in the 2 groups. Multivariate analysis showed that FMD was the only predictor of the presence of CAD (p = 0.0026). Receiver-operating characteristic analysis demonstrated that a cutoff value for FMD for detecting the presence of CAD was 6%, with a sensitivity of 0.93 (52 of 56) and a specificity of 0.88 (22 of 25). These findings suggest that FMD but not IMT may be used to detect the presence of CAD in patients with suspected CAD.

Effect of alcohol consumption on endothelial function in men with coronary artery disease

An inverse relationship between moderate alcohol consumption and coronary artery disease (CAD) has been observed in several epidemiologic studies. Whether improvement of endothelial function is involved in this beneficial effect is unknown. We investigated endothelial function of the brachial artery in 108 men with CAD, 54 of whom consumed alcohol on at least 1 day per week. Brachial artery diameter responses to hyperemic flow (FMD) and to administration of nitroglycerin (NTG) spray were measured using high- resolution ultrasonography. Coronary risk factors and hyperuricemia were present more frequently among drinkers, who also had higher concentrations of triglyceride and apolipoproteins C2, C3, and E. FMD was greater in drinkers (P<0.0001), while NTG-induced dilation was not. Multiple regression analysis showed alcohol consumption to be one of the factors favorably influencing FMD. These findings suggest that alcohol consumption may improve endothelial function in men with CAD.

Abnormal systolic blood pressure response during exercise recovery in patients with angina pectoris

OBJECTIVES This study was conducted to clarify the mechanisms of the abnormal systolic blood pressure response after exercise in patients with angina pectoris. BACKGROUND An abnormal systolic blood pressure response in patients with angina pectoris has been observed not only during exercise but also during the recovery period after exercise. However, the mechanisms of this abnormal response during recovery have not been elucidated. METHODS Thirty-five patients with angina pectoris and 17 control subjects underwent bicycle ergometric studies after insertion of a Swan-Ganz catheter. RESULTS In control subjects, all hemodynamic variables decreased rapidly after exercise. In 7 of the 35 patients, systolic blood pressure increased after exercise. The patients with angina were classified into two groups. In group I (17 patients), changes in systolic blood pressure during recovery were smaller than those in control subjects. In group II (18 patients) recovery of systolic blood pressure was normal. Changes in stroke index from rest to peak exercise were smaller in group I than in group II. Stroke index in both patient groups increased paradoxically during recovery. The increase in systemic vascular resistance index during recovery and the ratio of plasma norepinephrine concentration to cumulative work load were greater in group I than in group II. CONCLUSIONS An abnormal systolic blood pressure response after physical exercise in patients with angina pectoris is indicative of severe myocardial ischemia during exercise and may be caused by an increase in stroke volume due to recovery from myocardial ischemia and increased systemic vascular resistance secondary to exaggerated sympathetic nervous activity.

Coronary atherosclerosis and oxidative stress as reflected by autoantibodies against oxidized low-density lipoprotein and oxysterols.

Clinical studies and animal experiments have demonstrated that oxidized low-density lipoprotein (oxLDL) and oxysterols play important roles in atherogenesis. OxLDL is immunogenic, and autoantibodies (Ab) against oxLDL are detectable in serum. We investigated the relevance of oxysterols and Ab against-oxLDL to coronary artery disease (CAD) in 183 patients undergoing coronary angiography. Patient groups included angiographically normal subjects (< 75% stenosis), others with spasm (> 75% narrowing in response to acetylcholine), and some others with fixed stenosis (> 75%). The group with stenosis was subdivided into patients with stable and unstable angina. Serum concentrations of autoantibodies and 25-, 27-, and 7-beta-hydroxycholesterols were significantly higher in the stenotic group than in the normal group (P < 0.01, P < 0.05, P < 0.05, and P < 0.05, respectively). Antibodies, but not oxysterol concentrations, were significantly greater in subjects with unstable than with stable angina (P < 0.01). We conclude that anti-oxLDL antibody and oxysterol concentrations are associated with coronary artery stenosis, and that oxidative stress may be greatly increased in unstable angina.

Differential effect of pharmacological autonomic blockade on some electrophysiological properties of the human ventricle and atrium.

OBJECTIVE--This study investigated the dominance of each limb of the autonomic nervous system and tested sympathetic-vagal interactions in the human ventricle and atrium after administration of propranolol and atropine. PATIENTS AND METHODS--The 90% monophasic action potential duration (MAPD90) and the effective refractory period (ERP) at the right ventricular apex (RV) and the right lateral atrium (RA) were measured in 14 patients. The MAPD90 was measured during constant RV and RA pacing (cycle length 600 ms) and the ERP was measured at a driven cycle length of 600 ms. Electrophysiological variables were measured during a control period, after propranolol (0.15 mg/kg loading dose followed by 0.1 mg/min infusion), and after autonomic blockade (atropine 0.04 mg/kg). RESULTS--Both RV MAPD90 and RV ERP increased after propranolol (RV MAPD90 from 268 (26) ms to 275 (26) ms, p < 0.005; RV ERP from 252 (25) ms to 258 (26) ms, p < 0.0005) and then decreased to below the control values after autonomic blockade (RV MAPD90 256 (24) ms; RV ERP 239 (25) ms, p < 0.0005 v propranolol, p < 0.0005 v control). In contrast, both RA MAPD90 and RA ERP increased after propranolol (RA MAPD90 from 242 (19) ms to 260 (19) ms; RA ERP from 216 (21) ms to 230 (18) ms, p < 0.0005), and then increased slightly more after autonomic blockade (RA MAPD90 265 (16) ms, p = 0.09; RA ERP 235 (16) ms, p = 0.07), thus remaining above control values (p < 0.0005). CONCLUSIONS--The results indicate (a) that in the human ventricle vagal stimulation and sympathetic beta stimulation are antagonistic and that direct vagal stimulation predominates over beta stimulation, with sympathetic-vagal interaction being minimal and (b) that in the human atrium vagal stimulation and beta stimulation are synergistic and beta stimulation predominates over vagal stimulation, with direct vagal stimulation having a minimal effect.

Magnesium causes nitric oxide independent coronary artery vasodilation in humans

OBJECTIVE To determine how magnesium affects human coronary arteries and whether endothelium derived nitric oxide (EDNO) is involved in the coronary arterial response to magnesium. DESIGN Quantitative coronary angiography and Doppler flow velocity measurements were used to determine the effects of the nitric oxide synthase inhibitorN G-monomethyl-L-arginine (L-NMMA) on magnesium induced dilation of the epicardial and resistance coronary arteries. SETTING Hiroshima University Hospital a tertiary cardiology centre. PATIENTS 17 patients with angiographically normal coronary arteries. INTERVENTIONS Magnesium sulfate (MgSO4) (0.02 mmol/min and 0.2 mmol/min) was infused for two minutes into the left coronary ostium before and after intracoronary infusion of L-NMMA. MAIN OUTCOME MEASURES Diameter of the proximal and distal segments of the epicardial coronary arteries and coronary blood flow. RESULTS At a dose of 0.02 mmol/min, MgSO4 did not affect the coronary arteries. At a dose of 0.2 mmol/min, MgSO4 caused coronary artery dilation (mean (SEM) proximal diameter 3.00 (0.09) to 3.11 (0.09) mm; distal 1.64 (0.06) to 1.77 (0.07) mm) and increased coronary blood flow (79.3 (7.5) to 101.4 (9.9) ml/min, p < 0.001 vbaseline for all). MgSO4 increased the changes in these parameters after the infusion of L-NMMA (p < 0.001v baseline). CONCLUSIONS Magnesium dilates both the epicardial and resistance coronary arteries in humans. Furthermore, the coronary arterial response to magnesium is dose dependent and independent of EDNO.

Coronary Segmental Responses to Acetylcholine and Bradykinin in Patients With Atherosclerotic Risk Factors

This study was designed to elucidate the nature of coronary endothelial dysfunction in patients with hypertension and/or hypercholesterolemia and normal smooth coronary arteries by evaluating the coronary vascular responses to acetylcholine and bradykinin. The study included 19 patients (10 men; age [mean +/- SD] 61 +/- 9 years) with angiographically normal smooth coronary arteries and either hypertension (n = 7) and/or hypercholesterolemia (n = 13). Patients received acetylcholine (3 or 30 microg/min) infusions followed by bradykinin (0.5, 1.5, 2.5 microg/min) and nitroglycerin (200 microg/min) infusions into the left coronary ostium. Epicardial coronary artery diameters were measured by quantitative angiography. Angiography detected both vasoconstricted and dilated segments following acetylcholine infusion. Bradykinin significantly dilated both types of segments (p <0.001, respectively). However, bradykinin-induced dilation was significantly greater in segments exhibiting acetylcholine-induced vasodilation than in those exhibiting vasoconstriction (p <0.01 in the proximal portion and p <0.02 in the distal portion). Nitroglycerin-induced dilation was similar in all segments. These results suggest that coronary endothelial dysfunction may be a heterogeneous process in patients with coronary risk factors. Moreover, the mechanism underlying diminished endothelium-dependent dilation involves not only the muscarinic receptor, but also B2-kinin receptor.

Nitric oxide production by coronary conductance and resistance vessels in hypercholesterolemia patients

NG-monomethyl-L-arginine (L-NMMA), a specific inhibitor of nitric oxide (NO) synthesis, was used to investigate the effects of inhibition of NO synthesis on the coronary conductance and resistance vessels in hypercholesterolemic patients. Acetylcholine (3 and 30 micrograms/min) was administered to 10 hypercholesterolemic and 10 control patients before and after L-NMMA (25 micromol/min) infusion. Epicardial coronary diameter was measured by quantitative angiography, and coronary blood flow (CBF) was derived from Doppler flow-velocity and coronary diameter measurements. In hypercholesterolemic patients, acetylcholine-induced dilation of epicardial arteries was attenuated, and the percentage increase in CBF caused by acetylcholine was smaller than that in control patients. L-NMMA attenuated acetylcholine-induced dilation of epicardial arteries in control patients. L-NMMA had no effect on CBF responses to acetylcholine in both patient groups. L-NMMA significantly decreased the baseline coronary diameter and CBF in both groups. These results indicated that hypercholesterolemia impaired the acetylcholine-induced dilation of the conductance and resistance coronary vessels. This impairment in the conductance vessels was dependent on NO production; that of resistance vessels was not. The basal release of NO in conductance and resistance vessels was preserved in hypercholesterolemic patients.