Abstract 18592: Anti-arrhythmic Effect of a Novel Rycal, S44121 / Arm036, in a Post-myocardial Infarction Mouse Model of Heart Failure

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Jerome Thireau ◽  
Charlotte Farah ◽  
Muriel Bouly ◽  
Jerome Roussel ◽  
Alain Lacampagne ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Mouse Model ◽  
Ryanodine Receptors ◽  
Left Ventricular ◽  
Cardiac Contraction ◽  
Post Myocardial Infarction ◽  
Coronary Artery Ligation ◽  
Artery Ligation

Introduction: Targeting leaky cardiac ryanodine receptors (RyR2) to prevent diastolic Ca2+ release from the sarcoplasmic reticulum (SR) is a promising pharmacological approach, to rescue the impaired cardiac contraction and prevent Ca2+-dependent arrhythmias in heart failure (HF) and disease. Hypothesis: Based on prior work from the Marks group, the Rycal S44121 (also known as ARM036) is an experimental small molecule stabilizer of RyR. We investigated the effects of S44121 in a post-myocardial infarction (PMI) mouse model of HF. Methods and results: Mice were randomly assigned to 3 groups: Sham, PMI (subjected to left coronary artery ligation), and PMI-S (treated for 3 weeks with S44121 by subcutaneous osmotic pumps on day 7 post-MI, 10 mg/kg/day). Intracellular Ca2+ was measured on single left ventricular myocytes. PMI mice exhibited a 4-fold increase in the frequency of spontaneous Ca2+ release events, Ca2+ sparks, as measured in quiescent cells using the fluorescent Ca2+ indicator Fluo-4. PMI mice also exhibited higher global diastolic Ca2+, measured with the ratiometric fluorescent probe, Indo-1 AM, and increased the occurrence of ectopic diastolic Ca2+ waves. Acute application of S44121 (10 μM for 15 min) reduced Ca2+ sparks frequency. Chronic treatment of mice with S44121 also normalized the frequency of Ca2+ sparks and of ectopic Ca2+ waves, and corrected diastolic cellular Ca2+ overload. Effects were maximal at 20 mg/kg/day. Furthermore, treatment with S44121 abolished Ca2+ waves promoted by β-adrenergic challenge (acute application of isoproterenol, 10 nM). The potential anti-arrhythmic benefit of S44121 was assessed in vivo using telemetric surface electrocardiograms. S44121 had no effect on ECG intervals and did not alter the heart rate. However, anti-arrhythmic effects were confirmed by observation of a dose-dependent reduction of spontaneous ventricular extrasystoles and ventricular tachycardia. Near maximum benefits were observed at 10 mg/kg/day, both in basal conditions or following a challenge with acute treatment of isoproterenol (0.5 mg/kg, dosed ip). Conclusion: In mice with post-ischemic HF, treatment with S44121 prevented the abnormal diastolic SR Ca2+ leak and ectopic Ca2+ waves, and reduced ventricular arrhythmias.

scholarly journals Exercise Training Stabilizes RyR2-Dependent Ca2+ Release in Post-infarction Heart Failure

2021 ◽  
Vol 7 ◽  
Author(s):  
Tore Kristian Danielsen ◽  
Mani Sadredini ◽  
Ravinea Manotheepan ◽  
Jan Magnus Aronsen ◽  
Michael Frisk ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Exercise Training ◽  
Radioligand Binding ◽  
Left Ventricular ◽  
Post Myocardial Infarction ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Ventricular Cardiomyocytes ◽  
Male Wistar Rats

Aim: Dysfunction of the cardiac ryanodine receptor (RyR2) is an almost ubiquitous finding in animal models of heart failure (HF) and results in abnormal Ca2+ release in cardiomyocytes that contributes to contractile impairment and arrhythmias. We tested whether exercise training (ET), as recommended by current guidelines, had the potential to stabilize RyR2-dependent Ca2+ release in rats with post-myocardial infarction HF.Materials and Methods: We subjected male Wistar rats to left coronary artery ligation or sham operations. After 1 week, animals were characterized by echocardiography and randomized to high-intensity interval ET on treadmills or to sedentary behavior (SED). Running speed was adjusted based on a weekly VO2max test. We repeated echocardiography after 5 weeks of ET and harvested left ventricular cardiomyocytes for analysis of RyR2-dependent systolic and spontaneous Ca2+ release. Phosphoproteins were analyzed by Western blotting, and beta-adrenoceptor density was quantified by radioligand binding.Results: ET increased VO2max in HF-ET rats to 127% of HF-SED (P < 0.05). This coincided with attenuated spontaneous SR Ca2+ release in left ventricular cardiomyocytes from HF-ET but also reduced Ca2+ transient amplitude and slowed Ca2+ reuptake during adrenoceptor activation. However, ventricular diameter and fractional shortening were unaffected by ET. Analysis of Ca2+ homeostasis and major proteins involved in the regulation of SR Ca2+ release and reuptake could not explain the attenuated spontaneous SR Ca2+ release or reduced Ca2+ transient amplitude. Importantly, measurements of beta-adrenoceptors showed a normalization of beta1-adrenoceptor density and beta1:beta2-adrenoceptor ratio in HF-ET.Conclusion: ET increased aerobic capacity in post-myocardial infarction HF rats and stabilized RyR2-dependent Ca2+ release. Our data show that these effects of ET can be gained without major alterations in SR Ca2+ regulatory proteins and indicate that future studies should include upstream parts of the sympathetic signaling pathway.

scholarly journals Progression of heart failure after myocardial infarction in the rat

2001 ◽  
Vol 281 (5) ◽  
pp. R1734-R1745 ◽  
Author(s):  
J. Francis ◽  
R. M. Weiss ◽  
S. G. Wei ◽  
A. K. Johnson ◽  
R. B. Felder
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Ventricular Remodeling ◽  
Systolic Function ◽  
Left Ventricular Remodeling ◽  
Plasma Renin ◽  
Left Ventricular Systolic Function ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Artery Ligation

This study examined the early neurohumoral events in the progression of congestive heart failure (CHF) after myocardial infarction (MI) in rats. Immediately after MI was induced by coronary artery ligation, rats had severely depressed left ventricular systolic function and increased left ventricular end-diastolic volume (LVEDV). Both left ventricular function and the neurohumoral indicators of CHF underwent dynamic changes over the next 6 wk. LVEDV increased continuously over the study interval, whereas left ventricular stroke volume increased but reached a plateau at 4 wk. Plasma renin activity (PRA), arginine vasopressin, and atrial natriuretic factor all increased, but with differing time courses. PRA declined to a lower steady-state level by 4 wk. Six to 8 wk after MI, CHF rats had enhanced renal sympathetic nerve activity and blunted baroreflex regulation. These findings demonstrate that the early course of heart failure is characterized not by a simple “switching on” of neurohumoral drive, but rather by dynamic fluctuations in neurohumoral regulation that are linked to the process of left ventricular remodeling.

scholarly journals Integrative System Biology Analyses Identify Seven MicroRNAs to Predict Heart Failure

2019 ◽  
Vol 5 (1) ◽  
pp. 22 ◽  
Author(s):  
Henri Charrier ◽  
Marie Cuvelliez ◽  
Emilie Dubois-Deruy ◽  
Paul Mulder ◽  
Vincent Richard ◽  
...  
Keyword(s):  
Heart Failure ◽  
Systems Biology ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Mirna Signature ◽  
Artery Ligation ◽  
Proteomic Data

Heart failure (HF) has several etiologies including myocardial infarction (MI) and left ventricular remodeling (LVR), but its progression remains difficult to predict in clinical practice. Systems biology analyses of LVR after MI provide molecular insights into this event such as modulation of microRNA (miRNA) that could be used as a signature of HF progression. To define a miRNA signature of LVR after MI, we use 2 systems biology approaches, integrating either proteomic data generated from LV of post-MI rat induced by left coronary artery ligation or multi-omics data (proteins and non-coding RNAs) generated from plasma of post-MI patients from the REVE-2 study. The first approach predicted that 13 miRNAs and 3 of these miRNAs would be validated to be associated with LVR in vivo: miR-21-5p, miR-23a-3p and miR-222-3p. The second approach predicted that 24 miRNAs among 1310 molecules and 6 of these miRNAs would be selected to be associated with LVR in silico: miR-17-5p, miR-21-5p, miR-26b-5p, miR-222-3p, miR-335-5p and miR-375. We identified a signature of 7 microRNAs associated with LVR after MI that support the interest of integrative systems biology analyses to define a miRNA signature of HF progression.

scholarly journals Changes in myofilament proteins, but not Ca2+ regulation, are associated with a high-fat diet-induced improvement in contractile function in heart failure

2011 ◽  
Vol 301 (4) ◽  
pp. H1438-H1446 ◽  
Author(s):  
Y. Cheng ◽  
W. Li ◽  
T. A. McElfresh ◽  
X. Chen ◽  
J. M. Berthiaume ◽  
...  
Keyword(s):  
Heart Failure ◽  
Protein Expression ◽  
Contractile Function ◽  
Left Ventricular ◽  
Contractile Properties ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Cell Shortening ◽  
Regulatory Properties

Pathological conditions such as diabetes, insulin resistance, and obesity are characterized by elevated plasma and myocardial lipid levels and have been reported to exacerbate the progression of heart failure (HF). Alterations in cardiomyocyte Ca2+ regulatory properties and myofilament proteins have also been implicated in contractile dysfunction in HF. However, our prior studies reported that high saturated fat (SAT) feeding improves in vivo myocardial contractile function, thereby exerting a cardioprotective effect in HF. Therefore, we hypothesized that SAT feeding improves contractile function by altering Ca2+ regulatory properties and myofilament protein expression in HF. Male Wistar rats underwent coronary artery ligation (HF) or sham surgery (SH) and were fed normal chow (SHNC and HFNC groups) or a SAT diet (SHSAT and HFSAT groups) for 8 wk. Contractile properties were measured in vivo [echocardiography and left ventricular (LV) cannulation] and in isolated LV cardiomyocytes. In vivo measures of contractility (peak LV +dP/d t and −dP/d t) were depressed in the HFNC versus SHNC group but improved in the HFSAT group. Isolated cardiomyocytes from both HF groups were hypertrophied and had decreased percent cell shortening and a prolonged time to half-decay of the Ca2+ transient versus the SH group; however, SAT feeding reduced in vivo myocyte hypertrophy in the HFSAT group only. The peak velocity of cell shortening was reduced in the HFNC group but not the HFSAT group and was positively correlated with in vivo contractile function (peak LV +dP/d t). The HFNC group demonstrated a myosin heavy chain (MHC) isoform switch from fast MHC-α to slow MHC-β, which was prevented in the HFSAT group. Alterations in Ca2+ transients, L-type Ca2+ currents, and protein expression of sarco(endo)plasmic reticulum Ca2+-ATPase and phosphorylated phospholamban could not account for the changes in the in vivo contractile properties. In conclusion, the cardioprotective effects associated with SAT feeding in HF may occur at the level of the isolated cardiomyocyte, specifically involving changes in myofilament function but not sarcoplasmic reticulum Ca2+ regulatory properties.

Abstract P274: Cardiac-Specific Knockout of Capn4 Attenuates Myocardial Remodeling and Improves Function After Myocardial Infarction in Mice

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Jian Ma ◽  
Meng Wei ◽  
Hao Wang ◽  
Weihua Liu ◽  
Wei Zhu ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Mouse Model ◽  
Coronary Artery Ligation ◽  
Down Regulation ◽  
Artery Ligation ◽  
Cardiac Apoptosis ◽  
Myocardial Remodelling ◽  
Calpain 2 ◽  
Specific Deletion

Background - Calpain has been implicated in myocardial injury after myocardial infarction (MI). However, no direct evidence is available on the role of calpain in post-MI myocardial remodelling and dysfunction. The present study investigated the effects of cardiomyocyte-specific deletion of Capn4 , essential for calpain-1 and calpain-2 activities on myocardial remodelling and dysfunction following MI. Methods and Results - A novel mouse model with cardiomyocyte-specific deletion of Capn4 ( Capn4-ko ) was generated. MI was induced by left coronary artery ligation. Deficiency of Capn4 significantly reduced the protein levels and activities of calpain-1 and calpain-2 in the Capn4-ko heart. In vivo cardiac function was relatively improved in Capn4-ko mice at 7 and 30 days after MI compared with their wild-type littermates. Deletion of Capn4 reduced cardiac apoptosis, limited infarct expansion and infarct zone thinning, and prevented left ventricle dilation in Capn4-ko mice. Furthermore, myocardial collagen deposition and cardiomyocyte cross-sectional areas were significantly attenuated in Capn4-ko mice, which were accompanied by down-regulation of pro-fibrotic genes and hypertrophic genes. These effects of Capn4 knockout correlated with down-regulation of inflammatory mediators and normalization of matrix metalloproteinase (MMP)-9 activity in the non-infarct area of Capn4-ko mice after MI. In vivo mouse model of endotoxemia confirmed that calpain activation resulted in inflammatory gene expression and MMP-9 activity in the heart. Conclusions - Cardiomyocyte-specific knockout of calpain attenuates myocardial adverse remodelling and improves myocardial function after MI. These beneficial effects of calpain disruption may result from inhibition of cardiac apoptosis, inflammation and MMP-9 activity.

Abstract 277: Development of Anxiety- and Depression-Like Behavior in Mice After Myocardial Infarction

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Anna Frey ◽  
Sandy Popp ◽  
Antonia Post ◽  
Marc Lehmann ◽  
Anna-Leena Sirén ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Sucrose Solution ◽  
Left Ventricular ◽  
Neuronal Morphology ◽  
Brain Morphology ◽  
Anxiety And Depression ◽  
Coronary Artery Ligation ◽  
Normal Brain ◽  
Artery Ligation

Objective: Anxiety and depression are common and independently predict mortality in patients with heart failure. The mechanisms of these interrelations are still unclear. Consequently, we developed a model in C57BL/6 mice with experimental myocardial infarction (MI) and heart failure to study anxiety- or depression-like behavior. Methods: Heart failure was achieved after coronary artery ligation in 13 mice; 16 sham operated mice acted as controls. Left ventricular (LV) remodeling was assessed by echocardiography, infarct size by histology. Sucrose preference test was performed over a period of 8 weeks to assess depression-like behavior. The elevated plus maze (EPM), the light-dark box (LDB) and the open field (OF) tests were subsequently applied to determine general disinterest and anxiety-like behavior. Finally, the histological and immunohistochemical evaluation of the brain was performed. Results: Mice with MI size of at least 30% of LV (averaged 50±3%; increase in diastolic LV diameter from 0.40±0.02 cm to 0.62±0.03 cm) showed diminished intake (p=0.029) and preference (p=0.029) for sucrose solution. Besides, MI mice exhibited reduced exploratory behavior and markedly lower interest in unfamiliar environments, indicated by an increase in center time (p=0.016) and a reduced number of vertical rears (p=0.037) in the EPM. An increased latency to the first rear (p=0.018), covered shorter distances (p=0.048) and spent less time moving (p=0.028) in the OF were found in MI mice. MI did not affect anxiety-related measures in all three tests (all p>0.05). MI mice showed normal brain morphology with normal neuronal morphology and neuropil structure, also confirmed by normal expression of selected neuronal markers. Markers for neurodegeneration, apoptosis or inflammation showed no abnormalities in MI mice. Conclusions: Mice with MI exhibited anhedonia-like behavior, which was accompanied by other characteristics of depression-like behavior, such as decreased exploratory activity and interest in novelty. Hence, MI caused distinct behavioral changes in mice comparable to symptoms observed in humans with heart failure and comorbid depression, but did not affect anxiety-like behavior. The model is suitable for further mechanistic studies.

Abstract 249: Chronic Neuregulin-1β Treatment Mitigates the Progression of Post-myocardial Infarction Heart Failure in the Setting of Type 1 Diabetes Mellitus

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Manisha Gupte ◽  
Hind Lal ◽  
Firdos Ahmad ◽  
Lin Zhong ◽  
Douglas B Sawyer ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Type 1 Diabetes ◽  
Heart Function ◽  
Diabetic Rats ◽  
Left Ventricular ◽  
Lv Function ◽  
Coronary Artery Ligation ◽  
Artery Ligation

Aim: Neuregulin-1β (NRG-1β), a growth factor critical for cardiac development as well as maintenance of heart function after injury has been shown to significantly improve heart function in preclinical rodent models. Importantly, number of studies are ongoing to test the efficacy of NRG-1β as a treatment for patients with chronic heart failure. However, the efficacy of recombinant NRG-1β in a typ1 diabetic model of heart failure due to myocardial infarction (MI) has not been investigated. The aim of the present study was to determine the efficacy of exogenous NRG-1β to improve residual cardiac function after MI in type1 diabetic rats. Methods and Results: Sprague Dawley rats were induced type 1 diabetes by a single injection of streptozotocin (STZ) (65 mg/kg). Two weeks after induction of type 1 diabetes, rats underwent left coronary artery ligation to induce MI. STZ-diabetic rats were treated with saline or NRG-1β (100 ug/kg) twice a week for 7 weeks, starting two weeks prior to experimental MI. Residual left ventricular (LV) function was significantly greater in the NRG-1β-treated STZ-diabetic MI group compared to the vehicle-treated STZ-diabetic MI group 5 weeks after MI as assessed by high-resolution echocardiography. Furthermore, NRG-1β treatment in STZ-diabetic MI rats reduced myocardial fibrosis and apoptosis as well as decreased gene expression of key oxidant-producing enzymes. Conclusion: This study demonstrates that augmentation of NRG-1β signaling in STZ-diabetic post-MI rats via therapy with exogenous recombinant NRG-1β will alleviate subsequent HF through improvements in residual LV function via protection against adverse remodeling and apoptosis.

Abstract 14553: Mitochondrial Calcium Uptake via Mitochondrial Calcium Uniporter Suppress Ventricular Arrhythmia in the Ischemic Heart Failure Mice

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Hikaru Hagiwara ◽  
Masaya Watanabe ◽  
Yoichiro Fujioka, ◽  
Taro Koya ◽  
Motoki Nakao ◽  
...  
Keyword(s):  
Heart Failure ◽  
Left Ventricular ◽  
Epifluorescence Microscopy ◽  
Mitochondrial Calcium ◽  
Coronary Artery Ligation ◽  
Sham Operation ◽  
Artery Ligation ◽  
Mitochondrial Calcium Uniporter ◽  
Calcium Uniporter

Background: Delayed after depolarization by calcium (Ca 2+ ) leak from sarcoplasmic reticulum (SR) via Ryanodine receptor is one of the causes of ventricular arrhythmias (VAs) in heart failure (HF). Ca 2+ uptake into mitochondria via mitochondrial calcium uniporter (MCU) is participated in Ca 2+ handling, but the relationship between VAs in HF and Ca 2+ uptake into mitochondria is unclear. Purpose: We sought to investigate whether increased Ca 2+ uptake into mitochondria via MCU reduces diastolic Ca 2+ leak and suppresses VAs in ischemic HF mice. Methods: Ten-week-old male C57BL/6J mice were divided into 2 groups; sham operation mice (Sham) or HF mice (HF) in which myocardial infarction was induced by left coronary artery ligation. After 4-6 weeks, cardiomyocyte or mitochondria were isolated respectively from the myocardium of Sham and the non-infarct myocardium of HF. Ca 2+ waves (CaWs) were measured on an epifluorescence microscopy. Calcium transients and calcium sparks were measured on a confocal microscope in linescan mode. Mitochondrial Ca 2+ uptake were measured by estimating the extra-mitochondrial Ca 2+ reduction with Fluo-5N on a spectrofluoro-photometer. VAs was induced in the Langendorff perfused hearts. Left ventricular (LV) pressure was measured using a microtip transducer catheter . Results: HF mice showed left ventricular dysfunction and increased heart and lung weights compared to Sham. Kaempferol, a MCU activator, increased mitochondrial Ca 2+ uptake in the isolated mitochondria both in Sham and HF. CaWs and Ca spark frequency in the presence of isoproterenol was attenuated by 10 μM Kaempferol. Kaempferol did not show significant changes in Ca 2+ transient amplitude, however increased the time to 50% decay significantly. The incidence of induced VAs was suppressed by Kaempferol. In vivo measurements, intravenous administration of Kaempferol (5mg/kg) did not show significant changes in hemodynamic parameters in HF mice. Conclusions: Ca 2+ uptake into mitochondria via MCU suppresses VAs in HF. Despite the adverse influence of the traditional antiarrhythmic drugs for HF condition, a novel strategy that promotes Ca 2+ uptake into mitochondria might be a potential therapeutic approach for VA treatment in HF patients.

Na+/H+ exchange inhibition reduces hypertrophy and heart failure after myocardial infarction in rats

2001 ◽  
Vol 280 (2) ◽  
pp. H738-H745 ◽  
Author(s):  
Keiji Kusumoto ◽  
James V. Haist ◽  
Morris Karmazyn
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Coronary Artery ◽  
Hydrogen Exchange ◽  
Diastolic Pressure ◽  
Control Diet ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Large Infarct

We investigated the effect of sodium/hydrogen exchange inhibition (NHE-1) on hypertrophy and heart failure after coronary artery ligation (CAL) in the rat. Animals were subjected to occlusion (or sham) of the left main coronary artery and immediately administered a control diet or one consisting of the NHE-1 inhibitor cariporide for 13–15 wk. Hearts were separated by small [≤30% of left ventricle (LV)] and large (>30% of LV) infarcts. CAL depressed change in left ventricular increase in pressure over time (LV +dP/d t) in small and large infarct groups by 18.8% ( P < 0.05) and 34% ( P < 0.01), respectively, whereas comparative values for the cariporide groups were 8.7% (not significant) and 23.1% ( P < 0.01), respectively. LV end-diastolic pressure was increased by 1,225% in the control large infarct group but was significantly reduced to 447% with cariporide. Cariporide also significantly reduced the degree of LV dilation in animals with large infarcts. Hypertrophy, defined by tissue weights and cell size, was reduced by cariporide, and shortening of surviving myocytes was preserved. Infarct sizes were unaffected by cariporide, and the drug had no influence on either blood pressure or the depressed inotropic response of infarcted hearts to dobutamine. These results suggest an important role for NHE-1 in the progression of heart failure after myocardial infarction.

scholarly journals Integrative System Biology Analyses Identify Seven Micrornas to Predict Heart Failure

2019 ◽  
Author(s):  
Henri Charrier ◽  
Marie Cuvelliez ◽  
Emilie Dubois-Deruy ◽  
Paul Mulder ◽  
Vincent Richard ◽  
...  
Keyword(s):  
Heart Failure ◽  
Systems Biology ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Mirna Signature ◽  
Artery Ligation ◽  
Proteomic Data

Heart failure (HF) has several etiologies including myocardial infarction (MI) and left ventricular remodeling (LVR), but its progression remains difficult to predict in clinical practice. Systems biology analyses of LVR after MI predict molecular insights of this event such as modulation of microRNA (miRNA) that could be used as a signature of HF progression. To define a miRNA signature of LVR after MI, we use 2 systems biology approaches integrating either proteomic data generated from LV of post-MI rat induced by left coronary artery ligation or multi-omics data (proteins and non-coding RNAs) generated from plasma of post-MI patients from the REVE-2 study. The first approach predicts 13 miRNAs and 3 of these miRNAs were validated to be associated with LVR in vivo: miR-21-5p, miR-23a-3p and miR-222-3p. The second approach predicts 24 miRNAs among 1310 molecules and 6 of these miRNAs were selected to be associated with LVR in silico: miR-17-5p, miR-21-5p, miR-26b-5p, miR-222-3p, miR-335-5p and miR-375. We identified a signature of 7 microRNAs associated with LVR after MI that support the interest of integrative systems biology analyses to define a miRNA signature of HF progression.

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