Occlusion Of Left Coronary Artery Research Articles

Epoxyeicosatrienoic acid analog EET-B attenuates post-myocardial infarction remodeling in spontaneously hypertensive rats.

Epoxyeicosatrienoic acids (EETs) and their synthetic analogs have cardiovascular protective effects. Here, we investigated the action of a novel EET analog EET-B on the progression of post-myocardial infarction (MI) heart failure in spontaneously hypertensive rats (SHR). Adult male SHR were divided into vehicle- and EET-B (10 mg/kg/day; p.o., 9 weeks)-treated groups. After two weeks of treatment, rats were subjected to 30-min left coronary artery occlusion or sham operation. Systolic blood pressure and echocardiography measurements were performed at the beginning of study, 4 days before, and 7 weeks after MI. At the end of the study, tissue samples were collected for histological and biochemical analyses. We demonstrated that EET-B treatment did not affect blood pressure and cardiac parameters in SHR prior to MI. MI was induced and cardiac parameters were measured 7 weeks later. Fractional shortening (FS) was decreased to 18.4±1.0% in vehicle-treated MI rats compared with corresponding sham (30.6±1.0%) 7 weeks following MI induction. In infarcted SHR hearts, EET-B treatment improved FS (23.7±0.7%), markedly increased heme oxygenase-1 immunopositivity in cardiomyocytes and reduced cardiac inflammation and fibrosis (by 13% and 19%, respectively). In conclusion, these findings suggest that EET analog EET-B has beneficial therapeutic actions to reduce cardiac remodeling in SHR subjected to MI.

SAT-552 Oxidative Stress Induces Type 3 Deiodinase on Multiple Tissues in Disease: Implications to Nonthyroidal Illness Syndrome Pathophysiology

Imbalances in the redox status are involved in type 3 deiodinase (D3) induction in the non-thyroidal illness syndrome (NTIS). The mechanisms responsible for D3 dysfunction under systemic redox alterations in disease are poorly understood. Recently, the resemblance of D3 with peroxiredoxin-like proteins has been suggested. Objective: Evaluate the paths of redox alterations leading to D3 induction in liver, muscle, and brain in an animal model of NTIS. Methods: Male Wistar rats submitted to left anterior coronary artery occlusion (MI) were treated or not with N-acetylcysteine (NAC), an antioxidant that replenishes cysteine levels. Ten days post-MI animals were sacrificed and tissues collected. D3 activity was measured in liver, muscle, and brain. Total carbonyl and sulphydryl contents, as well as enzymatic and nonenzymatic oxidative parameters, were determined. Results: Compared to sham, D3 activity was increased in liver (P=0.002), muscle (P=0.03) and brain (P=0.01) in MI-placebo animals. All tissues from placebo group showed increased carbonyls, marker of oxidative damage to protein, and diminished sulphydryl levels, indicating cysteine and thiol consumption (all P=0.001). GSH/GSSG ratio was altered in all tissues (P=0.001). GSH is a critical antioxidant that depends on sulphydryl groups as a ready source of reducing equivalents. Liver and muscle had augmented glutathione peroxidase (GPx), glutathione reductase (GR) and thioredoxin reductase (TRx) levels (P=0.001). NAC prevented all the alterations described above. Conclusion: D3 induction in tissues correlates to MI-induced redox changes. NAC preventing D3 dysfunction indicates a role for altered cysteine/thiol in this process. The enzymatic profile suggests a functional regenerating GSH system. The set of these results adds to the present knowledge of NTIS physiopathology since they indicate a reversible oxidative post-transcriptional modification of D3 probably through a putative formation of mixed disulfides with cysteine and glutathione (glutathionylation process) that could be reduced by TRx as one of the causes for D3 induction in disease. The possibility that the thiols are being consumed to form disulphide bonds from augmented GSSG could also be considered. Antioxidant treatment prevents D3 dysfunction in multiple tissues, which probably contribute to avoiding NTIS.

Preventive Melatonin Administration Decreased Dispersion of Repolarization and Myocardium Susceptibility to Ventricular Tachyarrhythmias in a Model of Acute Coronary Occlusion in Rabbits

IntroductionMelatonin is known to have a spectrum of antioxidative and cardioprotective properties, which may be beneficial in ischemia/reperfusion conditions, but a mechanism of its antiarrhythmic effects remains to be established. This study aimed to assess effects of preventive melatonin treatment on spatiotemporal ventricular electrophysiological parameters and susceptibility of myocardium to ventricular tachycardia and/or ventricular fibrillation (VT/VF) in an experimental model of acute ischemia/reperfusion in rabbits.MethodsExperiments were performed in 28 anesthetized open‐chest rabbits. Melatonin (10 mg/kg, i.v.) was administrated to the animals (n = 5) one hour before coronary occlusion, whereas the control rabbits (n = 23) received placebo. Unipolar electrograms were recorded with 64‐electrodes epicardial sock connected to a custom‐designed high resolution system (4 kHz) in a baseline state, at 15 min of the left circumflex coronary artery occlusion and after subsequent 15‐min reperfusion. Activation times and repolarization times (RTs) were measured in each lead as dV/dt minimum during QRS complex and dV/dt maximum during T wave, respectively. A border dispersion of repolarization (DOR) was measured as a difference between the minimal and maximal RTs of ischemic and border zone. The VT/VF susceptibility was tested by high frequency stimulation.ResultsMelatonin administration did not change baseline spatiotemporal activation and repolarization parameters. Median RTs were shortened in the ischemic zone at 15 min of coronary occlusion as compared to baseline (control: 90 [IQR 77–109] vs 148 [IQR 112–174] ms, p<0.05; melatonin: 111 [IQR 108–117] vs 158 [IQR 155–160] ms, p<0.05, respectively], with the “ischemic” RTs being significantly longer in the melatonin group (p = 0.038). At 15 min of reperfusion, the melatonin group demonstrated partial restoration of RTs (132 [IQR 123–140] ms), which was not observed in the control group (102 [IQR 95–126] ms, p = 0.044 vs melatonin group). Thus, the border DOR was greater in the control group as compared to the melatonin group at 15 min of ischemia (42 [IQR 21–47] ms vs 21 [IQR 16–21] ms, p = 0.043, respectively) and at 15 min of reperfusion (19 [IQR 8–33] ms vs 7 [IQR 1–8] ms, p = 0.038, respectively). In ischemia the melatonin‐treated animals demonstrated a lower arrhythmia susceptibility (0 vs 13 VT/VF episodes, p = 0.022, respectively).ConclusionIn the rabbit model of acute coronary occlusion/reperfusion, the melatonin‐related mitigation of VT/VF susceptibility was associated with the limitation of repolarization shortening in ischemic zone and decrease of DOR.Support or Funding InformationThe study was supported by Russian Science Foundation (RSF 18‐15‐00309).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Successful percutaneous treatment of an anomalous left circumflex coronary artery occlusion after tricuspid valve repair.

The risk of coronary artery injury during valve surgery is higher in case of anomalous coronary artery origin and trajectory. Unlike previous reports on coronary obstruction related to aortic or mitral surgery, we report the first case, to the best of our knowledge, of an anomalous left circumflex artery occlusion after tricuspid valve repair, and its successful percutaneous treatment.

Optimal strategy of primary percutaneous coronary intervention for acute myocardial infarction due to unprotected left main coronary artery occlusion (OPTIMAL): study protocol for a randomised controlled trial

BackgroundPrimary percutaneous coronary intervention (PCI) for patients presenting with acute myocardial infarction (AMI) caused by left main coronary artery occlusion is associated with significantly higher mortality and risks of major adverse cardiovascular events. Deferred stent implantation may improve prognosis of primary PCI by reducing distal embolization and no-reflow phenomenon. There is no randomized clinical trial focusing on the effect and outcome of deferred stent implantation on primary PCI for left main coronary artery occlusion in contrast with conventional strategy.MethodsThe Optimal Strategy of Primary Percutaneous Coronary Intervention for Acute Myocardial Infarction due to Unprotected Left Main Coronary Artery Occlusion (OPTIMAL) study (ClinicalTrials.gov Identifier: NCT03282773) is an open-label, randomized, multicenter clinical trial in which 480 patients presenting with AMI caused by left main coronary artery occlusion recruited from 30 hospitals in mainland China will be randomly assigned 1:1 to immediate stenting or deferred stenting (scheduled 4–10 days after primary angioplasty) groups. The primary endpoint is a composite of all-cause mortality or recurrent myocardial infarction at 30 days after randomization. The secondary outcomes include all-cause mortality, cardiac death, recurrent myocardial infarction, and unplanned target vessel revascularization at 30 days, 6 months, and 12 months.DiscussionThe OPTIMAL study is designed to compare the clinical performance of deferred stenting with that of immediate stenting for AMI caused by left main coronary artery occlusion.Trial registrationClinicalTrials.gov Identifier: NCT03282773. Registered on 10 September 2017.

Remote ischemic perconditioning attenuates adverse cardiac remodeling and preserves left ventricular function in a rat model of reperfused myocardial infarction

AimsRemote ischemic conditioning (RIC) is considered a potential clinical approach to reduce myocardial infarct size and ameliorate adverse post-infarct left ventricular (LV) remodeling, however the mechanisms are unknown. The aim was to clarify the impact of RIC on Neuregulin-1 (NRG-1)/ErbBs expression, inflammation and LV hemodynamic function. Methods and resultsMale Sprague-Dawley rats were subjected to 30 min occlusion of the left coronary artery (LCA) followed by 2 weeks of reperfusion and separated into three groups: (1) sham operated (without LCA occlusion); (2) Myocardial ischemia/reperfusion (MIR) and (3) remote ischemic perconditioning group (MIR + RIPerc). Cardiac structural and functional changes were evaluated by echocardiography and on the isolated working heart system. The level of H3K4me3 at the NRG-1 promoter, and both plasma and LV tissue levels of NRG-1 were assessed. The expression of pro-inflammatory cytokines, ECM components and ErbB receptors were assessed by RT-qPCR. MIR resulted in a significant decrease in LV function and enlargement of LV chamber. This was accompanied with a decrease in the level of H3K4me3 at the NRG-1 promoter. Consequently NRG-1 protein levels were reduced in the infarcted myocardium. Subsequently, an upregulated influx of CD68+ macrophages, high expression of MMP-2 and -9 as well as an increase of IL-1β, TLR-4, TNF-α, TNC expression were observed. In contrast, RIPerc significantly decreased inflammation and improved LV function in association with the enhancement of NRG-1 levels and ErbB3 expression. ConclusionsThese findings may reveal a novel anti-remodeling and anti-inflammatory effect of RIPerc, involving activation of NRG-1/ErbB3 signaling.

In vivo gum arabic-coated tetrahydrobiopterin protects against myocardial ischemia reperfusion injury by preserving eNOS coupling

AimsExogenous tetrahydrobiopterin (BH4), an indispensable cofactor of endothelial nitric oxide synthase (eNOS), supplementation has been proved to be of advantage to improve cardiovascular function. Nevertheless, due to its highly redox-sensitive and easy to be oxidized, there is an urgent need to develop an appropriate BH4 formulation for clinical therapy. Gum Arabic (GA) has been considered as an alternative biopolymer for the stabilization and coating of drugs. The effects of GA on protecting BH4 from being oxidized were investigated in a rat model of myocardial ischemia-reperfusion (I/R). Main methodsRats were subjected to 60-min of in vivo left coronary artery occlusion and varying periods of reperfusion with or without pre-ischemic GA-coated BH4 supplementation (10 mg/kg, oral). Myocardial infarction, fibrotic area and left ventricle ejection fraction were correlated with cardiac BH4 content, eNOS protein, NOS enzyme activity, and ROS/NO generation. Key findingsPretreatment of rats with GA-coated 6R-BH4, 24 h before myocardial ischemia, resulted in smaller myocardial infarction, improved left ventricular function and inhibited fibrosis, correlated with maintained high levels of cardiac BH4 content, preserved eNOS activation and dimerization, and decreased ROS generation. However in uncoated group, 6R-BH4 treatment did not reduce acute and chronic myocardial I/R injury compared with control I/R rats, which was closely related with the marked loss of myocardial BH4 levels during I/R. SignificanceThese findings provide evidence that in vivo pre-ischemic oral GA-coated BH4 administration preserves eNOS function secondary to maintaining cardiac BH4 content, and confers cardioprotection after I/R.

Electrocardiographic Distinction of Left Circumflexand Right Coronary Artery Occlusion in PatientsWith Inferior Acute Myocardial Infarction

Previously reported electrocardiographic (ECG) criteria to distinguish left circumflex (LCCA) and right coronary artery (RCA) occlusion in patients with acute inferior ST-segment elevation myocardial infarction (STEMI) afford a modest diagnostic accuracy. We aimed to develop a new algorithm overcoming limitations of previous studies. Clinical, ECG, and coronary angiographic data were analyzed in 230 nonselected patients with acute inferior STEMI who underwent primary percutaneous coronary intervention. A decision-tree analysis was used to develop a new ECG algorithm. The diagnostic accuracy of reported ECG criteria was reviewed. LCCA occlusion occurred in 111 cases and RCA in 119. We developed a 3-step algorithm that identified LCCA and RCA occlusion with a sensitivity of 77%, specificity of 86%, accuracy of 82%, and Youden index of 0.63. The area under the ROC curve was 0.85 and resulted 0.82 after a 10-fold cross validation. The key leads for LCCA occlusion were V3 (ST depression in V3/ST elevation in III >1.2) and V6 (ST elevation ≥0.1 mV or greater than III). The key leads for RCA occlusion were I and aVL (ST depression ≥ 0.1 mV). Fifteen of 21 reviewed studies had less than 20 cases of LCCA occlusion, only 48% performed primary percutaneous coronary intervention, and previous infarction or multivessel disease were often excluded. The diagnostic accuracy of reported ECG criteria decreased when applied to our study population. In conclusion, we report a simple and highly discriminative 3-step ECG algorithm to differentiate LCCA and RCA occlusion in an "all comers" population of patients with acute inferior STEMI. The diagnostic key ECG leads were V3 and V6 for LCCA and I and aVL for RCA occlusion.

Left Main Coronary Artery Occlusion By External Compression With A Large Pulmonary Artery in Eisenmenger Syndrome

Left Main Coronary Artery Occlusion By External Compression With A Large Pulmonary Artery in Eisenmenger Syndrome

Three cases of acute myocardial infarction caused by left main coronary artery occlusion

Three cases of acute myocardial infarction caused by left main coronary artery occlusion

Cardioprotection of Ischemic Myocardium

Aim. Cardioprotective effect of precursors in the synthesis of the uridine-5ʼ-diphosphate (UDP) - the mitochondrial ATP-dependent potassium channels (mitoKATP channels) endogenous activator - uridine and uridine-5ʼ-monophosphate (UMP) and the relation between there mechanism of action and activity of mitoKATP channels were studied. Methods. The experiments were performed on the male Wistar rats weighing 300-350 g. Acute myocardial ischemia (MI) lasting 60 min was produced by occlusion of the descending branch of the left coronary artery (LCA) under artificial pulmonary ventilation. Animals were anesthetized with sodium ethaminal (50 mg/kg). Uridine or UMP in the dose of 30 mg/kg was injected intravenously 5 min prior to LCA occlusion. A selective blocker of these channels 5-hydroxydecanoate (5-HD, 5 mg/kg intravenously 5 min prior to injection of uridine or UMP) was used to detect the involvement of mitoKATP channels in the effects of drugs. ATP and creatine phosphate (CP) was determined in the heart homogenates. The intensity of lipid peroxidation (LPO) was estimated by the content of lipid hydroperoxides (LHP) and the state of the antioxidant system (AOS) by superoxidedismutase (SOD) activity and the reduced glutathione (GH) content. Results. Occlusion of the LCA during 60 min led to the decrease of ATP and CP content in the myocardium by 35% and 59% respectively. At the same time changes in LPO and AOS were observed. The amount of LHP increased by 97%, the activity of SOD was reduced by 28% and the content of GH decreased by 30%. Uridine and UMP given 5 minutes prior to LCA occlusion prevented the development of these metabolic disorders in the ischemic myocardium. Selective blocker of mitoKATP channels 5-HD eliminated the protective effect of both drugs. Conclusion. Uridin and UMP have the evident cardioprotective effect in the acute MI, stabilizing the miocardium energy metabolism, preventing the AOS function depression and excessive activation of LPO. The mechanism of protective action of the drugs is associated with the activation of mitoKATP channels. (For citation: Bulion VV, Krylova IB, Selina EN. Cardioprotection of ischemic myocardium. Reviews on Clinical Pharmacology and Drug Therapy. 2018;16(2):13-17. doi: 10.17816/RCF16213-17).

Correction of hypoxic state by metabolic precursors of endogenous activator of mitochondrial ATP-dependent K+channels

Aim. The antihypoxic properties of uridine and uridine-5'-monophosphate (UMP), which are the metabolic precursors of the natural activator of mitochondrial ATP-dependent K+ channels (mitoKATP channels) uridine diphosphat were investigated on the models of hypoxic hypoxia with hypercapnia (HHH), hemic hypoxia and local circulatory hypoxia.
 Methods. HHH was created in males and females white mice weighing 28-30 g. The animals were placed one by one in hermetically closed container and the duration of their life was determined. The antihypoxic activity of the substances was compared with the reference anthypoxant amtizole (50 mg/kg). Hemic hypoxia was caused in Wistar rats weighing 350-370 g by the injection of sodium nitrite (intramuscularly, 100 mg/kg). Uridine or UMP 30 mg/kg was injected intraperitoneally 30 minutes before the onset of HHH and hemic hypoxia. Local circulatory hypoxia was modeled in male Wistar rats weighing 250-300 g. Acute coronary occlusion lasting 60 min was reproduced by legation of descending branch of the left coronary artery (LCA). Uridine or UMP (30 mg/kg) was administered intravenously 5 minutes prior to LCA occlusion. Selective blocker of mitoKATP channels 5-hydroxydecanoate (5 mg/kg, intravenously, 5 minutes prior uridine or UMP) was used to determine the role of these channels in the mechanism of antihypoxic action of the studied drugs. The volume of the damaged myocardium was used as the marker of antihypoxic activity of uridine and UMP.
 Results. Different resistance to hypoxia in female and male mice was observed in HHH. The female mice were more resistant, their life duration was 43% more than the males. Uridine and UMP displayed antihypoxic activity only in male mice, increasing their life duration by 25% and 20% respectively. This effect was 2 times less than that of amtisol. In similar conditions in females mice the preparations did not show a protective effect. In hemic hypoxia the life duration of rats treated with uridine and UMP did not differ from the control values. Circulatory hypoxia, caused by occlusion of the LCA, led to the formation of a local zone of myocardial damage. Uridine or UMP decreased the damage zone in 2 and 3,5 times respectively. The inhibitor of mitoKATP channels blocked the protective effect of these compounds.
 Conclusion. Uridine and UMP have a distinct antihypoxic effect in HHH and a marked protective effect in local circulatory hypoxia. The antihypoxic activity of druges in HHH is manifested differently in female and male mice. It may be due to sexual differences in the resistance to hypoxia. The maximum effect is observed in male who have initially low resistance to oxygen deficiency. The mechanism of the protective action of uridine and UMP in the circulatory hypoxia is associated with the activation of mitoKATP channels.

Infarct size-limiting effect of epoxyeicosatrienoic acid analog EET-B is mediated by hypoxia-inducible factor-1α via downregulation of prolyl hydroxylase 3.

Epoxyeicosatrienoic acids (EETs) decrease cardiac ischemia-reperfusion injury; however, the mechanism of their protective effect remains elusive. Here, we investigated the cardioprotective action of a novel EET analog, EET-B, in reperfusion and the role of hypoxia-inducible factor (HIF)-1α in such action of EET-B. Adult male rats were subjected to 30 min of left coronary artery occlusion followed by 2 h of reperfusion. Administration of 14,15-EET (2.5 mg/kg) or EET-B (2.5 mg/kg) 5 min before reperfusion reduced infarct size expressed as a percentage of the area at risk from 64.3 ± 1.3% in control to 42.6 ± 1.9% and 46.0 ± 1.6%, respectively, and their coadministration did not provide any stronger effect. The 14,15-EET antagonist 14,15-epoxyeicosa-5( Z)-enoic acid (2.5 mg/kg) inhibited the infarct size-limiting effect of EET-B (62.5 ± 1.1%). Similarly, the HIF-1α inhibitors 2-methoxyestradiol (2.5 mg/kg) and acriflavine (2 mg/kg) completely abolished the cardioprotective effect of EET-B. In a separate set of experiments, the immunoreactivity of HIF-1α and its degrading enzyme prolyl hydroxylase domain protein 3 (PHD3) were analyzed in the ischemic areas and nonischemic septa. At the end of ischemia, the HIF-1α immunogenic signal markedly increased in the ischemic area compared with the septum (10.31 ± 0.78% vs. 0.34 ± 0.08%). After 20 min and 2 h of reperfusion, HIF-1α immunoreactivity decreased to 2.40 ± 0.48% and 1.85 ± 0.43%, respectively, in the controls. EET-B blunted the decrease of HIF-1α immunoreactivity (7.80 ± 0.69% and 6.44 ± 1.37%, respectively) and significantly reduced PHD3 immunogenic signal in ischemic tissue after reperfusion. In conclusion, EET-B provides an infarct size-limiting effect at reperfusion that is mediated by HIF-1α and downregulation of its degrading enzyme PHD3. NEW & NOTEWORTHY The present study shows that EET-B is an effective agonistic 14,15-epoxyeicosatrienoic acid analog, and its administration before reperfusion markedly reduced myocardial infarction in rats. Most importantly, we demonstrate that increased hypoxia-inducible factor-1α levels play a role in cardioprotection mediated by EET-B in reperfusion likely by mechanisms including downregulation of the hypoxia-inducible factor -1α-degrading enzyme prolyl hydroxylase domain protein 3.

Infarct-Sparing Effect of Adenosine A2B Receptor Agonist Is Primarily Due to Its Action on Splenic Leukocytes Via a PI3K/Akt/IL-10 Pathway

BackgroundAdenosine A2B receptor (A2BAR) agonist reduces myocardial reperfusion injury by acting on inflammatory cells. Recently, a cardiosplenic axis was shown to mediate the myocardial postischemic reperfusion injury. This study aimed to explore whether the infarct-squaring effect of A2BAR agonist was primarily due to its action on splenic leukocytes. MethodsC57BL6 (wild type [WT]) mice underwent 40 min of left coronary artery occlusion followed by 60 min of reperfusion. A2BAR knockout (KO) and interleukin (IL)-10KO mice served as donors for splenic leukocytes. Acute splenectomy was performed 30 min before ischemia. The acute splenic leukocyte adoptive transfer was performed by injecting 5 × 106 live splenic leukocytes into splenectomized mice. BAY 60-6583, an A2BAR agonist, was injected by i.v. 15 min before ischemia. The infarct size (IS) was determined using 2,3,5-triphenyltetrazolium chloride and Phthalo blue staining. The expression of p-Akt and IL-10 was estimated by Western blotting. Immunofluorescence staining assessed the localization of IL-10 expression. ResultsBAY 60-6583 reduced the myocardial IS in intact mice but failed to reduce the same in splenectomized mice, which had a smaller IS than intact mice. BAY 60-6583 reduced the IS in splenectomized mice with the acute transfer of WT splenic leukocytes; however, it did not protect the heart of splenectomized mice with the acute transfer of A2BRKO splenic leukocytes. Furthermore, BAY 60-6583 increased the levels of p-Akt and IL-10 in the WT spleen. Moreover, it did not exert any protective effect in IL-10KO mice. ConclusionsA2BAR activation before ischemia stimulated the IL-10 production in splenic leukocytes via a PI3K/Akt pathway, thereby exerting anti-inflammatory effects that limited the myocardial reperfusion injury.

Analysis of ischaemic crisis using the informational causal entropy-complexity plane

In the present work, an ischaemic process, mainly focused on the reperfusion stage, is studied using the informational causal entropy-complexity plane. Ischaemic wall behavior under this condition was analyzed through wall thickness and ventricular pressure variations, acquired during an obstructive flow maneuver performed on left coronary arteries of surgically instrumented animals. Basically, the induction of ischaemia depends on the temporary occlusion of left circumflex coronary artery (which supplies blood to the posterior left ventricular wall) that lasts for a few seconds. Normal perfusion of the wall was then reestablished while the anterior ventricular wall remained adequately perfused during the entire maneuver. The obtained results showed that system dynamics could be effectively described by entropy-complexity loops, in both abnormally and well perfused walls. These results could contribute to making an objective indicator of the recovery heart tissues after an ischaemic process, in a way to quantify the restoration of myocardial behavior after the supply of oxygen to the ventricular wall was suppressed for a brief period.

One-year Outcomes in Patients with ST-segment Elevation Myocardial Infarction Caused by Unprotected Left Main Coronary Artery Occlusion Treated by Primary Percutaneous Coronary Intervention

Background:Very few data have been reported for ST-segment elevation myocardial infarction (STEMI) caused by unprotected left main coronary artery (ULMCA) occlusion, and very little is known about the results of this subgroup of patients who underwent primary percutaneous coronary intervention (PCI). The aim of this study was to determine the clinical features and outcomes of patients with STEMI who underwent primary PCI for acute ULMCA occlusion.Methods:From January 2000 to February 2014, 372 patients with STEMI caused by ULMCA acute occlusion (ULMCA-STEMI) who underwent primary PCI at one of two centers were enrolled. The 230 patients with non-ST-segment elevation MI (NSTEMI) caused by ULMCA lesion (ULMCA-NSTEMI) who underwent emergency PCI were designated the control group. The main indexes were the major adverse cardiac events (MACEs) in-hospital, at 1 month, and at 1 year.Results:Compared to the NSTEMI patients, the patients with STEMI had significantly higher rates of Killip class≥III (21.2% vs. 3.5%, χ2 = 36.253, P < 0.001) and cardiac arrest (8.3% vs. 3.5%, χ2 = 5.529, P = 0.019). For both groups, the proportions of one-year cardiac death in the patients with a post-procedure thrombolysis in myocardial infarction (TIMI) flow grade<3 were significantly higher than those in the patients with a TIMI flow grade of 3 (STEMI group: 51.7% [15/29] vs. 4.1% [14/343], P < 0.001; NSTEMI group: 33.3% [3/9] vs. 13.6% [3/221], P = 0.001; respectively]. Landmark analysis showed that the patients in STEMI group were associated with higher risks of MACE (16.7% vs. 9.1%, P = 0.009) and cardiac death (5.4% vs. 1.3%, P = 0.011) compared with NSTEMI patients at 1 month. Meanwhile, in patients with ULMCA, the landmark analysis for incidences of MACE and cardiac death was similar between the STEMI and NSTEMI (all P = 0.72) in the intervals of 1–12 months. However, patients who were diagnosed with STEMI or NSTEMI had no significant difference in reinfarction (all P > 0.05) and TVR (all P > 0.05) in the intervals of 0–1 month as well as 1 month to 1 year. The results of Cox regression analysis showed that the differences in the independent predictors for MACE included the variables of Killip class ≥ III and intra-aortic balloon pump support for the STEMI patients and the variables of previous MI, ULMCA distal bifurcation, and 2-stent for distal ULMCA lesions for the NSTEMI patients.Conclusions:Compared to the NSTEMI patients, the patients with STEMI and ULMCA lesions still remain at a much higher risk for adverse events at 1 year, especially on 1 month. If a successful PCI procedure is performed, the 1-year outcomes in those patients might improve.

PCSK9 expression in the ischaemic heart and its relationship to infarct size, cardiac function, and development of autophagy.

Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a novel therapy to treat hypercholesterolaemia and related cardiovascular diseases. This study determined if PCSK9 can regulate infarct size, cardiac function, and autophagy during ischaemia. Mice hearts were subjected to left coronary artery (LCA) occlusion. There was intense expression of PCSK9 in the zone bordering the infarct area in association with marked cardiac contractile dysfunction in the wild-type mice. This region also revealed intense autophagy. To assess the role of PCSK9 in the evolution of infarct size and function and development of autophagy, we used wild-type mice pre-treated with two different PCSK9 inhibitors (Pep2-8 and EGF-A) or mice lacking PCSK9 gene. Both strategies resulted in smaller infarcts and improved cardiac function following LCA ligation. PCSK9 inhibition also markedly reduced autophagy. Relationship between myocardial ischaemia and PCSK9 expression and autophagy was examined in cultured mouse cardiomyocytes. Exposure of cardiomyocytes to hypoxia resulted in prompt PCSK9 expression and autophagy signals; both were blocked by HIF-1α siRNA. Further, treatment of cardiomyocytes with recombinant PCSK9 during hypoxia induced, and treatment with PCSK9 siRNA reduced, autophagy suggesting a possible role of PCSK9 in the determination of autophagy. Other studies revealed activation of ROS-ATM-LKB1-AMPK axis as a possible mechanism of PCSK-induced autophagy. Hearts of humans with recent infarcts also showed expression of PCSK9 and autophagy in the border zone-similar to that in the infarcted mouse heart. PCSK9 is up-regulated in the ischaemic hearts and determines development of infarct size, cardiac function, and autophagy.

Effects of hyperglycemia on remodeling of acute myocardial infarction in rats

Acute myocardial infarction (MI) remodeling consequences for cardiac function were investigated in diabetes (hyperglycemia) induced by streptozotocin (STZ) in rats. The measurements were performed after 15 days of STZ induction (50 mg/kg iv) and/or 48hs of MI. The following parameters were evaluated: levels of FFA, TG (in plasma and the left ventricle–LV) and glycogen in the LV, the cardiac remodeling, the autonomic nervous system activity, and the oxidative stress in the LV. The Wistar rats (n=8 per group) were divided into 4 groups: control (C); control infarcted (CI); diabetic (D); diabetic infarcted (DI). After 15 days of STZ, the MI was induced by left coronary artery occlusion (□ 25% MI area between the CI and DI groups). The CI group had increased: end‐posterior wall thickness (LVPW), interventricular septum thickness the relative wall thickness and reduced LV cavity, as consequence of cardiac remodeling and increased LV mass. The D group had reduced LVPW (0.11 ± 0.001 cm) as compared with the C (0.13 ± 0.003 cm). DI group had increased LVPW (0.14 ± 0.005 cm). The systolic function was not different between groups. However, the D and CI group exhibited increased isovolumetric relaxation time (IVRT ms): D: 34 ± 1; CI: 30 ± 2.4 vs C: 23 ± 0.7 and The E‐wave desaceleration (ms) was increased in D: 50 ± 0.9 vs C: 40 ± 0.6, having diastolic dysfunction in diabetic rats but there was no impairment in MI (DI: 35 ± 2.3). The variance of heart rate (HRV m2) was reduced by diabetes (D: 18 ± 2.5; DI: 25 ± 3) vs the C group (81 ± 3), as well as the low (LF) and high (HF) frequency bands (sympathetic and vagal components). The MI increased in non‐diabetic rats the HRV (CI: 99 ± 14) and the LF (m2) (CI: 1.8 ± 0.5 vs D: 0.6 ± 0.1; DI: 1 ± 0.2). The variance of blood pressure (mmHg) was reduced by diabetes (D: 8.6 ± 0.7; DI: 5.3 ± 0.6) as compared to C (24 ± 3) and CI (18 ± 3) and the LF were increased only in the CI group (2.7 ± 0.17) vs DI group (1 ± 0.2). The MI increased in non‐diabetic rats the lipid peroxidation (1156 ± 125) vs C: 645 ± 111; D: 945 ± 117; DI: 894 ± 112) and both the MI groups increased the anion superoxide, however, only DI had increased antioxidant enzyme activities (catalase, glutathione peroxidase, superoxide dismutase) improving the redox balance after MI. DI group had reduced TG (1.4 ± 0.19) and glycogen (43 ± 7) content in the LV that was increased before the MI (D: 5.4 ± 0.9 vs C: 1.1 ± 0.2; D: 316 ± 79 vs C: 20 ± 5, respectively mg/g of LV). Therefore, the hyperglycemia previous to ischemia promoted a more efficient metabolic response on remodeling and cardiac function with improved oxidative balance.Support or Funding InformationFAPESP, CNPq, and CAPES supported this research.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Aspirin Protects Heart Against Ischemia‐reperfusion Injury Via LKB1‐Sestrn2‐AMPK Signaling Cascade

IntroductionAMP‐activated protein kinase (AMPK) is a stress signaling enzyme that orchestrates the regulation of energy pathways. Intrinsic AMPK activation protects the heart against ischemic injury, but whether the pharmacologic AMPK stimulation by aspirin mitigates ischemia‐reperfusion (I/R) damage is unknown.HypothesisAspirin as an emerging AMPK agonist could stimulate the cardiac AMPK signaling pathway that attenuates myocardial ischemia‐reperfusion injury.MethodsThe cardioprotective activity of aspirin was evaluated in an in vivo regional I/R (45 min/24 hours) injury model in which the left anterior descending coronary artery (LAD) was occluded and released. The Langendroff perfused heart system was used to approach an ex vivo global ischemia and reperfusion model.ResultsIsolated mouse hearts ex vivo pre‐treated with aspirin had better recovery of left ventricular contractile function (55% vs. 29% of baseline heart rate‐pressure product; p&lt;0.05) and less myocardial necrosis (56% reduction in infarct size; p&lt;0.01) during post‐ischemic reperfusion. Pre‐treatment with aspirin in vivo attenuated myocardial infarction in C57BL/6J mice undergoing left coronary artery occlusion and reperfusion compared to vehicle (36% vs. 18%, p&lt;0.05). Mouse hearts with genetically inactivated AMPK catalytic subunit were not protected by aspirin treatment, indicating the critical role of cardiac AMPK activation by aspirin in cardioprotection against ischemic injury. Moreover, pre‐treatment with aspirin in vivo increased the AMPK downstream phosphorylation and inactivation of eukaryotic elongation factor 2 (eEF2), preserved energy charge during ischemia and delayed the development of ischemic contracture. Aspirin treatment augmented the interaction between AMPK upstream LKB1 and Sestrin2‐AMPK complex, also enhanced activation of AMPK downstream endothelial nitric oxide synthase (eNOS) during ischemia, which partially attenuated myocardial stunning.ConclusionsAMPK is a therapeutic target that can be stimulated by a direct‐acting small molecule in order to prevent injury during I/R. The use of aspirin may represent a novel strategy to protect the heart and other solid organs against ischemia.Support or Funding InformationAmerican Heart AssociationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Molecular Imaging of Apoptosis in Ischemia Reperfusion Injury With Radiolabeled Duramycin Targeting Phosphatidylethanolamine: Effective Target Uptake and Reduced Nontarget Organ Radiation Burden

ObjectivesThe purpose of this study was to evaluate the feasibility of imaging apoptosis in experimental ischemia-reperfusion model by technetium-99m (99mTc)-labeled Duramycin, and compare it to an established tracer, 99mTc-labeled Annexin-V, which has a relative disadvantage of high radiation burden to nontarget organs. BackgroundDuring apoptosis, the cell membrane phospholipids-phosphatidylserine (PS) and phosphatidylethanolamine (PE) are exposed and can be targeted by Annexin-V and Duramycin, respectively, for in vivo imaging. Identification of a reversible cell death process should permit therapeutic intervention to help reduce myocyte loss and left ventricle dysfunction. MethodsIn a 40-min left coronary artery ischemia-reperfusion model in 17 rabbits, 7 mCi of 99mTc-labeled Duramycin (n = 10), 99mTc-linear Duramycin (a negative tracer control; n = 3), or 99mTc-Annexin-V (a positive tracer-control; n = 4) were intravenously administered 30 min after reperfusion. Of the 10 Duramycin group animals, 4 animals were treated with an antiapoptotic agent, minocycline at the time of reperfusion. In vivo and ex vivo micro–single-photon emission computed tomography (μSPECT) and micro-computed tomography (μCT) imaging was performed 3 h after reperfusion, followed by quantitative assessment of tracer uptake and pathological characterization. Fluorescent Duramycin and Annexin-V were injected in 4 rats to visualize colocalization in infarct areas in a 40-min left coronary artery occlusion and 30-min reperfusion model. ResultsIntense uptake of Duramycin and Annexin-V was observed in the apical (infarcted) areas. The percent injected dose per gram uptake of Duramycin in apical region (0.751 ± 0.262%) was significantly higher than remote area in same animals (0.045 ± 0.029%; p < 0.01). Duramycin uptake was insignificantly lower than Annexin-V uptake (1.23 ± 0.304%; p > 0.01) but demonstrated substantially lower radiation burden to kidneys (0.358 ± 0.210% vs. 1.58 ± 0.316%, respectively; p < 0.001). Fluorescence studies with Duramycin and Annexin V showed colocalization in infarct areas. Minocycline treatment substantially resolved Duramycin uptake (0.354% ± 0.0624%; p < 0.01). ConclusionsDuramycin is similarly effective in imaging apoptotic cell death as Annexin-V with lower nontarget organ radiation. Clinical feasibility of apoptosis imaging with a PE-seeking tracer should be tested.