scholarly journals Integration of “omics” techniques: Dronedarone affects cardiac remodeling in the infarction border zone

2018 ◽  
Vol 243 (11) ◽  
pp. 895-910 ◽  
Author(s):  
Ravi K Chilukoti ◽  
Josefine Lendeckel ◽  
Katrin Darm ◽  
Alicja Bukowska ◽  
Andreas Goette ◽  
...  
Keyword(s):  
Gene Expression ◽  
Myocardial Infarction ◽  
Atrial Fibrillation ◽  
Acute Myocardial Infarction ◽  
Infarct Size ◽  
Ischemia Reperfusion ◽  
Border Zone ◽  
Matricellular Proteins ◽  
Integrated Network ◽  
And Function

Dronedarone improves microvascular flow during atrial fibrillation and reduces the infarct size in acute models of myocardial infarction. However, dronedarone might be harmful in patients with recent decompensated heart failure and increases mortality in patients with permanent atrial fibrillation. A pathophysiological explanation for these discrepant data is lacking. This study investigated the effects of dronedarone on gene and protein expression in the infarcted area and border zone in pigs subjected to anterior ischemia/reperfusion myocardial infarction. The ischemia/reperfusion myocardial infarction was induced in 16 pigs. Eight pigs were treated with dronedarone for 28 days after myocardial infarction, the remaining pigs served as control. Microarray-based transcriptome profiling and 2D-DIGE-based proteome analysis were used to assess the effects of dronedarone on left ventricular gene expression in healthy (LV), infarcted (MI), and border zone tissue. Selected targets were validated by RT-qPCR or immunoblot analyses, with special emphasize given to the transcriptome/proteome overlap. Combined “omics” analysis was performed to identify most significant disease and function charts affected by dronedarone and to establish an integrated network. The levels of 879 (BZ) or 7 (MI) transcripts and 51 (LV) or 15 (BZ) proteins were significantly altered by dronedarone, pointing to a substantial efficacy of dronedarone in the border zone. Transcriptome and proteome data indicate that dronedarone influences post-infarction remodeling processes and identify matricellular proteins as major targets of dronedarone in this setting. This finding is fully supported by the disease and function charts as well as by the integrated network established by combined “omics”. Dronedarone therapy alters myocardial gene expression after acute myocardial infarction with pronounced effects in the border zone. Dronedarone promotes infarct healing via regulation of periostin and might contribute to the limitation of its expansion as well as cardiac rupture. Thus, there are no experimental hints that dronedarone per se has direct harmful effects after MI in ventricular tissue. Impact statement Dronedarone reduced the infarct size in models of acute myocardial infarction (MI). Here, we show that dronedarone attenuates many of the substantial changes in gene expression that are provoked by acute myocardial infarction (AMI) in pigs. Dronedarone modifies the expression of gene panels related to post-infarction cardiac healing and remodeling processes and, most remarkably, this occurs predominantly in the infarction border-zone and much less so in the vital or infarcted myocardium. Combined “omics” identified matricellular proteins and ECM as major dronedarone-regulated targets and emphasizes their relevance for Disease Charts and Tox Function Charts associated with tissue remodeling and cellular movement. The results demonstrate dronedarone’s capability of regulating cardiac repair and remodeling processes specifically in the infarction border zone and identify underlying mechanisms and pathways that might be employed in future therapeutic strategies to improve long-term cardiac tissue function and stability.

Abstract 3379: Feasibility Of Adrenomedullin Infusion In Patients With Acute Myocardial Infarction -a Possible Cardioprotective Therapy Against Ischemic Injury-

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Satoshi Yasuda ◽  
Shunichi Miyazaki ◽  
Noritoshi Nagaya ◽  
Yu Kataoka ◽  
Teruo Noguchi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Infarct Size ◽  
Intravenous Administration ◽  
Ischemia Reperfusion ◽  
Coronary Intervention ◽  
Reperfusion Therapy ◽  
Left Ventricular ◽  
Stress Generation

Background : Adrenomedullin (ADM) is a 52-amino-acid vasodilator peptide that was originally isolated from human pheochromocytoma. In the previous experimental study with rat ischemia/reperfusion model, ADM reduced infarct size and inhibited myocyte apoptosis. ADM also suppressed the production of oxygen-free-radicals. The present study was designed to evaluate the feasibility of intravenous administration of ADM in patients with acute myocardial infarction (AMI). Methods : We studied 10 patients with first AMI (M/F;9/1, mean age;65 years, peak CPK level; 4090 U/L[median]), who were hospitalized within 12 hours of symptom onset. ADM infusion preceded percutaneous coronary intervention (PCI) and was continued at concentration of 0.0125 − 0.025μg/kg/minute for 12 hours. We also studied 10 control AMI patients matched for age, sex and infarct size, who did not receive ADM. Results : During ADM infusion, hemodynamics kept stable except one patient with right ventricular infarction. Urinary levels of 8-iso-prostaglandine F2α, which was measured after the reperfusion therapy with ADM infusion as a marker of oxidative stress, was significantly lower in patients who received ADM than those who did not (76 ± 40 vs 174±21 pmol/mol of creatinine, P<0.01). Infarct area (IA) evaluated by magnetic resonance imaging and brain natriuretic peptide (BNP) levels were also different between the two groups (Table ). Conclusions : Intravenous administration of ADM, which possesses a variety of cardiovascular protective actions, is feasible and can be adjunctive to PCI. Suppression of oxidative stress generation may be beneficial for attenuation of left ventricular dysfunction and remodeling following AMI.

scholarly journals Novel Combined Antioxidant Strategy against Hypertension, Acute Myocardial Infarction and Postoperative Atrial Fibrillation

Biomedicines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 620
Author(s):  
Ramón Rodrigo ◽  
Jaime González-Montero ◽  
Camilo G. Sotomayor
Keyword(s):  
Myocardial Infarction ◽  
Atrial Fibrillation ◽  
Acute Myocardial Infarction ◽  
Ischemia Reperfusion ◽  
Specific Interaction ◽  
Experimental Studies ◽  
Physiological Role ◽  
Vascular Wall ◽  
Postoperative Atrial Fibrillation ◽  
Protective Effects

Reactive oxygen species (ROS) play a physiological role in the modulation of several functions of the vascular wall; however, increased ROS have detrimental effects. Hence, oxidative stress has pathophysiological impacts on the control of the vascular tone and cardiac functions. Recent experimental studies reported the involvement of increased ROS in the mechanism of hypertension, as this disorder associates with increased production of pro-oxidants and decreased bioavailability of antioxidants. In addition, increased ROS exposure is found in ischemia-reperfusion, occurring in acute myocardial infarction and cardiac surgery with extracorporeal circulation, among other settings. Although these effects cause major heart damage, at present, there is no available treatment. Therefore, it should be expected that antioxidants counteract the oxidative processes, thereby being suitable against cardiovascular disease. Nevertheless, although numerous experimental studies agree with this notion, interventional trials have provided mixed results. A better knowledge of ROS modulation and their specific interaction with the molecular targets should contribute to the development of novel multitarget antioxidant effective therapeutic strategies. The complex multifactorial nature of hypertension, acute myocardial infarction, and postoperative atrial fibrillation needs a multitarget antioxidant strategy, which may give rise to additive or synergic protective effects to achieve optimal cardioprotection.

scholarly journals Colchicine to Prevent Sympathetic Denervation after an Acute Myocardial Infarction: The COLD-MI Trial Protocol

Medicina ◽  
2021 ◽  
Vol 57 (10) ◽  
pp. 1047
Author(s):  
Fabien Huet ◽  
Quentin Delbaere ◽  
Sylvain Aguilhon ◽  
Valentin Dupasquier ◽  
Delphine Delseny ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Single Photon ◽  
Ischemia Reperfusion ◽  
Photon Emission ◽  
Border Zone ◽  
Sympathetic Denervation ◽  
First Episode ◽  
Emission Computed Tomography

Inflammatory processes are deeply involved in ischemia-reperfusion injuries (IRI) and ventricular remodelling (VR) after a ST-segment elevation myocardial infarction (STEMI). They are associated with clinical adverse events (heart failure and cardiovascular death) adding damage to the myocardium after reperfusion. Moreover, acute myocardial infarction (AMI) induces a local sympathetic denervation leading to electrical instability and arrythmia. Colchicine, a well-known alkaloid with direct anti-inflammatory effects, was shown to reduce the myocardial necrosis size and limit the VR. In a recent proof of concept study, colchicine appears to prevent sympathetic denervation in a mice model of ischemia/reperfusion, but not in the necrosis or in the border zone areas. The Colchicine to Prevent Sympathetic Denervation after an AMI study (COLD-MI) is an ongoing, confirmative, prospective, monocentre, randomized, open-label trial. The COLD-MI trial aims to evaluate the intensity of sympathetic denervation after AMI and its potential modulation due to low dose colchicine. Sympathetic denervation will be noninvasively evaluated using single-photon emission computed tomography (SPECT). After a first episode of STEMI (Initial TIMI flow ≤1) and primary percutaneous coronary intervention (PPCI), patients will be randomized (n = 56) in a 1:1 ratio to either receive colchicine or not for 30 days. The primary end point will be the percentage of myocardial denervation measured by 123I-metaiodobenzylguanidine (123I-MIBG) SPECT at a 6-month follow-up. The main secondary end points will be basic ECG parameters (QRS duration, corrected QT) and HRV parameters from a 24 hour-recording Holter at 1- and 6-months follow-up. Results from this study will contribute to a better understanding of the cardioprotective effect of colchicine after AMI. The present study describes the rationale, design, and methods of the trial.

Abstract 16525: Left Ventricular Unloading Before, Not After, Reperfusion Limits Infarct Size and Improves Survival in Acute Myocardial Infarction: A Bench to Bedside Study

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Navin K Kapur ◽  
Vikram Paruchuri ◽  
Xiaoying Qiao ◽  
Kevin Morine ◽  
Lyanne Buiten ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Infarct Size ◽  
Clinical Utility ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Coronary Reperfusion ◽  
Infarct Zone ◽  
Mitochondrial Integrity ◽  
Phosphorylated Akt

Ischemia-reperfusion injury (IRI) is a major determinant of myocardial damage in acute myocardial infarction (AMI). We explored the hypothesis that reducing left ventricular wall stress (LV unloading) with an axial flow catheter (Impella) before, not after, coronary reperfusion reduces infarct size and improves survival. Methods: We first employed a model of AMI. After 90 minutes of LAD occlusion, adult, male swine (n=4/group) were randomized to: 1) 120 minutes of reperfusion alone (IRI), 2) 30 minutes of LV unloading before 120 minutes of reperfusion (Impella to Balloon Group; ITB) or 3) 30 minutes of reperfusion followed by LV unloading and an additional 120 minutes of reperfusion (Balloon to Impella Group; BTI). Infarct size, myocardial kinase activity, and mitochondrial integrity were quantified. To explore the clinical utility of LV unloading before reperfusion we retrospectively studied all patients in the USPella registry presenting with ST-segmentc elevation AMI and cardiogenic shock who received an Impella within 120 minutes before (n=41; STEMI-ITB) or within 120 minutes after (n=76; STEMI-BTI) percutaneous reperfusion between 2009 and 2014. Results: Compared to IRI alone, infarct size was reduced in the ITB group, not the BTI group (62±2% vs 33±6% vs 58±15%, IRI vs ITB vs BTI, p<0.01 for IRI vs ITB; p<0.05 for ITB vs BTI). Levels of phosphorylated Akt, Erk-1/2, and GSK3b were increased within the infarct zone in the ITB, not BTI group. Mitochondrial numbers and markers of integrity were higher within the infarct zone in the ITB, compared to IRI or BTI. In the registry, in-hospital (51% vs 28%, p=0.02) and 30-day survival (42% vs 20%, p=0.03) were higher in the STEMI-ITB than the STEMI-BTI group. A STEMI-ITB time of less than 60 minutes (n=38) was associated with higher in-hospital survival than a STEMI-BTI time of less than 60 minutes (n=40) (50% vs 25%, p=0.02). Conclusion: Primary LV unloading before, not after, coronary reperfusion reduces infarct size, increases cardioprotective signaling, and improves mitochondrial integrity. These findings are supported by improved survival among patients treated with an Impella before, not after reperfusion in AMI. Future studies are required to explore the clinical utility of primary LV unloading in AMI.

P6599Upregulation of protein and gene expression of arginase-1 in patients with ST elevation myocardial infarction

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
J Tengbom ◽  
S Cederstrom ◽  
D Verouhis ◽  
P Sorensson ◽  
F Bohm ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nitric Oxide ◽  
Myocardial Infarction ◽  
Infarct Size ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Arginase 1 ◽  
St Elevation ◽  
Myocardial Ischemia Reperfusion

Abstract Background The mechanisms underlying rupture of a coronary atherosclerotic plaque and development of myocardial ischemia-reperfusion injury in ST-elevation myocardial infarction (STEMI) remain unknown. Increased arginase-1 activity leads to reduced nitric oxide production and increased formation of reactive oxygen species due to uncoupling of the endothelial nitric oxide synthase (eNOS). These events lead to endothelial dysfunction, plaque instability and increased susceptibility to ischemia-reperfusion injury in acute myocardial infarction. Experimental studies have shown that arginase-1 expression and activity are increased in atherosclerosis and during myocardial ischemia-reperfusion. Accordingly, inhibition of arginase-1 reduces atherosclerotic lesion development and limits the extent of infarct size during ischemia-reperfusion via an eNOS-dependent mechanism. Furthermore, arginase-1 inhibition improves endothelial function in patients with coronary artery disease but the potential role of arginase-1 in patients with STEMI is poorly understood. Purpose The purpose of the current study was to test the hypothesis that arginase-1 is upregulated and correlate to infarct size in STEMI patients. Methods and results Two independent cohorts of STEMI patients were included. In cohort 1, plasma and buffy coat leukocytes were collected from 53 STEMI patients at the time of arterial puncture for percutaneous coronary intervention, at 24–48 hours post STEMI and at 3 months post STEMI. Gene expression in leukocytes was determined in 51 patients with Affymetrix Human Transcriptome Array 2.0. In cohort 2, plasma was collected from 82 STEMI patients at admission and at 6 months for determination of plasma arginase-1. These patients underwent cardiac magnetic resonance imaging performed at day 4–7 and at 6 months post STEMI. Plasma arginase-1 levels were quantified with ELISA. Control blood samples were collected from 56 healthy age matched subjects. In cohort 1, ARG1 gene expression was four-fold higher in STEMI patients at admission compared to controls (Figure A). This expression returned to control levels within 3 months. Plasma arginase-1 levels were two times higher in STEMI patients at admission compared to controls, and remained elevated at 24–48 hours and at 3 months post STEMI (Figure B). The increase in plasma arginase-1 in STEMI patients was confirmed in cohort 2 (Figure C). Arginase-1 levels did not correlate with infarct size. Conclusions STEMI patients demonstrate increased gene expression and plasma levels of arginase-1 in the acute setting. In contrast to gene expression plasma arginase-1 levels remain significantly elevated over time. The markedly increased expression of arginase-1 already at admission may suggest a mechanistic role of arginase-1 in the development of STEMI. Further studies are needed to elucidate whether increased expression, induction and activity of arginase-1 are contributing factors for the development of STEMI.

Cardiomyocyte-Specific JunD Overexpression Increases Infarct Size following Ischemia/Reperfusion Cardiac Injury by Downregulating Sirt3

2019 ◽  
Vol 120 (01) ◽  
pp. 168-180 ◽  
Author(s):  
Alexander Akhmedov ◽  
Fabrizio Montecucco ◽  
Sarah Costantino ◽  
Daria Vdovenko ◽  
Ariane Schaub Clerigué ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Infarct Size ◽  
Molecular Mechanisms ◽  
Potential Role ◽  
Cellular Proliferation ◽  
Ischemia Reperfusion ◽  
Myocardial Infarct Size ◽  
Data Set

AbstractIschemia/reperfusion (I/R) injury in acute myocardial infarction activates several deleterious molecular mechanisms. The transcription factor JunD regulates pathways involved in oxidative stress as well as in cellular proliferation, differentiation, and death. The present study investigated the potential role of JunD as a modulator of myocardial injury pathways in a mouse model of cardiac I/R injury. Infarct size, systemic and local inflammation, and production of reactive oxygen species, as well as cytosolic and mitochondrial apoptotic pathways were investigated in adult males after myocardial I/R. In wild-type (WT) mice, 30 minutes after ischemia and up to 24 hours following reperfusion, cardiac JunD messenger ribonucleic acid expression was reduced while JunB increased. Cardiac-specific JunD overexpressing mice (JunDTg/0 ) displayed larger infarcts compared with WT. However, postischemic inflammatory or oxidative responses did not differ. JunD overexpression reduced Sirt3 transcription by binding to its promoter, thus leading to mitochondrial dysfunction, myocardial cell death, and increased infarct size. On the other hand, JunD silencing reduced, while Sirt3 silencing increased infarct size. In human myocardial autopsy specimens, JunD-positive areas within the infarcted left ventricle staining corresponded to undetectable Sirt3 areas in consecutive sections of the same heart. Cardiac-specific JunD overexpression increases myocardial infarct size following I/R. These effects are mediated via Sirt3 transcriptional repression, mitochondrial swelling, and increased apoptosis, suggesting that JunD is a key regulator of myocardial I/R injury. The present data set the stage for further investigation of the potential role of Sirt3 activation as a novel target for the treatment of acute myocardial infarction.

scholarly journals Veno-occlusive unloading of the heart reduces infarct size in experimental ischemia–reperfusion

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Esben Søvsø Szocska Hansen ◽  
Tobias Lynge Madsen ◽  
Gregory Wood ◽  
Asger Granfeldt ◽  
Nikolaj Bøgh ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Ejection Fraction ◽  
Infarct Size ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Cardiac Work ◽  
Area At Risk ◽  
Lv Ejection Fraction

AbstractMechanical unloading of the left ventricle reduces infarct size after acute myocardial infarction by reducing cardiac work. Left ventricular veno-occlusive unloading reduces cardiac work and may reduce ischemia and reperfusion injury. In a porcine model of myocardial ischemia–reperfusion injury we randomized 18 pigs to either control or veno-occlusive unloading using a balloon engaged from the femoral vein into the inferior caval vein and inflated at onset of ischemia. Evans blue and 2,3,5-triphenyltetrazolium chloride were used to determine the myocardial area at risk and infarct size, respectively. Pressure–volume loops were recorded to calculate cardiac work, left ventricular (LV) volumes and ejection fraction. Veno-occlusive unloading reduced infarct size compared with controls (Unloading 13.9 ± 8.2% versus Control 22.4 ± 6.6%; p = 0.04). Unloading increased myocardial salvage (54.8 ± 23.4% vs 28.5 ± 14.0%; p = 0.02), while the area at risk was similar (28.4 ± 6.7% vs 27.4 ± 5.8%; p = 0.74). LV ejection fraction was preserved in the unloaded group, while the control group showed a reduced LV ejection fraction. Veno-occlusive unloading reduced myocardial infarct size and preserved LV ejection fraction in an experimental acute ischemia–reperfusion model. This proof-of-concept study demonstrated the potential of veno-occlusive unloading as an adjunctive cardioprotective therapy in patients undergoing revascularization for acute myocardial infarction.

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