Masashi Kimura

Effect of Different Intensities of Exercise on Endothelium-Dependent Vasodilation in Humans Role of Endothelium-Dependent Nitric Oxide and Oxidative Stress

Background—Aerobic exercise enhances endothelium-dependent vasodilation in hypertensive patients, patients with chronic heart failure, and healthy individuals. However, it is unclear how the intensity of exercise affects endothelial function in humans. The purpose of the present study was to determine the effects of different intensities of exercise on endothelium-dependent vasodilation in humans. Methods and Results—We evaluated the forearm blood flow responses to acetylcholine, an endothelium-dependent vasodilator, and isosorbide dinitrate, an endothelium-independent vasodilator, before and after different intensities of exercise (mild, 25% &OV0312;o2max; moderate, 50% &OV0312;o2max; and high, 75% &OV0312;o2max; bicycle ergometers, 30 minutes, 5 to 7 times per week for 12 weeks) in 26 healthy young men. Forearm blood flow was measured using a mercury-filled Silastic strain-gauge plethysmograph. Twelve weeks of moderate-intensity exercise, but not mild- or high-intensity exercise, significantly augmented acetylcholine-induced vasodilation (7.5±2.4 to 11.4±5.8 mL/min per 100 mL tissue; P <0.05). No intensity of aerobic exercise altered isosorbide dinitrate–induced vasodilation. The administration of NG-monomethyl-l-arginine, a nitric oxide synthase inhibitor, abolished the moderate-intensity exercise-induced augmentation of the forearm blood flow response to acetylcholine. High-intensity exercise increases plasma concentrations of 8-hydroxy-2′-deoxyguanosine (from 6.7±1.1 to 9.2±2.3 ng/mL; P <0.05) and serum concentrations of malondialdehyde-modified low-density lipoprotein (from 69.0±19.5 to 82.4±21.5 U/L; P <0.05), whereas moderate exercise tended to decrease both indices of oxidative stress. Conclusions—These findings suggest that moderate-intensity aerobic exercise augments endothelium-dependent vasodilation in humans through the increased production of nitric oxide and that high-intensity exercise possibly increases oxidative stress.

Autologous Bone-Marrow Mononuclear Cell Implantation Improves Endothelium-Dependent Vasodilation in Patients With Limb Ischemia

Background—Patients with limb ischemia were associated with endothelial dysfunction. The purpose of this study was to determine whether autologous bone-marrow mononuclear cell (BM-MNC) implantation improves endothelial dysfunction in patients with limb ischemia. Methods and Results—We evaluated the leg blood flow (LBF) response to acetylcholine (ACh), an endothelium-dependent vasodilator, and sodium nitroprusside (SNP), an endothelium-independent vasodilator, before and after BM-MNC implantation in 7 patients with limb ischemia. LBF was measured with a mercury-filled Silastic strain-gauge plethysmograph. The number of BM-MNCs implanted into ischemic limbs was 1.6×109±0.3×109. The number of CD34+ cells included in the implanted BM-MNCs was 3.8×107±1.6×107. BM-MNC implantation improved the ankle-brachial pressure index (0.33±0.21 to 0.39±0.17, P =0.06), transcutaneous oxygen pressure (28.4±11.5 to 36.6±5.2 mm Hg, P =0.03), and pain-free walking time (0.8±0.6 to 2.9±2.2 minutes, P =0.02). After BM-MNC implantation, LBF response to ACh was enhanced (19.3±6.8 versus 29.6±7.1 mL/min per 100 mL; P =0.002). The vasodilatory effect of SNP was similar before and after BM-MNC implantation. Conclusions—These findings suggest that BM-MNC implantation augments endothelium-dependent vasodilation in patients with limb ischemia.

Circadian Variation of Blood Pressure and Endothelial Function in Patients With Essential Hypertension: A Comparison of Dippers and Non-Dippers

OBJECTIVESnThe purpose of this study was to evaluate the relationship between the circadian blood pressure (BP) rhythm and endothelial function in patients with essential hypertension.nnnBACKGROUNDnHypertension is associated with alterations in resistance artery endothelial function. Patients with a non-dipper circadian pattern of BP have a greater risk of cerebrovascular and cardiovascular complications than do patients with a dipper circadian pattern.nnnMETHODSnWe evaluated the forearm blood flow (FBF) response to intra-arterial acetylcholine (ACh), an endothelium-dependent vasodilator, and isosorbide dinitrate (ISDN), an endothelium-independent vasodilator, infusion in 20 patients with non-dipper hypertension and 20 age- and gender-matched patients with dipper hypertension. The FBF was measured using a mercury-filled Silastic strain-gauge plethysmograph.nnnRESULTSnThe 24-h systolic BP, as well as nocturnal systolic and diastolic BPs were higher in non-dipper patients than in dipper patients. The 24-h urinary excretion of nitrite/nitrate and cyclic guanosine monophosphate was lower in non-dippers than in dippers. The response of FBF to ACh was smaller in non-dippers than in dippers (25.1 +/- 3.1 vs. 20.2 +/- 3.0 ml/min/100 ml tissue, p < 0.05). The FBF response to ISDN was similar in dippers and non-dippers. The FBF response to ACh was similar in the two groups following intra-arterial infusion of the nitric oxide (NO) synthase inhibitor N(G)-monomethyl-L-arginine.nnnCONCLUSIONSnThese findings suggest that endothelium-dependent vasodilation is blunted through a decrease in NO release in non-dippers compared with patients who have dipper hypertension.

The efficacy of a bilateral approach for treating lesions with chronic total occlusions the CART (controlled antegrade and retrograde subintimal tracking) registry.

OBJECTIVESnThe aim of this study was to evaluate the safety and feasibility of a new concept for chronic total occlusion (CTO) recanalization-using a bilateral approach that utilizes a Controlled Antegrade and Retrograde subintimal Tracking (CART) technique.nnnBACKGROUNDnSuccessful percutaneous recanalization of coronary CTOs results in improved long-term outcomes. The recanalization of CTOs in native coronary arteries no doubt represents one of the most technically challenging of interventional procedures.nnnMETHODSnA total of 224 consecutive patients (mean age 61 +/- 9 years; 86.2% men) were enrolled in this prospective multicenter registry. This technique combines the simultaneous use of antegrade and retrograde approaches. A subintimal dissection is created in both antegrade and retrograde fashion, thereby limiting the extension of the subintimal dissection within the CTO portion.nnnRESULTSnOf 224 CTO lesions (>3 months in duration) undergoing attempted recanalization using the CART technique, 145 cases (64.7%) had undergone previous CTO recanalization attempts. The success rates of crossing in a retrograde fashion with a wire and a balloon were 87.9% and 79.9%, respectively. The overall technical and procedural success rates achieved in this registry were 92.4% and 90.6%, respectively.nnnCONCLUSIONSnA bilateral approach for CTO lesions using the CART technique is feasible, safe, and has a higher success rate than previous approaches. These results indicate that a bilateral technique can solve a major dilemma that commonly affects CTO procedures.

A low-calorie diet improves endothelium-dependent vasodilation in obese patients with essential hypertension*

BACKGROUNDnBoth obesity and hypertension are associated with endothelial dysfunction. The purpose of this study was to investigate the effects of a low-calorie diet on endothelial function in obese patients with essential hypertension.nnnMETHODSnWe measured forearm blood flow (FBF) during intra-arterial infusion of acetylcholine (ACh; 7.5, 15, 30 microg/min), an index of endothelium-dependent vasodilation, and isosorbide dinitrate (ISDN; 0.75, 1.5, 3.0 microg/min), an index of endothelium-independent vasodilation, in obese patients with essential hypertension before and after 2 weeks on a low-calorie diet (800 kcal/d). The study included 11 obese hypertensive Japanese patients (mean body mass index, 30.8 +/- 3.6 kg/m2). Fifteen healthy Japanese normotensive individuals were recruited as a control group.nnnRESULTSnIn obese patients with hypertension, the response of FBF to ACh was attenuated compared to healthy individuals (P < .001). Caloric restriction reduced body weight from 77.5 +/- 15.0 to 73.2 +/- 13.5 kg (P < .01), the mean blood pressure from 118.4 +/- 8.7 to 105.7 +/- 8.5 mm Hg (P < .01), fasting plasma insulin from 85.8 +/- 22.8 to 64.8 +/- 27.0 pmol/L (P < .05), serum total cholesterol from 5.30 +/- 0.76 to 4.67 +/- 0.58 mmol/L (P < .05), and low density lipoprotein cholesterol from 3.80 +/- 0.48 to 3.29 +/- 0.44 mmol/L (P < .05). Basal FBF was similar before and after weight reduction. Caloric restriction enhanced the response of FBF to ACh (P < .05), but did not alter the response to ISDN. The intra-arterial infusion of NG-monomethyl-L-arginine (8 micromol/min), a nitric oxide synthase inhibitor, decreased the enhanced ACh-induced blood flow response induced by caloric restriction.nnnCONCLUSIONSnThe present findings suggest that the caloric restriction improves endothelial-dependent vasodilation through an increased release of nitric oxide in obese hypertensive patients.

Effect of fluvastatin on progression of coronary atherosclerotic plaque evaluated by virtual histology intravascular ultrasound.

OBJECTIVESnThe aim of this study was to evaluate the effect of treatment with statins on the progression of coronary atherosclerotic plaques of a nonculprit vessel by serial volumetric virtual histology (VH) intravascular ultrasound (IVUS).nnnBACKGROUNDnRecent clinical trials have demonstrated a reduction of atherosclerotic plaque, yet whether statin therapy affects the change in components of plaque remains unknown.nnnMETHODSnThis study was a nonrandomized and nonblinded design. Eighty patients with stable angina pectoris were divided into either the fluvastatin group (n = 40) or the control group (n = 40) according to their total or low-density lipoprotein (LDL) cholesterol level. The volume of each plaque component (dense calcium, fibrous tissue, fibro-fatty, or necrotic core) was evaluated at baseline and at 12-month follow-up.nnnRESULTSnThe LDL cholesterol and high-sensitivity C-reactive protein (hsCRP) levels in the fluvastatin group were significantly decreased at time of follow-up. In VH IVUS findings, fibro-fatty volume was significantly decreased (baseline 80.1 +/- 57.9 mm(3) vs. follow-up 32.5 +/- 27.7 mm(3), p < 0.0001) and fibrous tissue volume was increased (baseline 146.5 +/- 85.6 mm(3) vs. follow-up 163.3 +/- 94.5 mm(3), p < 0.0001) in the fluvastatin group. In the control group, the volumes of all plaque components without fibrous tissue were significantly increased. Change in fibro-fatty volume has a significant correlation with a change in LDL cholesterol level (R = 0.703, p < 0.0001) and change in hsCRP level (R = 0.357, p = 0.006).nnnCONCLUSIONSnOne-year lipid-lowering therapy by fluvastatin showed significant regression of plaque volume and alterations in atherosclerotic plaque composition with a significant reduction of fibro-fatty volume.

Effectiveness of Drug-Eluting Stent Implantation for Patients With Unprotected Left Main Coronary Artery Stenosis

This study was aimed to evaluate outcomes of patients with unprotected left main coronary artery (LMCA) stenosis who were treated with drug-eluting stents. Sixty-three consecutive patients with unprotected LMCA stenosis were treated with sirolimus-eluting stents in 52 (83%) patients and paclitaxel-eluting stents in 11 (17%) patients, in whom percutaneous intervention was considered the sole alternative because of high surgical risk and/or patient preference. Urgent percutaneous coronary intervention within 24 hours after angiography was performed in 6 (10%) patients. The patients were predominantly at high surgical risk with 35 (56%) having EuroSCORE >6 and 39 (62%) having Parsonnet score >15. Involvement of the distal LMCA was observed in 46 (73%) patients. Procedural success was achieved in all patients. Intravascular ultrasound was used in 51 (81%) patients. Single-stenting strategy was adopted in 36 (78%) patients with bifurcation stenosis. There were no death, Q-wave myocardial infarction, stent thrombosis, or urgent repeat revascularization events during hospitalization. Over a mean follow-up of 11.7 +/- 7.7 months, 18 (29%) patients experienced major adverse cardiac events, including 3 (5%) deaths, 7 (11%) myocardial infarctions, and 10 (16%) target lesion revascularizations. Stent thrombosis developed in 1 (0.6%) patient at 35 days after the procedure. Bifurcation involvement was an independent predictor of major adverse cardiac events by multivariate analysis (hazard ratio 12.90, 95% confidence interval 1.36 to 122.45, p = 0.0259). In conclusion, drug-eluting stent placement for unprotected LMCA stenosis may be a feasible therapeutic alternative in patients at high surgical risk. However, bifurcation stenosis remains a significant predictor of unfavorable clinical outcome.

PDE5 inhibitor sildenafil citrate augments endothelium-dependent vasodilation in smokers

Abstract—Smoking is associated with endothelial dysfunction. The purpose of this study was to determine the effect of sildenafil, an inhibitor of phosphodiesterase type 5 (PDE5), on endothelial function in smokers. We evaluated the forearm blood flow (FBF) responses to acetylcholine (ACh), an endothelium-dependent vasodilator, and to sodium nitroprusside (SNP), an endothelium-independent vasodilator, before and after oral sildenafil administration (100 mg) with a strain-gauge plethysmograph in 10 young healthy male smokers and 10 young healthy male nonsmokers. FBF response to ACh was lower in smokers than in nonsmokers. The vasodilatory effects of SNP were similar in both groups. Sildenafil increased the FBF response to ACh from 9.3±2.0 to 12.5±3.5 mL/min per 100 mL tissue in smokers and from 12.6±5.6 to 19.6±8.4 mL/min per 100 mL tissue in nonsmokers, and it increased the response to SNP from 13.3±3.9 to 15.1±4.3 mL/min per 100 mL tissue in smokers and from 14.8±5.2 to 18.4±6.0 mL/min/100 mL tissue in nonsmokers (P <0.05 for all). The ratio of maximal ACh-stimulated FBF expressed as a ratio of maximal SNP-stimulated FBF significantly increased after administration of sildenafil in both groups. Infusion of NG-monomethyl-l-arginine, a nitric oxide synthase inhibitor, abolished sildenafil-induced augmentation of the FBF response to ACh in both groups. The findings suggest that endothelial function is impaired in smokers compared with that in nonsmokers, that inhibition of PDE5 by sildenafil significantly increases nitric oxide-mediated vasodilation, and that the activities of PDE5 in smokers and nonsmokers may be similar.

Repetition of Ischemic Preconditioning Augments Endothelium-Dependent Vasodilation in Humans: Role of Endothelium-Derived Nitric Oxide and Endothelial Progenitor Cells

Background—Several studies have shown that both early and late effects of ischemic preconditioning (IPC) protect against myocardial injury after ischemic reperfusion. Methods and Results—The purpose of this study was to evaluate the late effects of IPC on endothelial function in humans. Late phase of IPC was induced by upper limb ischemia (cuff inflation of over 200 mm Hg for 5 minutes) 6 times a day for 1 month. We evaluated forearm blood flow (FBF) responses to acetylcholine (ACh) and to sodium nitroprusside (SNP) before and after IPC stimulus in 30 young healthy men. FBF was measured using a strain-gauge plethysmograph. The IPC stimulus significantly increased plasma concentration of vascular endothelial growth factor (VEGF), circulating level of endothelial progenitor cells (EPCs), and FBF responses to ACh, but these did not change in the control group. The FBF responses to SNP were similar before and after the IPC stimulus. Infusion of NG-monomethyl-L-arginine, a nitric oxide synthase inhibitor, completely eliminated the IPC stimulus-induced augmentation of FBF responses to ACh. In the cotralateral arms of subjects that received the IPC stimulus, FBF responses to ACh did not change, but levels of VEGF and circulating EPCs increased. Conclusions—These findings suggest that repetition of late IPC stimulus augments endothelium-dependent vasodilation in humans through increases in nitric oxide production and number of EPCs under a local condition. Repetition of IPC stimulus may be a simple, safe, and feasible therapeutic technique for endothelial protection of peripheral vessels.

Smoking, Endothelial Function, and Rho-Kinase in Humans

Objective—Smoking is associated with endothelial dysfunction and activated Rho-kinase in vascular smooth muscle cells (VSMCs) in humans. The purpose of this study was to elucidate the relationship between endothelial function and Rho-kinase activity in forearm VSMCs in healthy young men. Methods and Results—We evaluated the forearm blood flow (FBF) responses to acetylcholine (ACh), fasudil, a Rho-kinase inhibitor, and sodium nitroprusside (SNP) in male smokers (n=10) and nonsmokers (n=14). FBF was measured by using a strain-gauge plethysmography. The vasodilatory effect of ACh was significantly smaller in smokers than that in nonsmokers. The vasodilatory effect of fasudil was significantly greater in smokers than that in nonsmokers. The vasodilatory effects of SNP in the 2 groups were similar. There was a significant correlation between the maximal FBF response to fasudil and that to ACh (r=−0.67; P<0.01). There was no significant correlation between the maximal FBF response to fasudil and that to SNP. The intra-arterial coinfusion of fasudil significantly increased the FBF response to ACh in smokers but not in nonsmokers. There were no significant differences between FBF response to fasudil alone and that in combination with NG-monomethyl-l-arginine in smokers and in nonsmokers. The intra-arterial coinfusion ascorbic acid did not alter the FBF response to fasudil in both groups. Conclusions—These findings suggest that smoking is involved in not only endothelial dysfunction but also activation of Rho-kinase in VSMCs in forearm circulation, and that there is a significant correlation between endothelial function and Rho-kinase activity in VSMCs.