Light-Activated Gold-Selenium Core-Shell Nanocomposites with NIR-II Photoacoustic Imaging Performances for Heart-Targeted Repair.

Mitochondrial dysfunction and oxidative damage represent important pathological mechanisms of myocardial ischemia-reperfusion injury (MI/RI). Searching for potential antioxidant agents to attenuate MI/RI is of great significance in clinic. Herein, gold-selenium core-shell nanostructures (AS-I/S NCs) with good near-infrared (NIR)-II photoacoustic imaging were designed for MI/RI treatment. The AS-I/S NCs after ischemic myocardium-targeted peptide (IMTP) and mitochondrial-targeted antioxidant peptide SS31 modification achieved cardiomyocytes-targeted cellular uptake and enhanced antioxidant ability and significantly inhibited oxygen-glucose deprivation-recovery (OGD/R)-induced cardiotoxicity of H9c2 cells by inhibiting the depletion of mitochondrial membrane potential (MMP) and restoring ATP synthase activity. Furthermore, the AS-I/S NCs after SS31 modification achieved mitochondria-targeted inhibition of reactive oxygen species (ROS) and subsequently attenuated oxidative damage in OGD/R-treated H9c2 cells by inhibition of apoptosis and oxidative damage, regulation of MAPKs and PI3K/AKT pathways. The in vivo AS-I/S NCs administration dramatically improved myocardial functions and angiogenesis and inhibited myocardial fibrosis through inhibiting myocardial apoptosis and oxidative damage in MI/RI of rats. Importantly, the AS-I/S NCs showed good safety and biocompatibility in vivo. Therefore, our findings validated the rational design that mitochondria-targeted selenium-gold nanocomposites could attenuate MI/RI of rats by inhibiting ROS-mediated oxidative damage and regulating MAPKs and PI3K/AKT pathways, which could be a potential therapy for the MI/RI treatment.

Neurochemical alterations of different cerebral regions in rats with myocardial ischemia-reperfusion injury based on proton nuclear magnetic spectroscopy analysis.

BACKGROUND: Recent studies have demonstrated a complex and dynamic neural crosstalk between the heart and brain. A heart-brain interaction has been described regarding cardiac ischemia, but the cerebral metabolic mechanisms involved are unknown. METHODS: Male Sprague Dawley rats were randomly allocated into 2 groups: those receiving myocardial ischemia-reperfusion surgery (IR group, n =10) and surgical controls (Con group, n=10). These patterns of metabolic abnormalities in different brain regions were assessed using proton magnetic resonance spectroscopy (PMRS). RESULTS: Results assessed by echocardiography showed resultant cardiac dysfunction following heart ischemia-reperfusion. Compared with the control group, the altered metabolites in the IR group were taurine and choline, and differences mainly occurred in the thalamus and brainstem. CONCLUSIONS: Alterations in cerebral taurine and choline are important findings offering new avenues to explore neuroprotective strategies for myocardial ischemia-reperfusion injury. These results provide preliminary evidence for understanding the cerebral metabolic process underlying myocardial ischemia-reperfusion injury in rats.

Metoprolol blunts the time-dependent progression of infarct size.

Early metoprolol administration protects against myocardial ischemia-reperfusion injury, but its effect on infarct size progression (ischemic injury) is unknown. Eight groups of pigs (total n = 122) underwent coronary artery occlusion of varying duration (20, 25, 30, 35, 40, 45, 50, or 60 min) followed by reperfusion. In each group, pigs were randomized to i.v. metoprolol (0.75 mg/kg) or vehicle (saline) 20 min after ischemia onset. The primary outcome measure was infarct size (IS) on day7 cardiac magnetic resonance (CMR) normalized to area at risk (AAR, measured by perfusion computed tomography [CT] during ischemia). Metoprolol treatment reduced overall mortality (10% vs 26%, p = 0.03) and the incidence and number of primary ventricular fibrillations during infarct induction. In controls, IS after 20-min ischemia was ≈ 5% of the area AAR. Thereafter, IS progressed exponentially, occupying almost all the AAR after 35 min of ischemia. Metoprolol injection significantly reduced the slope of IS progression (p = 0.004 for final IS). Head-to-head comparison (metoprolol treated vs vehicle treated) showed statistically significant reductions in IS at 30, 35, 40, and 50-min reperfusion. At 60-min reperfusion, IS was 100% of AAR in both groups. Despite more prolonged ischemia, metoprolol-treated pigs reperfused at 50 min had smaller infarcts than control pigs undergoing ischemia for 40 or 45 min and similar-sized infarcts to those undergoing 35-min ischemia. Day-45 LVEF was higher in metoprolol-treated vs vehicle-treated pigs (41.6% vs 36.5%, p = 0.008). In summary, metoprolol administration early during ischemia attenuates IS progression and reduces the incidence of primary ventricular fibrillation. These data identify metoprolol as an intervention ideally suited to the treatment of STEMI patients identified early in the course of infarction and requiring long transport times before primary angioplasty.

Evaluation of a real-time magnetic resonance imaging-guided electrophysiology system for structural and electrophysiological ventricular tachycardia substrate assessment.

AIMS: Potential advantages of real-time magnetic resonance imaging (MRI)-guided electrophysiology (MR-EP) include contemporaneous three-dimensional substrate assessment at the time of intervention, improved procedural guidance, and ablation lesion assessment. We evaluated a novel real-time MR-EP system to perform endocardial voltage mapping and assessment of delayed conduction in a porcine ischaemia-reperfusion model. METHODS AND RESULTS: Sites of low voltage and slow conduction identified using the system were registered and compared to regions of late gadolinium enhancement (LGE) on MRI. The Sorensen-Dice similarity coefficient (DSC) between LGE scar maps and voltage maps was computed on a nodal basis. A total of 445 electrograms were recorded in sinus rhythm (range: 30-186) using the MR-EP system including 138 electrograms from LGE regions. Pacing captured at 103 sites; 47 (45.6%) sites had a stimulus-to-QRS (S-QRS) delay of ≥40 ms. Using conventional (0.5-1.5 mV) bipolar voltage thresholds, the sensitivity and specificity of voltage mapping using the MR-EP system to identify MR-derived LGE was 57% and 96%, respectively. Voltage mapping had a better predictive ability in detecting LGE compared to S-QRS measurements using this system (area under curve: 0.907 vs. 0.840). Using an electrical threshold of 1.5 mV to define abnormal myocardium, the total DSC, scar DSC, and normal myocardium DSC between voltage maps and LGE scar maps was 79.0 ± 6.0%, 35.0 ± 10.1%, and 90.4 ± 8.6%, respectively. CONCLUSION: Low-voltage zones and regions of delayed conduction determined using a real-time MR-EP system are moderately associated with LGE areas identified on MRI.

Protective Effects of Shenfu Injection against Myocardial Ischemia-Reperfusion Injury via Activation of eNOS in Rats.

The aim of the present study was to investigate the protective effects of Shenfu injection (SFI) against myocardial ischemia-reperfusion injury (MIRI) in model rats and to explore its mechanism of action. Sprague-Dawley (SD) rats were pretreated with SFI and NG-nitro-L-arginine methyl ester (L-NAME) via tail vein injection and then rats were subjected to ischemia by occlusion of the left anterior descending coronary artery for 30 min followed by reperfusion for 120 min. Left ventricular function was evaluated by echocardiography. Hemodynamic was measured by the Millar pressure-volume system; serum creatine kinase (CK), lactate dehydrogenase (LDH) and serum troponin (TNNI3) levels were determined. Myocardial infarct size was observed by 2,3,5-triphenyl-2H-tetrazolium chloride (TTC) staining; p-Akt/Akt, and p-endothelial nitric oxide synthase (p-eNOS)/eNOS levels were assessed by Western blotting; nitric oxide (NO) content in serum was determined by the Griess reaction. SFI significantly decreased serum CK, LDH and TNNI3 levels in MIRI rats, while it significantly increased the level of left ventricular systolic pressure (LVSP), left ventricular diastolic pressure (LVDP), maximal rate of the increase of left ventricular pressure (+dp/dtmax), maximal rate of the decrease of left ventricular pressure (-dp/dtmax), left ventricle ejection fraction percentage (EF), and stroke volume (SV). In addition, SFI significantly reduced myocardial infarction area and activated the phosphorylation of eNOS via Akt. The phosphorylation of eNOS and the concurrent increase of NO production contributed significantly to the protective effects of SFI. These results demonstrate that SFI protects the rat heart against MIRI and that this effect is mediated in part by Akt/eNOS signaling.

Cardioprotection of tilianin ameliorates myocardial ischemia-reperfusion injury: Role of the apoptotic signaling pathway.

Our previous research demonstrated that tilianin protects the myocardium in a myocardial ischemia reperfusion injury (MIRI) rat model and has prominent pharmacological potential as a cardiovascular drug. Our study aimed to investigate the molecular signaling implicated in the improvement of myocardial survival induced by tilianin, a flavonoid antioxidant. Tilianin (2.5, 5, and 10 mg/kg/d) or saline was orally administered to rats for 14 days. On the 15th day, ischemia was induced by ligating the left anterior descending artery for 45 min, followed by 4 h of reperfusion. The levels of MIRI-induced serum myocardial enzymes and cardiomyocyte apoptosis as well as infarct size were examined to assess the cardioprotective effects. Cardiac tissues were collected for western blot analyses to determine the protein expression of anti-apoptotic signaling molecules. In MIRI-treated rats, our results revealed that pre-administration of high dose-tilianin the reduced release of LDH, MDA, and CK-MB and increased the plasma SOD level, and significantly attenuated the infarct size. Western blot analysis showed that a remarkable rise in expression of Bcl-2 and XIAP, and decline in expression of Bax, Smac/Diablo, HtrA2/Omi, cleaved caspase-3, caspase-7 and caspase-9 was observed in the myocardium. The apoptosis index of cardiomyocytes further supports the cardioprotective effect of tilianin. Additionally, compared with the MIRI model group, pretreatment with high dose-tilianin group upregulated phosphorylated Akt and PI3K. In contrast, using the PI3K inhibitor LY294002 to block Akt activation effectively inhibited the protective effects of tilianin against MIRI. Tilianin pretreatment was beneficial for activating the PI3K/Akt signaling pathway and inhibiting myocardial apoptosis.

Anti-arrhythmogenic and anti-inflammatory effects of troxerutin in ischemia/reperfusion injury of diabetic myocardium.

INTRODUCTION: Medicinal plants are increasingly used in the treatment of cardiovascular diseases due to their multifaceted properties. This study was designed to investigate anti-arrhythmic and anti-inflammatory potentials of the natural bioflavonoid, troxerutin (TXR) in myocardial ischemia/reperfusion (I/R) injury in diabetic rats. METHODS: Male Wistar rats were randomly divided into 4 groups (control, control + TXR [150 mg/kg, daily], diabetic, and diabetic + TXR). Type-1 diabetes was induced by an intraperitoneal injection of streptozotocin (50 mg/kg) and lasted for 10 weeks. After mounting on the Langendorff apparatus, isolated hearts in all groups received a normal Krebs-Henseleit solution for 20 min of stabilization period, followed by 30 min of regional ischemia through ligation of the left anterior descending coronary artery, and 60 min of full reperfusion. During the experiment, the electrocardiograms were recorded and the arrhythmias [number, duration and incidence of premature ventricular complexes (PVC), ventricular tachycardia (VT), ventricular fibrillation (VF), and arrhythmia score] during I/R phases were assessed based on the Lambeth Convention. Ischemic left ventricular samples were used to determine the activities of lactate dehydrogenase (LDH), interleukin-1beta (IL-1ß), and tumor necrosis factor (TNF-α). RESULTS: The arrhythmias induced by I/R were not significantly changed in diabetic group as compared to the control group. However, pretreatment with TXR significantly reduced the number of PVC and duration and incidence of VF in ischemic phase in comparison to the untreated animals (P < 0.05). In addition, the duration, and incidence of most arrhythmias during reperfusion phase were significantly declined by TXR administration in both control and diabetic groups (P < 0.05). Pretreatment of rats with TXR significantly reduced myocardial inflammatory cytokines TNF-α and IL-1ß levels after I/R insult in diabetic as well as control hearts (P < 0.05). CONCLUSION: Preconditioning with TXR could provide cardioprotection by anti-arrhythmic and anti-inflammatory effects against I/R injury in rat hearts. This effect of TXR can introduce this material as a protective agent in cardiovascular diseases.

Protection from Reperfusion Injury with Intracoronary N-Acetylcysteine in Patients with STEMI Undergoing Primary Percutaneous Coronary Intervention in a Cardiac Tertiary Center.

BACKGROUND: Evidence suggests that oxidative stress plays a principal role in myocardial damage following ischemia/reperfusion events. Recent studies have shown that the antioxidant properties of N-acetylcysteine (NAC) may have cardioprotective effects in high doses, but-to the best of our knowledge-few studies have assessed this. OBJECTIVES: Our objective was to investigate the impact of high-dose NAC on ischemia/reperfusion injury. METHODS: We conducted a randomized double-blind placebo-controlled trial in which 100 consecutive patients with ST-elevation myocardial infarction undergoing percutaneous coronary intervention (PCI) were randomly assigned to the case group (high-dose NAC 100 mg/kg bolus followed by intracoronary NAC 480 mg during PCI then intravenous NAC 10 mg/kg for 12 h) or the control group (5% dextrose). We measured differences in peak creatine kinase-myocardial band (CK-MB) concentration, highly sensitive troponin T (hs-TnT), thrombolysis in myocardial infarction (TIMI) flow, myocardial blush grade (MBG), and corrected thrombolysis in myocardial infarction frame count (cTFC). RESULTS: The peak CK-MB level was comparable between the two groups (P = 0.327), but patients receiving high-dose NAC demonstrated a significantly larger reduction in hs-TnT (P = 0.02). In total, 94% of the NAC group achieved TIMI flow grade 3 versus 80% of the control group (P = 0.03). No significant differences were observed between the two groups in terms of changes in the cTFC and MBG. CONCLUSIONS: In this study, NAC improved myocardial reperfusion markers and coronary blood flow, as revealed by differences in peak hs-TnT and TIMI flow grade 3 levels, respectively. Further studies with large samples are warranted to elucidate the role of NAC in this population. ClinicalTrials.gov identifier: NCT01741207, and the Iranian Registry of Clinical Trials (IRCT; http://irct.ir ) registration number: IRCT201301048698N8.

Cardioprotective effect of Malva sylvestris L. in myocardial ischemic/reprefused rats.

PURPOSE: The present investigation evaluated the cardioprotective effect of Malva sylvestris L. (MS) on myocardial ischemic/reperfusion (MI/R) in rats. METHODS: All animals were divided into four groups: the sham operated group, ischemia/reperfusion group (MI/R), and the MS (250 and 500mg/kg) treated groups, who received MS 250 and 500mg/kg intragastrically for 15 consecutive days, respectively. At the end of the protocol, concentrations of aspartate transaminase (AST), creatine kinase-MB fraction (CK-MB) and lactate dehydrogenase (LDH) were estimated in serum and the concentrations of other parameters, such as C-reactive protein, macrophage inflammatory protein 1 alpha (MIP-1α), and nitric oxide (NO) were also estimated in the blood. Tissue homogenate concentrations of inflammatory cytokines, such as tumour necrosis factor-α (TNF-α), interlukin-1ß (IL-1ß), IL-10 and IL-6 as well as oxidative stress parameters, such as lipid peroxidation, catalase, and superoxide dismutase were estimated in MI/R rats. RESULT: Significant decreases (p<0.01) in AST, LDH, and CK-MB levels were observed in the MS-treated group compared with those in the MI/R group. C-reactive protein and MIP-1α levels decreased in the MS-treated group compared with those in the MI/R group. Plasma NO level was significantly enhanced in the MS-treated group than in the MI/R group. Moreover, treatment with MS significantly reduced TNF-α, IL-1ß, and IL-6 levels and increased IL-10 levels in the MS group compared with the MI/R group. Treatment with MS also attenuated the altered oxidative stress parameters in MI/R rats. CONCLUSION: The present results indicate the cardioprotective effects of MS of reducing oxidative stress and the inflammatory response in MI/R rats.

Cardioprotective effects and mechanism of Radix Salviae miltiorrhizae and Lignum Dalbergiae odoriferae on rat myocardial ischemia/reperfusion injury.

Radix Salviae miltiorrhizae (SM) and Lignum Dalbergiae odoriferae (DO) are traditional Chinese medicinal herbs used to treat ischemic heart disease and other cardiovascular diseases; however, to the best of our knowledge, there are currently few studies regarding their effects. The present study aimed to investigate the cardioprotective effects of SM and DO during myocardial ischemia/reperfusion (MI/R) injury in rats, and explore the molecular mechanisms that underlie their actions. In the present study, Sprague­Dawley rats were pretreated with SM, the aqueous extract of DO (DOA) and the volatile oil of DO (DOO), either as a monotherapy or in combination for 7 days. Subsequently, the rats were subjected to 30 min of ischemia followed by 180 min of reperfusion. Traditional pharmacodynamic evaluation and metabonomics based on gas chromatography/time­of­flight mass spectrometry were used to identify the therapeutic effects of these traditional Chinese medicines. The results revealed that SM, DOA and DOO monotherapies ameliorated cardiac function, and this effect was strengthened further when used in combined therapies. Among the combined treatments, SM + DOO exhibited the greatest potential (P<0.05) to improve electrocardiogram results and heart rate, reduce the heart weight index and myocardial infarct size, and decrease the levels of creatine kinase­MB and lactate dehydrogenase. In addition, metabonomics­based findings, including the principal component analysis and partial least squares discriminant analysis score plot of the metabolic state in rat serum, provided confirmation for the aforementioned results, verifying that SM + DOO exerted synergistic therapeutic efficacies to exhibit a greater effect on rats with MI/R injury when compared with the other pretreatment groups. Furthermore, the most effective duration of SM + DOO treatment was 30 min and the least effective duration was 180 min. Treatment with SM + DOO also significantly (P<0.01) reduced the number of terminal deoxynucleotidyl transferase­mediated dUTP nick end­labeling­positive cells, tumor necrosis factor­α andinterleukin­6 expression, and malondialdehyde content, and increased the serum and tissue activity of superoxide dismutase. These results indicated that the combined effects of SM + DOO may be more effective compared with the single pretreatments against MI/R injury in rats. This effect may be achieved partly through anti­apoptotic, antioxidant and anti­inflammatory activities. Therefore, SM + DOO may be considered an effective and promising novel strategy for the prophylaxis and treatment of ischemic heart disease.

Ozone protects rat heart against ischemia-reperfusion injury: A role for oxidative preconditioning in attenuating mitochondrial injury.

Ischemia-reperfusion injury (IRI) is a major cause of cardiac dysfunction during cardiovascular surgery, heart transplantation and cardiopulmonary bypass procedures. The purpose of the present study was to explore, firstly, whether ozone induces oxidative preconditioning by activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and, secondly, whether ozone oxidative preconditioning (OzoneOP) can protect the heart against IRI by attenuating mitochondrial damage. Rats were subjected to 30min of cardiac ischemia followed by 2h of reperfusion, with or without prior OzoneOP (100µg/kg/day) for 5 days. Antioxidant capacity, myocardial apoptosis and mitochondrial damage were evaluated and compared at the end of reperfusion. OzoneOP was found to increase antioxidant capacity and to protect the myocardium against IRI by attenuating mitochondrial damage and myocardial apoptosis. The study suggests a potential role for OzoneOP in protecting the heart against IRI during cardiovascular surgery, cardiopulmonary bypass procedures or transplantation.

Conjugated linoleic acid and nitrite attenuate mitochondrial dysfunction during myocardial ischemia.

Cardiovascular health is influenced by dietary composition and the western diet is composed of varying types/amounts of fat. Conjugated linoleic acid (cLA) is an abundant dietary unsaturated fatty acid associated with health benefits but its biological signaling is not well understood. Nitrite is enriched in vegetables within the diet and can impact signaling of unsaturated fatty acids; however, its role on cLA signaling is not well understood. Elucidating how nitrite may impact the biological signaling of cLA is important due to the dietary consumption of both cLA and nitrite in the western diet. Since co-administration of cLA and nitrite results in cardioprotection during myocardial infarction (MI), it was hypothesized that cLA and nitrite may affect cardiac mitochondrial respiratory function and complex activity in MI. C57BL/6J mice were treated with cLA and nitrite for either 10 or 13days, where MI was induced on day 3. Following treatment, respiration and complex activity were measured. Among the major findings of this study, cLA treatment (10days) decreases state 3 respiration in vivo. Following MI, nitrite alone and in combination with cLA attenuates increased state 3 respiration and decreases hydrogen peroxide levels. Further, nitrite and cLA co-treatment attenuates increased complex III activity after MI. These results suggest that cLA, nitrite and the combination significantly alter cardiac mitochondrial respiratory and electron transport chain activity in vivo and following MI. Overall, the daily consumption of cLA and nitrite in the diet can have diverse cardiovascular implications, some of which occur at the mitochondrial level.

Cardioprotection against ischemia/reperfusion injury by QiShenYiQi Pill® via ameliorate of multiple mitochondrial dysfunctions.

AIM: To investigate the potential cardioprotective effects of QiShenYiQi Pill(®) (QSYQ) on myocardial ischemia/reperfusion (I/R) injury through antioxidative stress and mitochondrial protection. METHODS AND RESULTS: Sprague Dawley rats were pretreated with QSYQ or saline for 7 days and subjected to ischemia (30 minutes occlusion of the left anterior descending coronary artery) and reperfusion (120 minutes). Cardiac functions were evaluated by echocardiogram and hemodynamics. Myocardial mitochondria were obtained to evaluate changes in mitochondrial structure and function, immediately after 120 minutes reperfusion. Pretreatment with QSYQ protected against I/R-induced myocardial structural injury and improved cardiac hemodynamics, as demonstrated by normalized serum creatine kinase and suppressed oxidative stress. Moreover, the impaired myocardial mitochondrial structure and function decreased level of ATP (accompanied by reduction of ATP5D and increase in the expression of cytochrome C). Myocardial fiber rupture, interstitial edema, and infiltrated leukocytes were all significantly ameliorated by pretreatment with QSYQ. CONCLUSION: Pretreatment of QSYQ in Sprague Dawley rats improves ventricular function and energy metabolism and reduces oxidative stress via ameliorating multiple mitochondrial dysfunctions during I/R injury.

High dose intracoronary N-acetylcysteine in a porcine model of ST-elevation myocardial infarction.

We sought to evaluate the safety and efficacy of N-acetylcysteine (NAC) on ischemia and reperfusion in a pig model focusing on cardio-renal protection. High doses of NAC may provide protection from contrast induced nephropathy (CIN). NAC has also been demonstrated to reduce myocardial infarction size and improve left ventricular function after ischemia in both humans and animals studies. In this study we tested the safety and cardiorenal protective efficacy of intracoronary NAC delivered in the radiographic contrast agent in a pig model that simulates the catheter based reperfusion therapy of ST elevation myocardial infarctions. 27 pigs underwent 45 min of ischemia after surgical ligation of distal left descending coronary artery. With coronary reperfusion the animals received at total of 200 mL of the contrast agent Iopamidol with and without NAC to mimic radiographic contrast use during invasive reperfusion therapy. At 24 h the following endpoints were compared: LV function (MRI, echocardiography), myocardial injury (infarct size, area-at-risk, troponin, creatinine kinase) and CIN (creatinine, BUN and renal histology). The effects of NAC on platelet reactivity were also evaluated. Intracoronary administration of NAC administered in the contrast agent is safe. NAC reduces platelet reactivity and there was a trend towards a better cardiac function at 24 h. There was no significant difference in the size of the myocardial infarction. In this model of ischemia-reperfusion high dose NAC did not protect from CIN. High dose intracoronary NAC administered with the radiographic contrast is safe but does not provide significant cardio-renal protection.

Endogenous and natural complement inhibitor attenuates myocardial injury and arterial thrombogenesis.

BACKGROUND: Coagulation disorders and reperfusion of ischemic myocardium are major causes of morbidity and mortality. Lectin pathway initiation complexes are composed of multimolecular carbohydrate recognition subcomponents and 3 lectin pathway-specific serine proteases. We have recently shown that the lectin pathway-specific carbohydrate recognition subcomponent mannose-binding lectin plays an essential role in the pathophysiology of thrombosis and ischemia/reperfusion injury. Thus, we hypothesized that the endogenous mannose-binding lectin (MBL)/ficolin-associated protein-1 (MAP-1) that inhibits complement activation in vitro also could be an in vivo regulator by attenuating myocardial schema/reperfusion injury and thrombogenesis when used at pharmacological doses in wild-type mice. METHODS AND RESULTS: In 2 mouse models, MAP-1 preserves cardiac function, decreases infarct size, decreases C3 deposition, inhibits MBL deposition, and prevents thrombogenesis. Furthermore, we demonstrate that MAP-1 displaces MBL/ficolin-associated serine protease (MASP)-1, MASP-2, and MASP-3 from the MBL complex. CONCLUSIONS: Our results suggest that the natural, endogenous inhibitor MAP-1 effectively inhibits lectin pathway activation in vivo. MAP-1 at pharmacological doses represents a novel therapeutic approach for human diseases involving the lectin pathway and its associated MASPs.

EP 80317, a selective CD36 ligand, shows cardioprotective effects against post-ischaemic myocardial damage in mice.

AIMS: The CD36 receptor plays an important role in facilitating fatty acid transport to the heart. The present study aimed to assess whether EP 80317, a selective synthetic peptide ligand of CD36, is cardioprotective in a murine model of myocardial ischaemia and reperfusion (MI/R) injury. METHODS AND RESULTS: Mice were pretreated with daily subcutaneous injections of EP 80317 for 14 days before being subjected to a 30 min ligation of the left anterior descending coronary artery. The treatment reduced the infarct area and improved myocardial haemodynamics and function, as shown by an increase in cardiac output, ejection fraction and stroke work, and a reduced total peripheral resistance. In contrast, administration of EP 51389, a tripeptide analogue devoid of binding affinity to CD36, did not protect against myocardial injury. Six hours after myocardial reperfusion, EP 80317-treated mice showed reduced myocardial fatty acid uptake, as assessed by micro-positron emission tomography, in agreement with reduced levels of circulating non-esterified fatty acids. Studies using [(14)C]-palmitate infusion revealed reduced lipolysis, although no significant change in insulin or catecholamine plasma levels were observed. Increased expression levels of adipogenic and anti-lipolytic genes further supported an effect of EP 80317 in preventing fatty acid mobilization from adipose tissue. No effect of the treatment was observed in CD36(-/-) mice. CONCLUSION: Our results show that pretreatment with EP 80317 protected the heart against damage and dysfunction elicited by MI/R, along with a transient reduction in peripheral lipolysis. Our findings support CD36 as a novel target for the treatment of ischaemic cardiopathy.

Oral ß-glucan reduces infarction size and improves regional contractile function in a porcine ischaemia/reperfusion model.

OBJECTIVES: We previously reported a cardioprotective effect of oral ß-glucan in patients who underwent coronary artery bypass grafting. The present study was conducted to determine whether oral ß-glucan could reduce myocardial infarction size and whether these changes would be reflected by better preservation of contractile indices measured by speckle tracking echocardiography (STE). METHODS: Fourteen pigs were randomized to receive oral ß-glucan 50 mg/kg (n = 7) or placebo (control, n = 7) 10 days before they were anaesthetized and subjected to 1 h clamping of the left anterior descending coronary artery followed by reperfusion for 3 h. Longitudinal strain, circumferential strain and radial strain were assessed by STE after 3 h of reperfusion. Infarction size and area at risk were determined by Evans blue and 2,3,5-triphenyltetrazolium chloride staining. RESULTS: Pretreatment with ß-glucan reduced the infarct area/area at risk ratio by 36% (P < 0.05) and the total necrotic area of the left ventricle by 37% (P < 0.05) compared with controls. Viable myocardium at risk was 30% higher in the ß-glucan vs. control group (P < 0.05). Anterior apical strain values for ß-glucan vs. control were -4.7 ± 9.4 vs. 5.9 ± 6.1% (P < 0.05) for longitudinal strain, -14.7 ± 6.6 vs. -7.7 ± 4.3 (P < 0.05) for circumferential strain, 15.1 ± 7.7 vs. 7.1 ± 11.8 (ns) for radial strain. CONCLUSIONS: Oral ß-glucan pretreatment reduces infarction size and improves regional contractile function in a porcine ischaemia/reperfusion model.

Protective effects of salvianolate on microvascular flow in a porcine model of myocardial ischaemia and reperfusion.

BACKGROUND: Microvascular reflow is crucial for myocyte survival during ischaemia/reperfusion injury. AIMS: We aimed to assess if salvianolate, a highly purified aqueous extract from Radix salviae miltiorrhizae, could improve impaired microvascular reflow induced by ischaemia/reperfusion injury, using a porcine closed-chest model. METHODS: Left anterior descending coronary artery ligation was created by balloon occlusion for 2 h followed by reperfusion for 14 days. Salvianolate was administrated intravenously for 7 days at low dose (5 mg/kg/day), high dose (10 mg/kg/day) or high dose combined with one 20 mg intracoronary bolus injection just at the beginning of reperfusion. Control-group animals were only given the same volume of saline. RESULTS: After 14 days of reperfusion, animals treated with high-dose salvianolate showed improved myocardial perfusion assessed by real-time myocardial contrast echocardiography and coloured microspheres. The beneficial effect was further supported by increased capillary density and decreased infarct size. All these effects eventually resulted in well-preserved cardiac function detected by echocardiography. Moreover, we also demonstrated that salvianolate administration was associated with elevated superoxide dismutase activity, thioredoxin activity and glutathione concentration, and reduced malondialdehyde concentration, which, in turn, resulted in a significant decrease in terminal deoxynucleotide transferase-mediated dUTP nick end labelling-positive cells and an increased ratio of Bcl-2 to Bax expression. CONCLUSION: Intravenous salvianolate at a dose of 10 mg/kg/day for 7 days had significant beneficial effects on myocardial microvascular reflow, which were associated with decreased oxidative stress and apoptosis.

Reduced cardioprotective action of adiponectin in high-fat diet-induced type II diabetic mice and its underlying mechanisms.

Diabetes exacerbates ischemic heart disease morbidity and mortality via incompletely understood mechanisms. Although adiponectin (APN) reduces myocardial ischemia/reperfusion (MI/R) injury in nondiabetic animals, whether APN's cardioprotective actions are altered in diabetes, a pathologic condition with endogenously reduced APN, has never been investigated. High-fat diet (HD)-induced diabetic mice and normal diet (ND) controls were subjected to MI via coronary artery ligation, and given vehicle or APN globular domain (gAPN, 2 µg/g) 10 min before reperfusion. Compared to ND mice (where gAPN exerted pronounced cardioprotection), HD mice manifested greater MI/R injury, and a tripled gAPN dose was requisite to achieve cardioprotective extent seen in ND mice (i.e., infarct size, apoptosis, and cardiac function). APN reduces MI/R injury via AMP-activated protein kinase (AMPK)-dependent metabolic regulation and AMPK-independent antioxidative/antinitrative pathways. Compared to ND, HD mice manifested significantly blunted gAPN-induced AMPK activation, basally and after MI/R (p<0.05). Although both low- and high-dose gAPN equally attenuated MI/R-induced oxidative stress (i.e., NADPH oxidase expression and superoxide production) and nitrative stress (i.e., inducible nitric oxide synthase expression, nitric oxide production, and peroxynitrite formation) in ND mice, only high-dose gAPN efficaciously did so in HD mice. We demonstrate for the first time that HD-induced diabetes diminished both AMPK-dependent and AMPK-independent APN cardioprotection, suggesting an unreported diabetic heart APN resistance.

Impact of percutaneous coronary intervention or coronary artery bypass grafting on outcome after nonfatal cardiac arrest outside the hospital.

Survivors of cardiac arrest due to ventricular arrhythmias are at risk for recurrent events. The role of revascularization in secondary prevention for survivors of cardiac arrest has been addressed in various studies with conflicting results. A total of 142 survivors of cardiac arrest with coronary artery disease were evaluated according to a standardized protocol, including 2-dimensional echocardiography, myocardial perfusion scintigraphy, coronary angiography, and electrophysiologic testing. Revascularization of scintigraphically documented ischemic myocardial regions was performed in 44 patients (31%). Final therapy was based on the results of electrophysiologic testing. Four-year survival rates were 100% for revascularized noninducible patients, 84% for revascularized inducible patients, 91% for nonrevascularized noninducible patients, and 72% for nonrevascularized inducible patients. Only 1 patient (<1% of study population) died suddenly. Recurrences were much more frequent in patients without revascularization (38% vs 7%, p <0.001) and the recurrence rate was 0% in the revascularized noninducible patients. Thus, revascularization of ischemically jeopardized myocardium in survivors of cardiac arrest resulted in excellent survival; moreover, in absence of inducible ventricular arrhythmias, the recurrence rate was 0%. Systematic evaluation of survivors of cardiac arrest due to ventricular arrhythmias allows risk stratification and guidance of subsequent antiarrhythmic therapy.