Teneligliptin, a DPP-4 Inhibitor, Improves Vascular Endothelial Function via Divergent Actions Including Changes in Circulating Endothelial Progenitor Cells.

Purpose: Dipeptidyl peptidase-4 (DPP-4) inhibitors increase endothelial progenitor cells (EPCs) in peripheral blood circulation. However, the underlying mechanisms and effects on vascular endothelial function remain unclear. We evaluated whether the DPP-4 inhibitor teneligliptin increases circulating EPCs by inhibiting stromal-derived factor-1α (SDF-1α) and improves flow-mediated vascular dilatation (FMD) in type 2 diabetes mellitus patients with acute coronary syndrome (ACS) or its risk factors. Patients and Methods: This single-center, open-label, prospective, randomized controlled trial evaluated 17 patients (hemoglobin A1c ≤7.5% and peak creatinine phosphokinase <2000 IU/mL) with ACS or a history of ACS or multiple cardiovascular risk factors. Metabolic variables of glucose and lipids, circulating EPCs, plasma DPP-4 activity, and SDF-1α levels, and FMD were evaluated at baseline and 28 ± 4 weeks after enrollment. Patients were randomly assigned to either the teneligliptin (n = 8) or control (n = 9) groups. Results: The DPP-4 activity (∆-509.5 ± 105.7 vs ∆32.8 ± 53.4 µU/mL) and SDF-1α levels (∆-695.6 ± 443.2 vs ∆11.1 ± 193.7 pg/mL) were significantly decreased after 28 weeks in the teneligliptin group than those in the control group. The number of EPCs showed an increasing trend in the teneligliptin treated group; albeit this did not reach statistical significance. Glucose and lipid levels were not significantly different between the groups before and after 28 weeks. However, FMD was significantly improved in the teneligliptin group when compared to the control group (∆3.8% ± 2.1% vs ∆-0.3% ± 2.9%, P=0.006). Conclusion: Teneligliptin improved FMD through a mechanism other than increasing the number of circulating EPCs.

Report of a rare case of periaortitis at the aortic arch and successful therapeutic strategy with prednisolone.

Periaortitis is one of the less common manifestations of the aorta pathology. Periaortitis mostly arises from the outer layers of the abdominal aorta and iliac arteries. However, other large arteries may also be involved, but rarely the thoracic aorta. Here we present a successful conservative treatment using prednisolone therapy for periaortitis of the aortic arch which shows various clinical symptoms. .

Clinical characteristics associated with pacing-induced cardiac dysfunction: a high incidence of undiagnosed cardiac sarcoidosis before permanent pacemaker implantation.

Previous studies suggested that right ventricular pacing was associated with pacing-induced cardiac dysfunction (PICD). The purpose of this study was to investigate the clinical characteristics including the incidence of undiagnosed cardiac sarcoidosis (CS) in patients with atrioventricular block (AVB) who manifest PICD. We retrospectively investigated consecutive patients with permanent pacemaker (PPM) undergoing a first-generator replacement surgery with a new PPM or an upgrade procedure to a cardiac resynchronization therapy (CRT) device between December 1, 2011 and June 30, 2017. Patients with AVB showing normal echocardiographic findings before PPM implantation were included and divided into 2 groups: patients with post-PPM left ventricular ejection fraction (LVEF) < 40% and/or undergoing an upgrade procedure to CRT (PICD group) and patients with post-PPM LVEF ≥ 40% who underwent replacement surgery with a new PPM (no-PICD group). There were 15 and 41 patients in the PICD and no-PICD groups, respectively. A wider-paced QRS duration just after the PPM implantation and/or lower pre-PPM LVEF was observed in the PICD group. Furthermore, 46.7% of the PICD patients (7/15) satisfied the diagnostic criteria for CS according to the guideline of the Japanese Circulation Society, although no patients fulfilled these criteria before PPM implantation. In conclusion, a high incidence of CS was observed in patients with AVB who had PICD. However, none of these patients was diagnosed with CS before PPM implantation.

A Case of Pulmonary Hypertension Associated with Idiopathic Hypereosinophilic Syndrome.

Hypereosinophilic syndrome (HES) is characterized by multi-organ damage that is associated with tissue hypereosinophilia. A persistently elevated eosinophilic count is also required for the diagnosis of HES. Although HES affects various organs, damage to pulmonary artery is rarely reported. We present a case of a 39-year-old man who was diagnosed with pulmonary hypertension (PH) associated with idiopathic HES. Although the pulmonary arterial hypertension specific drugs including intravenous epoprostenol could not control his PH, corticosteroid was effective for both hypereosinophilia and PH. Our case suggests the importance of steroid therapy as well as specific drugs for pulmonary arterial hypertension in the treatment of PH associated with HES.

Clinical background including anticoagulant therapy in patients with atrial fibrillation in a community-based survey: the Saitama AF Registry.

Atrial fibrillation (AF) is one of the most common cardiac arrhythmias, and carries an increased risk of cardiogenic embolism. Oral anticoagulants (OACs) including warfarin and/or non-vitamin K antagonists can prevent the majority of these events. The Saitama AF Registry was a community-based survey of patients with AF in Saitama City, which represents an urban community in Japan. A total of 75 institutions participated in the registry and attempted to enroll consecutive patients with AF from September 2014 to August 2015. The aim of the present study was to examine the clinical characteristics of patients with AF using data of the Saitama AF Registry. In addition, we investigated the difference in clinical characteristics of the patients between small-sized hospitals and large-sized hospitals. A total of 3591 patients were enrolled; 57.7% of all patients were enrolled from small-sized hospitals, whereas 42.3% were from large-sized hospitals. The patients from small-sized hospitals had higher CHADS2 score than those from large-sized hospitals. Approximately, 80% of all patients were treated with OACs, and the prescription rate was higher in patients with CHADS2 score ≥ 2 from both small-sized hospitals and large-sized hospitals. In conclusion, the present study demonstrated an appropriate use of OACs for high-risk patients with CHADS2 score ≥2 in Saitama City regardless of hospital size.

Eicosapentaenoic acid shows anti-inflammatory effect via GPR120 in 3T3-L1 adipocytes and attenuates adipose tissue inflammation in diet-induced obese mice.

BACKGROUND: Saturated fatty acids have been shown to cause insulin resistance and low-grade chronic inflammation, whereas unsaturated fatty acids suppress inflammation via G-protein coupled receptor 120 (GPR120) in macrophages. However, the anti-inflammatory effects of unsaturated fatty acids in adipocytes have yet to be elucidated. Hence, the aims of the present study were to evaluate the anti-inflammatory effects of eicosapentaenoic acid (EPA) via GPR120 in adipocytes. METHODS: We used 250 µM palmitate as a representative saturated fatty acid. 3T3-L1 adipocytes were used for in vitro studies. We further evaluated the effect of EPA supplementation in a high-fat/high-sucrose (HFHS) diet-induced adipose tissue inflammatory mouse model. RESULTS: EPA attenuated palmitate-induced increases in inflammatory gene expression and NF-κB phosphorylation in 3T3-L1 adipocytes. Silencing of GPR120 abolished the anti-inflammatory effects of EPA. In GPR120 downstream signal analysis, EPA was found to decrease palmitate-induced increases in TAK1/TAB1 complex expression. EPA supplementation suppressed HFHS-induced crown-like structure formation in epididymal adipose tissue and altered macrophage phenotypes from M1 to M2 in the stromal vascular fraction. Moreover, the EPA-containing diet attenuated increases in adipose p-JNK and phospho-p65 NF-κB levels. CONCLUSIONS: In conclusion, the findings of the present study demonstrate that EPA suppresses palmitate-induced inflammation via GPR120 by inhibiting the TAK1/TAB1 interaction in adipocytes. EPA supplementation reduced HFHS diet-induced inflammatory changes in mouse adipose tissues. These results demonstrate adipose GPR120 as a potential therapeutic target for decreasing inflammation.

Pravastatin improves postprandial endothelial dysfunction and hemorheological deterioration in patients with effort angina pectoris.

Postprandial hypertriglyceridemia and hyperglycemia may promote endothelial and hemorheological dysfunction. The present study investigated the effects of pravastatin on endothelial function and hemorheology in patients with stable angina pectoris (AP) before and after eating a test meal. We recruited 26 patients with stable AP who had impaired glucose tolerance and mild dyslipidemia and six healthy men as controls to assess endothelial function and hemorheological behavior. In each group, we measured forearm blood flow (FBF) during post-ischemic reactive hyperemia and obtained blood samples before and 2 h after the test meal. Pravastatin 20 mg/day was then commenced in the 26 AP patients. The above tests were repeated after 2 days and 6 months. Maximum FBF during hyperemia in the baseline fasting phase was significantly lower in the AP patients than in the controls (p < 0.05). Fasting and postprandial FBF during reactive hyperemia time-dependently improved after pravastatin treatment (p < 0.05 vs. baseline data for each phase). Pravastatin treatment for 6 months, but not for 2 days, inhibited leukocyte activation and improved hemorheological parameters. In conclusion, pravastatin treatment for 6 months improved fasting and postprandial endothelial and hemorheological dysfunction in AP patients.

High-density lipoprotein and apolipoprotein A-I inhibit palmitate-induced translocation of toll-like receptor 4 into lipid rafts and inflammatory cytokines in 3T3-L1 adipocytes.

Saturated fatty acids (SFAs) activate toll-like receptor 4 (TLR4) signal transduction in macrophages and are involved in the chronic inflammation accompanying obesity. High-density lipoprotein (HDL) and apolipoprotein A-I (apoA-I) produce anti-inflammatory effects via reverse cholesterol transport. However, the underlying mechanisms by which HDL and apoA-I inhibit inflammatory responses in adipocytes remain to be determined. Here we examined whether palmitate increases the translocation of TLR4 into lipid rafts and whether HDL and apoA-I inhibit inflammation in adipocytes. Palmitate exposure (250 µM, 24 h) increased interleukin-6 and tumor necrosis factor-α gene expressions and translocation of TLR4 into lipid rafts in 3T3-L1 adipocytes. Pretreatment with HDL and apoA-I (50 µg/mL, 6 h) suppressed palmitate-induced inflammatory cytokine expression and TLR4 translocation into lipid rafts. Moreover, HDL and apoA-I inhibited palmitate-induced phosphorylation of nuclear factor-kappa B. HDL showed an anti-inflammatory effect via ATP-binding cassette transporter G1 and scavenger receptor class B, member 1, whereas apoA-I showed an effect via ATP-binding cassette transporter A1. These results demonstrated that HDL and apoA-I reduced palmitate-potentiated TLR4 trafficking into lipid rafts and its related inflammation in adipocytes via these specific transporters.

Determinants of Left Ventricular Systolic Function Improvement Following Coronary Artery Revascularization in Heart Failure Patients With Reduced Ejection Fraction (HFrEF).

Revascularization therapy such as percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) should be considered for heart failure with reduced ejection fraction (HFrEF). However, revascularization therapy does not always improve left ventricular ejection fraction (LVEF). The purpose of this study was to investigate the determinants of LVEF improvement following revascularization in HFrEF patients. From 2,229 consecutive decompensated heart failure patients, a total of 47 HFrEF patients who underwent revascularization were included in the analysis. Improvement of LVEF was defined as [(LVEF during chronic phase) - (LVEF during acute phase)] ≥ 10%. Univariate and multivariate logistic regression analyses were applied to investigate the determinants of LVEF improvement. The prevalence of revascularization by PCIs including chronic total occlusion (CTO) was significantly greater in the improved EF group (45.0%) as compared to the non-improved EF group (11.1%) (P = 0.02). Multivariate logistic regression analysis revealed that revascularization by PCIs including CTO was the significant determinant of the LVEF improvement after adjusting for confounding factors (OR 5.43, 95% CI 1.06-27.74, P = 0.04). Optimal medical therapy (angiotensin-converting enzyme (ACE) inhibitor and/or angiotensin II receptor blocker (ARB) and beta-blockers) was less frequently prescribed in patients with CABG (50.0% for ACE inhibitor and/or ARB and 41.7% for beta-blocker) than in patients without CABG (94.3% for both) (P < 0.01 and P < 0.001, respectively). In conclusion, revascularization by PCIs including CTO was the significant determinant of LVEF improvement in HFrEF patients. Our results underscore the importance of optimal medical therapy even if patients receive complete revascularization such as CABG.

Predictors of prolonged fluoroscopy time in diagnostic coronary angiography.

BACKGROUND: Prolonged fluoroscopy time during coronary angiography is a major concern for interventional cardiologists as well as for patients. It is unknown which factors affect the prolonged fluoroscopy time. METHODS: A total of 458 patients who underwent diagnostic coronary angiography were included. The patients who had the highest decile of fluoroscopy time were assigned to the prolonged fluoroscopy group (fluoroscopy time ≥15.7min), while the other patients were assigned to the non-prolonged fluoroscopy group (fluoroscopy time <15.7min). We performed univariate and multivariate logistic regression analysis to identify the predictors of prolonged fluoroscopy time. RESULTS: Mean fluoroscopy time in 458 patients was 8.5±5.8min. Median and ranges of fluoroscopy time were 19.0 [15.7-47.0]min in the prolonged fluoroscopy group and 6.0 [2.0-15.3]min in the non-prolonged fluoroscopy group, respectively. The multivariate logistic regression analysis showed that significant predictors of prolonged fluoroscopy time were prior surgery of ascending aorta replacement [odds ratios (OR) 11.46, 95% confidence intervals (CI) 1.53-85.74, p=0.02] and the prevalence of moderate to severe aortic regurgitation (OR 2.83, 95% CI 1.20-6.66, p=0.02). CONCLUSIONS: The prior surgery of ascending aorta replacement and moderate to severe aortic regurgitation were significant predictors of the prolonged fluoroscopy time.

Lower 1,5-anhydroglucitol is associated with adverse clinical events after percutaneous coronary intervention.

Diabetes mellitus and impaired glucose tolerance are well-known risk factors for coronary artery disease (CAD) and adverse clinical events after percutaneous coronary intervention (PCI). Postprandial hyperglycemia is an important risk factor for CAD and serum 1,5-anhydroglucitol (1,5-AG) reflects postprandial hyperglycemia more robustly than hemoglobin (Hb)A1c. We aimed to clarify the relationship between serum 1,5-AG level and adverse clinical events after PCI. We enrolled 141 patients after PCI with follow-up coronary angiography. We evaluated associations between glycemic biomarkers including HbA1c and 1,5-AG and cardiovascular events during follow-up. Median serum 1,5-AG level was significantly lower in patients with any coronary revascularization and target lesion revascularization (TLR) [13.4 µg/ml (first quartile, third quartile 9.80, 18.3) vs. 18.7 (12.8, 24.2), p = 0.005; 13.4 µg/ml (10.2, 16.4) vs. 18.7 (12.9, 24.2), p = 0.001, respectively]. Multivariate logistic analysis showed lower 1,5-AG was independently associated with any coronary revascularization and TLR (odds ratio 0.93, 95 % confidence interval 0.86-0.99, p = 0.04; 0.90, 0.81-0.99, p = 0.044, respectively), whereas higher HbA1c was not. Postprandial hyperglycemia and lower 1,5-AG are important risk factors for adverse clinical events after PCI.

Apolipoprotein AI and high-density lipoprotein have anti-inflammatory effects on adipocytes via cholesterol transporters: ATP-binding cassette A-1, ATP-binding cassette G-1, and scavenger receptor B-1.

RATIONALE: Macrophage accumulation in adipose tissue associates with insulin resistance and increased cardiovascular disease risk. We previously have shown that generation of reactive oxygen species and monocyte chemotactic factors after exposure of adipocytes to saturated fatty acids, such as palmitate, occurs via translocation of NADPH oxidase 4 into lipid rafts (LRs). The anti-inflammatory effects of apolipoprotein AI (apoAI) and high-density lipoprotein (HDL) on macrophages and endothelial cells seem to occur via cholesterol depletion of LRs. However, little is known concerning anti-inflammatory effects of HDL and apoAI on adipocytes. OBJECTIVE: To determine whether apoAI and HDL inhibit inflammation in adipocytes and adipose tissue, and whether this is dependent on LRs. METHODS AND RESULTS: In 3T3L-1 adipocytes, apoAI, HDL, and methyl-ß-cyclodextrin inhibited chemotactic factor expression. ApoAI and HDL also disrupted LRs, reduced plasma membrane cholesterol content, inhibited NADPH oxidase 4 translocation into LRs, and reduced palmitate-induced reactive oxygen species generation and monocyte chemotactic factor expression. Silencing ATP-binding cassette A-1 abrogated the effect of apoAI, but not HDL, whereas silencing ATP-binding cassette G-1 or scavenger receptor B-1 abrogated the effect of HDL but not apoAI. In vivo, apoAI transgenic mice fed a high-fat, high-sucrose, cholesterol-containing diet showed reduced chemotactic factor and proinflammatory cytokine expression and reduced macrophage accumulation in adipose tissue. CONCLUSIONS: ApoAI and HDL have anti-inflammatory effects in adipocytes and adipose tissue similar to their effects in other cell types. These effects are consistent with disruption and removal of cholesterol from LRs, which are regulated by cholesterol transporters, such as ATP-binding cassette A-1, ATP-binding cassette G-1, and scavenger receptor B-1.

Inhibition of intestinal cholesterol absorption decreases atherosclerosis but not adipose tissue inflammation.

Adipose tissue inflammation is associated with insulin resistance and increased cardiovascular disease risk in obesity. We previously showed that addition of cholesterol to a diet rich in saturated fat and refined carbohydrate significantly worsens dyslipidemia, insulin resistance, adipose tissue macrophage accumulation, systemic inflammation, and atherosclerosis in LDL receptor-deficient (Ldlr(-/-)) mice. To test whether inhibition of intestinal cholesterol absorption would improve metabolic abnormalities and adipose tissue inflammation in obesity, we administered ezetimibe, a dietary and endogenous cholesterol absorption inhibitor, to Ldlr(-/-) mice fed chow or high-fat, high-sucrose (HFHS) diets without or with 0.15% cholesterol (HFHS+C). Ezetimibe blunted weight gain and markedly reduced plasma lipids in the HFHS+C group. Ezetimibe had no effect on glucose homeostasis or visceral adipose tissue macrophage gene expression in the HFHS+C fed mice, although circulating inflammatory markers serum amyloid A (SSA) and serum amyloid P (SSP) levels decreased. Nevertheless, ezetimibe treatment led to a striking (>85%) reduction in atherosclerotic lesion area with reduced lesion lipid and macrophage content in the HFHS+C group. Thus, in the presence of dietary cholesterol, ezetimibe did not improve adipose tissue inflammation in obese Ldlr(-/-) mice, but it led to a major reduction in atherosclerotic lesions associated with improved plasma lipids and lipoproteins.

NADPH oxidase-derived reactive oxygen species increases expression of monocyte chemotactic factor genes in cultured adipocytes.

Excess glucose and free fatty acids delivered to adipose tissue causes local inflammation, which contributes to insulin resistance. Glucose and palmitate generate reactive oxygen species (ROS) in adipocytes, leading to monocyte chemotactic factor gene expression. Docosahexaenoate (DHA) has the opposite effect. In this study, we evaluated the potential sources of ROS in the presence of excess nutrients. Differentiated 3T3-L1 adipocytes were exposed to palmitate and DHA (250 µM) in either 5 or 25 mM glucose to evaluate the relative roles of mitochondrial electron transport and NADPH oxidases (NOX) as sources of ROS. Excess glucose and palmitate did not increase mitochondrial oxidative phosphorylation. However, glucose exposure increased glycolysis. Of the NOX family members, only NOX4 was expressed in adipocytes. Moreover, its activity was increased by excess glucose and palmitate and decreased by DHA. Silencing NOX4 inhibited palmitate- and glucose-stimulated ROS generation and monocyte chemotactic factor gene expression. NADPH, a substrate for NOX, and pentose phosphate pathway activity increased with glucose but not palmitate and decreased with DHA exposure. Inhibition of the pentose phosphate pathway by glucose-6-phosphate dehydrogenase inhibitors and siRNA suppressed ROS generation and monocyte chemotactic factor gene expression induced by both glucose and palmitate. Finally, both high glucose and palmitate induced NOX4 translocation into lipid rafts, effects that were blocked by DHA. Excess glucose and palmitate generate ROS via NOX4 rather than by mitochondrial oxidation in cultured adipocytes. NOX4 is regulated by both NADPH generated in the PPP and translocation of NOX4 into lipid rafts, leading to expression of monocyte chemotactic factors.

Circulating CD34+/133+ progenitor cells in patients with stable angina pectoris undergoing percutaneous coronary intervention.

BACKGROUND: This study explored the clinical significance of CD34(+)/133(+) circulating progenitor cell (CPC) counts in patients with stable angina pectoris (AP) who underwent percutaneous coronary intervention (PCI). METHODS AND RESULTS: Subjects comprised 52 patients with stable AP requiring PCI and 50 control patients without AP. In the AP group, blood samples were taken before and 20 min and 24 h after PCI to measure CPC counts by fluorescence-activated cell sorter analysis. The baseline number of CPCs was smaller in the AP group than in controls. In the AP group, body mass index (BMI) correlated positively with the baseline number of CPCs and was an independent predictor of CPC count in multivariate regression analysis. Other conventional risk factors, daily exercise activity and statin administration showed no association with CPC count. CPC counts remained unchanged within 24 h after PCI. CONCLUSIONS: CPC counts in patients with AP are influenced by BMI, but not by other coronary risk factors. CPC counts remain unchanged within 24 h after PCI.

Cardioprotection by a nonerythropoietic, tissue-protective peptide mimicking the 3D structure of erythropoietin.

Erythropoietin (EPO), originally identified for its critical hormonal role in regulating production and survival of erythrocytes, is a member of the type 1 cytokine superfamily. Recent studies have shown that EPO has cytoprotective effects in a wide variety of tissues, including the heart, by preventing apoptosis. However, EPO also has undesirable effects, such as thrombogenesis. In the present study, we investigated whether a helix B-surface peptide (HBSP), a nonerythropoietic, tissue-protective peptide mimicking the 3D structure of erythropoietin, protects cardiomyocytes from apoptosis in vitro and in vivo. In cultured neonatal rat cardiomyocytes, HBSP clearly inhibited apoptosis (approximately 80%) induced by TNF-alpha, which was comparable with the effect of EPO, and activated critical signaling pathways of cell survival, including Akt, ERK1/2, and STAT3. Among these pathways, Akt was shown to play an essential role in HBSP-induced prevention of apoptosis, as assessed by using a small interfering RNA approach. In the dilated cardiomyopathic hamster (J2N-k), whose cardiac tissues diffusely expressed TNF-alpha, HBSP also inhibited apoptosis (approximately 70%) and activated Akt in cardiomyocytes. Furthermore, the levels of serum creatine kinase activity and of cardiac expression of atrial natriuretic peptide, a marker of chronic heart failure, were down-regulated in animals treated with HBSP. These data demonstrate that HBSP protects cardiomyocytes from apoptosis and leads to a favorable outcome in failing hearts through an Akt-dependent pathway. Because HBSP does not have the undesirable effects of EPO, it could be a promising alternative for EPO to treat cardiovascular diseases, such as myocardial infarction and heart failure.

Effects of submaximal exercise on blood rheology and sympathetic nerve activity.

BACKGROUND: To explore the acute effects of submaximal exercise on blood rheology and sympathetic nerve activity. METHODS AND RESULTS: The effects of exercise (20 or 80 Watts (W)) on blood rheology and sympathetic nerve activity were assessed in 10 healthy Japanese men. Blood sampling and heart rate variability (HRV) recording were performed during 20-min supine rest and standing ergometric exercise (20 W for 10 min, 80 W for 10 min) and recovery. Blood passage time across the microchannels (diameter, 7 microm) as a parameter of blood rheology, and the number of adhesive leukocytes on microchannel terraces as a parameter of leukocyte activation were measured. Sympathetic nerve activity was evaluated by plasma noradrenalin levels and the ratio of low-frequency (LF)/high-frequency (HF) by spectral analysis of HRV. Compared with values while supine at rest, significant increases in hematocrit, leukocyte count, noradrenalin level and blood passage time were seen after strenuous ergometer exercise at 80 W (P<0.01 each). The LF/HF ratio and nitric oxide metabolites tended to be increased with 80 W exercise. CONCLUSIONS: Strenuous exercise dynamically alters blood rheological parameters, probably by changes in hematocrit and sympathetic nerve activity.

Effects of pitavastatin on fasting and postprandial endothelial function and blood rheology in patients with stable coronary artery disease.

BACKGROUND: Because postprandial hypertriglyceridemia and hyperglycemia may promote atherosclerosis, the present study investigated the effects of a clinical dose of pitavastatin on endothelial function and blood rheology in patients with coronary artery disease (CAD) before and after eating a test meal. METHODS AND RESULTS: The 16 patients with stable CAD and mild dyslipidemia and 6 age-matched healthy men as controls were recruited. In each group, forearm blood flow (FBF) was measured during postischemic reactive hyperemia and blood samples were taken before and 2 h after the test meal. Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) was also measured. The patients were started on pitavastatin 2 mg/day. The tests were repeated after 6 months. Maximum FBF during hyperemia in the baseline fasting phase was significantly lower in CAD patients than in control subjects (P=0.040). Fasting and postprandial FBF during reactive hyperemia significantly improved after pitavastatin treatment (P<0.05 vs baseline data for each phase) associated with reduced urine 8-OHdG, increased plasma adiponectin and improved lipid profile. No significant differences in baseline rheological parameters were seen between controls and CAD patients. CONCLUSIONS: Pitavastatin significantly improved fasting and postprandial dyslipidemia and endothelial dysfunction in CAD patients, partly via reducing oxidative stress and increasing plasma adiponectin, although rheological parameters remained unchanged.

C-reactive protein induces endothelial cell apoptosis and matrix metalloproteinase-9 production in human mononuclear cells: Implications for the destabilization of atherosclerotic plaque.

C-reactive protein (CRP) has been suggested to directly induce the inflammatory response leading to the progression of atherosclerosis. However, recent in vitro studies raised the possibility that the effects of CRP are caused by biologically active contaminants such as sodium azide and endotoxin. In this study, we tested whether azide- and endotoxin-free CRP induces endothelial cell apoptosis and production of proinflammatory mediators. In human endothelial cells, CRP significantly inhibited cell proliferation and increased endothelial cell apoptosis evaluated by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling and caspase-3 activity assay, which is reversed by a function-blocking antibody to Fc gamma RIIIB by 78%. Western blot analysis showed that CRP significantly attenuated flow-mediated activation of Akt, a key molecule for endothelial cell survival pathways. In human mononuclear cells, CRP-induced production of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and matrix metalloproteinase-9 (MMP-9) in a concentration-dependent manner. This CRP-induced MMP-9 production was significantly inhibited by function-blocking antibodies to TNF-alpha, IL-1 beta, and Fc gamma RIIA. These findings suggest that CRP itself induces endothelial cell apoptosis and production of proinflammatory mediators. Because endothelial cell apoptosis and MMP-9 production are critical for the destabilization of atherosclerotic plaque, this study may provide insight into a role of CRP in the development of plaque rupture.