Pre-mixed nitrous oxide/oxygen mixture treatment of pain induced by postoperative dressing change for perianal abscess: Study protocol for a randomized, controlled trial.

AIM: This study aims to evaluate the safety and analgesic efficacy of pre-mixed nitrous oxide/oxygen mixture treatment of pain induced by dressing change for perianal abscess. DESIGN: This protocol is a randomized, double-blind, placebo-controlled trial. METHODS: This study will be implemented in the Hospital of Traditional Chinese Medicine. Subjects enrolled in this study are hospitalized patients who suffered from moderate to severe pain due to dressing change after incision and drainage. Two hundred patients will be selected and randomly assigned to either an intervention or a control group. The intervention group will get routine pain treatment plus pre-mixed nitrous oxide/oxygen mixture treatment and the control group will be treated with routine pain management plus medical air treatment. All these patients, medical staff and investigators are blind to the nature of the gas in each cylinder, which is randomized. Data will be collected at baseline (T0), 5 min (T1) after the starting of intervention and 5 min post intervention (T2) for each group. The primary outcome is the level of pain relief at T1 and T2. The secondary outcomes cover physiological parameters, adverse events, satisfaction of patients and health professionals and the acceptance from patients. DISCUSSION: Results of this study will be discussed and the safety and effect of nitrous oxide/oxygen treatment of pain induced by dressing change will be proven. IMPACT: When the finding of this study has an active effect on the treatment of pain caused by dressing change, it may provide more options for nursing staff to choose nurse-led analgesia techniques and then improving the level and quality of pain care as well as patients' overall satisfaction with the Anorectal Department in China.

BRD7 mediates hyperglycaemia-induced myocardial apoptosis via endoplasmic reticulum stress signalling pathway.

Bromodomain-containing protein 7 (BRD7) is a tumour suppressor that is known to regulate many pathological processes including cell growth, apoptosis and cell cycle. Endoplasmic reticulum (ER) stress-induced apoptosis plays a key role in diabetic cardiomyopathy (DCM). However, the molecular mechanism of hyperglycaemia-induced myocardial apoptosis is still unclear. We intended to determine the role of BRD7 in high glucose (HG)-induced apoptosis of cardiomyocytes. In vivo, we established a type 1 diabetic rat model by injecting a high-dose streptozotocin (STZ), and lentivirus-mediated short hairpin RNA (shRNA) was used to inhibit BRD7 expression. Rats with DCM exhibited severe myocardial remodelling, fibrosis, left ventricular dysfunction and myocardial apoptosis. The expression of BRD7 was up-regulated in the heart of diabetic rats, and inhibition of BRD7 had beneficial effects against diabetes-induced heart damage. In vitro, H9c2 cardiomyoblasts was used to investigate the mechanism of BRD7 in HG-induced apoptosis. Treating H9c2 cardiomyoblasts with HG elevated the level of BRD7 via activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and increased ER stress-induced apoptosis by detecting spliced/active X-box binding protein 1 (XBP-1s) and C/EBP homologous protein (CHOP). Furthermore, down-regulation of BRD7 attenuated HG-induced expression of CHOP via inhibiting nuclear translocation of XBP-1s without affecting the total expression of XBP-1s. In conclusion, inhibition of BRD7 appeared to protect against hyperglycaemia-induced cardiomyocyte apoptosis by inhibiting ER stress signalling pathway.

Poly(ADP-ribose) polymerase 1 deficiency increases nitric oxide production and attenuates aortic atherogenesis through downregulation of arginase II.

Poly (ADP-ribose) polymerase (PARP) plays an important role in endothelial dysfunction, leading to atherogenesis and vascular-related diseases. However, whether PARP regulates nitric oxide (NO), a key regulator of endothelial function, is unclear so far. We investigated whether inhibition of PARP-1, the most abundant PARP isoform, prevents atherogenesis by regulating NO production and tried to elucidate the possible mechanisms involved in this phenomenon. In apolipoprotein E-deficient (apoE-/- ) mice fed a high-cholesterol diet for 12 weeks, PARP-1 inhibition via treatment with 3,4-dihydro-54-(1-piperindinyl) butoxy-1(2H)-isoquinoline (DPQ) or PARP-1 gene knockout reduced aortic atherosclerotic plaque areas (49% and 46%, respectively). Both the groups showed restored NO production in mouse aortas with reduced arginase II (Arg II) expression compared to that in the controls. In mouse peritoneal macrophages and aortic endothelial cells (MAECs), PARP-1 knockout resulted in lowered Arg II expression. Moreover, phosphorylation of endothelial NO synthase (eNOS) was preserved in the aortas and MAECs when PARP-1 was inhibited. Reduced NO production in vitro due to PARP-1 deficiency could be restored by treating the MAECs with oxidized low-density lipoprotein treatment, but this effect could not be achieved with peritoneal macrophages, which was likely due to a reduction in the expression of induced NOS expression. Our findings indicate that PARP-1 inhibition may attenuate atherogenesis by restoring NO production in endothelial cells and thus by reducing Arg II expression and consequently arginase the activity.

Epigallocatechin gallate attenuated the activation of rat cardiac fibroblasts induced by angiotensin II via regulating ß-arrestin1.

BACKGROUND/AIMS: Angiotensin II (AngII) activated cardiac fibroblasts (CFs) predominantly through AngII subtype 1a receptor (AT1aR). This study was carried out to explore the potential inhibitory effects and mechanisms of epigallocatechin gallate (EGCG) on AngII induced rat CFs. METHODS: Viability, proliferation and collagen production of CFs were measured by MTT assay, [3H]-thymidine and [3H]-proline incorporation respectively. ß-arrestin1 (ßarr1), AT1aR and AT1bR mRNA levels were determined by quantitative PCR. AT1R, Gq, ßarr 1/2, phosphorylated kinase C (p-PKC)-delta expressions were detected by western blotting. We blocked ßarr1 expression using ßarr1 small interfering RNA (siRNA). RESULTS: EGCG inhibited the activation of CFs induced by AngII. ßarr1 mRNA level revealed a positive correlation with the viability of CFs. SiRNA targeting ßarr1 blocked the activation of CFs. In vitro, AngII increased ßarr1 mRNA, total and membrane ßarr1 protein expressions, but reduced AT1aR mRNA, global and membrane AT1R, total Gq and cytoplasmic p-PKC-delta levels. Administration of EGCG restored the above abnormalities, whereas Gq levels were not affected. CONCLUSION: Our findings showed that ßarr1 is essential for AngII-mediated activation of CFs. EGCG attenuated CFs activation induced by AngII via regulating ßarr1 and thus, modulating AT1aR mediated signaling.

Elevated lipoprotein-associated phospholipase A2 is associated with progression of nonculprit lesions after percutaneous coronary intervention.

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an enzyme that hydrolyzes oxidized phospholipids to generate bioactive proatherogenic products. Nonculprit lesions have been assumed to contribute to the pathogenesis of recurrent acute coronary syndrome (ACS). The role of LP-PLA2 in the progression of nonculprit coronary lesions after successful percutaneous coronary intervention (PCI) remains unclear. Our study included 123 patients with ACS who underwent initial PCI and a long-term follow-up (mean interval, one year) with coronary angiography. Among them, 19 patients were diagnosed as the progression of nonculprit lesions, based on the presence of at least one of the following factors: (1) ≥ 10% reduction in the diameter of a preexisting ≥ 50% stenosis; (2) ≥ 30% reduction in the diameter of a < 50% stenosis; and (3) early-onset stenosis with ≥ 30% reduction in the diameter of a segment that was normal on the primary angiogram. Blood sampling was drawn from all patients at 12-14 hours after PCI. The ACS patients with progression had higher total cholesterol (4.47 ± 1.02 mmol/L vs. 3.59 ± 0.57 mmol/L, P < 0.05), higher levels of Lp-PLA2 activity (14.39 ± 6.13 nmol/min/ml vs. 8.86 ± 3.14 nmol/min/ml, P < 0.001) and a higher proportion of multi-vessel disease than those without progression. Multivariate logistic regression analysis showed that Lp-PLA2 activity (ß = 0.024, P = 0.005) was an independent predictor for rapid progression of nonculprit coronary lesions. In conclusion, elevated Lp-PLA2 activity is associated with rapid progression of nonculprit coronary lesions in ACS patients who underwent PCI.

[Jinshuibao capsule combined losartan potassium intervened early renal damage of hypertension patients of yin and yang deficiency: a clinical research].

OBJECTIVE: To observe the effects of Jinshuibao Capsule (JC) combined losartan potassium on some indices of early renal damage of hypertension patients of yin and yang deficiency syndrome (YYDS), such as levels of serum cystatin C (Cys C), beta2-microglobulin (beta2-MG), hypersensitive C-reactive protein (hs-CRP), uric acid (UA), blood pressure, blood lipids, and fasting blood glucose (FBG), and to explore their protective effects on early renal damage of hypertension patients and on the metabolisms of blood lipids and blood glucose. METHODS: Totally 106 hypertension patients of YYDS were randomly assigned to two groups, 53 patients in the control group (treated by losartan potassium) and 53 patients in the treatment group (treated by JC + losartan potassium). The treatment lasted for 16 weeks. The serum changes of UA, Cys C, beta2-MG, hs-CRP, blood lipids [including total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C), and high density lipoprotein cholesterol (HDL-C)], and FBG levels were measured to evaluate the renal protective effects and to assess their effect on the metabolisms of blood lipids and blood glucose. RESULTS: Compared with before treatment in the same group, the systolic blood pressure (SBP) decreased in the two groups after treatment, showing statistical difference (P < 0.05, P < 0.01), but there was no statistical difference between the two groups (P > 0.05). The diastolic blood pressure (DBP) was not obviously declined in the two groups after treatment, showing no statistical difference. Compared with before treatment in the same group, the LDL-C level decreased obviously after treatment in the control group. But there was no obvious change in FBG, TC, HDL-C, and TG in the control group, showing no statistical difference when compared with before treatment (P < 0.05). The FBG, TC, and LDL-C obviously decreased in the treatment group more obviously after treatment than before treatment, showing statistical difference (P < 0.05, P < 0.01). There was no statistical difference when compared with the control group after treatment (P > 0.05). Compared with before treatment in the same group, the levels of UA, Cys C, beta2-MG, and hs-CRP all decreased in the two groups, showing statistical difference (P < 0.05, P < 0.01). The SCr level decreased in the treatment group more obviously after treatment than before treatment, showing statistical difference (P < 0.05). Compared with the control group after treatment, the levels of Cys C, beta2-MG, and hs-CRP decreased more obviously after treatment in the treatment group, showing statistical difference (P < 0.05). CONCLUSIONS: JC combined losartan potassium showed better effects in treating early renal damage of hypertension patients of YYDS. They could protect and stabilize the renal functions more effectively. JC could regulate blood lipids and blood glucose.

Urotensin-2 promotes collagen synthesis via ERK1/2-dependent and ERK1/2-independent TGF-ß1 in neonatal cardiac fibroblasts.

U2 (urotensin-2) is the most potent vasoconstrictor in mammals which is involved in cardiac remodelling, including cardiac hypertrophy and cardiac fibrosis. Although the cellular mechanisms of the U2-induced vasoconstriction have been extensively studied, the signalling pathways involved in U2-induced TGF-ß1 (transforming growth factor-ß1) expression and collagen synthesis remain unclear. In this study, we show that U2 promoted collagen synthesis and ERK1/2 (extracellular signal-regulated kinase 1/2) activation in neonatal cardiac fibroblasts. The U2-induced collagen synthesis and TGF-ß1 production were significantly but not completely inhibited by blocking ERK1/2. Both ERK1/2 inhibitor and TGF-ß1 antibody could separately inhibit U2-induced collagen synthesis, and the synergistic inhibition effect was observed by blocking ERK1/2 and TGF-ß1 simultaneously. These data suggest that U2 promotes collagen synthesis via ERK1/2-dependent and independent TGF-ß1 pathway in neonatal cardiac fibroblasts.

Efficacy and safety of atorvastatin during early hospitalization in elderly patients with unstable angina.

1. Previous studies have demonstrated that early statin therapy after acute coronary syndrome decreases inflammation and mortality rates. The dose-response relationship for atorvastatin in elderly patients with unstable angina (UA) during early hospitalization in terms of lowering inflammatory factors, improving vascular endothelium function and safety is unclear. 2. In the present study, 166 consecutive patients with UA who were >/= 60 years of age were randomly assigned, in a double-blind manner, to receive 80 or 20 mg/day atorvastatin. High-sensitivity C-reactive protein, interleukin-6, tumour necrosis factor-alpha, fibrinogen and lipid levels were measured at admission and 1, 2 and 8 weeks later. Vascular endothelial function was measured and the safety of the drug was monitored. 3. Levels of inflammatory factors were significantly lower in patients on 80 mg atorvastatin than in those on 20 mg atorvastatin at 2 and 8 weeks. Atorvastatin 80 mg not only resulted in a significant improvement in vascular endothelial function during early hospitalization for UA over that seen in patients on 20 mg atorvastatin, but also reduced lipid levels to a greater extent. At 8 weeks, almost all patients showed good tolerance of 80 mg/day atorvastatin. 4. The results of the present study indicate that intensive statin therapy with high-dose (80 mg/day) atorvastatin is more efficacious than and as safe as 20 mg/day atorvastatin when administered to elderly patients during early hospitalization for UA.

Elevated expression of urotensin II and its receptor in diabetic cardiomyopathy.

OBJECTIVE: Urotensin II (UII) is a somatostatin-like peptide recently identified to have several cardiovascular effects, including potent vasoactive, cardiac inotropic and chronotropic properties. Our aim was to determine the degree of expression of UII and UII receptor (UT) in the myocardium of rats with streptozotocin (STZ)-induced diabetes. METHODS: Real-time polymerase chain reaction, Western blot, and immunohistochemistry were used to determine the degree of expression and location of UII and UT in the myocardium of STZ-induced diabetic rats. RESULTS: UII and UT expression were significantly enhanced in the myocardium of rats with diabetes compared with healthy controls on both messenger RNA and protein levels. Both UII and UT protein expression were mainly concentrated in the cardiomyocytes, endothelial cells, cardiac fibroblasts, and smooth muscle cells of diabetic cardiomyopathy (DCM). CONCLUSIONS: Our results suggest a possible role for the UII/UT system in the pathophysiology of DCM.

Impact of the number of image planes of real-time three-dimensional echocardiography on the accuracy of left atrial and ventricular volume measurements.

Real-time three-dimensional (3D) echocardiography (RT-3DE) has emerged as a new technique in measuring left atrial and ventricular volume. However, the impact of cutting planes of RT-3DE on the accuracy of volume measurement in patients with a normal or enlarged heart is still unknown. We enrolled 30 normal subjects (control group) and 30 patients with heart failure (patient group). RT-3DE was performed to measure maximal volume of the left atrium (LAVmax) and left ventricular end-diastole volume (LVEDV) with 2-, 4-, 8- and 16-cutting planes, compared with cardiac magnetic resonance imaging (CMRI). In both groups, LAVmax by RT-3DE using 2- and 4-cutting planes was significantly underestimated (mean difference: -10.4 +/- 16.6 mL, p = 0.001 and -8.8 +/- 14.2 mL, p = 0.002 in the control group and -13.4 +/- 19.6 mL, p = 0.001 and -11.2 +/- 17.5 mL, p = 0.001 in the patient group, respectively). These differences became nonsignificant when 8- and 16-cutting planes were adopted (mean difference: -2.1 +/- 7.6 mL and -1.9 +/- 7.4 mL in the control group and -2.7 +/- 8.4 mL and -2.2 +/- 8.3 mL in the patient group, respectively). The agreement for LVEDV was acceptable when 4- or more cutting planes were used in the control group and when 8- or 16-cutting planes were used in the patient group. The time expense for data analysis of LAVmax with 8-image planes was only 7 +/- 4 min in the control group and 6 +/- 5 min in the patient group, almost halving that of the 16-image planes. Similarly, 4- and 8-cutting planes were required for an accurate measurement of LVEDV in the control and patient groups, respectively. In conclusion, RT-3DE with 8-cutting planes is both accurate and timesaving for measurement of LAVmax and LVEDV in patients with normal or enlarged left atria and ventricles.

Relationship between tissue type plasminogen activator and coronary vulnerable plaque in patients with acute coronary syndrome: virtual histological study.

BACKGROUND: The association between vulnerability of plaque assessed with intravascular ultrasound (IVUS) and plasma levels of fibrinolytic biomarkers was determined in patients with acute coronary syndrome (ACS). However, few data are available on the relationship between the levels of tissue type plasminogen activator (t-PA) and virtual histological intravascular ultrasound (VH-IVUS) signs of plaque instability. METHODS: Eighty-nine patients with ACS were enrolled in the study. Blood was collected to measure t-PA levels by liquid phase bead flow cytometry. Eighty-nine nonbifurcate lesions (identified by coronary angiography and ECG) were investigated using IVUS before catheterization. IVUS radiofrequency data obtained with a 20 MHz catheter were analyzed with IVUS virtual histological software. The areas of plaque and media were calculated and lesions were classified into two groups: VH-IVUS derived thin cap fibroatheroma (VH-TCFA) and non-VH-TCFA plaque. RESULTS: Plasma t-PA level in the patients with TCFA was significantly lower than that with non-TCFA ((1489+/-715) pg/ml vs (2163+/-1004) pg/ml). Decreased plasma levels of t-PA were associated with plaque vulnerability. Plasma levels of t-PA correlated negatively with plaque plus media and necrotic core in plaque in patients with ACS. CONCLUSIONS: t-PA is an independent risk factor and a powerful predictor of vulnerable plaques. Decreased levels of t-PA may reflect instability of atherosclerotic plaques and might therefore serve as noninvasive determinants of those at high risk for consequent adverse events.

The involvement of transforming growth factor-beta1 secretion in urotensin II-induced collagen synthesis in neonatal cardiac fibroblasts.

As the most potent vasoconstrictor in mammals, urotensin II (U II) has recently been demonstrated to play an important role in adverse cardiac remodeling and fibrosis. However, the mechanisms of U II-induced myocardial fibrosis remain to be clarified. We postulated that U II alters transforming growth factor-beta1 (TGF-beta1) expression, and thereby modulates cardiac fibroblast collagen metabolism. Experiments were conducted using cardiac fibroblast from neonatal Wistar rats to determine the expression of TGF-beta1, and the role of U II receptor UT in this process. The functional role of TGF-beta1 and UT in modulating U II effects on type I, III collagen mRNA expression and 3H-proline incorporation was also analyzed. TGF-beta1 gene and protein expression were consistently identified in quiescent cardiac fibroblasts. U II increased the expression of TGF-beta1 mRNA and protein in a time-dependent manner. This effect was UT mediated, because UT antagonist urantide abolished U II-induced TGF-beta1 expression. U II-induced increase in type I, III collagen mRNA expression and 3H-proline incorporation were both inhibited by a specific TGF-beta1 neutralizing antibody and UT receptor antagonist urantide. Hence, our results indicate that TGF-beta1 is upregulated in cardiac fibroblasts by U II via UT and modulates profibrotic effects of U II. These findings provide novel insights into U II-induced cardiac remodeling.

Predictors of in-hospital mortality difference between male and female patients with acute myocardial infarction.

Many studies have demonstrated that, compared with men, women have increased long- and short-term mortality after acute myocardial infarction (AMI). The reasons for this mortality difference remain in dispute. We analyzed baseline characteristics, in-hospital management, and short-term outcomes of 1,246 men and 537 women with AMI to identify clinical variables that can predict the in-hospital mortality difference between genders. A higher in-hospital mortality was found in women with AMI than in men (11.9% vs 6.9%, p <0.001). Women were generally older, had a higher incidence of hypertension, diabetes mellitus, and hyperlipidemia, and had a higher Killip class of cardiac function compared with men. Reperfusion therapy and beta-receptor blockers were underused in women. Using a multivariate logistic regression model, we identified age, history of hypertension and diabetes mellitus, Killip class of cardiac function, and administration of reperfusion therapy and beta-receptor blockers as significant predictors of in-hospital mortality in patients with AMI, with odds ratios of 1.05 (95% confidence interval [CI] approximately 1.03 to 1.07), 1.65 (95% CI 1.12 to 2.41), 1.92 (95% CI 1.27 to 2.90), 3.62 (95% CI 2.88 to 4.56), 0.39 (95% CI 0.24 to 0.66), and 0.63 (95% CI 0.43 to 0.93), respectively. In conclusion, women with AMI had a higher in-hospital mortality rate than did men, probably due to older age, higher incidence of hypertension, diabetes mellitus, and hyperlipidemia, a higher Killip class of cardiac function, and less utilization of reperfusion therapy and beta-receptor blockers.

[Effect of urotensin II on proliferative potential and phosphorylation of extracellular signal-regulated kinase 1/2 of adventitial fibroblasts from spontaneously hypertensive rat].

OBJECTIVE: To study the effect of urotensin II ( U II ) on the proliferative potential of adventitial fibroblasts (AFs) from spontaneously hypertensive rat (SHR) and to determine whether extracellular signal-regulated kinase 1/2 (ERK1/2) pathway is involved in this progress. METHODS: 3H-thymidine incorporation test was used to estimate the U II -induced proliferative potential of AFs from SHR and the influence of Urantide (U II receptor antagonist) and PD98059 (ERK1/2 inhibitor). Western blotting was used to test the U II -induced ERK1/2 phosphorylation as well as the effect of Urantide and PD98059 on U II -induced ERKl/2 phosphorylation. RESULTS: U 11 increased the proliferative potential of AFs from SHR in a dose-dependent way. Urantide and PD98059 wholly or partly inhibited U II -induced proliferation of SHR-AFs. In SHR-AFs, U II induced the phosphorylation of ERK1/2 in a time-dependent way, which was completely inhibited by Urantide and PD98059. CONCLUSION: U II can increase the proliferative potential of AFs from SHR and ERK1/2 pathway is partly involved in this progress.

[siRNA inhibits efgl7 expression in human endothelial cell line HUVEC].

OBJECTIVE: To evaluate the effects of small interference RNA (siRNA) on epidermal growth factor-like domain 7 (egfl7) gene expression in human endothelial cell line HUVEC. METHODS: siRNA targeting egfl7 (siRNA1, siRNA2, siRNA3 and siRNA4) was constructed through online design of Amnion company and transfected into human endothelial cell line HUVEC with lipofectamine. The nontransfected cells and cells treated with control siRNA were taken as controls. At 24, 48 and 72 hours post various interventions, cell viability was determined by MTS method as well as LDH and ATP releasing tests. egfl7 expressions at protein and mRNA levels were detected by Western blot and RT-PCR respectively. RESULTS: Cell survival rate, LDH and ATP release were significantly reduced in siRNA treated cells compared to control cells (P < 0.05). Similarly, egfl7 expression at protein and mRNA levels was also significantly reduced in siRNA treated cells (P < 0.01), especially in siRNA1 treated cells. CONCLUSION: siRNA inhibited egfl7 gene expression and cell survival in HUVEC.

[Effects of losartan, ramipril and their combination on left ventricular remodeling and function in spontaneous hypertensive rats].

OBJECTIVE: To evaluate the effects of losartan, an angiotensin receptor blocker, ramipril, an angiotensin converting enzyme inhibitor, and their combination on left ventricular remodeling and diastolic function in SHR at the same level of blood pressure. METHODS: Sixty-two SHRs and 20 WKYs were divided randomly into 5 groups: WKY-control group, SHR-control group, SHR-ramipril group, SHR-losartan group, and SHR-combination group. Twelve weeks after feeding, 6 rats from each group were randomly selected to undergo hemodynamic examination and then killed to undergo further examinations, and 24 weeks after the remaining rats underwent the same examinations. The hemodynamic examination included the systolic blood pressure (SBP) of the caudal artery, left ventricular systolic pressure (LVSP), left ventricle end diastolic pressure (LVEDP), maximum uprising velocity of left ventricle pressure (dP/dtmax), and maximum declining velocity of left ventricle pressure (-dP/dtmax), and tau. Then the hearts were taken out to measure the weight of heart, undergo pathological examination, measure the intracellular free calcium concentrations, hydroxyproline concentration, interstitial collagen volume fraction (CVF), perivascular collagen area/luminal area (PVCA/LA), the mRNA expression of SR Ca(2+)-ATPase, phospholamban and L-type calcium channel, and the protein levels of SR Ca(2+)-ATPase. The myocardial ultrastructure was analyzed by electron microscopy. RESULTS: The speed, extent, and sustained time of blood pressure decrease were better in the combination group than in the other 2 treatment groups. Twelve and 24 weeks after treatment the levels of LVM/BW in the combination group were significantly lower than those of the control group, however, without significant differences among the 3 treatment groups. The values of LVSP, LVEDP, and tau 12 and 24 weeks after treatment in the 3 treatment groups were all significantly lower and the levels of -dP/dtmax significantly higher than those of the control group (all P < 0.01). The values of CVF in the myocardium and PCVA/VA of the heart wall arteriole 12 and 24 weeks after in the 3 treatment groups were significantly lower than those of the control group, and the CVF in the myocardium 12 weeks after in the combination group was significantly than that of the ramipril group. Microscopy showed that the degree of myocardial fibrosis in the 3 treatment groups were significantly milder than those of the control group, and the ultrastructure improvement improved along with the lapse of time in the sequence of combination group > losartan group > ramipril group. The concentrations of hydroxyproline in cardiac muscle cells of the 3 treatment 12 and 24 weeks after were significantly than those of the control group and decreased gradually time-dependently. The expression of Ca(2+)-ATPase mRNA 24 weeks after of the ramipril, losartan, and combination groups were 53.5%, 72.9%, and 76.7% higher than that of the control group, and the Ca(2+)-ATPase protein expression of the 3 treatment groups were 28.9%, 33.3%, and 49.3% higher than that of the control group. The expression of L-type Ca(2+) channel mRNA of the 3 treatment groups were 51.8%, 76.8%, and 98.2% than that of the control group. CONCLUSION: Both losartan and ramipril reverse LVH and left ventricular diastolic dysfunction. A combination of these two drugs is more effective than single drug treatment for improvement of myocardial fibrosis and ultrastructure. All three-treatment groups can raise calcium-handling proteins mRNA and protein expressions, which may be the underlying molecular mechanisms for their therapeutic effects.

[Effects of matrix metalloproteinase-9 and tissue inhibitor-1 of metalloproteinase expression on atrial structural remodeling during chronic atrial fibrillation].

OBJECTIVE: To investigate the matrix metalloproteinase-9 (MMP-9) and tissue inhibitor-1 of metalloproteinase (TIMP-1) mRNA and protein expression in chronic fibrillating human atria and to evaluate the influence of MMP-9 and TIMP-1 expression on the progress of atrial structural remodeling. METHODS: Twenty-four patients with chronic atrial fibrillation (AF) and 12 patients with sinus rhythm as control group underwent transthoracic echocardiography and left atrial appendage (LAA) tissue samples were obtained from these patients during mitral/aortic valve replacement operation. MMP-9 and TIMP-1 protein expressions were detected by immunohistochemistry and their mRNA expressions were determined by reverse transcription polymerase chain reaction (RT-PCR). RESULTS: The left atrial and right atrial diameters increased significantly in the fibrillation group in comparison with the control group (57 +/- 6 vs 45 +/- 7, 62 +/- 10 vs 51 +/- 17, P < 0.05 approximately 0.001) The expressions of MMP-9 mRNA and protein in the LAA tissue of the AF group is upregulated (0.70 +/- 0.12 vs 0.53 +/- 0.22, and 2.25 +/- 0.73 vs 1.12 +/- 0.58, P < 0.05 approximately 0.001) and the expressions of TIMP-1 mRNA and protein were downregulated significantly (0.20 +/- 0.07 vs 0.31 +/- 0.15, and 1.12 +/- 0.48 vs 1.75 +/- 0.46, P < 0.05 approximately 0.01). The MMP-9 mRNA level was positively correlated with AF duration and the left atrial diameter (P < 0.05 approximately 0.001). CONCLUSION: There is a selective downregulation of TIMP-1 expression along with the upregulation of MMP-9 in AF, which indicates that the disturbance expression of MMP/TIMP system may promote the process of atrial structural remodeling. Enhanced MMP-9 activity may be a molecular mechanism contributing to the dilation of fibrillating human atria.

Rutin alleviates diabetic cardiomyopathy in a rat model of type 2 diabetes.

Diabetic cardiomyopathy (DCM), an independent coronary heart disease that develops in diabetic individuals, is characterized by changes in the myocardial structure and function. The aim of the present study was to investigate the protective effect of rutin on DCM in a streptozotocin-induced diabetic rat model. Rutin was orally administrated at a dose of 8 mg/kg body weight. Metabolic profiles, myocardial enzymes and oxidative stress were examined by biochemical tests. The expression levels of cellular proteins associated with apoptosis were measured by western blot analysis, while the levels of inflammatory factors were assessed by immunohistochemical analyses. Rats with DCM exhibited an abnormal metabolic profile, aberrant myocardial enzymes, elevation of oxidative stress markers, increased levels of inflammatory factors and enhanced apoptotic cell death. Notably, rutin was shown to protect and improve myocardial dysfunction, oxidative stress, apoptosis and inflammation in the hearts of the diabetic rats. In conclusion, these results indicated that rutin may have great therapeutic potential in the treatment of DCM, and possibly other cardiovascular disorders, by preventing oxidative stress, inflammation and cell death. However, further detailed studies are required to reveal the exact mechanisms underlying the protective effect of rutin.

[Relationship between regression of hypertensive left ventricular hypertrophy and improvement of coronary flow reserve].

OBJECTIVE: To elucidate the relationship between regression of hypertensive left ventricular hypertrophy (LVH) and changes of coronary flow reserve (CFR). METHODS: Ninety-six essential hypertensive patients with LVH were randomly divided into 3 groups: ramipril group, losartan group, and combination group. Before the treatment and 6 months after the treatment, left ventricular mass (LVM) was calculated by three-dimensional echocardiography and CFR was evaluated by transesophageal echocardiography with left anterior descending artery. CFR was calculated as the ratio of coronary flow velocity, after intravenous injection of dipyridamole (D), to rest peak velocity (R). All the indexes of the CFR were corrected by LVM. RESULTS: (1) The systolic blood pressure (SBP), diastolic blood pressure (DBP) and LVM were significantly decreased in ramipril group, losartan group and combination group after 6 months treatment (all P < 0.01). Diastolic flow velocity integral was used as one representative index of CFR. Compared with baseline values, the diastolic flow velocity intergral corrected by LVM (D/R DVi(C)) was significantly increased in ramipril group, losartan group and combination group (1.83 +/- 0.61 vs 1.57 +/- 0.58, P < 0.05; 1.94 +/- 0.45 vs 1.53 +/- 0.64, P < 0.01; 2.03 +/- 0.38 vs 1.49 +/- 0.34, P < 0.01). (3) The changes of D/R DVi(C) showed a positive correlation with the changes of LVM (r = 0.579, P < 0.05) and no significant correlation with the decrease of blood pressure (r = 0.288 and 0.295,both P > 0.05). CONCLUSION: Ramipril, losartan and combination of these two drugs all reduce blood pressure and LVH, and increases CFR. CFR corrected by LVM may help assess drug's effect on CFR. Improvement of CFR is associated with the regression of hypertensive LVH.

A novel PITX2c loss­of­function mutation underlies lone atrial fibrillation.

Atrial fibrillation (AF) is the most common form of sustained cardiac arrhythmia responsible for substantial morbidity and significantly increased mortality rates. A growing body of evidence documents the important role of genetic defects in the pathogenesis of AF. However, AF is a heterogeneous disease and the genetic determinants for AF in an overwhelming majority of patients remain unknown. In the present study, a cohort of 100 unrelated patients with lone AF and a total of 200 unrelated, ethnically matched healthy individuals used as controls, were recruited. The whole coding exons and splice junctions of the pituitary homeobox 2c (PITX2c) gene, which encodes a paired­like homeobox transcription factor required for normal cardiovascular morphogenesis, were sequenced in the 100 patients and 200 control subjects. The causative potential of the identified mutation of PITX2c was predicted by MutationTaster and PolyPhen­2. The functional characteristics of the PITX2c mutation were assayed using a dual­luciferase reporter assay system. Based on the results, a novel heterozygous PITX2c mutation (p.T97A) was identified in a patient with AF. The missense mutation was absent in the 400 reference chromosomes and was automatically predicted to be disease­causing. Multiple alignments of PITX2c protein sequences across species revealed that the altered amino acid was completely conserved evolutionarily. Functional analysis demonstrated that the mutant PITX2c protein was associated with significantly decreased transcriptional activity when compared with its wild­type counterpart. The findings of the present study firstly link the PITX2c loss­of­function mutation to lone AF, and provide novel insight into the molecular mechanisms underlying AF, suggesting the potential implications for the early prophylaxis and allele­specific therapy of this common type of arrhythmia.