bluuebunny/crossref_metadata_2025_split huggingface dataset:
Functional remodeling of the mitochondrial Ca2+ uniporter complex in metabolic cardiomyopathy
Authors: Panel M , Fossier L , Lacote M , Azria L , Notarnicola C , Sicard P , Thireau J , Meli AC , Lacampagne A , Fauconnier J 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: Foundation. Main funding source(s): Fondation pour la Recherche Médicale
ANR

Background
Calcium (Ca2+) uptake through the mitochondrial Ca2+ uniporter complex (MCUC) controls keys steps of the oxidative metabolism. In metabolic cardiomyopathy, myocardial mitochondrial Ca2+ uptake is impaired, but whether it is an early feature of the pathology remain unsolved.

Purpose
To establish whether mitochondrial Ca2+ dynamics and MCUC structure and function are affected at the early stage of the metabolic cardiomyopathy.

Methods and Results
Mice fed two weeks with a high fat sucrose diet display early features of metabolic disorders and diastolic dysfunction. Concomitantly, mitochondrial Ca2+-dependent pyruvate dehydrogenase activity and the beat-to-beat mitochondrial Ca2+ uptake are reduced. The impaired mitochondrial Ca2+ uptake was further confirmed by single channel recordings of the native MCUC incorporated in planar lipid bilayer demonstrating a reduction of the ion conductance and the open probability. The MCUC biochemical analysis showed an elevation of the EMRE subunit expression and an increase interaction of EMRE with the MICU1 subunits. Co-immunoprecipitation also revealed a deceased interaction of the pore forming subunits MCU with EMRE-MICU1 subcomplex. The displacement of the MCUC assembly was confirmed by the decrease in m-AAA protease-interacting protein 1 expression as well as its loss of binding with EMRE.

Conclusions
The remodeling of the MCUC integrity impacts mitochondrial Ca2+ homeostasis at the early stage of the metabolic cardiomyopathy and provides a novel post-translational paradigm of the MCUC regulation in pathophysiological context.
Hypoxic preconditioning effects change in hypertrophied or insulin resistant rat hearts
Authors: Babicheva V , Kozlovska M , Vasylenko M , Portnychenko A 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: Public Institution(s). Main funding source(s): Ministry of Education and Science of Ukraine

Purpose
Cardioprotective mechanisms in the hypertrophied or insulin resistant heart is not fully elucidated. Insulin like growth factor IGF-1 through downstream kinases PI3K/Akt/GSK3beta is known to exert cardioprotective effects and regulate myocardial remodeling, glucose metabolism, cell survival, apoptosis, oxidative stress etc. The aim was to characterize IGF-1/PI3K/Akt-mediated cardioprotection in hypertrophied or insulin resistant hearts after hypoxic preconditioning in response to severe whole body hypoxia or isolated heart ischemia/reperfusion.

Methods
Experiments were performed in male adult Wistar rats, and SHR with long-term heart hypertrophy. Insulin resistance (IR) was induced by high fat diet (58% kcal from fat). The animals were exposed to hypoxic preconditioning using mild hypobaric hypoxia séances in barochamber (5600 m, 3 h). In 24 h, hearts were isolated with urethane narcosis and subjected to ischemia/reperfusion in a Langendorff mode, infarct size was detected with TTC staining. The other group of rats after preconditioning were subjected to severe hypoxia (9000 m, 3 h). Inhibitor of PI3K wortmannin or blocker of IGF-1R picropodophyllin were used for testing of cytoprotective signalling. Protein expression were examined using Western blotting.

Results
In SHR, the myocardial expression of IGF-1 and Akt was lower by 42% or 63%, respectively, compared to Wistar. IR increased GSK-3beta expression and phosphorylation. Hypoxic preconditioning intensified IGF-1/PI3K/Akt-mediated cardioprotection, less pronounced in hypertrophied or insulin resistant hearts. Blockade of PI3K or IGF-1Rdecreased Akt phosphorylation, and abolished cytoprotective effects of preconditioning in view of mortality caused severe hypoxia, or of infarct size and cardiac function recovery in postischemic reperfusion. In SHR, hypoxia-induced cardioprotective effects and influences of the blockers were significantly reduced.

Conclusions
The long-term left ventricular hypertrophy is accompanied with reduction of IGF-1/IGF-1R/PI3K/Akt-dependent prohypertrophic and cardioprotective signalling. Hypoxic preconditioning mediated by IGF-1/PI3K/Akt-signalling loses its effectiveness during prolonged cardiac hypertrophy, as well as insulin resistance development.
Autopsy and genetic characterization of juvenile sudden cardiac arrest and death: the ToRSADE experience
Authors: Spinelli V , Girolami F , Maurizi N , Grifoni R , Maio V , Focardi M , Albora G , Nesi G , Coppini R , Cerbai E , Olivotto I 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: Public Institution(s). Main funding source(s): FAS-Salute 2014, regione Toscana

Background
Sudden cardiac arrest (SCA) or death (SCD) in young people represents a dramatic event, often leading to severe neurologic outcomes or death. However, the incidence of this phenomenon remains largely unknown, since the recording of cases, and consequently the identification of the underlying causes, requires a multi-professional and disciplinary approach, including genetic counselling.

Purpose
In this study, we aimed to monitor and investigate SCA and SCD in young people (≤50 years) recorded in the ToRSADE© registry comparing clinical and molecular data.

Methods and Results
A total of 22 blood samples were analyzed; 14 were collected from dead patients during autopsy and 8 from resuscitated patients after cardiac arrest. Next Generation Sequencing (NGS) analysis revealed 38% of total cases with Likely Pathogenetic (LP) variants associated to Cardiomyopathy (CM) or Channelopathy, and 61% with Variant of Uncertain Significance (VUS). In three cases, NGS confirmed autopsy and histology findings: the p.(Leu466Phe) variant in SCN5A associated with Brugada Syndrome (1a), the p.(Glu173del) in TNNT2 for Hypertrophic CM (1b) and the p. (Asn480Lysfs*20) in PKP2 for Arrhythmogenic Cardiomyopathy (AC) (1c).

Conclusions
Creation of the ToRSADE© registry allowed implementation of a blood repository for molecular and genetic analysis. Genetic analysis combined with clinical information and post-mortem evaluation constitute a multi-disciplinary approach to juvenile SCD and SCA, while providing medical and genetic assistance to families, public awareness especially among youths and athletes, as well as up-to-date research on the underlying mechanisms of cardiomyopathies.
Exogenous Growth Differentiation Factor 15 (GDF15) exerts direct cardioprotective properties towards myocardial ischemia reperfusion injury
Authors: Dogon G , Rigal ER , Rochette LR , Bejot YB , Vergely CV 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Agence National de la Recherche (ANR)

Introduction
Growth differentiation factor 15 (GDF15) is a stress-responsive cytokine which can be produced under certain pathological situations, mainly related to inflammatory stress, aging and disease. While clinical data suggest that GDF15 is a powerful risk factor in several high cardiovascular risks situations such as myocardial infarction and coronary artery disease, experimental studies rather consider this cytokine as a cardioprotective molecule.

Objective
We therefore aimed to clarify the direct cardiac effects of GDF15 during ischemia-reperfusion (I-R) injury, at concentrations found in patients with high cardiovascular risk, such as these of patients presenting with acute myocardial infarction or stroke.

Method
In vivo ischemia reperfusion: Wistar male rats (200-340 g) were anesthetized with isoflurane and intubated before a left thoracotomy was performed between the 3rd and the 4th intercostal space. Rats were injected with either saline (Control groups) or 2.5 µg/kg of GDF15 (GDF15 groups), 20 minutes before the transient ligation of the left anterior descending artery for 30 min followed by 24h of reperfusion.
Ex vivo ischemia reperfusion: Wistar male rats (250-400 g) were anesthetized with isoflurane before their hearts were isolated and perfused in a Langendorff model. Hearts were perfused either with saline (Control groups) or 2,000 ng/L of GDF15 upstream the coronary bed (GDF15 groups) for 10 minutes, then subjected to either 20 or 30 minutes of global normothermic total ischemia, followed by 2 h of reperfusion.

Results
GDF15 decreased the infarct size in vivo (42.4 ± 6 % vs. 65.3 ± 4.5 %, p&lt;0.01) as well as in ex vivo (45.6 ± 3.8 % vs. 60.8 ± 3.8 %, p&lt;0.05). Moreover, in our ex vivo model, GDF15 induced a better recovery of most contractile parameters after ischemia (higher left ventricular developed pressure, better heart rate recovery, better recovery in left ventricular contractility and relaxation, p&lt;0.05 for all parameters).

Conclusion
These results demonstrate for the first time that exogenous preischemic short-term administration of GDF15 decreased cardiac cell death in vivo and also ex vivo, a situation where inflammatory, endocrine and nervous systems are not interfering. These original results suggest that GDF15 exerts direct cardioprotective properties towards ischemia-reperfusion injury. The molecular mechanisms have now to be investigated.
Diurnal Variation in thrombolytic status in patients presenting with STEMI
Authors: Gue Y X , Farag M , Spinthakis N , Wellsted D , Gorog D 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: None.

Background
Prior studies mainly in healthy volunteers and patients with stable coronary artery disease (CAD) indicate circadian variation in spontaneous fibrinolytic activity. This is predominantly attributable to changes plasminogen activator inhibitor-1 (PAI-1) levels peaking between midnight and 06:00 hr, with a nadir at 18:00 hr. Whether circadian variation in spontaneous fibrinolysis exists amongst patients with ST-elevation myocardial infarction (STEMI) is unknown.

Purpose
It was our aim to assess circadian variation in fibrinolytic status in the acute setting in patients presenting with STEMI.

Methods
A prospective, observational study was conducted in patients presenting with STEMI for primary percutaneous coronary intervention (PPCI). Blood was tested on arrival pre-PPCI, after aspirin and P2Y12 inhibitor administration, but before any anticoagulant or antithrombotic agent administration in the cardiac cath lab. Venous blood was assessed to determine endogenous fibrinolysis using the Global Thrombosis Test, which utilises non-anticoagulated blood to assess the formation of an occlusive thrombus under high shear and the time taken for spontaneous restart of flow as a measure of endogenous fibrinolysis (lysis time, LT).

Results
A total of 527 patients were included, aged 64±13 years and 78% were male. 304 (58%) patients presented within working hours (08:00-17:00) with peak presentation between 11:00-12:00 and trough between 03:00 to 05:00 hrs.
Lysis time was not related to time of presentation. Time of presentation was divided into 4 groups (A 00:00-05:59, B 06:00-11:59, C 12:00-17:59, D 18:00-23:59 hrs). There was no significant difference in LT between patients presenting at the 4 timepoints (median 1362s [interquartile range IQR 1077-1808] vs 1503s [1182-2056] vs 1440s [1164-1998] vs. 1420s [1125-1820], respectively, p=0.340). When comparing Group A to C, the LT was not significantly different (1362s [1077-1808] vs. 1440 [1164-1998], p=0.413). The presentation time of patients with impaired endogenous fibrinolysis (LT&gt;3000 sec) did not differ significantly from patients with normal endogenous fibrinolysis. The hourly variation was similar in diabetics and non-diabetics, but the variation in lysis time appeared blunted in patients taking long term aspirin prior to presentation compared to non-aspirin takers.

Conclusion
In contrast to the known circadian variation in fibrinolysis in normal volunteers, and stable CAD, in our large cohort of STEMI patients, there appears to be no relationship between time of presentation/onset of STEMI and the effectiveness spontaneous fibrinolysis. This is reflected in our observation, supported by most contemporary studies, that peak time of STEMI presentation is during the late morning, and this does not relate to known circadian variation in fibrinolysis markers in CAD.
Long-term impact of postnatal overfeeding on cardio-metabolism risk and on sensitivity to ischemia-reperfusion injury in vivo
Authors: Rigal E , Josse MJ , Dogon GD , Porcherot IP , Rochette LR , Guenancia CG , Vergely CV 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: None.

Introduction
Nutritional disturbances during the postnatal period may be responsible for a predisposition, or "programming", to increased cardio-metabolic risk and to a progressive alteration of left ventricular contractility in adulthood. However, these data have mainly obtained in young male mice, but less is known for older animals.

Purpose
Our aim was to evaluate the impact of postnatal overfeeding (PNOF) on cardiac function, on cardiac sensitivity to ischemia-reperfusion (I-R) injury in vivo and on glucose metabolism in young (4 months), adult (6 months) and old (12 months) male mice.

Methods
PNOF was induced by the reduction of litter size of C57/BL6 mice immediately after birth: normally-fed group (NF) was composed of 9 male pups/mother and overfed group (OF) of 3 pups/mother. Echocardiography and blood sugar tests (glucose tolerance and insulin resistance) have been performed at all ages. An in vivo ischemia-reperfusion injury was induced by the ligation of the anterior interventricular artery for 45 minutes followed by 24 h of reperfusion. All experiments have been done on 4-, 6- and 12-months aged male mice.

Results
PNOF induced an early and permanent increase in body weight in OF group, independently of mice’s age (+23% at 24 days of life, +14% at 4 months, +23% at 6 and 12 months, compared to NF group). The echocardiographic measurements showed an alteration of contractile function from 6 months aged males and up to 12 months as evidenced by a decrease of the left ventricular ejection fraction (-11 % for OF males from 6 to 12 months, compared to NF groups). These cardiac alterations were associated with glucose metabolism imbalance: OF males presented glucose intolerance and insulin resistance from 4 to 12 months of age. To finish, PNOF induced a significant increase of infarct size at 4 months (+37%, p&lt;0.01, n=8), 6 months (+32%, p&lt;0.05, n=9) and 12 months (+38%, p&lt;0,05, n=9) after cardiac surgery.

Conclusion
Nutritional programming through short-term PNOF induced an early alteration of glucose metabolism and was associated with a constant higher susceptibility to myocardial I-R injury in vivo. Moreover, mice which were submitted to PNOF developed altered cardiac contractility at 6 months and up to 12 months. The cellular and biochemical mechanism of these pathological modifications induced by PNOF need further exploration but could involve alterations in cardiomyocyte pathways, and/or modification of global inflammatory status.
Relevance of necroptosis in the hearts subjected to acute versus chronic ischemia/reperfusion injury
Authors: Horvath C , Szobi A , Young M , Jarabicova I , Hrdlicka J , Neckar J , Lewis M , Kolar F , Ravingerova T , Suleiman MS , Adameova A 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: Public Institution(s). Main funding source(s): Slovak Research and Development Agency
Medical Research Council Grant
Necroptosis, a necrosis-like programmed cell death modality dependent on the activity of receptor-interacting protein kinase 3 (RIP3) and mixed lineage domain kinase domain-like pseudokinase (MLKL), plays a prominent role in mediating myocardial ischemia/reperfusion injury. However, the extent to which necroptosis contributes to such damage under short and long reperfusion has not been evaluated in detail. In Wistar rat hearts, subjected to global 30-min ischemia followed by an acute 10-min reperfusion period, with compromised cardiac function, no changes in the protein expression of the main necroptotic markers (pThr231/Ser232-RIP3, MLKL) were found. Likewise, the non-canonical pathways of necroptosis involving Ca2+/calmodulin dependent protein kinase II–mitochondrial permeability transition pore (CaMKII–mPTP) or phosphoglycerate mutase 5–dynamin-related protein 1 (PGAM5–Drp1) axes were unlikely affected by such short reperfusion. In contrast, hearts subjected to global 30-min ischemia followed by a prolonged 40-min reperfusion period exhibited worsened hemodynamic parameters what was accompanied by the increased levels of RIP3, pSer229-RIP3 and MLKL. Moreover, this reperfusion period induced MLKL translocation to the plasma membrane, indicating necroptosis execution with resultant very likely cell disruption. Similarly, activated necroptosis, evidenced by the higher levels of proteins of the canonical pathway, has been suggested to contribute to the pathogenesis of post-infarction heart failure (30-min ischemia, 42-day reperfusion). Collectively, these findings suggest that short reperfusion seems to be insufficient to induce necroptosis in the heart and the molecular mechanisms being activated during the longer reperfusion phase are needed to promote necroptotic cell dying. Therefore, inhibition of necroptosis might represent a cardioprotective strategy in the settings of chronic, but not acute myocardial ischemia/reperfusion injury.
Searching for cardioprotective microRNA families by bioinformatics analysis of cross-species transcriptomic datasets
Authors: Agg B , Benczik B , Kemendi BV , Makkos A , Petervari M , Varga ZV , Ferdinandy P 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This study was supported by the National Research, Development and Innovation Office of Hungary (NKFIA; NVKP-16-1-2016-0017 National Heart Program) and the Thematic Excellence Programme (2020-4.1.1.-TKP2020) of the Ministry for Innovation and Technology in Hungary, within the framework of the Therapeutic Development and Molecular Biology thematic programmes of the Semmelweis University.

Introduction
There is a growing body of evidence that changes in cardiac microRNA expression pattern plays an important role in cardioprotective cellular signaling.

Purpose
Our aim was to identify evolutionarily conserved cardioprotective microRNA (protectomiR) families with a high probability of translation into human clinical practice.

Methods
Global cardiac microRNA expression profiles were measured in both a rat and a porcine model of myocardial infarction with or without ischemic preconditioning and postconditioning by microarray and high-throughput polymerase chain reaction, respectively. A software developed by our team was used to identify cross-species microRNA families (i.e. microRNAs with identic seed sequence) with cardioprotective expression patterns. By selecting experimentally validated human target genes from the miRTarBase database we built a microRNA family-target interaction network by the miRNAtarget.com software. Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed on the selected target genes.

Results
Due to potential patenting, microRNAs and microRNA families were anonymized. We identified 7 microRNA families, showing cardioprotective expression pattern. Based on the analysis of the microRNA family-target network, expression change of the target hubs were predicted to be consistent with previously described changes in pathways with high relevance in cardioprotection (e.g. positive regulation of TGF-beta, HIF-1, PI3K-Akt signaling pathways).

Conclusion
By an unbiased transcriptomics and bioinformatics based approach we successfully identified microRNA families with robust cross-species protectomiR expression pattern and targets involved in well-established cardioprotective pathways. These cardioprotective microRNA families are of high translational value for human clinical application.
Implication of Orai1 in the diastolic calcium dysregulation during Ischemia and Reperfusion in cardiomyocytes
Authors: Falcon Boyano D , Mayoral Gonzalez I , Calderon Sanchez E , Ordonez A , Smani T 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Agencia Estatal de Investigación

Background
It is well established that abnormalities in the regulation of the intracellular concentration of Ca2+ ([Ca2+]i) occurrs in diseased heart. Ischemia/Reperfusion (I/R) syndrome is characterized by [Ca2+]i overload that might be associated with the increase of left ventricular pressure, which might trigger diastolic dysfunction. Several studies have demonstrated that Orai1/2/3 isoforms of the Store Operated Calcium Channels (SOCC) and TRPC channels play a role in cardiac pathologies. Previously, we demonstrated that the expression of Orai1 increased after I/R although their role in the diastolic [Ca2+]i regulation is unknown.

Objective
The aim of this study was to examine the role of SOCC in the diastolic [Ca2+] after I/R in cardiomyocytes and the activation of transcription factors by I/R.

Materials and Methods
The experiments were performed in adult (ARVM) and neonatal rat ventricular cardiomyocytes (NRVM) and in a rat model of myocardial I/R. Ca2+ studies were realized using microfluorimetric technique in FURA-2AM loaded cardiomyocytes. To evoke [Ca2+]i transients, ARVM were field stimulated at 0.5Hz and NRVMs at 1Hz. Immunofluorescence was used to investigated CREB activation using a specific phospho-CREB antibody and protein expression was analysed by Western Blot. Orai1 expression was assessed in rat samples and in ventricular biopsies of patients with ischemic heart failure.

Results
We found that field stimulation of ARVM from I/R animal showed significant increase in the diastolic [Ca2+]i as compare to AVRM isolated from sham rats. Also, NRVM subjected to simulated protocol of I/R presented similar increase in the diastolic [Ca2+]i. These responses correlated with significant increase in the expression of Orai1 in both cardiomyocytes. Interestingly, NRVM and ARVM preincubation with SYNTA-66 and GSK-7975A to block SOCC successfully reduced the increase in the diastolic [Ca2+]I induced by IR. Moreover, we found that I/R promoted CREB activation through PKA activation, but not though EPAC2 or ERK1/2. Finally, we found that Orai1 is overexpressed in ventricle biopsies of patient with heart failure from ischemic origin.

Conclusions
Our results confirms that I/R induced an upregulation of Orai1 which was associated with diastolic dysfunction, suggesting that Orai1 plays a role in the I/R induced diastolic [Ca2+]i increase. Moreover, our data demonstrated the activation of the transcription factor CREB in cardiomyocytes after I/R, known to activate a plethora of genes involved in the adverse cardiac remodelling.