PKA-mediated eNOS phosphorylation in the protection of ischemic preconditioning against no-reflow.

OBJECTIVE: To investigate whether ischemic preconditioning (IP) can reduce myocardial no-reflow by activating endothelial (e-) nitric oxide synthase (NOS) via the protein kinase A (PKA) pathway. METHODS AND RESULTS: In a 90-min ischemia and 3-h reperfusion model, minipigs were assigned into sham, ischemia-reperfusion (IR), IR+IP, IR+IP+L-NNA (an eNOS inhibitor, 10mg·kg(-1)), IR+IP+H-89 (a PKA inhibitor, 1.0µg·kg(-1)·min(-1)), IR+L-NNA, and IR+H-89 groups. IP pretreatment improved cardiac function and coronary blood flow, decreased the activities of creatine kinase by 36.6% after 90 min of ischemia and by 32.8% after 3 h of reperfusion (P<0.05), reduced the no-reflow areas from 49.9% to 11.0% (P<0.01), and attenuated the infarct size from 78.2% to 35.4% (P<0.01). IP stimulated myocardial PKA activities and the expression of PKA and Ser(133) phosphorylated (p-) cAMP response element-binding protein (CREB) in the reflow and no-reflow myocardium, and enhanced the activities of constitutive NOS and the phosphorylation of eNOS at Ser(1179) and Ser(635) in the no-reflow myocardium. IP suppressed the expression of tumor necrosis factor-α and P-selectin, and attenuated cardiomyocytes apoptosis by regulating the expression of Bcl-2 and caspase-3 in the reflow and no-reflow myocardium. The eNOS inhibitor L-NNA completely canceled these beneficial effects of IP without any influence on PKA activity, whereas the PKA inhibitor H-89 partially blocked the IP cardioprotective effects and eNOS phosphorylation at the same time. CONCLUSION: IP attenuates myocardial no-reflow and infarction after ischemia and reperfusion by activating the phosphorylation of eNOS at Ser(1179) and Ser(635) in a partly PKA-dependent manner.

Phosphorylation of endothelial NOS contributes to simvastatin protection against myocardial no-reflow and infarction in reperfused swine hearts: partially via the PKA signaling pathway.

AIM: The cholesterol-lowering drugs statins could enhance the activities of endothelial nitric oxide synthase (eNOS) and protect myocardium during ischemia and reperfusion. The aim of this study was to examine whether protein kinase A (PKA) was involved in statin-mediated eNOS phosphorylation and cardioprotection. METHODS: 6-Month-old Chinese minipigs (20-30 kg) underwent a 1.5-h occlusion and 3-h reperfusion of the left anterior descending coronary artery (LAD). In the sham group, the LAD was encircled by a suture but not occluded. Hemodynamic and cardiac function was monitored using a polygraph. Plasma activity of creatine kinase and the tissue activities of PKA and NOS were measured spectrophotometrically. p-CREB, eNOS and p-eNOS levels were detected using Western blotting. Sizes of the area at risk, the area of no-reflow and the area of necrosis were measured morphologically. RESULTS: Pretreatment of the animals with simvastatin (SIM, 2 mg/kg, po) before reperfusion significantly decreased the plasma activity of creatine kinase, an index of myocardial necrosis, and reduced the no-reflow size (from 50.4%±2.4% to 36.1%±2.1%, P<0.01) and the infarct size (from 79.0%±2.7% to 64.1%±4.5%, P<0.01). SIM significantly increased the activities of PKA and constitutive NOS, and increased Ser(133) p-CREB protein, Ser(1179) p-eNOS, and Ser(635) p-eNOS in ischemic myocardium. Intravenous infusion of the PKA inhibitor H-89 (1 µg·kg(-1)·min(-1)) partially abrogated the SIM-induced cardioprotection and eNOS phosphorylation. In contrast, intravenous infusion of the eNOS inhibitor L-NNA (10 mg·kg(-1)) completely abrogated the SIM-induced cardioprotection and eNOS phosphorylation during ischemia and reperfusion, but did not affect the activity of PKA. CONCLUSION: Pretreatment with a single dose of SIM 2.5 h before reperfusion attenuates myocardial no-reflow and infarction through increasing eNOS phosphorylation at Ser(1179) and Ser(635) that was partially mediated via the PKA signaling pathway.

[Ischemic preconditioning attenuates myocardial no-reflow and reperfusion injury after revascularization of acute myocardial infarction by reducing myocardial edema via the protein kinase A pathway].

OBJECTIVE: Myocardial edema plays an important role in the development of myocardial no-reflow and reperfusion injury after the revascularization of acute myocardial infarction (AMI). The present study investigated whether the effect of ischemic preconditioning (IPC) against myocardial no-reflow and reperfusion injury was related to the reduction of myocardial edema through the protein kinase A (PKA) pathway. METHODS: Twenty-four minipigs were randomized into sham, AMI, IPC, and IPC + H-89 (PKA inhibitor, 1.0 µg · kg(-1) · min(-1)) groups. The area of no-reflow (ANR), area of necrosis (AN), and water content in left ventricle and ischemic-myocardium and non-ischemic area were determined by pathological studies. Microvascular permeability was determined by FITC-labeled dextran staining. Cardiomyocyte cross-sectional area (CSA) and mitochondria cross-sectional area (MSA) were evaluated by histological analysis. Myocardial expression of aquaporins (AQPs) was detected by Western blot. RESULTS: Compared with the MI group, the sizes of no-reflow and infarct were reduced by 31.9% and 46.6% in the IPC group (all P < 0.01), water content was decreased by 5.7% and 4.6% in the reflow and no-reflow myocardium of the IPC group (all P < 0.05), microvascular permeability and cardiomyocytes swelling in the reflow area were inhibited by 29.8% and 21.3% in the IPC group (all P < 0.01), mitochondrial water accumulation in the reflow and no-reflow areas of the IPC group were suppressed by 45.5% and 34.8% respectively (all P < 0.01), and the expression of aquaporin-4, -8, and -9 in the reflow and no-reflow myocardium were blocked in the IPC group. However, these beneficial effects of IPC were partially abolished in the IPC + H-89 group. CONCLUSIONS: The cardioprotective effects of IPC against no-reflow and reperfusion injury is partly related to the reduction of myocardial edema by inhibition of microvascular permeability and aquaporins up-regulation via PKA pathway.

No-reflow disrupts the expression and distribution of connexin 43 in a swine model.

INTRODUCTION AND OBJECTIVES: Ischemia and ischemia/reperfusion can dephosphorylate and redistribute connexin 43 (Cx43). But it is unknown whether no-reflow phenomenon has an effect on the expression and distribution of Cx43 after acute infarction and reperfusion. METHODS: 21 open-chest pigs were divided into three groups. Left anterior descending artery (LAD) occlusion for 90 min before 180 min of reperfusion was made in ischemia/reperfusion group. The pigs in ischemia groups were either subjected to LAD ligation for 90 min or for 270 min. No-reflow and risk regions were determined pathologically by dye staining. Cx43 expression was measured by western blotting and quantitative RT-PCR analysis. Cx43 spatial distribution was shown by immunofluorescence examination. RESULTS: The content of phosphorylated and mRNA of Cx43 were higher in reflow region than in the no-reflow or sustained ischemic region. The distribution of Cx43 was also altered in no-reflow region. CONCLUSIONS: There are some differences in synthesis, expression and distribution of myocardial Cx43 at microvascular level after ischemia/reperfusion. Cx43 is partially rephosphorylated with reperfusion only in the reflow myocardium.

Expression of FLK1 and CD146 at day 7 following reperfused acute myocardial infarction.

OBJECTIVES: To investigate the expression of FLK1, CD146 and microvessel density of angiogenesis at the first week of reperfused acute myocardial infarction (AMI). METHODS: 16 of mini-swines (20 to 30 Kg) were randomly assigned to the sham-operated group and the AMI group. Pathologic myocardial tissue was collected at day 7 following reperfusion and detected by dual immunochemistry, real-time quantitative polymerase chain reaction and western blot. RESULTS: The infarcted area had higher FLK1 mRNA expression than the sham-operated area and the normal area (all P < 0.05), and the infarcted and marginal areas showed higher CD146 protein expression than the sham-operated area (all P < 0.05), but the microvessel density (CD31 positive expression of microvessels/HP) was not significantly different between the infarcted area and the sham-operated area (8.92 ± 3.05 vs 6.43 ± 1.54)(P > 0.05). CONCLUSION: FLK1 and CD146 expression significantly increase in the infarcted and marginal areas, and the microvessel density of angiogenesis in the infarcted area is similar to normal microvessel density of healthy heart tissue, suggesting that FLK1 and CD146 are possible associated with angiogenesis at day 7 following reperfused acute myocardial infarction.

Balloon internal fixation: A novel approach to manipulate catheter knotting.

A successful alternative technique to resolve the catheter knotting during radial access using balloon internal fixation of 5F angiographic catheter in the cath laboratory.

Blood lead level in Chinese adults with and without coronary artery disease.

BACKGROUND: The Trial to Assess Chelation Therapy study found that edetate disodium (disodium ethylenediaminetetraacetic acid) chelation therapy significantly reduced the incidence of cardiac events in stable post-myocardial infarction patients, and a body of epidemiological data has shown that accumulation of biologically active metals, such as lead and cadmium, is an important risk factor for cardiovascular disease. However, limited studies have focused on the relationship between angiographically diagnosed coronary artery disease (CAD) and lead exposure. This study compared blood lead level (BLL) in Chinese patients with and without CAD. METHODS: In this prospective, observational study, 450 consecutive patients admitted to Beijing Anzhen Hospital with suspected CAD from November 1, 2018, to January 30, 2019, were enrolled. All patients underwent coronary angiography, and an experienced heart team calculated the SYNTAX scores (SXscore) for all available coronary angiograms. BLLs were determined with atomic absorption spectrophotometry and compared between patients with angiographically diagnosed CAD and those without CAD. RESULTS: In total, 343 (76%) patients had CAD, of whom 42% had low (0-22), 22% had intermediate (23-32), and 36% had high (≥ 33) SXscore. BLLs were 36.8 ± 16.95 µg/L in patients with CAD and 31.2 ± 15.75 µg/L in those without CAD (P = 0.003). When BLLs were categorized into three groups (low, middle, high), CAD prevalence increased with increasing BLLs (P < 0.05). In the multivariate regression model, BLLs were associated with CAD (odds ratio (OR): 1.023, 95% confidence interval (CI): 1.008-1.039; P = 0.0017). OR in the high versus low BLL group was 2.36 (95% CI: 1.29-4.42,P = 0.003). Furthermore, BLLs were independently associated with intermediate and high SXscore (adjusted OR: 1.050, 95% CI: 1.036-1.066; P < 0.0001). CONCLUSION: BLLs were significantly associated with angiographically diagnosed CAD. Furthermore, BLLs showed excellent predictive value for SXscore, especially for complex coronary artery lesions.

Tongxinluo reduces myocardial no-reflow and ischemia-reperfusion injury by stimulating the phosphorylation of eNOS via the PKA pathway.

The objective of the present study was to investigate whether pretreatment with single low loading dose of tongxinluo (TXL), a traditional Chinese medicine, 1 h before myocardial ischemia could attenuate no-reflow and ischemia-reperfusion injury by regulating endothelial nitric oxide synthase (eNOS) via the PKA pathway. In a 90-min ischemia and 3-h reperfusion model, minipigs were randomly assigned to the following groups: sham, control, TXL (0.05 g/kg, gavaged 1 h before ischemia), TXL + H-89 (a PKA inhibitor, intravenously infused at a dose of 1.0 µg·kg(-1)·min(-1) 30 min before ischemia), and TXL + N(ω)-nitro-L-arginine (L-NNA; an eNOS inhibitor, intravenously administered at a dose of 10 mg/kg 30 min before ischemia). TXL decreased creatine kinase (CK) activity (P < 0.05) and reduced the no-reflow area from 48.6% to 9.5% and infarct size from 78.5% to 59.2% (P < 0.05), whereas these effects of TXL were partially abolished by H-89 and completely reversed by L-NNA. TXL elevated PKA activity and the expression of PKA, Thr(198) phosphorylated PKA, Ser(1179) phosphorylated eNOS, and Ser(635) phosphorylated eNOS in the ischemic myocardium. H-89 repressed the TXL-induced enhancement of PKA activity and phosphorylation of eNOS at Ser(635), and L-NNA counteracted the phosphorylation of eNOS at Ser(1179) and Ser(635) without an apparent influence on PKA activity. In conclusion, pretreatment with a single low loading dose of TXL 1 h before ischemia reduces myocardial no-reflow and ischemia-reperfusion injury by upregulating the phosphorylation of eNOS at Ser(1179) and Ser(635), and this effect is partially mediated by the PKA pathway.

Revascularization versus drug therapy for coronary artery disease in patients aged over 80 years: a real-world study.

BACKGROUND: Revascularization for the treatment of coronary artery disease (CAD) is advancing rapidly and is used increasingly in old patients. This study aimed to compare the efficacy and safety of revascularization with drug therapy in CAD patients aged over 80 years at a real-world clinical setting. METHODS: A total of 501 CAD patients aged over 80 years were consecutively enrolled from January 2011 to January 2016 in Anzhen Hospital (Beijing, China), Capital Medical University. The patients were treated with percutaneous coronary intervention (PCI) (n=283), coronary artery bypass grafting (CABG) (n=106), or drug therapy (n=112). All-cause mortality, cardiovascular-related mortality, readmission rate, and Seattle Angina Questionnaire (SAQ) score were compared between the three treatment methods. RESULTS: A total of 411 patients (82.04%) were followed with a median duration of 25 months. All-cause mortality and cardiovascular-related mortality in the drug therapy group were significantly higher than the PCI and CABG groups (both P<0.05). Readmission rate for cardiovascular events in the CABG group was significantly lower than the PCI and drug therapy groups (both P<0.05). Scores of physical limitation, angina frequency, treatment satisfaction, and disease perception of the SAQ in the PCI and CABG groups were significantly higher than the drug therapy group (both P<0.05). Scores of angina stability did not differ significant between the three groups (P=0.127). CONCLUSIONS: Revascularization is superior to drug therapy in efficacy and safety in the treatment of oldest-old patients with CAD.

[Effects of tongxinluo on mini-swine vascular endothelial integrity and myocardial no-reflow in early reperfusion of acute myocardial infarction].

OBJECTIVE: To assess the effects of tongxinluo on vascular endothelial integrity and myocardial no-reflow in early reperfusion of acute myocardial infarction. METHODS: Forty mini-swines were divided into five groups randomly, sham group, control group, low dose (0.1 g/kg), medium dose (0.2 g/kg) and high dose (0.4 g/kg) groups of Tongxinluo. It was administered at 2 hours pre-reperfusion. Animals except in sham group were subjected to 1.5 hour of coronary occlusion followed by 3 hours of reperfusion. Content of VE-cadherin, beta-catenin, matrix metalloproteinase (MMP)-2 and 9 in myocardium were evaluated; no-reflow area was examined with myocardial contrast echocardiography (MCE) at 1.5 hour of AMI and 3 hours of reperfusion. RESULTS: (1) Compared with that of normal myocardium, content of VE-cadherin and beta-catenin decreased in reperfusion and no-reflow myocardium while MMP-2 and 9 increased significantly (all P < 0.05); (2) Compared with that of control group, a high dose of Tongxinluo could increase significantly the content of VE-cadherin in both reperfusion and no-reflow myocardium, (22.2 +/- 3.2)% vs (32.0 +/- 3.9)% and (14.5 +/- 2.8)% vs (28.3 +/- 2.2)% respectively, beta-catenin, (20.5 +/- 3.5)% vs (27.3 +/- 2.9)% and (13.3 +/- 2.1)% vs (20.6 +/- 2.4)%, while reduce MMP-2, (48.3 +/- 4.1)% vs (29.4 +/- 3.5)% and (57.3 +/- 4.3)% vs (38.2 +/- 4.0)% respectively, MMP-9, (55.6 +/- 4.0)% vs (34.3 +/- 3.5)% and (62.4 +/- 4.8)% vs (44.4 +/- 4.1)%, all P < 0.05; (3) Compared with that of control group, a high dose of Tongxinluo could reduce significantly both no-reflow area, (6.6 +/- 1.7) cm2 vs (4.7 +/- 1.5) cm2, P < 0.05, and percentage (90.8 +/- 3.8)% vs (71.4 +/- 4.1)%, P < 0.05, at 3 hours of reperfusion. CONCLUSION: A high dose of tongxinluo could effectively maintain the integrity of vascular endothelium and attenuate no-reflow area in early reperfusion of acute myocardial infarction.

[Effect of tongxinluo on mini-swine cytokines and myocardial no-reflow in early reperfusion of acute myocardial infarction].

OBJECTIVE: To assess the effect of Tongxinluo on cytokines and myocardial no-reflow in early reperfusion of acute myocardial infarction (AMI). METHODS: Forty mini-swine were divided into five groups randomly, sham group, control group, low dose (0.1 g/kg), medium dose (0.2 g/kg) and high dose (0. 4 g/kg) group of Tongxinluo (which were administered 2 h before reperfusion), eight swine in each group. Animals except those in the sham group were subjected to 1.5 h of coronary occlusion followed by 3 h of reperfusion. Serum contents of P-selectin, intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), interleukin 6 (IL-6) and interleukin 10 (IL-10), as well as myocardial contrast echocardiography (MCE) were evaluated at baseline, and after 1.5 h of AMI and 3 h of reperfusion. RESULTS: (1) Compared with that of the control group, high dose of Tongxinluo could reduce serum contents of P-selectin and ICAM-1 at 1.5 h of AMI (all P<0.05), and P-selectin, ICAM-1, VCAM-1, and IL-6 at 3 h of reperfusion significantly (all P< 0.05), accompanied by significantly elevated IL-10 (P<0.05). (2) Compared with that of control group, high dose of Tongxinluo could reduce no-reflow area at 3 h of reperfusion significantly [(6.59 +/- 1.73) cm2 vs (4.68 +/- 1.53) cm2, P<0.05]. CONCLUSION: High dose of Tongxinluo could effectively reduce serum contents of adhesion and pro-inflammatory cytokines, regulate anti-inflammatory factor levels, and attenuate no-reflow area in the early reperfusion of AMI. It thus provided experimental basis for its clinical application.

Clinical efficacy of different treatments and their impacts on the quality of life of octogenarians with coronary artery disease.

BACKGROUND: Coronary artery disease (CAD) in octogenarians (age of ≥80 years) has a high risk of mortality and high medical expenses. Research shows that the prevalence of CAD is higher among octogenarians than that among younger people, but few such patients undergo percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). This study aimed to evaluate different treatments with respect to their clinical effects and impacts on quality of life of octogenarians with CAD. METHODS: Data of 519 octogenarians with CAD consecutively treated at Beijing Anzhen Hospital, Capital Medical University (Beijing, China) from January 2010 to January 2016 were collected in this study. The patients were categorized into three groups based on the treatments they received: the PCI group (n = 292), CABG group (n = 110), and medical treatment group (n = 117). The followings were recorded during follow-up: clinical data, death (all-cause and cardiovascular-related), re-hospitalization time, Seattle Angina Questionnaire (SAQ) score, and occurrence of hemorrhagic events (cerebral bleeding, gastrointestinal bleeding, and dermal ecchymosis). RESULTS: The median follow-up duration was 25.0 (25th, 75th percentile: 17.0, 55.5) months among 417 patients. The all-cause death rates (28.2% vs. 12.0% and 14.6%, respectively) and cardiovascular-related death rates (15.4% vs. 3.8% and 6.4%, respectively) were significantly higher in the medical treatment group than those in the PCI group and CABG group (all P < 0.05). The re-hospitalization rate for cardiovascular events was significantly lower in the CABG group than those in the PCI group and medical treatment group (3.8% vs. 12.8% and 14.9%, respectively) (χ = 8.238, P = 0.018). The SAQ scores of physical limitation, angina frequency, treatment satisfaction, and disease perception were significantly higher in the PCI group and CABG group than those in the medical treatment group (all P < 0.05). No significant difference in the angina stability score was observed among the three groups (F = 3.179, P = 0.204). CONCLUSION: PCI and CABG result in reduced mortality and better quality of life in octogenarians with CAD.

Unfractionated Heparin with Sequential Enoxaparin in Patients with Complex Coronary Artery Lesions during Percutaneous Coronary Intervention.

BACKGROUND: Unfractionated heparin (UFH), despite its limitations, has been used as the primary anticoagulant alternative during the percutaneous coronary intervention (PCI). Some studies indicated that intravenous enoxaparin could be an effective and safe option. Our team used enoxaparin alone at one time according to the guidelines (Class IIA) and found a little catheter thrombosis during PCI. We recommend a new anticoagulation strategy using enoxaparin in combination with UFH. Enoxaparin has a more predictable anticoagulant response with no need of repeatedly monitoring anticoagulation during PCI. This retrospective study aimed to evaluate the efficacy and safety of using enoxaparin in combination with UFH in PCI patients with complex coronary artery disease. METHODS: Between January 2015 and April 2017, 600 PCI patients who received intravenous UFH at an initial dose of 3000 U plus intravenous enoxaparin at a dose of 0.75 mg/kg (observation group) and 600 PCI patients who received UFH at a dose of 100 U/kg (control group) were consecutively included in this retrospective study. The endpoints were postoperative 48-h thrombolysis in myocardial infarction (TIMI) bleeding and transfusion and 30-day and 1-year major adverse cardio-cerebrovascular events (MACCE). RESULTS: Baseline clinical, angiographic, and procedural characteristics were similar between groups, except there was less stent implantation per patient in the observation group (2.13 vs. 2.25 in the control group, P = 0.002). TIMI bleeding (3.3% vs. 4.7%) showed no significant difference between the observation group and control group. During the 30-day follow-up, the rate of MACCE was 0.9% in the observation group and 1.5% in the control group. There was no significant difference in the rates of MACCE, death, myocardial infarction, target vessel revascularization, cerebrovascular event, and angina within 30 days and 1 year after PCI between groups as well as in the subgroup analysis of transfemoral approach. CONCLUSIONS: UFH with sequential enoxaparin has similar anticoagulant effect and safety as UFH in PCI of complex coronary artery disease.

A successful team treatment for left main shock syndrome.

Acute myocardial infarction complicated by cardiogenic shock and left main coronary artery disease is called left main shock syndrome. It is reported that the morbility and mortality of the syndrome is approximately 0.46% and 55%-80%, respectively. However, the best treatment strategy in these cases is unknown. In this article, we present a patient with LMSS who successively underwent emergency percutaneous coronary intervention and coronary artery bypass grafting with hemodynamic support within 5 days. The patient is now on his three month uneventful out-patient follow-up.

Protein kinase A-mediated cardioprotection of Tongxinluo relates to the inhibition of myocardial inflammation, apoptosis, and edema in reperfused swine hearts.

BACKGROUND: Our previous studies have demonstrated that Tongxinluo (TXL), a traditional Chinese medicine, can protect hearts against no-reflow and reperfusion injury in a protein kinase A (PKA)-dependent manner. The present study was to investigate whether the PKA-mediated cardioprotection of TXL against no-reflow and reperfusion injury relates to the inhibition of myocardial inflammation, edema, and apoptosis. METHODS: In a 90-minute ischemia and 3-hour reperfusion model, minipigs were randomly assigned to sham, control, TXL (0.05 g/kg, gavaged one hour prior to ischemia), and TXL + H-89 (a PKA inhibitor, intravenously and continuously infused at 1.0 µg/kg per minute) groups. Myocardial no-reflow, necrosis, edema, and apoptosis were determined by pathological and histological studies. Myocardial activity of PKA and myeloperoxidase was measured by colorimetric method. The expression of PKA, phosphorylated cAMP response element-binding protein (p-CREB) (Ser(133)), tumor necrosis factor α (TNF-α), P-selectin, apoptotic proteins, and aquaporins was detected by Western blotting analysis. RESULTS: TXL decreased the no-reflow area by 37.4% and reduced the infarct size by 27.0% (P < 0.05). TXL pretreatment increased the PKA activity and the expression of Ser(133) p-CREB in the reflow and no-reflow myocardium (P < 0.05). TXL inhibited the ischemia-reperfusion-induced elevation of myeloperoxidase activities and the expression of TNF-α and P-selectin, reduced myocardial edema in the left ventricle and the reflow and no-reflow areas and the expression of aquaporin-4, -8, and -9, and decreased myocytes apoptosis by regulation of apoptotic protein expression in the reflow and no-reflow myocardium. However, addition of the PKA inhibitor H-89 counteracted these beneficial effects of TXL. CONCLUSION: PKA-mediated cardioprotection of TXL against no-reflow and reperfusion injury relates to the inhibition of myocardial inflammation, edema, and apoptosis in the reflow and no-reflow myocardium.

The cardioprotection of simvastatin in reperfused swine hearts relates to the inhibition of myocardial edema by modulating aquaporins via the PKA pathway.

BACKGROUND AND OBJECTIVE: Myocardial edema plays a role in myocardial no-reflow and infarction during ischemia and reperfusion. The effects of statins against no-reflow and infarction may relate to the inhibition of myocardial edema. The current study investigated the role of protein kinase A (PKA) in statin-reduced myocardial edema in reperfused swine hearts. METHODS AND RESULTS: Minipigs were treated with simvastatin (SIM, 2mg/kg), SIM+H-89 (a PKA inhibitor, 1.0 µg/kg/min), or H-89 alone 1h before 90-min ischemia and 3-h reperfusion or sham operation. Ischemia or ischemia-reperfusion induced severe myocardial edema, PKA activation, and up-regulation of aquaporin-1, -4, -8, and -9 in the reflow and no-reflow myocardium. SIM pretreatment reduced the sizes of no-reflow and infarct areas by 18.5% and 11.1% (P<0.01), decreased water content in the left ventricle, reflow and no-reflow myocardium by 1.4%, 5.3%, and 4.3% (P<0.05), inhibited cardiomyocytes swelling in the reflow and no-reflow areas by 19.8% and 13.1% (P<0.01), suppressed mitochondrial water accumulation in the reflow and no-reflow areas by 49.0% and 35.9% (P<0.01), increased PKA activity (P<0.01), and blocked the up-regulation of aquaporin-1, -4, -8, and -9 in the reflow and no-reflow myocardium. However, these beneficial effects of SIM were partially abolished by inhibiting PKA with H-89. CONCLUSIONS: The cardioprotective effects of acute SIM therapy against myocardial no-reflow and infarction relate to the reduction of myocardial edema by suppressing the expression of aquaporin-1, -4, -8, and -9 in a partially PKA-dependent manner.

Severe coronary artery disease in Chinese patients with abdominal aortic aneurysm: prevalence and impact on operative mortality.

BACKGROUND: Little is known about the prognosis of coronary artery disease (CAD) in Chinese patients with abdominal aortic aneurysm (AAA). The aim of this study was to evaluate the predictors of in-hospital all-cause mortality of severe CAD in Chinese patients who were hospitalized for AAAs. METHODS: From January 2003 to August 2009, 368 patients were operated on for AAAs. The clinical characteristics were retrospectively collected. The primary outcome was the in-hospital all-cause mortality. The clinical risk factors were subjected to a multivariate analysis to determine the predictors of in-hospital all-cause mortality. RESULTS: During their hospitalization, 23% (85/368) of the patients underwent coronary angiography, which revealed significant lesions in 93% (79/85) of the patients. In 25 cases, coronary artery bypass grafting (CABG) was performed before the AAA repair and in 16 cases of percutaneous coronary intervention (PCI) was performed. Ten patients with AAA alone died before discharge, and eight patients diagnosed with AAA combined with CAD died. There was no statistical difference in the postoperative death between the two groups. The logistic analysis showed that age > 70 years and CAD (vessels ≥ 2) were the significant factors in predicting the adverse clinical outcome. CONCLUSIONS: The prevalence of severe CAD in Chinese patients with AAAs seemed lower than those that were reported. Myocardial evaluation and subsequent revascularization before AAA surgery could improve the clinical outcome for these patients who have severe CAD.

Tacrolimus-related hypertrophic cardiomyopathy in an adult cardiac transplant patient.

Left ventricular hypertrophy associated with the use of tacrolimus is a rare complication of solid organ transplantation in adult recipients. We present a cardiac transplant recipient who developed severe concentric left ventricular hypertrophy with congestive heart failure related to myocardial hypertrophy on tacrolimus. Hypertrophy improved when the drug was discontinued and replaced with sirolimus.

Expressions of eNOS3 and Ve-cadherin in microvascular endothelium at 7-day of reperfused acute myocardial infarction.

OBJECTIVE: To investigate the expressions of eNOS3 and Ve-cadherin at the first week of reperfused acute myocardial infarction (AMI). METHODS: 16 of mini-swines (20 to 30 Kg) were randomly assigned to the sham-operated group and the AMI group. Pathologic myocardial tissue was collected at 7-day of LAD reperfusion and assessed by immunofluorescence and laser co-focus microscope scan, in-situ hybridization, real-time quantitative polymerase chain reaction and western blot. RESULTS: At 7-day of reperfusion, the eNOS3 mRNA and protein expressions in the infarcted and marginal areas were lower than those in the normal area and sham-operated area (all P<0.05), similarly the infarcted and marginal areas had lower Ve-cadherin mRNA expression than the normal area and the sham-operated area (all P<0.05), and Ve-cadherin protein expression was lower in the infarcted area compared with the marginal area, the normal area and the sham-operated area (all P<0.05). CONCLUSION: Low expressions of eNOS3 and Ve-cadherin in the salvaged sub-healthy microvascular endothelium of infarcted and marginal areas suggest that endothelial system is impaired at 7-day of reperfused acute myocardial infarction.

Pretreatment with Tongxinluo protects porcine myocardium from ischaemia/reperfusion injury through a nitric oxide related mechanism.

BACKGROUND: The traditional Chinese medicine Tongxinluo can protect myocardium against ischaemia/reperfusion injury, but the mechanism of its action is not well documented. We examined the involvement of nitric oxide in the protective role of Tongxinluo. METHODS: Miniswine were randomized to four groups of seven: sham, control, Tongxinluo and Tongxinluo coadministration with a nitric oxide synthase inhibitor N(omega)-nitro-L-arginine (L-NNA, 10 mg/kg i.v.). Three hours after administration of Tongxinluo, the animals were anaesthetised and the left anterior descending coronary artery ligated and maintained in situ for 90 minutes followed by 3 hours of reperfusion before death. Area of no reflow and necrosis and risk region were determined pathologically by planimetry. The degree of neutrophil accumulation in myocardium was obtained by measuring myeloperoxidase activity and histological analysis. Myocardial endothelial nitric oxide synthase activity and vascular endothelial cadherin content were measured by colorimetric method and immunoblotting analysis respectively. RESULTS: Tongxinluo significantly increased the local blood flow and limited the infarct and size of no reflow. Tongxinluo also attenuated myeloperoxidase activity and neutrophil accumulation in histological sections and maintained the level of vascular endothelial cadherin and endothelial nitric oxide synthase activity in the reflow region when compared with control group. The protection of Tongxinluo was counteracted by coadministration with L-NNA. CONCLUSIONS: Tongxinluo may limit myocardial ischaemia and protect the heart against reperfusion injury. Tongxinluo regulates synthesis of nitric oxide by altering activity of endothelial nitric oxide synthase.