Nur77 deficiency exacerbates cardiac fibrosis after myocardial infarction through promoting endothelial to mesenchymal transition

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
Q Qin ◽  
J.H Chen ◽  
J.B Jia ◽  
J.Y Qian ◽  
J.B Ge
Keyword(s):  
Myocardial Infarction ◽  
Nuclear Receptor ◽  
Cardiac Fibrosis ◽  
Vascular Endothelial Cells ◽  
Funding Source ◽  
Orphan Nuclear Receptor ◽  
Mesenchymal Transition ◽  
National Budget ◽  
Endothelial To Mesenchymal Transition ◽  
Public Grant

Abstract Background Cardiac fibrosis is a reparative process after myocardial infarction (MI), which leads to cardiac remodeling and finally heart failure. Endothelial-to-mesenchymal transition (EndMT) is induced after MI and contributes to cardiac fibrosis after MI. Orphan nuclear receptor Nur77 is a key regulator of inflammation, angiogenesis, proliferation, and apoptosis in vascular endothelial cells. Here, we investigated the role of orphan nuclear receptor Nur77 in EndMT and cardiac fibrosis after MI. Methods and results Cardiac fibrosis was induced through MI by ligation of the left anterior descending coronary artery. Results suggested that Nur77 knockout aggravated cardiac dysfunction and cardiac fibrosis 30 days after MI. Moreover, Nur77 deficency resulted in enhanced EndMT as shown by increased expression of FSP-1, SM22α, Snail and decreased expression of PECAM-1 and eNOS compared with WT mice after MI. Then we found overexpression Nur77 in HCAECs significantly inhibited IL-1β and TGFβ2 induced EndMT, as shown by reduced transition to a fibroblast-like phenotype and preserved angiogenesis potential. Mechanistically, we demonstrated that Nur77 downregulated EndMT through inhibiting NF-κB-dependent pathway Conclusion Nur77 plays a role in cardiac fibrosis through inhibition of EndMT, and may be a promising target for therapy of cardiac fibrosis after MI. Nur77 inhibited EndMT Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Natural Science Foundation of China

scholarly journals Quantitative 4D Flow CMR analysis of intracardiac blood flow energetics in ischemic cardiomyopathy patients

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
A Riva ◽  
A Camporeale ◽  
F Sturla ◽  
S Pica ◽  
L Tondi ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Ischemic Cardiomyopathy ◽  
Inverse Correlation ◽  
Lv Function ◽  
Funding Source ◽  
4D Flow ◽  
Anterior Myocardial Infarction ◽  
National Budget ◽  
4D Flow Cmr ◽  
Public Grant

Abstract Background Ischemic cardiomyopathy (ICM) is often associated with negative LV remodelling after myocardial infarction, sometimes resulting in impaired LV function and dilation (iDCM). 4D Flow CMR has been recently exploited to assess intracardiac hemodynamic changes in presence of LV remodelling. Purpose To quantify 4D Flow intracardiac kinetic energy (KE) and viscous energy loss (EL) and investigate their relation with LV dysfunction and remodelling. Methods Patients with prior anterior myocardial infarction underwent a CMR study with 4D Flow sequences acquisition; they were divided into ICM (n=10) and iDCM (n=10, EDV>208 ml and EF<40%). 10 controls were used for comparison. LV was semi-automatically segmented using short axis CMR stacks and co-registered with 4D Flow. Global KE and EL were computed over the cardiac cycle. NT-proBNP measurements were correlated with average and peak values, during systole and diastole. Results Both LV volume and EF significantly differ (P<0.0001) between iDCM (EDV=294±56 ml, EF=24±8%), ICM (EDV=181±32 ml, EF=34±6%) and controls (EDV=124±29 ml, EF=72±5%). If compared to controls, both ICM and iDCM showed significantly lower KE (P≤0.0008); though lower than controls, EL was higher in iDCM than ICM. Within the iDCM subgroup, diastolic mean KE and peak EL reported good inverse correlation with NT-proBNP (r=−0.75 and r=−0.69, respectively). EL indexed (ELI) to average KE during systole was higher in the entire ischemic group as compared to controls (ELI(ischemic) = 0.17 vs. ELI(controls) = 0.10, P=0.0054). Conclusions 4D Flow analyses effectively mapped post-ischemic LV energetic changes, highlighting the disproportionate intraventricular EL relative to produced KE; preliminary good correlation between LV energetic changes and NT-proBNP will deserve further investigation in order to contribute to early detection of heart failure. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Italian Ministry of Health

Impact of pre-hospital resuscitation on short-and long-term mortality in patients with cardiogenic shock and multivessel disease. Results of the CULPRIT trial

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
U Zeymer ◽  
B Alushi ◽  
A Lauten ◽  
I Akin ◽  
S Desch ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Cardiogenic Shock ◽  
Coronary Intervention ◽  
Funding Source ◽  
National Budget ◽  
Cardio Pulmonary Resuscitation ◽  
Percutaneous Coronary ◽  
Public Grant ◽  
The Impact

Abstract Background There are only a few prospective data on the outcome of patients with cardio-pulmonary resuscitation (CPR) admitted with acute myocardial infarction (AMI) complicated by cardiogenic shock and an invasive strategy including primary percutaneous coronary intervention (PCI). Therefore, we evaluated the impact of pre-hospital CPR on outcomes in a large group of patients with AMI complicated by cardiogenic shock. Methods We used the data of the prospective CULPRIT-Shock trial and registry and including patients with acute myocardial infarction complicated by cardiogenic shock. The primary endpoint was 30-day mortality or renal replacement therapy. Results Between 2013 and 2017, a total of 1055 patients were included in the randomized trial (n=686) and in the registry (n=369), 550 (54%) had CPR, 40 had no information regarding CPR. Baseline characteristics, procedural features and outcomes in the two groups with and without CPR are given in the table. Conclusion Patients with pre-hospital CPR represent more than half of the population with AMI complicated by cardiogenic shock. They are younger, have less risk factors and more often LAD as infarct vessel. Despite the younger age and a high success rate of PCI patients with CPR have a high 30-day mortality. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Deutsches Zentrum fuer Herz-Kreislauf-Forschung - DZHK

scholarly journals Macrophages promote endothelial-to-mesenchymal transition via MT1-MMP/TGFβ1 after myocardial infarction

2020 ◽  
Author(s):  
Laura Alonso-Herranz ◽  
Álvaro Sahún-Español ◽  
Pilar Gonzalo ◽  
Polyxeni Gkontra ◽  
Vanessa Núñez ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Endothelial Cells ◽  
Cardiac Dysfunction ◽  
Cardiac Fibrosis ◽  
Cell Types ◽  
Cardiac Repair ◽  
Wild Type ◽  
Mesenchymal Transition ◽  
Adverse Remodeling ◽  
Endothelial To Mesenchymal Transition

ABSTRACTMacrophages produce factors that participate in cardiac repair and remodeling after myocardial infarction (MI); however, how these factors crosstalk with other cell types mediating repair is not fully understood. In this study, we demonstrated that cardiac macrophages increased expression of Mmp14 (MT1-MMP) 7 days post-MI. Specific macrophage-targeting of MT1-MMP (MT1-MMPΔLysM mice) attenuates post-MI cardiac dysfunction, reduces fibrosis, and preserves the cardiac capillary network. Mechanistically, we showed that MT1-MMP activates latent TGFβ1 in macrophages, leading to paracrine SMAD2-mediated signaling in endothelial cells and endothelial-to-mesenchymal transition (EndMT). Post-MI MT1-MMPΔLysM hearts contained fewer cells undergoing EndMT than their wild-type counterparts, and MT1-MMP-deficient macrophages showed a reduced ability to induce EndMT in co-cultures with endothelial cells. Our results demonstrate the contribution of EndMT to cardiac fibrosis and adverse remodeling post-MI and identify macrophage MT1-MMP as a key regulator of this process. The identified mechanism has potential as a therapeutic target in ischemic heart disease.

scholarly journals Macrophages promote endothelial-to-mesenchymal transition via MT1-MMP/TGFβ1 after myocardial infarction

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Laura Alonso-Herranz ◽  
Álvaro Sahún-Español ◽  
Ana Paredes ◽  
Pilar Gonzalo ◽  
Polyxeni Gkontra ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Endothelial Cells ◽  
Cardiac Dysfunction ◽  
Cardiac Fibrosis ◽  
Cell Types ◽  
Cardiac Repair ◽  
Wild Type ◽  
Mesenchymal Transition ◽  
Adverse Remodeling ◽  
Endothelial To Mesenchymal Transition

Macrophages (Mφs) produce factors that participate in cardiac repair and remodeling after myocardial infarction (MI); however, how these factors crosstalk with other cell types mediating repair is not fully understood. Here we demonstrated that cardiac Mφs increased the expression of Mmp14 (MT1-MMP) 7 days post-MI. We selectively inactivated the Mmp14 gene in Mφs using a genetic strategy (Mmp14f/f:Lyz2-Cre). This conditional KO (MAC-Mmp14 KO) resulted in attenuated post-MI cardiac dysfunction, reduced fibrosis, and preserved cardiac capillary network. Mechanistically, we showed that MT1-MMP activates latent TGFβ1 in Mφs, leading to paracrine SMAD2-mediated signaling in endothelial cells (ECs) and endothelial-to-mesenchymal transition (EndMT). Post-MI MAC-Mmp14 KO hearts contained fewer cells undergoing EndMT than their wild-type counterparts, and Mmp14-deficient Mφs showed a reduced ability to induce EndMT in co-cultures with ECs. Our results indicate the contribution of EndMT to cardiac fibrosis and adverse remodeling post-MI and identify Mφ MT1-MMP as a key regulator of this process.

scholarly journals Endothelial-to-mesenchymal transition in lipopolysaccharide-induced acute lung injury drives a progenitor cell-like phenotype

2016 ◽  
Vol 310 (11) ◽  
pp. L1185-L1198 ◽  
Author(s):  
Toshio Suzuki ◽  
Yuji Tada ◽  
Rintaro Nishimura ◽  
Takeshi Kawasaki ◽  
Ayumi Sekine ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Endothelial Cells ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Vascular Endothelial Cells ◽  
Repair Process ◽  
Vascular Endothelial ◽  
Mesenchymal Transition ◽  
Oxidase Inhibition ◽  
Endothelial To Mesenchymal Transition

Pulmonary vascular endothelial function may be impaired by oxidative stress in endotoxemia-derived acute lung injury. Growing evidence suggests that endothelial-to-mesenchymal transition (EndMT) could play a pivotal role in various respiratory diseases; however, it remains unclear whether EndMT participates in the injury/repair process of septic acute lung injury. Here, we analyzed lipopolysaccharide (LPS)-treated mice whose total number of pulmonary vascular endothelial cells (PVECs) transiently decreased after production of reactive oxygen species (ROS), while the population of EndMT-PVECs significantly increased. NAD(P)H oxidase inhibition suppressed EndMT of PVECs. Most EndMT-PVECs derived from tissue-resident cells, not from bone marrow, as assessed by mice with chimeric bone marrow. Bromodeoxyuridine-incorporation assays revealed higher proliferation of capillary EndMT-PVECs. In addition, EndMT-PVECs strongly expressed c- kit and CD133. LPS loading to human lung microvascular endothelial cells (HMVEC-Ls) induced reversible EndMT, as evidenced by phenotypic recovery observed after removal of LPS. LPS-induced EndMT-HMVEC-Ls had increased vasculogenic ability, aldehyde dehydrogenase activity, and expression of drug resistance genes, which are also fundamental properties of progenitor cells. Taken together, our results demonstrate that LPS induces EndMT of tissue-resident PVECs during the early phase of acute lung injury, partly mediated by ROS, contributing to increased proliferation of PVECs.

Effect of infarct stiffness on non-infarcted left and right ventricular tissue remodeling: a computational study based on myocardial mechano-transduction

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
T Koopsen ◽  
N Van Osta ◽  
E Willemen ◽  
F.A Van Nieuwenhoven ◽  
J Gorcsan ◽  
...  
Keyword(s):  
Computational Model ◽  
Computational Study ◽  
Compensatory Hypertrophy ◽  
Funding Source ◽  
Tissue Mass ◽  
Model Simulations ◽  
National Budget ◽  
End Diastolic Volume ◽  
Public Grant ◽  
Infarcted Tissue

Abstract Background/Introduction The mechanical properties of infarcted myocardium are important determinants of cardiac pump function and risk of developing heart failure following myocardial infarction (MI). Purpose To better understand the effects of infarct stiffness on compensatory hypertrophy and dilation of non-infarcted tissue in the left (LV) and right ventricle (RV), by using a computational model. Methods The CircAdapt computational model of the human heart and circulation was applied to simulate an acute MI involving 20% of LV wall mass. The simulation was validated using previously published experimental data. Subsequently, two degrees of increased infarct stiffness were simulated. In all three simulations, a model of structural myocardial adaptation of the non-infarcted tissue was applied, based on sensing of mechanical loading of myocytes and extracellular matrix (ECM). Results Mild and severe stiffening of the infarct reduced the increase of LV end-diastolic volume (EDV) from +23 mL to +17 mL and +16 mL, respectively, and the increase of LV non-infarcted tissue mass from +31% to +21% and +18%. RV EDV decreased after adaptation, and mild and severe infarct stiffening reduced the decrease of RV EDV from −21 mL to −12 mL and −10 mL, respectively. Increase of RV tissue mass was reduced from +13% to +8% and +7% with mild and severe infarct stiffening. In the LV, reduced dilation and hypertrophy were driven mainly by a reduction of maximum stress in the ECM and a higher stress between the myocytes and ECM following infarct stiffening. The decreased RV hypertrophy, but not EDV reduction, was caused by a reduction of maximum RV ECM stress and maximum RV active myofiber stress. Conclusions Model simulations predicted that a stiffened LV infarct reduces both LV and RV non-infarcted tissue hypertrophy as well as LV dilation. In LV remodeling, maximum ECM stress and stress between myocyte and ECM played a more prominent role than in RV remodeling, while maximum active stress was more important in the RV. Overview of all model simulations Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): This work was funded by the Netherlands Organisation for Scientific Research and the Dutch Heart Foundation.

Is there an exercise duration threshold for exercise-induced troponin elevation in healthy recreational athletes? The NEEDED 2014 advanced heart rate monitor substudy

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M Bjorkavoll-Bergseth ◽  
B Auestad ◽  
O Kleiven ◽  
O Skadberg ◽  
T Eftestol ◽  
...  
Keyword(s):  
Heart Rate ◽  
Clinical Status ◽  
Exercise Duration ◽  
Strenuous Exercise ◽  
Clinical Consequence ◽  
Funding Source ◽  
Recreational Athletes ◽  
National Budget ◽  
Exercise Induced ◽  
Public Grant

Abstract Background/Introduction Following prolonged strenuous exercise there is an exercise-induced troponin (cTn) elevation in healthy individuals. The precise mechanisms and clinical consequence of this cTn elevation remain to be determined. It has recently been demonstrated that exercise intensity, exceeding a heart rate (HR) of 150 bpm, is correlated with exercise-induced cTn elevation. Purpose The present work aims to determine if there is a threshold for exercise duration with a HR exceeding 150 bpm associated with an excessive exercise-induced cTn elevation. Methods A total of 177 healthy subjects were included in the present analysis of HR data obtained from sport watches used during a 91-km recreational mountain bike cycle race. Clinical status, cTnI, ECGs, blood pressure and demographics were obtained 24 h prior to- and at 3 h and 24 h after the race. Results are reported as median and 25th and 75th percentile. We used Tree regression to determine the association between elevated cTnI and exercise duration exceeding a HR of 150 bpm. Results Subjects were 82% (n=146) males, 44 (39–51) years, with a race time of 3.5 (3.1–3.9) h. Baseline cTnI was 1.9 (1.6–3.3) ng/L. There was a cTnI elevation in all study participants at 3 h, cTnI: 60.0 (36.0–99.3) ng/L, with a significant (p<0.001) reduction at 24 hours following exercise, cTnI: 10.9 (6.1–22.4) ng/L. Tree regression identified 168 min of exercise, with a HR exceeding 150 bpm, to be associated with an excessive increase in cTnI both at 3 h, and at 24 h following the race (figure). The median cTn values above and below the threshold are presented in the Table. Conclusion The present analysis suggests that exceeding a specific duration of high intensity exercise may be associated with excessive cTn elevation in susceptible individuals. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Western Norway Health authoritites.

scholarly journals Distinguishing sinus rhythm from atrial fibrillation on single-lead ECGs using a deep neural network

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M Oudkerk Pool ◽  
B.D De Vos ◽  
J.M Wolterink ◽  
S Blok ◽  
M.J Schuuring ◽  
...  
Keyword(s):  
Neural Network ◽  
Atrial Fibrillation ◽  
Sinus Rhythm ◽  
Roc Curve ◽  
Model Development ◽  
Independent Set ◽  
Funding Source ◽  
National Budget ◽  
Validation Set ◽  
Public Grant

Abstract Background The growing availability of mobile phones increases the popularity of portable telemonitoring devices. An atrial fibrillation diagnosis can be reached with a recording of 30s on such telemonitoring devices. However, current commercially available automatic algorithms still require approval by experts. Purpose In this research we aimed to build an artificial intelligence (AI) algorithm to improve automatic distinction of atrial fibrillation (AF) from sinus rhythm (SR), to ultimately save time, costs, and to facilitate telemonitoring programs. Methods We developed a deep convolutional neural network (CNN), based on a residual neural network (ResNet), tailored to single-lead ECG analysis. The CNN was trained using publicly available single-lead ECGs from the 2017 PhysioNet/ Computing in Cardiology Challenge. This dataset consists of 60% SR, 9% AF, 30% alternative rhythm, and 1% noise ECGs. The 8528 available ECGs were divided into a training (90%) and validation set (10%) for model development and hyperparameter optimization. Results The trained CNN was applied to an independent set containing single-lead ECGs of 600 patients equally divided into two groups: SR and AF. Both groups comprised of 300 unique ECGs (SR; 60% male, 63±11 years, AF; 38% male, 56±14 years). In distinguishing between AF and SR, the method achieved an accuracy of 0.92, an F1-score of 0.91, and area under the ROC-curve of 0.98. Conclusion The results demonstrate that distinguishing SR and AF by a fully automatic AI algorithm is feasible. This approach has the potential to reduce cost by minimizing expert supervision, especially when extending the algorithm to other heart rhythms, like premature atrial/ventricular contractions and atrial flutter. Figure 1. ROC curve Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Dekkerbeurs - Hartstichting

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