Kenji Nishioka

Diabetes mellitus prevents ischemic preconditioning in patients with a first acute anterior wall myocardial infarction.

OBJECTIVES This study was undertaken to assess whether prodromal angina could have beneficial effects in diabetic patients with acute myocardial infarction (AMI). BACKGROUND Prodromal angina occurring shortly before the onset of AMI is associated with favorable outcomes by the mechanism of ischemic preconditioning. However, little is known about the impact of diabetes on ischemic preconditioning. METHODS We studied 611 patients with a first anterior wall AMI who underwent emergency catheterization within 12 h after the onset of chest pain: 490 patients without diabetes and 121 patients with non-insulin treated diabetes. Prodromal angina was defined as angina episode(s) occurring within 24 h before the onset of AMI. Serial contrast left ventriculograms were obtained in 424 patients at the time of acute and predischarge catheterization. RESULTS In non-diabetic patients, prodromal angina was associated with lower peak creatine kinase (CK) value (3,068 +/- 2,647 IU/l vs. 3,601 +/- 2,462 IU/l, p = 0.037), larger increase in left ventricular ejection fraction (LVEF) (10.1 +/- 13.0% vs. 5.8 +/- 13.4%, p = 0.004) and lower in-hospital mortality (3.4% vs. 9.3%, p = 0.015). On the contrary, in diabetic patients, there was no significant difference in peak CK value (3,382 +/- 2,520 IU/l vs. 3,233 +/- 2,412 IU/l, p = NS), the change in LVEF (6.7 +/- 13.8% vs. 7.1 +/- 12.4%, p = NS) and in-hospital mortality (8.8% vs. 11.0%, p = NS) between patients with and patients without prodromal angina. CONCLUSIONS Prodromal angina limited infarct size, enhanced recovery of LV function and improved survival in non-diabetic patients with AMI. However, such beneficial effects of prodromal angina were not observed in diabetic patients, suggesting that diabetes might prevent ischemic preconditioning.

Periodontal Infection Is Associated With Endothelial Dysfunction in Healthy Subjects and Hypertensive Patients

The purpose of this study was to evaluate endothelial function in patients with periodontitis. We evaluated forearm blood flow responses to acetylcholine and sodium nitroprusside in patients with periodontitis who had no other cardiovascular risk factors (32 men; 25±3 years of age), in a normal control group (20 men; 26±3 years of age), and in hypertensive patients with periodontitis (28 men and 10 women; 56±12 years of age) and without periodontitis (control group; 18 men and 6 women; 54±13 years of age). Forearm blood flow was measured using strain-gauge plethysmography. Circulating levels of C-reactive protein and interleukin-6 were significantly higher in the periodontitis group than in the control group. Both in healthy and hypertensive subjects, forearm blood flow responses to acetylcholine were significantly smaller in the periodontitis group than in the control group. Sodium nitroprusside–stimulated vasodilation was similar in the 2 groups. Periodontal therapy reduced serum concentrations of C-reactive protein and interleukin-6 and augmented acetylcholine-induced vasodilation in periodontitis patients with and without hypertension. After administration of NG-monomethyl-l-arginine, an NO synthase inhibitor, forearm blood flow response to acetylcholine was similar before and after treatment. These findings suggest that periodontitis is associated with endothelial dysfunction in subjects without cardiovascular risk factors, as well as hypertensive patients, through a decrease in NO bioavailability and that systemic inflammation may be, at least in part, a cause of endothelial dysfunction, leading to cardiovascular diseases.

Impact of acute hyperglycemia on left ventricular function after reperfusion therapy in patients with a first anterior wall acute myocardial infarction

OBJECTIVE This study was undertaken to assess the relationship between acute hyperglycemia and left ventricular function after reperfusion therapy for acute myocardial infarction (AMI). METHODS This study consisted of 529 patients with a first anterior wall AMI who underwent coronary angiography followed by coronary angioplasty or thrombolysis within 12 hours after the onset of chest pain. Plasma glucose was measured at the time of hospital admission. Acute hyperglycemia was defined as plasma glucose >10 mmol/L. RESULTS Although acute hyperglycemia was associated with both lower acute left ventricular ejection fraction (LVEF) (46% +/- 12% vs 48% +/- 10%, P =.026) and lower predischarge LVEF (51% +/- 15% vs 56% +/- 15%, P =.001), the difference was more pronounced in the latter and the change in LVEF was significantly smaller in patients with acute hyperglycemia (4.8% +/- 11.2% vs 8.0% +/- 13.8%, P =.022). Multivariable analysis showed that there was a significant correlation between plasma glucose and impaired predischarge LVEF, even after adjustment of acute LVEF (r = -0.13, P =.005). Thirty-day mortality tended to be higher in patients with acute hyperglycemia than in patients without (7.1% vs 3.5%, P =.06). Multivariable analysis showed that plasma glucose (per 1 mmol/L increase) was an independent predictor of 30-day mortality after AMI (odds ratio 1.12, 95% CI 1.03-1.22, P =.009). CONCLUSION Acute hyperglycemia was independently associated with impaired left ventricular function and higher 30-day mortality after AMI. These results may provide a potential explanation for poor outcomes of patients with AMI and acute hyperglycemia.

Beneficial effect of prodromal angina pectoris is lost in elderly patients with acute myocardial infarction

BACKGROUND Prodromal angina pectoris occurring shortly before the onset of acute myocardial infarction is associated with a favorable outcome by the mechanism of ischemic preconditioning. Recent experiments have reported that the beneficial effect of ischemic preconditioning are reversed in the aged heart. METHODS We studied 990 patients who underwent coronary angiography within 12 hours after the onset of acute myocardial infarction. Patients were divided into 2 groups: those aged <70 years (nonelderly patients, n = 722) and those aged >/=70 years (elderly patients, n = 268). Prodromal angina in the 24 hours before infarction was found in 190 of 722 nonelderly patients and in 66 of 268 elderly patients (26% vs 25%, P =.61). RESULTS In nonelderly patients, prodromal angina was associated with lower peak creatine kinase levels (2438 +/- 1939 IU/L vs 2837 +/- 2341 IU/L, P =.04), lower in-hospital mortality rates (3.7% vs 8.8%, P =.02), and better 5-year survival rates (P =. 007). On the contrary, in elderly patients there was no significant difference in peak creatine kinase levels (2427 +/- 2142 IU/L vs 2256 +/- 1551 IU/L, P =.51), in-hospital mortality rate (21.2% vs 17. 4%, P =.49), and 5-year survival rates (P =.47). A multivariate analysis showed that prodromal angina in the 24 hours before infarction was associated with 5-year survival rate in nonelderly patients (odds ratio 0.49, P =.009) but not in elderly patients (odds ratio l.12, P =.65). CONCLUSIONS In nonelderly patients, prodromal angina in the 24 hours before infarction was associated with a smaller infarct size and better short- and long-term survival, suggesting a relation to ischemic preconditioning. However, such a beneficial effect was not observed in elderly patients.

Autologous Bone-Marrow Mononuclear Cell Implantation Reduces Long-Term Major Amputation Risk in Patients With Critical Limb Ischemia A Comparison of Atherosclerotic Peripheral Arterial Disease and Buerger Disease

Background— Bone-marrow mononuclear cell (BM-MNC) implantation improves ischemic symptoms in patients with critical limb ischemia (CLI). The purpose of this study was to evaluate long-term clinical outcomes after autologous BM-MNC implantation in patients with CLI. Methods and Results— We assessed long-term clinical outcomes after BM-MNC implantation in 51 patients with CLI, including 25 patients with peripheral arterial disease (PAD) and 26 patients with Buerger disease. Forty-six CLI patients who had no BM-MNC implantation served as control subjects. Median follow-up period was 4.8 years. The 4-year amputation-free rates after BM-MNC implantation were 48% in PAD patients and 95% in Buerger disease, and they were 0% in control PAD patients and 6% in control Buerger disease. The 4-year overall survival rates after BM-MNC implantation were 76% in PAD patients and 100% in Buerger disease, and they were 67% in control PAD patients and 100% in control Buerger disease. Multivariable Cox proportional hazards analysis revealed that BM-MNC implantation correlated with prevention of major amputation and that hemodialysis and diabetes mellitus correlated with major amputation. In Buerger disease, ankle brachial pressure index and transcutaneous oxygen pressure were significantly increased after 1 month and remained high during 3-year follow-up. However, in patients with PAD, ankle brachial pressure index and transcutaneous oxygen pressure significantly increased after 1 month and gradually decreased during 3-year follow-up and returned to baseline levels. Conclusions— These findings suggest that BM-MNC implantation is safe and effective in patients with CLI, especially in patients with Buerger disease. Clinical Trial Registration— URL: . Unique identifier: 001769.Background—Bone-marrow mononuclear cell (BM-MNC) implantation improves ischemic symptoms in patients with critical limb ischemia (CLI). The purpose of this study was to evaluate long-term clinical outcomes after autologous BM-MNC implantation in patients with CLI. Methods and Results—We assessed long-term clinical outcomes after BM-MNC implantation in 51 patients with CLI, including 25 patients with peripheral arterial disease (PAD) and 26 patients with Buerger disease. Forty-six CLI patients who had no BM-MNC implantation served as control subjects. Median follow-up period was 4.8 years. The 4-year amputation-free rates after BM-MNC implantation were 48% in PAD patients and 95% in Buerger disease, and they were 0% in control PAD patients and 6% in control Buerger disease. The 4-year overall survival rates after BM-MNC implantation were 76% in PAD patients and 100% in Buerger disease, and they were 67% in control PAD patients and 100% in control Buerger disease. Multivariable Cox proportional hazards analysis revealed that BM-MNC implantation correlated with prevention of major amputation and that hemodialysis and diabetes mellitus correlated with major amputation. In Buerger disease, ankle brachial pressure index and transcutaneous oxygen pressure were significantly increased after 1 month and remained high during 3-year follow-up. However, in patients with PAD, ankle brachial pressure index and transcutaneous oxygen pressure significantly increased after 1 month and gradually decreased during 3-year follow-up and returned to baseline levels. Conclusions—These findings suggest that BM-MNC implantation is safe and effective in patients with CLI, especially in patients with Buerger disease. Clinical Trial Registration—URL: http://home.hiroshima-u.ac.jp/angio/. Unique identifier: 001769.

Aging and hypertension are independent risk factors for reduced number of circulating endothelial progenitor cells.

BACKGROUND Recent studies have revealed the existence of bone marrow-derived endothelial progenitor cells (EPCs). The number of circulating EPCs might reflect the pathogenesis of atherosclerosis and progression of cardiovascular diseases (CVDs). The purpose of this study was to evaluate the relationship between the number of EPCs and cardiovascular risk factors. METHODS Flow cytometry analysis was used to quantify the number of EPCs (CD34(+)AC133(+)CD45(low)) in 135 consecutive hospitalized patients with CVD and 25 healthy subjects. RESULTS The number of EPCs was less in the patients than in the healthy subjects (1,047.4 +/- 521.1 vs. 612.8 +/- 461.6/ml, P < 0.0001). The number of EPCs significantly correlated with the number of risk factors (r = 0.424, P < 0.0001). The numbers of EPCs in patients with hypertension and diabetes mellitus were less than those in patients without those diseases (762.6 +/- 579.5 vs. 495.2 +/- 297.7/ml, P < 0.01 and 666.8 +/- 505.5 vs. 477.0 +/- 290.4/ml, P < 0.05, respectively). In healthy subjects a reduced number of EPCs was found in smokers compared with nonsmokers (833.3 +/- 347.5 vs. 1,274.6 +/- 560.9/ml, P < 0.05), whereas smoking did not alter the number of EPCs in the patients group. In multivariate analysis, hypertension and age were independent predictors of reduced number of EPCs. Renin-angiotensin system (RAS) inhibitors increased the number of EPCs (464.7 +/- 252.1/ml vs. 617.5 +/- 343.5/ml, P < 0.05), while calcium antagonists, diuretics, and beta-blockers did not alter the number of EPCs in patients with hypertension. CONCLUSIONS These findings suggest that both aging and hypertension are risk factors for reduced number of EPCs and that RAS inhibitors increase the number of EPCs.

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.

Effect of acute hyperglycemia on the ischemic preconditioning effect of prodromal angina pectoris in patients with a first anterior wall acute myocardial infarction

Acute hyperglycemia abolishes the ischemic preconditioning effect of prodromal angina pectoris in patients with acute myocardial infarction. We investigated a potential explanation for the association between acute hyperglycemia and adverse outcomes after acute myocardial infarction.

Pycnogenol ® , French Maritime Pine Bark Extract, Augments Endothelium-Dependent Vasodilation in Humans

Pycnogenol®, an extract of bark from the French maritime pine, Pinus pinaster Ait., consists of a concentrate of water-soluble polyphenols. Pycnogenol® contains the bioflavonoids catechin and taxifolin as well as phenolcarbonic acids. Antioxidants, such as bioflavonoids, enhance endothelial nitric oxide (NO) synthase expression and subsequent NO release from endothelial cells. The purpose of this study was to determine Pycnogenol®s effects on endothelium-dependent vasodilation in humans. This was a double-blind, randomized, placebo and active drug study. We evaluated forearm blood flow (FBF) responses to acetylcholine (ACh), an endothelium-dependent vasodilator, and to sodium nitroprusside (SNP), an endothelium-independent vasodilator, in healthy young men before and after 2 weeks of daily oral administration of Pycnogenol® (180 mg/day) (n=8) or placebo (n=8). FBF was measured by using strain-gauge plethysmography. Neither the placebo nor Pycnogenol® altered forearm or systemic hemodynamics. Pycnogenol®, but not placebo, augmented FBF response to ACh, from 13.1±7.0 to 18.5±4.0 mL/min per 100 mL tissue (p<0.05). SNP-stimulated vasodilation was similar before and after 2 weeks of treatment in the control and Pycnogenol® groups. The administration of NG-monomethyl-L-arginine, an NO synthase inhibitor, completely abolished Pycnogenol®-induced augmentation of the FBF response to ACh. These findings suggest that Pycnogenol® augments endothelium-dependent vasodilation by increasing in NO production. Pycnogenol® would be useful for treating various diseases whose pathogeneses involve endothelial dysfunction.