Yukihiro Fukuda

Tetrahydrobiopterin enhances forearm vascular response to acetylcholine in both normotensive and hypertensive individuals.

BACKGROUND A deficiency of tetrahydrobiopterin (BH4), an essential cofactor for nitric oxide (NO) synthase, decreases NO synthesis and increases superoxide production. Supplementation of BH4 has been postulated to improve endothelial function in atherosclerotic patients. The purpose of this study was to determine whether BH4 restores endothelium-dependent vasodilation in patients with essential hypertension. METHODS We evaluated the effects of BH4 on forearm vascular responses to acetylcholine (ACh), an endothelium-dependent vasodilator, and isosorbide dinitrate (ISDN), an endothelium-independent vasodilator, both in patients with essential hypertension and in age- and sex-matched normal control subjects. Forearm blood flow (FBF) was measured using strain gauge plethysmography. RESULTS The response of FBF to ACh was less in hypertensive patients (n = 8) than in normal control subjects (n = 8). There was no significant difference in FBF response to ISDN in the two groups. During coinfusion of BH4 (500 mg/min), the FBF response to ACh in hypertensive patients increased significantly (14.8 +/- 4.6 to 25.6 +/- 7.3 mL/min/100 mL tissue, P < .05) to the level of normal control subjects. In the control subjects, also, BH4 augmented the FBF response to ACh (27.8 +/- 8.7 to 36.1 +/- 9.6 mL/min/100 mL tissue, P < .05). The increase in FBF after ISDN was not altered by BH4 in either group (each group, n = 6). CONCLUSION Supplementation of BH4 augments endothelium-dependent vasodilation in both normotensive and hypertensive individuals.

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.

Relation between C reactive protein concentrations and coronary microvascular endothelial function

Objective: To determine how C reactive protein (CRP), a sensitive marker of inflammation, is related to coronary endothelial function. Design: Changes in quantitative coronary angiographic findings and Doppler flow velocity measurements in response to locally infused acetylcholine were assessed. Setting: Tertiary cardiology centre. Patients: 46 patients with angiographically normal coronary arteries were divided into groups with normal (⩽ 3 mg/l) or increased (> 3 mg/l) CRP concentrations. Interventions: Acetylcholine (3 and 30 μg/min) was infused into the left coronary ostium for two minutes. Main outcome measures: Percentage change in diameter of epicardial coronary arteries and coronary blood flow (CBF) in response to acetylcholine; and correlations between these parameters and serum CRP concentrations. Results: 15 patients had increased CRP concentrations. The change in coronary artery diameter induced by acetylcholine infusion was similar between the groups but the increase in CBF induced by acetylcholine was smaller in patients with increased CRP concentrations (54.9% v 139.4% with acetylcholine 30 μg/min, p  =  0.0030). Multivariate analysis identified increased CRP concentration as independently associated with attenuated CBF response to acetylcholine at 30 μg/min (p  =  0.0078, R2  =  0.434). Conclusions: These findings suggest that inflammation appears to be associated with impaired coronary endothelial function in resistance but not conduit vessels. The data suggest a close relation between chronic vascular inflammation and endothelial dysfunction in atherosclerosis.

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.

Better stent expansion by two-time inflation of stent balloon and its responsible mechanism

OBJECTIVES We determined the effect of two-time inflation of the stent balloon on stent expansion and its responsible factor. METHODS Subjects included 61 patients with de novo coronary artery lesions, in whom 12 sirolimus-eluting, 27 paclitaxel-eluting, and 22 other stents were deployed twice at identical inflation pressures (11.3±2.3 atm) and inflation times (5, 10, 20, and 40 s). After the first and second deployments, minimum lumen diameter (MLD), minimum lumen area (MLA), and distensibility index (DI) were determined using intravascular ultrasound. RESULTS After the second inflation, MLA was significantly increased (5 s: 12.9%, 10 s: 14.5%, 20 s: 9.4%, 40 s: 9.5%). MLD and DI were also significantly increased. In the single and double inflation groups, DI in each group was significantly correlated with inflation time (single: r=0.409, double: r=0.351). DI was not significantly different between double 5-s and single 10-s inflations, between double 10-s and single 20-s inflations, or between double 20-s and single 40-s inflations. Additional stent balloon inflation by higher pressure in 30% and another balloon in 18% of the patients were required. CONCLUSIONS Two-time stent balloon inflation may allow better stent expansion regardless of inflation time and two-time inflation may be equivalent to longer inflation.

Effects of myocardial perfusion abnormalities on the accuracy of left ventricular volume and ejection fraction measured by thallium-201 gated single-photon emission tomography: comparison with echocardiography as the reference standard.

BackgroundWe assessed the accuracy of left ventricular end-diastolic volume (EDV), end-systolic volume (ESV), and ejection fraction (EF) using quantitative gated single-photon emission computed tomography (QGS) in comparison with echocardiography as the reference standard. We also assessed the effects of total perfusion deficit (TPD) on the accuracy of QGS measurements. MethodsA total of 258 patients underwent single-photon emission computed tomography and transthoracic echocardiography within 4 weeks of each investigation for evaluating coronary artery disease. Patients were divided into four groups according to TPD scores. ResultsThere were 138 patients with no/minimal TPD, 64 patients with small TPD, 35 patients with middle TPD, and 21 patients with large TPD. There were good correlations and agreements in EDV (r=0.87, 0.90, 0.71, and 0.94, respectively), ESV (r=0.92, 0.94, 0.79, and 0.94, respectively), and EF (r=0.61, 0.79, 0.61, and 0.83, respectively) between QGS and echocardiography in patients with any TPD. QGS significantly underestimated EDV and ESV in patients with no/minimal or small TPD, and significantly overestimated ESV in patients with large TPD. QGS significantly underestimated EF in patients with middle or large TPD. ConclusionOur results suggest that QGS is a useful tool for assessing the left ventricular volume and function in patients with any TPD, but myocardial perfusion abnormalities should be taken into consideration when interpreting QRS measurements.

Role of transthoracic left atrial appendage wall motion velocity in patients with persistent atrial fibrillation and a low CHADS2 score

BACKGROUND AND PURPOSE Thromboembolic risk has been examined by semi-invasive transesophageal echocardiography. We assessed the risk of thrombogenesis in patients with persistent atrial fibrillation (AF) noninvasively by using transthoracic tissue Doppler echocardiography (TDE) in relation to a low CHADS2 score. METHODS Eighty patients with persistent AF underwent both transthoracic and transesophageal echocardiography. Peak left atrial appendage (LAA), wall motion velocity (WV) during LAA contraction was measured by transthoracic and transesophageal TDE. LAA flow velocity was also determined by transesophageal echocardiography. RESULTS Transthoracic LAAWV could be measured in 78 of the 80 patients, and the values were closely correlated with transesophageal TDE values (r=0.98) and with transesophageal LAA flow velocity (r=0.82). Transthoracic LAAWV was significantly lower with increasing spontaneous echo contrast (SEC) severity (severe SEC, mild SEC, no SEC: 5.7±2.4, 10.2±3.3, and 14.5±5.5cm/s, respectively). Severe SEC was noted in 31 of 61 patients with a CHADS2 score ≤2, in 19 of 46 patients with a CHADS2 score ≤1 and in 6 of 21 patients with a CHADS2 score=0. For diagnosing severe SEC, a transthoracic LAAWV <10cm/s had a sensitivity of 81% and specificity of 92% in the patients with a CHADS2 score ≤2, a sensitivity of 74% and specificity of 91% in the patients with a CHADS2 score ≤1 and a sensitivity of 44% and specificity of 83% in the patients with a CHADS2 score=0. CONCLUSIONS A transthoracic LAAWV <10cm/s in persistent AF patients with a low CHADS2 score may be a very specific diagnostic tool for evaluating severe SEC, one of the high risk factors for thromboembolism.

Association of mitral annular velocity with myocardial ischemia assessed by single-photon emission computed tomography in patients with suspected coronary artery disease and preserved ejection fraction.

BackgroundLeft ventricular diastolic dysfunction is a sensitive and early sign of myocardial ischemia. We assessed whether mitral annular velocity reflected the severity of myocardial ischemia evaluated by single-photon emission computed tomography in patients with suspected coronary artery disease (CAD) and preserved ejection fraction. Methods and resultsThe study population consisted of 125 patients with suspected CAD who underwent both single-photon emission computed tomography and transthoracic echocardiography. There were 68 patients with no ischemia, 42 patients with mild ischemia, and 15 patients with severe ischemia. With increasing severity of myocardial ischemia, septal e’ decreased. Compared with patients with no ischemia, septal e’ was significantly lower even in patients with mild ischemia (6.6±1.4 vs. 6.1±1.4 cm/s, P<0.05). Septal E/e’ (9.9±2.6 vs. 13.6±4.0, P<0.01) and lateral E/e’ (7.7±2.3 vs. 10.3±3.6, P<0.01) were significantly higher finally in patients with severe ischemia. Multivariate logistic regression analyses showed that BMI [odds ratio (OR) 1.13, 95% confidence interval (CI) 1.01–1.29; P=0.03] and septal e’ (OR 0.71, 95% CI 0.53–0.94; P=0.02) were independent predictors of any myocardial ischemia and that diabetes (OR 5.78, 95% CI 1.58–23.0; P=0.008) and septal E/e’ (OR 1.38, 95% CI 1.13–1.76; P=0.001) were independent predictors of severe myocardial ischemia. ConclusionOur data suggested that decreased e’ was useful in detecting mild myocardial ischemia and increased E/e’ was useful in detecting severe myocardial ischemia in patients with suspected CAD and preserved ejection fraction.

Reduction of Central Blood Pressure in Response to Oral Glucose Loading Is Blunted in Patients With Diabetes Mellitus

BACKGROUND Recent studies have shown that arterial stiffness is reduced after meal intake. We evaluated the acute response of central hemodynamics to glucose loading and the variation in their responses among normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and diabetes mellitus (DM). METHODS The study enrolled 85 patients with known or suspected coronary artery disease who underwent a 75-g oral glucose tolerance test. Central hemodynamic measurements were assessed using radial applanation tonometry at fasting, 60, and 120 minutes after glucose loading. RESULTS Glucose loading decreased the augmentation index normalized to a heart rate of 75 bpm (AIx@75) (81.6±13.9 to 74.5±14.1%, P < 0.01) and central systolic blood pressure (SBP) (115±22 to 109±21mm Hg, P < 0.01) at 120 minutes without a significant change in brachial SBP (126±25 to 125±25mm Hg, P = 0.93). Glucose loading decreased central SBP in NGT and IGT groups but did not affect the DM group. Change in AIx@75 at 120 minutes after glucose loading was blunted in IGT and DM groups compared with the NGT group (-5.7±4.4 vs. -3.6±4.1 vs. -9.3±6.2%, P < 0.01). Multivariate logistic regression analysis identified DM as an independent factor associated with the presence of blunted response of AIx to glucose loading. CONCLUSIONS Oral glucose loading decreased central SBP and AIx@75 without a significant change in brachial SBP, and these central hemodynamic responses were blunted in patients with DM.

Impact of Malondialdehyde-Modified Low-Density Lipoprotein on Tissue Characteristics in Patients With Stable Coronary Artery Disease – Integrated Backscatter-Intravascular Ultrasound Study –

BACKGROUND Malondialdehyde-modified low-density lipoprotein (MDA-LDL) is considered to play an essential role in plaque destabilization. We aimed to investigate the association between the tissue characteristics of culprit plaque assessed by integrated backscatter (IB)-intravascular ultrasound (IVUS) and the serum MDA-LDL levels in patients with stable coronary artery disease. METHODSANDRESULTS The study group consisted of 179 patients undergoing IB-IVUS during elective percutaneous coronary intervention. Patients were classified into 2 groups based on serum MDA-LDL level: low MDA-LDL group (<102 U/L, n=88) and high MDA-LDL group (≥102 U/L, n=91). Plaques in the high MDA-LDL group had higher %lipid (45.2±12.5% vs. 54.9±14.5%, P<0.001) and lower %fibrosis (43.0±9.1% vs. 36.4±11.4%, P<0.001) than did plaques in the low MDA-LDL group. Lipid-rich plaque (%lipid >60% or %fibrosis <30%) was significantly more frequently found in the high MDA-LDL group than in the low MDA-LDL group (14.3% vs. 39.8%, P<0.001). The incidence of MACE (cardiac death, myocardial infarction and/or hospitalization for heart failure) during 3 years was significantly higher in the high MDA-LDL group than in the low MDA-LDL group (6.6% vs. 15.9%, P=0.02). CONCLUSIONS Higher MDA-LDL might be associated with greater lipid and lower fibrous content, contributing to coronary plaque vulnerability. (Circ J 2016; 80: 2173-2182).