Biodegradable polymer-coated versus durable polymer-coated sirolimus-eluting stents: the final 5-year outcomes of the I-LOVE-IT 2 trial.

AIMS: This analysis presents the final five-year results of the I-LOVE-IT 2 trial, a non-inferiority study comparing a biodegradable polymer (BP) sirolimus-eluting stent (SES) with a durable polymer (DP) SES in patients with coronary artery disease. METHODS AND RESULTS: Overall, 2,737 Chinese patients eligible for coronary stenting were treated with BP-SES or DP-SES in a 2:1 ratio. Patients who were randomised to the BP-SES group were additionally re-randomised to receive either six-month or 12-month dual antiplatelet therapy (DAPT) in a 1:1 ratio. The primary endpoint was 12-month target lesion failure (TLF: cardiac death, target vessel myocardial infarction (MI), or clinically indicated target lesion revascularisation). At five years, the overall follow-up rate was 90.8%, and the cumulative incidence of TLF as the primary endpoint was similar between BP-SES and DP-SES (hazard ratio [HR] 1.01, 95% confidence interval [CI]: 0.79 to 1.28), as was that for the patient-oriented composite endpoint (PoCE: all-cause death, all MI and any revascularisation) (HR 1.03, 95% CI: 0.86 to 1.23), or definite/probable stent thrombosis (ST) (HR 0.91, 95% CI: 0.70 to 1.77). Cumulative events were also similar between the six-month DAPT and 12-month DAPT groups after BP-SES implantation. CONCLUSIONS: I-LOVE-IT 2 showed that the five-year safety and efficacy of BP-SES and DP-SES were similar, as were those between six months and 12 months of DAPT after BP-SES implantation.

Ginsenoside Re Improves Isoproterenol-Induced Myocardial Fibrosis and Heart Failure in Rats.

Objective. Panax ginseng is used widely for treatment of cardiovascular disorders in China. Ginsenoside Re is the main chemical component of P. ginseng. We aimed to investigate the protective effect of ginsenoside Re on isoproterenol-induced myocardial fibrosis and heart failure in rats. Methods. A model of myocardial fibrosis and heart failure was established by once-daily subcutaneous injection of isoproterenol (5 mg/kg/day) to rats for 7 days. Simultaneously, rats were orally administrated ginsenoside Re (5 or 20 mg/kg) or vehicle daily for 4 weeks. Results. Isoproterenol enhanced the heart weight, myocardial fibrosis, and hydroxyproline content in rat hearts. Ginsenoside Re inhibited (at least in part) the isoproterenol-induced increase in heart weight, myocardial fibrosis, and hydroxyproline content. Compared with the isoproterenol group, treatment with ginsenoside Re ameliorated changes in left ventricular systolic pressure, left ventricular end diastolic pressure, and the positive and negative maximal values of the first derivative of left ventricular pressure. Ginsenoside Re administration also resulted in decreased expression of transforming growth factor (TGF)-ß1 in serum and decreased expression of Smad3 and collagen I in heart tissue. Conclusion. Ginsenoside Re can improve isoproterenol-induced myocardial fibrosis and heart failure by regulation of the TGF-ß1/Smad3 pathway.

Alprostadil attenuates myocardial ischemia/reperfusion injury by promoting antioxidant activity and eNOS activation in rats

Abstract Purpose: To investigate the effect of alprostadil on myocardial ischemia/reperfusion (I/R) in rats. Methods: Rats were subjected to myocardial ischemia for 30 min followed by 24h reperfusion. Alprostadil (4 or 8 μg/kg) was intravenously administered at the time of reperfusion and myocardial infarct size, levels of troponin T, and the activity of creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH) in the serum were measured. Antioxidative parameters, nitric oxide (NO) content and phosphorylated endothelial nitric oxide synthase 3 (p-eNOS) expression in the left ventricles were also measured. Histopathological examinations of the left ventricles were also performed. Results: Alprostadil treatment significantly reduced myocardial infarct size, serum troponin T levels, and CK-MB and LDH activity (P<0.05). Furthermore, treatment with alprostadil significantly decreased malondialdehyde (MDA) content (P<0.05) and markedly reduced myonecrosis, edema and infiltration of inflammatory cells. Superoxide dismutase and catalase activities (P<0.05), NO level (P<0.01) and p-eNOS (P<0.05) were significantly increased in rats treated with alprostadil compared with control rats. Conclusion: These results indicate that alprostadil protects against myocardial I/R injury and that these protective effects are achieved, at least in part, via the promotion of antioxidant activity and activation of eNOS.

Ginsenoside Re Attenuates Isoproterenol-Induced Myocardial Injury in Rats.

Objective. Panax ginseng is widely used for treatment of cardiovascular disorders in China. Ginsenoside Re is the main chemical component of Panax ginseng. This study aimed to investigate the protective effect of Ginsenoside Re on isoproterenol-induced myocardial injury in rats. Methods. Male Wistar rats were orally given Ginsenoside Re (5, 20 mg/kg) daily for 7 days. Isoproterenol was subcutaneously injected into the rats for two consecutive days at a dosage of 20 mg/kg/day (on 6th and 7th day). Six hours after the last isoproterenol injection, troponin T level and creatine kinase-MB (CK-MB) activity were assayed. Histopathological examination of heart tissues was performed. The levels of malondialdehyde (MDA) and glutathione (GSH) in heart tissues were measured. The nuclear factor erythroid 2-related factor 2 (Nrf2) content in nucleus and the proteins of glutathione cysteine ligase catalytic subunit (GCLC) and glutathione cysteine ligase modulatory subunit (GCLM) in heart tissues were assayed by western blotting method. Results. Treatment with Ginsenoside Re at dose of 5, 20 mg/kg reduced troponin T level and CK-MB activity of rats subjected to isoproterenol. The cardioprotective effect of Ginsenoside Re was further confirmed by histopathological examination which showed that Ginsenoside Re attenuated the necrosis and inflammatory cells infiltration. Ginsenoside Re inhibited the increase of MDA content and the decrease of GSH in heart tissues. Moreover, the Nrf2 content in nucleus and the expressions of GCLC and GCLM were significantly increased in the animals treated with Ginsenoside Re. Conclusion. These findings suggested that Ginsenoside Re possesses the property to attenuate isoproterenol-induced myocardial ischemic injury by regulating the antioxidation function in cardiomyocytes.

Cardiomyocyte-specific deletion of Sirt1 gene sensitizes myocardium to ischaemia and reperfusion injury.

Aims: A longevity gene, Sirtuin 1 (SIRT1) and energy sensor AMP-activated protein kinase (AMPK) have common activators such as caloric restriction, oxidative stress, and exercise. The objective of this study is to characterize the role of cardiomyocyte SIRT1 in age-related impaired ischemic AMPK activation and increased susceptibility to ischemic insults. Methods and results: Mice were subjected to ligation of left anterior descending coronary artery for in vivo ischemic models. The glucose and fatty acid oxidation were measured in a working heart perfusion system. The cardiac functions by echocardiography show no difference in young wild-type C57BL/6 J (WT, 4-6 months), aged WT C57BL/6 J (24-26 months), and young inducible cardiomyocyte-specific SIRT1 knockout (icSIRT1 KO) (4-6 months) mice under physiological conditions. However, after 45 mins ischaemia and 24-h reperfusion, the ejection fraction of aged WT and icSIRT1 KO mice was impaired. The aged WT and icSIRT1 KO hearts vs. young WT hearts also show an impaired post-ischemic contractile function in a Langendorff perfusion system. The infarct size of aged WT and icSIRT1 KO hearts was larger than that of young WT hearts. The immunoblotting data demonstrated that aged WT and icSIRT1 KO hearts vs. young WT hearts had impaired phosphorylation of AMPK and downstream acetyl-CoA carboxylase during ischaemia. Intriguingly, AMPK upstream LKB1 is hyper-acetylated in both aged WT and icSIRT1 KO hearts; this could blunt activation of LKB1, leading to an impaired AMPK activation. The working heart perfusion results demonstrated that SIRT1 deficiency significantly impaired substrate metabolism in the hearts; fatty acid oxidation is augmented and glucose oxidation is blunted during ischaemia and reperfusion. Adeno-associated virus (AAV9)-Sirt1 was delivered into the aged hearts via a coronary delivery approach, which significantly rescued the protein level of SIRT1 and the ischemic tolerance of aged hearts. Furthermore, AMPK agonist can rescue the tolerance of aged heart and icSIRT1 KO heart to ischemic insults. Conclusions: Cardiac SIRT1 mediates AMPK activation via LKB1 deacetylation, and AMPK modulates SIRT1 activity via regulation of NAD+ level during ischaemia. SIRT1 and AMPK agonists have therapeutic potential for treatment of aging-related ischemic heart disease.

Alprostadil attenuates myocardial ischemia/reperfusion injury by promoting antioxidant activity and eNOS activation in rats.

PURPOSE: To investigate the effect of alprostadil on myocardial ischemia/reperfusion (I/R) in rats. METHODS: Rats were subjected to myocardial ischemia for 30 min followed by 24h reperfusion. Alprostadil (4 or 8 µg/kg) was intravenously administered at the time of reperfusion and myocardial infarct size, levels of troponin T, and the activity of creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH) in the serum were measured. Antioxidative parameters, nitric oxide (NO) content and phosphorylated endothelial nitric oxide synthase 3 (p-eNOS) expression in the left ventricles were also measured. Histopathological examinations of the left ventricles were also performed. RESULTS: Alprostadil treatment significantly reduced myocardial infarct size, serum troponin T levels, and CK-MB and LDH activity (P<0.05). Furthermore, treatment with alprostadil significantly decreased malondialdehyde (MDA) content (P<0.05) and markedly reduced myonecrosis, edema and infiltration of inflammatory cells. Superoxide dismutase and catalase activities (P<0.05), NO level (P<0.01) and p-eNOS (P<0.05) were significantly increased in rats treated with alprostadil compared with control rats. CONCLUSION: These results indicate that alprostadil protects against myocardial I/R injury and that these protective effects are achieved, at least in part, via the promotion of antioxidant activity and activation of eNOS.

Extracts of Magnolia Species-Induced Prevention of Diabetic Complications: A Brief Review.

Diabetic complications are the major cause of mortality for the patients with diabetes. Oxidative stress and inflammation have been recognized as important contributors for the development of many diabetic complications, such as diabetic nephropathy, hepatopathy, cardiomyopathy, and other cardiovascular diseases. Several studies have established the anti-inflammatory and oxidative roles of bioactive constituents in Magnolia bark, which has been widely used in the traditional herbal medicines in Chinese society. These findings have attracted various scientists to investigate the effect of bioactive constituents in Magnolia bark on diabetic complications. The aim of this review is to present a systematic overview of bioactive constituents in Magnolia bark that induce the prevention of obesity, hyperglycemia, hyperlipidemia, and diabetic complications, including cardiovascular, liver, and kidney.

Six Versus 12 Months of Dual Antiplatelet Therapy After Implantation of Biodegradable Polymer Sirolimus-Eluting Stent: Randomized Substudy of the I-LOVE-IT 2 Trial.

BACKGROUND: There are no reports on a large-scale randomized trial exploring optimal dual antiplatelet therapy (DAPT) duration after biodegradable polymer sirolimus-eluting stent implantation. We sought to report the outcomes of a randomized substudy of the prospective Evaluate Safety and Effectiveness of the Tivoli DES and the Firebird DES for Treatment of Coronary Revascularization (I-LOVE-IT 2) trial. METHODS AND RESULTS: In the prospective noninferiority randomized I-LOVE-IT 2 trial, 1829 patients allocated to the biodegradable polymer sirolimus-eluting stent group were also randomized to receive either 6-month (n=909) or 12-month DAPT (n=920). The primary end points of this noninferiority substudy were 12-month target lesion failure (composite of cardiac death, target vessel myocardial infarction or clinically indicated target lesion revascularization), and the major secondary end points were 12-month net adverse clinical and cerebral events (composite of all-cause death, all myocardial infarction, stroke, or major bleeding [Bleeding Academic Research Consortium type ≥3]). The 12-month target lesion failure in 6-month DAPT group was comparable with the 12-month DAPT group (6.8% versus 5.9%; difference and 95% confidence interval, 0.87% [-1.37% to 3.11%], P for noninferiority=0.0065). Further follow-up at 18 months showed that incidence of target lesion failure and net adverse clinical and cerebral events were similar between the 2 groups (7.5% versus 6.3%, log-rank P=0.32; 7.8% versus 7.3%, log-rank P=0.60; respectively), as well as their individual end point components. CONCLUSIONS: This study indicated noninferiority in safety and efficacy of 6-month versus 12-month DAPT after implantation of a novel biodegradable polymer sirolimus-eluting stent. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01681381.

Cardiac-Specific Deletion of the Pdha1 Gene Sensitizes Heart to Toxicological Actions of Ischemic Stress.

Pyruvate dehydrogenase (PDH) plays a key role in aerobic energy metabolism and occupies a central crossroad between glycolysis and the tricarboxylic acid cycle. We generated inducible cardiac-specific PDH E1α knockout (CreER(T2)-PDH(flox/flox)) mice that demonstrated a high mortality rate. It was hypothesized that PDH modulating cardiac glucose metabolism is crucial for heart functions under normal physiological and/or stress conditions. The myocardial infarction was conducted by a ligation of the left anterior descending coronary arteries. Cardiac PDH E1α deficiency caused large myocardial infarcts size and macrophage infiltration in the hearts (P < .01 vs wild-type [WT]). Wheat germ agglutinin and Masson trichrome staining revealed significantly increased hypertrophy and fibrosis in PDH E1α-deficient hearts (P < .05 vs WT). Measurements of heart substrate metabolism in an ex vivo working heart perfusion system demonstrated a significant impairment of glucose oxidation in PDH E1α-deficient hearts during ischemia/reperfusion (P < .05 vs WT). Dichloroacetate, a PDH activator, increased glucose oxidation in WT hearts during ischemia/reperfusion and reduced myocardial infarct size in WT, but not in PDH E1α-deficient hearts. Immunoblotting results demonstrated that cardiac PDH E1α deficiency leads to an impaired ischemic AMP-activated protein kinase activation through Sestrin2-liver kinase B1 interaction which is responsible for an increased susceptibility of PDH E1α-deficient heart to ischemic insults. Thus, cardiac PDH E1α deficiency impairs ischemic AMP-activated protein kinase signaling and sensitizes hearts to the toxicological actions of ischemic stress.

Ginsenoside Rg3 Improves Cardiac Function after Myocardial Ischemia/Reperfusion via Attenuating Apoptosis and Inflammation.

Objectives. Ginsenoside Rg3 is one of the ginsenosides which are the main constituents isolated from Panax ginseng. Previous study demonstrated that ginsenoside Rg3 had a protective effect against myocardial ischemia/reperfusion- (I/R-) induced injury. Objective. This study was designed to evaluate the effect of ginsenoside Rg3 on cardiac function impairment induced by myocardial I/R in rats. Methods. Sprague-Dawley rats were subjected to myocardial I/R. Echocardiographic and hemodynamic parameters and histopathological examination were carried out. The expressions of P53, Bcl-2, Bax, and cleaved caspase-3 and the levels of TNF-α and IL-1ß in the left ventricles were measured. Results. Ginsenoside Rg3 increased a left ventricular fractional shortening and left ventricular ejection fraction. Treatment with ginsenoside Rg3 also alleviated increases of left ventricular end diastolic pressure and decreases of left ventricular systolic pressure and ±dp/dt in myocardial I/R-rats. Ginsenoside Rg3 decreased apoptosis cells through inhibiting the activation of caspase-3. Ginsenoside Rg3 also caused significant reductions of the contents of TNF-α and IL-1ß in left ventricles of myocardial I/R-rats. Conclusion. The findings suggested that ginsenoside Rg3 possessed the effect of improving myocardial I/R-induced cardiac function impairment and that the mechanism of pharmacological action of ginsenoside Rg3 was related to its properties of antiapoptosis and anti-inflammation.

Panaxquin quefolium diolsaponins dose-dependently inhibits the proliferation of vascular smooth muscle cells by downregulating proto-oncogene expression.

OBJECTIVES: Panax quinquefolium saponins (PQS) potentially prevent atherosclerosis in vivo. The proliferation of vascular smooth muscle cells (VSMCs) plays an important role in coronary heart disease and restenosis after percutaneous coronary intervention. Here, we investigated the potential effect of Panax quinquefolium diolsaponins (PQDS), a subtype of PQS, on angiotensin II (AngII)-induced VSMC proliferation. MATERIALS AND METHODS: Isolated rat VSMCs were identified by immunocytochemical analysis. Cell proliferation was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The cell cycle and proliferation index were analyzed using flow cytometry. The messenger ribonucleic acid (mRNA) expression of proto-oncogenes was evaluated using reverse transcription polymerase chain reaction. RESULTS: Over 98% of cultured VSMCs were immunopositive for anti-α-smooth muscle actin. AngII promoted cell proliferation, whereas PQDS significantly suppressed VSMC growth in a dose-dependent manner. Moreover, PQDS suppressed AngII-induced proliferation of VSMCs by arresting the Gap 0/Gap 1 phase. Down-regulated mRNA expressions of proto-oncogenes occurred after PQDS application. CONCLUSIONS: Our study demonstrates that PQDS may reduce AngII-stimulated VSMC proliferation by suppressing the expression of proto-oncogenes. These results may provide insights for the development of novel traditional Chinese medicines to prevent atherosclerosis.

[Comparison on clinical features between dilated cardiomyopathy patients with or without pulmonary hypertension].

OBJECTIVE: The clinical data of dilated cardiomyopathy (DCM) patients with or without pulmonary hypertension (PH) diagnosed by echocardiography were compared. METHODS: During January 2007 to December 2009, 61 cases of DCM with PH and 51 cases of DCM without PH were admitted in our department. The demographic and clinical data, heart function, echocardiography and serum total bilirubin and creatinine levels of all patients were analyzed. RESULTS: Sex, age, vital signs, combined diseases and arrhythmias as well as the serum creatinine level [(103.5 ± 49.7) µmol/L vs. (90.3 ± 37.3) µmol/L, P > 0.05] were similar between the two groups, while the incidence of NYHA III and IV (95% vs. 65%), the left ventricle end-systolic dimension[(71.0 ± 9.6) mm vs. (65.5 ± 7.2) mm], dimension of the left atrium [(52.8 ± 8.93) mm vs. (43.9 ± 6.3) mm], right ventricular outflow tract [(29.1 ± 5.3) mm vs. (22.1 ± 3.3) mm] incidence of pericardial effusion (29/61 vs. 7/51) and the serum total bilirubin level [(45.3 ± 31.8) µmol/L vs. (19.5 ± 9.08) µmol/L] were significantly higher while ejective fraction was significantly lower in DCM with PH than those in DCM without PH (0.28 ± 0.10 vs. 0.36 ± 0.10, all P < 0.05). CONCLUSION: DCM patients with PH is linked with worse clinical features than DCM patients without PH.

Hypolipidemic effects of kaempferide-7-O-(4''-O-acetylrhamnosyl)-3-O-rutinoside in hyperlipidemic rats induced by a high-fat diet.

Kaempferide-7-O-(4''-O-acetylrhamnosyl)-3-O-rutinoside (A-F-B) is a novel flavonoid which is extracted from the leaves of Actinidia kolomikta. The aim of this study was to investigate the hypolipidemic effects of A-F-B in hyperlipidemic rats induced by a high-fat diet. Male Wistar rats were randomly divided into six groups: normal diet group, high-fat diet group, lovastatin (2.5 mg/kg) group and A-F-B (12.5, 25 or 50 mg/kg) groups. To evaluate the lipid-lowering effects of A-F-B, total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), atherogenic index (AI) and coronary risk index (CRI) were investigated. The activities of phosphatidate phosphohydrolase (PAP) and hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase in hepatic tissue were evaluated. Treatment with A-F-B to hyperlipidemic rats resulted in a significant decline in TC, TG, LDL-C, AI and CRI, with an increase in HDL-C level. The results also showed that A-F-B significantly decreased the activities of PAP and HMG-CoA reductase in hepatic tissue. These findings suggest that A-F-B improves lipid profiles. The mechanisms of A-F-B were associated with regulating the activities of PAP and HMG-CoA reductase in hepatic tissue.

[Risk factors of pulmonary embolism among 303 patients in the First Clinical Hospital of Jilin University].

OBJECTIVE: To study the trend and changes regarding risk factors of pulmonary embolism among inpatients in the last 10 years from the First Clinical Hospital of Jilin University. METHODS: 303 cases of pulmonary embolism inpatients in our hospital from 2001 - 2010 were included and analyzed on related incidence, mortality and risk factors. RESULTS: Data showed that: (1) the incidence of pulmonary embolism increased from 0.09‰ to 1.12‰ while the mortality dropped from 73.3% to 12.0%; (2) major risk factors would include thrombosis of deep veins, surgical operations, heart diseases, varicosity or phlebitis of lower extremities, trauma and fracture etc., according to the order of incidence rates. Surgical operations had become the second major risk factor in the last 10 years. CONCLUSION: The incidence of pulmonary embolism in our hospital showed a gradual drop while the mortality had a remarkable drop. Surgical operations had become one of the major risk factors of pulmonary embolism.