Value of acoustic cardiography in the clinical diagnosis of coronary heart disease.

BACKGROUND: To investigate the clinical value of acoustic cardiography in the diagnosis of coronary artery disease (CAD) and post-percutaneous coronary intervention (PCI) early asymptomatic left ventricular systolic dysfunction. METHODS: Inpatients in the department of cardiology were included in the research (n = 315); including 180 patients with angina pectoris and 135 patients with acute anterior wall myocardial infarction after emergency PCI did not present with signs and symptoms of heart failure. Color Doppler echocardiography, brain natriuretic peptide, acoustic cardiography examination were performed. The patients were divided into four groups: non-CAD group (n = 60), CAD group (n = 120), MIREF group (EF% < 50%, n = 75), and MINEF group (EF% ≥ 50%, n = 60). RESULTS: Acoustic cardiography parameters EMATc, systolic dysfunction index, S3 strength and S4 strength in the MIREF group were higher than those in MINEF group (p < .05), and the MINEF group was higher than CAD group (p < .05). S3 strength (area under the curve [AUC] 0.67, 95% CI 0.585-0.755, p < .001) and S4 strength (AUC 0.617, 95% CI 0.536-0.698, p = .011) are useful in the diagnosis of CAD. S3 strength (AUC 0.942, 95% CI 0.807-0.978, p < .001) was superior to other indicators in the diagnosis of early left ventricular systolic dysfunction after myocardial infarction. CONCLUSION: S4 combined with STT standard change can improve the diagnosis of CAD. Acoustic cardiography can be used as a non-invasive, rapid, effective, and simple method for the diagnosis of asymptomatic left ventricular systolic dysfunction in the early stage after myocardial infarction.

Prasugrel or ticagrelor relative to clopidogrel in triple-antiplatelet treatment combined with glycoprotein IIb/IIIa inhibitor for patients with STEMI undergoing PCI: a meta-analysis.

BACKGROUND: For patients with ST-segment elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI), the efficacy and safety of novel P2Y12 antagonists, including prasugrel or ticagrelor, has not been established relative to that of the clopidogrel-based triple-antiplatelet treatments (TAPTs; in combination with glycoprotein IIb/IIIa inhibitor). The present meta-analysis evaluated the efficacy and safety of prasugrel- or ticagrelor-based TAPTs relative to that of clopidogrel TAPTs in patients with STEMI undergoing PCI. METHODS: The databases PubMed, Embase, and Cochrane's Library were systematically searched for relevant randomized controlled trials concerning prasugrel or ticagrelor (test) relative to clopidogrel (control). Depending on heterogeneity, studies were pooled with a random effects or a fixed effects model. Outcomes of blood flow after PCI were evaluated, including TIMI (thrombolysis in myocardial infarction), bleeding events, and major adverse cardiovascular events (MACEs). RESULTS: Seven studies comprising 11,874 patients conformed to the inclusion criteria. The pooled results with the fixed effects model indicated that after PCI patients in the prasugrel or ticagrelor groups were as likely as those treated with clopidogrel to achieve TIMI grade 3 flow or experience bleeding events. However, compared with the control, the test groups had significantly less risk of MACE (OR: 0.81, 95% CI: 0.70-0.94, P = 0.004), especially at the 1-year follow-up (OR: 0.79, 95% CI: 0.66-0.95, P = 0.01). CONCLUSIONS: A prasugrel- or ticagrelor-based TAPT may reduce the rate of MACEs, without increasing bleeding in STEMI patients undergoing PCI. However, due to the limited RCT studies and variations in study weight, results of this meta-analysis should be confirmed in a large RCT with adequate sample size and follow-up duration.

Activation of adenosine A2b receptor attenuates high glucose-induced apoptosis in H9C2 cells via PI3K/Akt signaling.

High glucose plays a vital role in apoptosis in H9C2 cells. However, the exact molecular mechanism remains unclear. In this study, we aimed to evaluate the cardio-protective role of A2b receptor in high glucose-induced cardiomyocyte apoptosis via PI3K/Akt pathway. Adenosine A2b receptor agonist (Bay506583), antagonist (MRS1754), and Akt inhibitor (LY294002) were applied respectively to H9C2 cells before exposed to high glucose for 12 h. Apoptosis of H9C2 cells was determined by TUNEL assay and the apoptosis rate by flow cytometry. The protein level of adenosine A2b receptor, p-Akt, total Akt, cleaved capase-3, cleaved capase-9, bax, and bcl-2 was measured by western blotting. The results demonstrated that apoptosis of H9C2 cardiomyocytes triggered by high-glucose treatment was time-dependent. The protein level of A2b receptor and activated Akt was both decreased in cardiomyocyte with high-glucose treatment. Moreover, we found that high glucose-induced apoptosis in H9C2 cells could be attenuated by administration of adenosine A2b receptor agonist Bay606583. This effect could be reversed by Akt inhibitor LY294002. In conclusion, activation of A2b receptor could prevent high glucose-induced apoptosis of H9C2 cells in vitro to a certain extent by activating PI3K/Akt signaling. In conclusion, these results suggested that activation of A2b receptor could be a novel therapeutic approach to high glucose-induced cardiomyocyte injury.

Klotho attenuates isoproterenol-induced hypertrophic response in H9C2 cells by activating Na+/K+-ATPase and inhibiting the reverse mode of Na+/Ca2+-exchanger.

Cardiac hypertrophy plays a major role in heart failure and is related to patient morbidity and mortality. Calcium overloading is a main risk for cardiac hypertrophy, and Na+/K+-ATPase (NKA) has been found that it could not only regulate intracellular Na+ levels but also control the intracellular Ca2+ ([Ca2+]i) level through Na+/Ca2+-exchanger (NCX). Recent studies have reported that klotho could affect [Ca2+]i level. In this study, we aimed at exploring the role of klotho in improving isoproterenol-induced hypertrophic response of H9C2 cells. The H9C2 cells were randomly divided into control and isoproterenol (ISO) (10 µM) groups. Klotho protein (10 µg/ml) or NKAα2 siRNA was used to determine the changes in isoproterenol-induced hypertrophic response. The alterations of [Ca2+]i level were measured by spectrofluorometry. Our results showed that H9C2 cells which were treated with isoproterenol presented a higher level of [Ca2+]i and hypertrophic gene expression at 24 and 48 h compared with the control group. Moreover, the expressions of NKAα1 and NKAα2 were both increased in control and ISO groups after treating with klotho protein; meanwhile, the NKA activity was increased and NCX activity was decreased after treatment. Consistently, the [Ca2+]i level and hypertrophic gene expression were decreased in ISO group after klotho protein treatment. However, these effects were both prevented by transfecting with NKAα2 siRNA. In conclusion, these findings demonstrated that klotho inhibits isoproterenol-induced hypertrophic response in H9C2 cells by activating NKA and inhibiting the reverse mode of NCX and this effect may be associated with the upregulation of NKAα2 expression.

The CD4/CD8 ratio is associated with coronary artery disease (CAD) in elderly Chinese patients.

OBJECTIVE: The aim of this study was to investigate the relationship between number of circulating T cells and coronary artery disease (CAD) in an elderly Chinese population. METHODS: A total of 295 elderly inpatients (age≥60) were included in this cross-sectional study. Their clinical and biochemical characteristics were recorded. Patients were divided to two groups: control patients and CAD patients. The risk factors of CAD were explored by binary logistic regression analysis. RESULTS: Compared with control patients, the ratio of CD4 to CD8 T cells was significantly increased in CAD patients. There was no difference in the number of CD3, CD4, and CD8 T cells between the two groups. Multiple logistic regression analysis showed that CAD was independently associated with age, gender, body mass index (BMI), systolic blood pressure (SBP), chronic heart failure (CHF) and the CD4/CD8 ratio. In addition, after adjusting for different clinical parameters (including gender, age, CHF, hypertension, arrhythmia, SBP, and BMI), the risk of CAD was significantly increased in patients with a CD4/CD8 ratio>1.5. CONCLUSIONS: There was a strong and independent association between the ratio of CD4/CD8 and CAD in elderly Chinese population.

FGF21 represses cerebrovascular aging via improving mitochondrial biogenesis and inhibiting p53 signaling pathway in an AMPK-dependent manner.

Cerebrovascular aging has a high relationship with stroke and neurodegenerative disease. In the present study, we evaluated the influence of fibroblast growth factor 21 (FGF21) on angiotensin (Ang II)-mediated cerebrovascular aging in human brain vascular smooth muscle cells (hBVSMCs). Ang II induced remarkable aging-phenotypes in hBVSMCs, including enhanced SA-ß-gal staining and NBS1 protein expression. First, we used immunoblotting assay to confirm protein expression of FGF21 receptor (FGFR1) and the co-receptor ß-Klotho in cultured hBVSMCs. Second, we found that FGF21 treatment partly prevented the aging-related changes induced by Ang II. FGF21 inhibited Ang II-enhanced ROS production/superoxide anion levels, rescued the Ang II-reduced Complex IV and citrate synthase activities, and suppressed the Ang II-induced meprin protein expression. Third, we showed that FGF21 not only inhibited the Ang II-induced p53 activation, but also blocked the action of Ang II on Siah-1-TRF signaling pathway which is upstream factors for p53 activation. At last, either chemical inhibition of AMPK signaling pathway by a specific antagonist Compound C or knockdown of AMPKα1/2 isoform using siRNA, successfully abolished the anti-aging action of FGF21 in hBVSMCs. These results indicate that FGF21 protects against Ang II-induced cerebrovascular aging via improving mitochondrial biogenesis and inhibiting p53 activation in an AMPK-dependent manner, and highlight the therapeutic value of FGF21 in cerebrovascular aging-related diseases such as stroke and neurodegenerative disease.

Triglycerides are Independently Associated with Atherosclerosis in Elderly Chinese Patients.

BACKGROUND: The aim of this study was to investigate the relationship between serum triglycerides (TG) levels and atherosclerosis and to explore its predicated value for atherosclerosis in elderly Chinese population. METHODS: A total of 593 elderly patients (age ≥ 60) were included in this cross-sectional study. Their clinical and biochemical characteristics were detected. Patients were divided into two groups: with atherosclerosis and without. The risk factors of atherosclerosis were explored by binary logistic regression analysis. RESULTS: The serum concentrations of TG were 1.72 ± 1.30 and 1.43 ± 0.88 mmol/L in patients with and without atherosclerosis, respectively. Binary logistic regression analysis showed that the significant risk factors were age (p = 0.000, OR = 1.094), TG (p = 0.008, OR = 1.315), type 2 diabetes (p = 0.042, OR = 1.499), and HTN (p = 0.006, OR = 1.724). The risk of atherosclerosis significantly increased in patients with TG > 1.3 mmol/L. After adjusting for different clinical parameters, the risk of atherosclerosis still significantly increased in patients with TG > 1.3 mmol/L. CONCLUSIONS: There was a strong and independent association between TG and atherosclerosis in elderly Chinese population, and TG > 1.3 mmol/L indicated a great increased risk of atherosclerosis.

Association Between Serum Cystatin C and High Blood Pressure (HBP): A Cross-Sectional Study of an Elder Chinese Type 2 Diabetic Population.

BACKGROUND: The aim of this study was to investigate the relationship between serum CysC levels and high blood pressure (HBP) and to explore its diagnostic value for HBP in elder type 2 diabetic (T2D) population. METHODS: A total of 369 elder T2D patients (age > 60) were included in this cross-sectional study. Their clinical and biochemical characteristics were detected. Patients were divided into two groups: with HBP and without. The risk factors of HBP were explored by binary logistic regression analysis. RESULTS: The serum concentrations of CysC were 1.08 ± 0.42 and 0.90 ± 0.21 mg/L in patients with and without HBP, respectively. Binary logistic regression analysis showed that the significant risk factors were CysC (p = 0.000, OR = 16.977), systolic blood pressure (p = 0.000, OR = 1.087), and diabetes duration (p = 0.000, OR = 1.289). The prevalence of HBP increased with CysC (p < 0.05), and the prevalence of HBP in patients with CysC ≥ 1.2 mg/L was much higher than the other three quartile groups. The risk of HBP dramatically increased in patients with cystatin C ≥ 1.2 mg/L (OR = 1.601, 95% confidence interval 1.239 - 2.069, p = 0.000). After adjusting for gender, age, and diabetes duration, its OR still remained 1.633 (95% confidence interval 1.181 - 2.257, p = 0.003). CONCLUSIONS: There was a strong and independent association between CysC and HBP in elder diabetic population, and cystatin C ≥ 1.2 mg/L indicated a great increased risk of HBP.

Klotho ameliorated isoproterenol-induced pathological changes in cardiomyocytes via the regulation of oxidative stress.

AIMS: Oxidative stress is a common pathological process in stress-stimulated heart failure. Klotho, known as an anti-aging protein, has been shown to play important pleiotropic roles. This study characterized the effect of klotho on the mechanism of pathological alternations in isoproterenol-treated cardiomyocytes. MAIN METHODS: Cardiac injury was induced for 9 days by isoproterenol (subcutaneous injection, 5mg/kg) in BALB/c mice. Klotho (intraperitoneal injection, 0.01 mg/kg) was administered every other day for 4 days, to detect its effects on isoproterenol-induced cardiac alternations. Mouse hearts were harvested at day 9 after isoproterenol injection. KEY FINDINGS: Isoproterenol increased the heart weight/body weight (HW/BW) ratio representing abnormal hypertrophic growth, induced disarranged myocardial fibers, and altered cardiomyocyte morphology. However, klotho partly reversed the above pathological alternations. The same effects were also observed in cultured H9c2 cardiomyocytes. Klotho significantly reduced production of isoproterenol-induced reactive oxygen species. However, oxidative stress inhibited the transcriptional activity of the klotho gene promoter. SIGNIFICANCE: The results suggested that the cardioprotective effects of klotho were related to the attenuation of oxidative stress, and oxidative stress suppressed the transcription of klotho. The results provided a rational basis for the treatment of clinical heart failure.

Fibroblast growth factor 21 protects against high glucose induced cellular damage and dysfunction of endothelial nitric-oxide synthase in endothelial cells.

AIMS: Fibroblast growth factor 21 (FGF21) is a powerful endocrine hormone modulating glucose and lipid metabolism and represents a promising drug for type 2 diabetes. The present study was to determine the effect of FGF21 on high glucose-induced damage and dysfunction in endothelial cells. METHODS: The protein expression of ß-klotho was examined in human umbilical vein endothelial cell (HUVECs) using immunofluorescence and Western blotting. HUVECs were cultured in medium with normal glucose (NG), high glucose (HG) and HG + FGF21 (30 nM). Cell viability, migration, reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase, nitric oxide (NO) production, intracellular cyclic guanosine monophosphate (cGMP) and endothelial nitric oxide synthase (eNOS) phosphorylation at Ser-1177/Ser-633 sites were measured. RESULTS: ß-klotho, the anchor protein of FGF21, is expressed in HUVECs. Administration of FGF21 prevented HG-induced impairment of cell viability, migration, oxidant stress, NO production and intracellular cGMP levels in HUVECs. FGF21 also rescued HG-induced decrease of eNOS phosphorylation at Ser-1177 and Ser-633. HG and FGF21 had no effects on eNOS phosphorylation at Ser-617 and Thr-495. Inhibition of AMP-activated protein kinase (AMPK), but not Akt or Ca(2+)/calmodulin-dependent protein kinase II, abolished the protective effect of FGF21 on eNOS phosphorylation at Ser-1177. The protective effect of FGF21 on eNOS phosphorylation at Ser-633 was also abolished by inhibition of AMPK but not by Akt or cAMP-dependent protein kinase A. CONCLUSION: Our results provide the first evidence that FGF21 protects against high glucose induced cell damage and eNOS dysfunction in an AMPK-dependent manner in HUVECs, and suggest that FGF21 may be a promoting therapeutic agent for vascular complications in diabetes.

An accurate, flexible and small optical fiber sensor: a novel technological breakthrough for real-time analysis of dynamic blood flow data in vivo.

Because of the limitations of existing methods and techniques for directly obtaining real-time blood data, no accurate microflow in vivo real-time analysis method exists. To establish a novel technical platform for real-time in vivo detection and to analyze average blood pressure and other blood flow parameters, a small, accurate, flexible, and nontoxic Fabry-Perot fiber sensor was designed. The carotid sheath was implanted through intubation of the rabbit carotid artery (n = 8), and the blood pressure and other detection data were determined directly through the veins. The fiber detection results were compared with test results obtained using color Doppler ultrasound and a physiological pressure sensor recorder. Pairwise comparisons among the blood pressure results obtained using the three methods indicated that real-time blood pressure information obtained through the fiber sensor technique exhibited better correlation than the data obtained with the other techniques. The highest correlation (correlation coefficient of 0.86) was obtained between the fiber sensor and pressure sensor. The blood pressure values were positively related to the total cholesterol level, low-density lipoprotein level, number of red blood cells, and hemoglobin level, with correlation coefficients of 0.033, 0.129, 0.358, and 0.373, respectively. The blood pressure values had no obvious relationship with the number of white blood cells and high-density lipoprotein and had a negative relationship with triglyceride levels, with a correlation coefficient of -0.031. The average ambulatory blood pressure measured by the fiber sensor exhibited a negative correlation with the quantity of blood platelets (correlation coefficient of -0.839, P<0.05). The novel fiber sensor can thus obtain in vivo blood pressure data accurately, stably, and in real time; the sensor can also determine the content and status of the blood flow to some extent. Therefore, the fiber sensor can obtain partially real-time vascular rheology information and may thus enable the early diagnosis of blood rheology disorders and diseases.

Klotho suppresses cardiomyocyte apoptosis in mice with stress-induced cardiac injury via downregulation of endoplasmic reticulum stress.

Cardiomyocyte apoptosis is a common pathological alteration in heart disease which results in systolic dysfunction or sudden death. Klotho is a novel anti-aging hormone. We tested the effects of klotho on cell apoptosis in isoproterenol-treated cardiomyocytes. In BALB/c mice, cardiac injury was induced by subcutaneous injection of isoproterenol (5 mg/kg, for 9 days, s.c.). Klotho (0.01 mg/kg, every other day for 4 days, i.p.) was administered to determine the changes in isoproterenol-induced apoptosis. Mouse heart was harvested at day 2, day 5, and day 9 after isoproterenol injection. Isoproterenol induced cardiac apoptosis and endoplasmic reticulum (ER) stress in a time-dependent manner. However, klotho partly reversed isoproterenol-induced cardiac apoptosis and ER stress. These same effects were observed in cultured cardiomyocytes. Furthermore, the results also showed that SB203580, a p38 inhibitor, and SP600125, a c-Jun NH2-terminal kinase (JNK) inhibitor, reduced cardiomyocyte apoptosis and ER stress, however, klotho suppressed isoproterenol-induced activation of p38 and JNK. Taken together, these results indicated that cardioprotection by klotho was related to the attenuation of ER stress and ER stress-induced apoptosis, at least partly, through suppressing activation of the p38 and JNK pathway.

A transendocardial delivery and intracardiac ultrasound irradiation treatment catheter.

OBJECTIVES: This study introduces the structural design, working principles, performance testing and treatment effects of a newly developed ultrasonic irradiation delivery and treatment catheter system that integrates interventional catheterization technology. BACKGROUND: Systemic administration method needs a high dose of gene and induces side effect of non-target organ delivery. Direct intramyocardial injection of a low-dose angiogenic gene followed by insonation treatment can enhance gene expression. So, a novel transendocardial gene delivery and intracardiac ultrasound irradiation strategy was tested. METHODS: The medical interventional ultrasonic therapeutic apparatus is comprised of an ultrasonic irradiation catheter and a host. The ultrasonic irradiation catheter, which is equipped with an advance-and-retreat convenient miniature syringe needle and a miniature piezoelectric transducer on the tip, was used. Twelve dogs were divided into three groups: (1) EGFP and US (EGFP + US), (2) EGFP alone and (3) control group. In the EGFP + US group, EGFP plasmid DNA (500 µg) was injected and followed by intracardiac insonation. In the EGFP alone group, EGFP plasmid DNA (500 µg) was injected without insonation. In the control group, saline was injected. RESULTS: The catheter can enter the heart through percutaneous intervention to realize intramyocardial injection, directly irradiate cardiac muscular tissues at close range and correctly control the ultrasonic irradiation energy delivered to cardiac muscular tissues. Compared with the EGFP gene group, an average sixfold enhancement in gene expression was achieved in the EGFP EGFP + US group (p < 0.05). CONCLUSIONS: The experimental results confirmed that the treatment catheter was safe and reliable, which can realize transendocardial intramyocardial gene injection in the left ventricular chamber, and the ultrasonic parameter can increase gene expression after intracardiac ultrasonic irradiation. The intracardiac ultrasound irradiation treatment catheter may be a useful delivery and therapy tool in the future.

Adenosine A2A receptor: a target for regulating renal interstitial fibrosis in obstructive nephropathy.

Renal interstitial fibrosis (RIF) is the common pathological process of chronic kidney diseases leading inevitably to renal function deterioration. RIF and its preceding epithelial-mesenchymal transition (EMT) are commonly triggered by an early occurring renal inflammation. However, an effective approach to prevent EMT and RIF is still lacking and of urgent need. Recently, the adenosine A2A receptor (A2AR) emerges as a novel inflammation regulator, therefore manipulation of A2AR may suppress the EMT process and as such protect against RIF. To test this hypothesis we applied a unilateral ureteral obstruction (UUO) model of RIF on A2AR knockout mice and their wild-type littermates, combined with the intervention of a selective A2AR agonist, CGS 21680. On days 3, 7 and 14 post-UUO we evaluated the effects of A2AR manipulation on the molecular pathological progresses of RIF, including the cellular component of interstitial infiltration, expression of profibrotic factors, cellular biomarkers of EMT, and collagen deposition of extracellular matrix. Our data demonstrated that activation of A2AR significantly suppressed the deposition of collagen types I and III, reduced the infiltration of CD4+ T lymphocytes, and attenuated the expression of TGF-ß1 and ROCK1, which in turn inhibited and postponed the EMT progress. Conversely, genetic inactivation of A2AR exacerbated the aforementioned pathological processes of UUO-induced RIF. Together, activation of A2AR effectively alleviated EMT and RIF in mice, suggesting A2AR as a potential therapeutic target for the treatment of RIF.

Hypoxia-inducible factor-1α and vascular endothelial growth factor in the cardioprotective effects of intermittent hypoxia in rats.

OBJECTIVE: This study investigated the effects of short-term intermittent hypoxia (IH) preconditioning on cardiac structure and function in rats and the influence of ischemia reperfusion (I/R) injury. Special attention was then paid to the involvement of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF). METHODS: Wistar rats were given IH treatment for 1, 7, 14, or 28 days. Some of them were thereafter subject to myocardial infarction surgery. Right ventricle systolic pressure (RVSP), myocardial capillary density (CD), and mRNA/protein expression of HIF-1α, VEGF, and Bcl-2 in rat myocardial tissue were determined. Apoptotic cell number was determined by TUNEL staining, and concentrations of malondialdehyde (MDA) and superoxide dismutase (SOD) were measured. RESULTS: IH treatment for 1, 7, 14, and 28 days reduced the myocardial infarction size, whereas IH for 28 days increased the RVSP, ratio of right to left ventricle weight (RV/LV+S), and CD. IH up-regulated the mRNA and protein levels of HIF-1α, VEGF, and Bcl-2 both under normal and I/R conditions. The induced expression of HIF-1α and VEGF by IH reached a peak after 7 days of treatment. Moreover, IH for 28 days induced cardiomyocyte apoptosis, whereas prior treatment with IH for 1, 7, 14, and 28 days all markedly attenuated the apoptosis effected by the subsequent I/R injury. IH also decreased the concentrations of MDA but increased those of SOD in myocardial tissue of both in normal rats and following I/R. CONCLUSIONS: The present study demonstrates that short-term IH protects the heart from I/R injury through inhibiting apoptosis and oxidative stress. The up-regulation of HIF-1α and VEGF by short-term IH may participate in the cardioprotective effect of IH.

Efficacy and safety of early versus late glycoprotein IIb/IIIa inhibitors for PCI.

BACKGROUND: Glycoprotein (Gp) IIb/IIIa inhibitors are beneficial for patients with ST-segment elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI). However, optimal drug timing remains inconclusive. Therefore, this study was to perform a meta-analysis of the clinical efficiency and safety of early versus late GpIIb/IIIa inhibitors in STEMI patients undergoing PCI. METHODS: A comprehensive search was to identify randomized trials of early versus late GpIIb/IIIa inhibitors in STEMI patients undergoing PCI. The GpIIb/IIIa inhibitors were abciximab and small-molecular Gp inhibitors (SMGP) namely eptifibatide and tirofiban. The efficacy endpoints included pre-procedural Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow, post-procedural TIMI 3 flow, complete ST-segment resolution, left ventricle ejection fraction (LVEF), and mortality. The safety endpoint was the occurrence of major bleeding complications. RESULTS: Nineteen trials were included in the meta-analysis, involving 4209 patients (early 2124 versus late 2085). Early GpIIb/IIIa inhibitors significantly improved pre-procedural TIMI 3 flow, while early abciximab, but not SMGP, further enhanced post-procedural TIMI 3 flow, complete ST-segment resolution, LVEF, and reduced six-month mortality. In addition to clopidogrel loading, only early abciximab improved pre-procedural TIMI 3 flow and complete ST-segment resolution. The rate of major bleeding complications was not increased in early GpIIb/IIIa inhibitors with/without clopidogrel loading. CONCLUSIONS: Early GpIIb/IIIa inhibitors improved pre-procedural TIMI 3 flow and early abciximab provided favorable clinical outcomes in STEMI patients undergoing PCI. On the basis of clopidogrel loading, early abciximab enhanced pre-procedural TIMI 3 flow and ST-segment resolution. These beneficial effects were achieved without increased risks of major bleeding complications.

Induction of oxidative stress by oxidized LDL via meprinα-activated epidermal growth factor receptor in macrophages.

AIMS: The aim of this study was to explore meprinα-mediated transactivation of the epidermal growth factor receptor (EGFR) and reactive oxygen species (ROS) production in macrophages. METHODS AND RESULTS: Accelerated atherosclerotic lesions were established by administration of a high-fat diet in apolipoprotein E-deficient (apoE(-/-)) mice. Lentiviral overexpression of meprinα in the thoracic aortic artery during plaque formation enhanced intra-plaque macrophage induction of ROS as well as formation of atherosclerotic plaques, whereas AG1478 (specific inhibitor of the EGFR) treatment exerted the opposite effect. A meprinα inhibitor abrogated EGFR activation in mice. In cultured J774a.1 macrophages, oxidized low-density lipoprotein (OxLDL) increased ROS formation and EGFR activation through a ligand [heparin-binding epidermal growth factor-like growth factor (HB-EGF)]-dependent pathway. However, a meprinα inhibitor or specific siRNA inhibited ROS production and EGFR activation. Recombinant mouse meprinα enhanced OxLDL-stimulated production of ROS and induced HB-EGF. Inhibition of p38 mitogen-activated protein kinase by SB203580 decreased OxLDL-stimulated production of ROS. Conversely, inhibition of meprinα or PI3K-Rac1 inhibitors also decreased p38 activity in OxLDL-stimulated macrophages. In addition, inhibition of meprinα reversed OxLDL-stimulated activation of PI3K. CONCLUSION: Meprinα promotes OxLDL-induced plaque formation and ROS release by transactivation of the EGFR, followed by activation of the PI3K/Rac1/p38 pathway.

The effects of adenosine A2A receptor knockout on renal interstitial fibrosis in a mouse model of unilateral ureteral obstruction.

Adenosine A2A receptor (A2AR) plays an important regulatory role in the processes of inflammation and fibrosis. However, it is unknown whether A2AR can mediate renal interstitial fibrosis (RIF). To evaluate the effect of genetic A2AR knockout (KO) on the pathological progress of RIF, we applied a unilateral ureteral obstruction (UUO) model of RIF on A2AR KO mice and their wild-type (WT) littermates. Renal pathological assessment was performed at different post-UUO stages using hematoxylin and eosin (H&E) and Masson's trichrome staining as well as quantitative morphological analysis. Our data demonstrated that: (i) the extent of RIF was determined by the development of UUO in a time-dependent manner; (ii) A2AR KO exacerbated the pathological progress of RIF in mice at the early post-UUO stage, i.e. day 3 and day 7; (iii) the profibrotic effect of A2AR KO was prominent until the late post-UUO stage, i.e. day 14, at which RIF reached a similar severity level in A2AR KO and WT mice. Our findings revealed that A2AR KO significantly exacerbated the progression of UUO-induced RIF in mice, prominently at the initial stage.

Transendocardial delivery of HGF via microbubbles and ultrasound to treat acute myocardial infarction.

To enhance the safety of transendocardial delivery and the efficacy of intramyocardial angiogenic gene expression, a visible, less invasive, targeted, high-efficiency gene delivery strategy was tested. Progress toward clinical approval of systemic administration of genes and microbubbles (MBs) has been limited. The feasibility of transendocardially delivering MBs as extracellular markers and gene carriers in conjunction with intracardiac ultrasound (US) treatment remains unknown. In a canine acute myocardial infarction (MI) model, a naked plasmid encoding 500 µg human hepatocyte growth factor (HGF) was delivered transendocardially to the myocardium via US/MB (HGF-US/MB), insonation (HGFUS), or alone (HGF alone). Control MI dogs received saline without US/MB (control group). During US/MB, intracardiac insonation was performed for 30 s with a 10-s pause, at 4.3-MHz, 1-W/cm(2), for 60 s at each site. Gene and MB distribution in the myocardium was visualized. Compared to the HGF alone group at 28 days, the HGF-US/MB group had an average 7.1-fold enhancement in gene expression (P < 0.01). Compared to the control group, there were 16% decreases in the ratio of left ventricle (LV) weight/body weight in the HGF-US/MB group and decreases in collagen volume fraction (CVF) of type I (33%) and type III (23%) collagen. Capillary density increased from 22.8 ± 6.3/mm(2) in the control group to 154.3 ± 42.9/mm(2) in the HGF-US/MB group (P < 0.01). This less invasive catheter-based US therapeutic procedure offers observable gene delivery with higher therapeutic efficiency, enhanced angiogenesis, and improved myocardial perfusion and ventricular function following MI.

Resveratrol role in cardiovascular and metabolic health and potential mechanisms of action.

Resveratrol is a polyphenolic flavonoid found in a diversity of plants, especially berry fruits and is a popular nutritional supplement. It is known to have antioxidant, anti-inflammatory, and anticarcinogenic properties. Recently, additional evidence has been found that resveratrol is beneficial to metabolic and cardiovascular health and may increase the life expectancy of various organisms. These biological effects are widely believed to be due to the ability of resveratrol to activate silent mating-type information regulation 2 homolog 1, a nicotinamide adenine dinucleotide-dependent deacetylase. However, other research has shown that 5'-adenosine monophosphate-activated kinase and not silent mating-type information regulation 2 homolog 1 may be the target of resveratrol. A recent study reported that resveratrol directly inhibits cyclic adenosine monophosphate-specific phosphodiesterases and then activates 5'-adenosine monophosphate-activated kinase. Therefore, the mechanism underlying the diverse nutritional and therapeutic activities of resveratrol needs to be further explored. Furthermore, the optimal dose and possible adverse effects of resveratrol in humans are completely clear. The purpose of this review is to present some of the newly discovered biological effects of resveratrol, including autophagy and stem cell regulation, and research opportunities for the application of resveratrol in cardiovascular and metabolic health. Described herein is the recent understanding of the mechanism of action of resveratrol and future research directions to ascertain the potential of this flavonoid that is present in food.