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 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.

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 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 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.

Abstract 15058: Disruption of Extracellular Cytotoxic Chromatin by Acute DNase1 Administration Improves Left Ventricular Remodeling after Myocardial Infarction

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Benjamin Vogel ◽  
Hisahito Shinagawa ◽  
Ullrich Hofmann ◽  
Georg Ertl ◽  
Stefan Frantz
Keyword(s):  
Myocardial Infarction ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Left Ventricular ◽  
Pcr Analysis ◽  
Coronary Artery Ligation ◽  
Protective Effects ◽  
Artery Ligation ◽  
High Concentrations

Rationale: Myocardial infarction (MI) leads to necrosis of multinucleated and polyploid myocytes. This causes uncontrolled release of cellular content like chromatin to the infarct area. Chromatin is mainly comprised of histones which are essential for controlling and packing of DNA but paradoxically are also known to be cytotoxic. This makes free chromatin a toxic DNA polymer creating local high concentrations of hazardous histones. Objective: We hypothesized that chromatin from necrotic cells accumulates in ischemic myocardium, creates local high concentrations of cytotoxic histones, and thereby potentiates ischemic damage to the heart after MI. The endonuclease DNase1 is capable of dispersing extracellular chromatin through linker DNA digestion and could decrease local histone concentrations and cytotoxicity. Methods and Results: After permanent coronary artery ligation in mice we found extracellular histones accumulated within the infarcted myocardium. Histone cytotoxicity towards isolated myocytes was confirmed in vitro. To reduce histone related cytotoxicity in vivo DNase1 was injected within the first 6 hours after induction of MI. DNase1 accumulated in the infarcted region of the heart, effectively disrupted extracellular cytotoxic chromatin and thereby reduced high local histone concentration. Animals acutely treated with DNase1 revealed significantly improved left ventricular remodeling as measured by serial echocardiography up to 28 days after MI (e.g. NaCl vs DNase1, papillary end diastolic area [mm 2 ]: 23.26 ± 2.06 vs 18.90 ± 1.24, n=9 vs 10, p<0,05). Treatment did not influence mortality, infarct size or inflammatory parameters as determined by neutrophil infiltration and RTQ-PCR analysis of characteristic cytokines. However improved myocyte survival was discovered within the infarct region which might account for the protective effects in DNase1 treated animals (NaCl vs DNase1: 3.0 ± 0.7% vs 8.3 ± 2.3%; p<0.05; n=7 vs 8). Conclusions: Targeting extracellular cytotoxic chromatin within the infarcted heart by DNase1 is a promising approach to preserve myocytes from histone induced cell death and to conserve left ventricular function after MI. The efficacy of other chromatin degrading agents is now under investigation.

Myocardial creatine kinase kinetics in hearts with postinfarction left ventricular remodeling

1999 ◽  
Vol 276 (3) ◽  
pp. H892-H900 ◽  
Author(s):  
Yo Murakami ◽  
Jianyi Zhang ◽  
Marcel H. J. Eijgelshoven ◽  
Wei Chen ◽  
Wenda C. Carlyle ◽  
...  
Keyword(s):  
Creatine Kinase ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
High Energy ◽  
Left Ventricular ◽  
Forward Rate ◽  
Rate Pressure Product ◽  
Resonance Spectroscopy ◽  
Coronary Artery Ligation ◽  
Artery Ligation

This study examined whether alterations in myocardial creatine kinase (CK) kinetics and high-energy phosphate (HEP) levels occur in postinfarction left ventricular remodeling (LVR). Myocardial HEP and CK kinetics were examined in 19 pigs 6 wk after myocardial infarction was produced by left circumflex coronary artery ligation, and the results were compared with those from 9 normal pigs. Blood flow (microspheres), oxygen consumption (MV˙o2), HEP levels [31P magnetic resonance spectroscopy (MRS)], and CK kinetics (31P MRS) were measured in myocardium remote from the infarct under basal conditions and during dobutamine infusion (20 μg ⋅ kg−1⋅ min−1iv). Six of the pigs with LVR had overt congestive heart failure (CHF) at the time of study. Under basal conditions, creatine phosphate (CrP)-to-ATP ratios were lower in all transmural layers of hearts with CHF and in the subendocardium of LVR hearts than in normal hearts ( P < 0.05). Myocardial ATP (biopsy) was significantly decreased in hearts with CHF. The CK forward rate constant was lower ( P < 0.05) in the CHF group (0.21 ± 0.03 s−1) than in LVR (0.38 ± 0.04 s−1) or normal groups (0.41 ± 0.03 s−1); CK forward flux rates in CHF, LVR, and normal groups were 6.4 ± 2.3, 14.3 ± 2.1, and 20.3 ± 2.4 μmol ⋅ g−1⋅ s−1, respectively ( P < 0.05, CHF vs. LVR and LVR vs. normal). Dobutamine caused doubling of the rate-pressure product in the LVR and normal groups, whereas CHF hearts failed to respond to dobutamine. CK flux rates did not change during dobutamine in any group. The ratios of CK flux to ATP synthesis (from MV˙o2) under baseline conditions were 10.9 ± 1.2, 8.03 ± 0.9, and 3.86 ± 0.5 for normal, LVR, and CHF hearts, respectively (each P < 0.05); during dobutamine, this ratio decreased to 3.73 ± 0.5, 2.58 ± 0.4, and 2.78 ± 0.5, respectively ( P = not significant among groups). These data demonstrate that CK flux rates are decreased in hearts with postinfarction LVR, but this change does not limit the response to dobutamine. In hearts with end-stage CHF, the changes in HEP and CK flux are more marked. These changes could contribute to the decreased responsiveness of these hearts to dobutamine.

Targeted inhibition of activin receptor-like kinase 5 signaling attenuates cardiac dysfunction following myocardial infarction

2010 ◽  
Vol 298 (5) ◽  
pp. H1415-H1425 ◽  
Author(s):  
Sih Min Tan ◽  
Yuan Zhang ◽  
Kim A. Connelly ◽  
Richard E. Gilbert ◽  
Darren J. Kelly
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Dysfunction ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Systolic Dysfunction ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Type I ◽  
Artery Ligation ◽  
Receptor Like Kinase

Following myocardial infarction (MI), the heart undergoes a pathological process known as remodeling, which in many instances results in cardiac dysfunction and ultimately heart failure and death. Transforming growth factor-β (TGF-β) is a key mediator in the pathogenesis of cardiac remodeling following MI. We thus aimed to inhibit TGF-β signaling using a novel orally active TGF-β type I receptor [activin receptor-like kinase 5 (ALK5)] inhibitor (GW788388) to attenuate left ventricular remodeling and cardiac dysfunction in a rat model of MI. Sprague-Dawley rats underwent left anterior descending coronary artery ligation to induce experimental MI and then were randomized to receive GW788388 at a dosage of 50 mg·kg−1·day−1 or vehicle 1 wk after surgery. After 4 wk of treatment, echocardiography was performed before the rats were euthanized. Animals that received left anterior descending coronary artery ligation demonstrated systolic dysfunction, Smad2 activation, myofibroblasts accumulation, collagen deposition, and myocyte hypertrophy (all P < 0.05). Treatment with GW788388 significantly attenuated systolic dysfunction in the MI animals, together with the attenuation of the activated (phosphorylated) Smad2 ( P < 0.01), α-smooth muscle actin ( P < 0.001), and collagen I ( P < 0.05) in the noninfarct zone of MI rats. Cardiomyocyte hypertrophy in MI hearts was also attenuated by ALK5 inhibition ( P < 0.05). In brief, treatment with a novel TGF-β type I receptor inhibitor, GW788388, significantly reduced TGF-β activity, leading to the attenuation of systolic dysfunction and left ventricular remodeling in an experimental rat model of MI.

scholarly journals Attenuation of Adverse Postinfarction Left Ventricular Remodeling with Empagliflozin Enhances Mitochondria-Linked Cellular Energetics and Mitochondrial Biogenesis

2021 ◽  
Vol 23 (1) ◽  
pp. 437
Author(s):  
Yang Song ◽  
Chengqun Huang ◽  
Jon Sin ◽  
Juliana de F. Germano ◽  
David J. R. Taylor ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Remodeling ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Sglt2 Inhibitor ◽  
Left Ventricular ◽  
Sglt2 Inhibitors ◽  
Coronary Artery Ligation ◽  
Adverse Remodeling ◽  
Cellular Energetics

Sodium–glucose cotransporter 2 (SGLT2) inhibitors such as empagliflozin are known to reduce the risk of hospitalizations related to heart failure irrespective of diabetic state. Meanwhile, adverse cardiac remodeling remains the leading cause of heart failure and death in the USA. Thus, understanding the mechanisms that are responsible for the beneficial effects of SGLT2 inhibitors is of the utmost relevance and importance. Our previous work illustrated a connection between adverse cardiac remodeling and the regulation of mitochondrial turnover and cellular energetics using a short-acting glucagon-like peptide-1 receptor agonist (GLP1Ra). Here, we sought to determine if the mechanism of the SGLT2 inhibitor empagliflozin (EMPA) in ameliorating adverse remodeling was similar and/or to identify what differences exist, if any. To this end, we administered permanent coronary artery ligation to induce adverse remodeling in wild-type and Parkin knockout mice and examined the progression of adverse cardiac remodeling with or without EMPA treatment over time. Like GLP1Ra, we found that EMPA affords a robust attenuation of PCAL-induced adverse remodeling. Interestingly, unlike the GLP1Ra, EMPA does not require Parkin to improve/maintain mitochondria-related cellular energetics and afford its benefits against developing adverse remodeling. These findings suggests that further investigation of EMPA is warranted as a potential path for developing therapy against adverse cardiac remodeling for patients that may have Parkin and/or mitophagy-related deficiencies.

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.

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