bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exercise-induced right ventricular alterations in a rodent model of athletes heart
Authors: Olah A , Bodi B , Sayour AA , Barta BA , Ruppert M , Bottlik O , Merkely B , Papp Z , Radovits T 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): János Bolyai Research Scholarship of the Hungarian Academy of Sciences (BO/00837/21) to AO
National Research, Development and Innovation Office (NKFIH) of Hungary (K120277 and K135076 to BM)

Background
Intense sports activity leads to the adaptation of cardiac structure and function, the so-called athlete’s heart. Research over the last years has focused on exercise-induced adaptation of the right ventricle (RV), because the disproportionate load on the RV - when compared with left ventricle - might lead to pathological consequences, such as interstital fibrosis or chamber dilation.

Purpose
We aimed at investigating right ventricular alterations induced by regular aerobic exercise training in a rat model of athlete's heart.

Methods
Young, adult rats were divided into control (Co) and exercised (Ex) groups. Trained rats swam 200 min/day for 12 weeks. In vivo electrophysiological study and in vitro force measurements on isolated permeabilized cardiomyocytes were carried out to investigate electrical and functional alterations, respectively. Molecular biological (qRT-PCR, Western-blot) and histological investigations were applied to reveal underlying mechanisms.

Results
Exercise training was associated with increased RV cardiomyocyte width (12.5±0.1µm Co vs. 13.8±0.2µm Ex, p&lt;0.05) and corresponding hyperphosphorylation of protein kinase B (Akt). RV myofilaments from exercised animals showed increased maximal force development and improved calcium sensitivity. Sarcomere protein investigations revealed marked overall and site-specific hypophosphorylation of troponin I. We found prolonged QT interval and right ventricular effective refracter period (RVERP: 44.0±1.6ms Co vs. 52.8±2.1ms Ex, p&lt;0.05) along with decreased gene expression of potassium channels. Picrosirius staining did not reveal fibrosis, that was underlied by unchanged protein expression of connective tissue growth factor (CTGF) and gene expression of profibrotic markers. Gene expression of apoptotic markers and fetal gene program did not differ between the groups.

Conclusions
According to our data, regular swim training induced RV hypertrophy, that was associated with functional improvement adn hypophosphorilation of troponin I. Prolonged repolarization without pathological alterations in RV myocardial tissue suggest physiological remodeling after balanced training.
FGF15/FGF19 is involved in the development of cardiac hypertrophy
Authors: Planavila A , Moron-Ros S , Villarroya F , Gavalda-Navarro A 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: Public grant(s) – EU funding. Main funding source(s): Funded by MCIN/AEI/ 10.13039/501100011033 and, by “ERDF A way of making Europe”, by the “European Union”

Introduction
FGF15 (and its human orthologue, FGF19) are members of the endocrine FGF family. They are produced by ileal enterocytes in response to bile acids. The liver is its main target tissue but recent studies indicate that FGF19 also regulates skeletal muscle mass and adipose tissue plasticity.

Objective
To determine the role of the enterokine FGF15/19 during the development of cardiac hypertrophy

Methods
Circulating FGF19 levels were assessed in patients with heart failure (HF) and myocardial infarction. The hypertrophic response was characterized in Fgf15-null mice subjected to a high-fat diet for 16 weeks or isoproterenol infusion with osmotic minipumps for 7 days. Effects of experimentally increased FGF15 and FGF19 levels in vivo were determined in mice using adenoviral (Ad-Fgf15) and adeno-associated vectors (AAV8-Fgf19) for 1-week or 3-weeks injection, respectively.

Results
In humans, we found that the FGF19 levels were significantly reduced in patients suffering from heart failure or myocardial infarction, reciprocally to FGF21 levels. We found that mice lacking Fgf15 do not develop cardiac hypertrophy in response to high-fat diet or isoproterenol induced cardiac hypertrophy. Specifically, we found that the ratio heart weight/tibia length (HW/TL), the quantification of cardiomyocyte area and the hypertrophy marker gene atrial natriuretic factor (Anf) -as measures of cardiac hypertrophy development- were reduced in Fgf15-null mice subjected to hypertrophy compared to their corresponding wild-type mice. By contrast, we found that experimental increases in FGF15 or FGF19 induced cardiac hypertrophy development in vivo, characterized by an increase in the HW/TL ratio, area of the cardiomyocytes and hypertrophy marker genes.

Conclusions
We stablish a cross-talk between the intestine and the myocardium through the enterokine FGF15/19 which seems a key factor required for cardiac hypertrophy development.
Dapagliflozin alleviates left ventricular hypertrophy and cardiac dysfunction in mice
Authors: Weber L , Pilz PM , Baumgartner N , Szabo PL , Arnold Z , Dostal C , Kiss A , Podesser BK 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: Public Institution(s). Main funding source(s): Ludwig Boltzmann Institute for Cardiovascular Research

Introduction
Sodium glucose cotransporter 2 inhibitors (SGLT2i) are a class of oral antidiabetic drugs. Recent clinical trials demonstrated and proved the cardiovascular benefit of SGLT2i in patients suffering from ischemic heart disease. In addition, left ventricular hypertrophy (LVH) is associated with cardiovascular events and using SGLT2i alleviated LVH in diabetic patients. However, only few studies investigated the effect of SGLT2i on regression of LVH in absence of diabetes.

Aim of the study
This study aimed to investigate whether the SGLT2i Dapagliflozin (DAPA) could attenuate LVH and cardiac dysfunction in a mouse model of pressure overload-induced LVH.

Methods
Male C57BL/6J mice (body weight 20-25g) were used. LVH was induced surgically by transverse aortic constriction (TAC). DAPA (1 mg/kg bodyweight/day) was administered through drinking water. The animals were divided in four groups: Group 1 underwent TAC for eight weeks (n=8). Group 2 concomitantly received DAPA for eight weeks after TAC (n=5). Group 3 received DAPA for only two weeks (in week 7 and 8 after TAC, n=5) to clarify if DAPA treatment could alleviate LVH at a later timepoint. Group 4 served as a sham control group (no LVH, n=8). Cardiac function was assessed using transthoracic echocardiography and invasive LV hemodynamic measurements.

Results
TAC resulted in a significant reduction in LV ejection fraction (LVEF) and significant increase in heart weight to body weight ratio (HW/BW) compared to sham (p&lt;0.001). In addition, TAC mice showed a significant increase of LV systolic pressure and end-diastolic pressure compared to sham (p&lt;0.01). Both the LVEF and LV functional parameters were markedly improved in mice treated with DAPA for eight weeks (p&lt;0.05). LV mass decreased compared to the untreated group. More importantly, DAPA treatment for only two weeks also improved LVEF and alleviated LVH compared to untreated TAC mice (p&lt;0.05). Furthermore, we also found that mice with only two weeks of DAPA treatment showed a tendency to improve LV hemodynamics.

Conclusions
DAPA was cardioprotective in a mouse model of pressure overload-induced LVH in absence of diabetes. It improved LV contractile function and LVH. DAPA also alleviated LVH and induced LV regression. Our findings uncovered that the SGLT2i DAPA contributed to the regression of LVH and cardiac fibrosis. Thus, administration of SLGT2i may be a novel adjunct therapy to boost reverse remodeling e.g. in patients with elective cardiac surgery and hypertrophic cardiomyopathy.
EDEM2 regulation of cardiac lipid metabolism in heart failure with preserved ejection fraction
Authors: Raja R , Liu W 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: Foundation. Main funding source(s): British Heart Foundation

Background
Heart failure with preserved ejection fraction (HFpEF) is the most predominant form of heart failure (HF) worldwide, one which confers substantial mortality and has no efficacious treatments. Lipid mishandling greatly contributes to the pathophysiology of HFpEF, nevertheless, the key mechanistic features regulating cardiac lipid overload remain poorly understood. EDEM2 plays a crucial role in the ER-associated degradation (ERAD) pathway. Recent studies show that ERAD-associated proteins are implicated in cellular lipid homeostasis, however, the role of EDEM2 is cardiac lipid metabolism remains poorly understood. Here, we investigate the mechanisms by which EDEM2 regulates cardiomyocyte lipid metabolism and cardiac dysfunction in HFpEF.

Methods
In vivo two-hit disease model of HFpEF, Adeno-associated virus serotype 9 (AAV9)-mediated cardiac-specific gene overexpression, tail-cuff blood pressure recordings, echocardiography, histology and qPCR.

Results
Under HFpEF inducing conditions, AAV9-Gfp injected mice (as controls) displayed an increased E/A ratio and IVRT both of which are indicative of diastolic dysfunction. Conversely, cardiac-specific EDEM2 overexpression prevented diastolic dysfunction in mice subjected to HFpEF conditions. Systolic function remained unchanged between groups. Interestingly, EDEM2 overexpression reduced myocardial neutral lipid accumulation and prevented severe oxidative stress and cardiac pathological remodeling. More importantly, although genes participating in fatty acid uptake and lipid droplets synthesis in the heart were comparable between AAV9-Gfp and AAV9-EDEM2 groups, those involved in lipolysis and fatty acid oxidation were upregulated in mice with cardiac-specific EDEM2 overexpression.

Conclusion
Cardiomyocyte-specific EDEM2 overexpression mitigates myocardial steatosis in a two-hit murine model of HFpEF, likely through enhancing fatty acid utilisation in the myocardium.
Evaluation of the interplay between NASH and HFpEF in varied murine age groups
Authors: Kucsera D , Sayour N V , Ruppert M , Radovits T , Fabian A , Kovacs A , Ferdinandy P , Varga ZV 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Union's Horizon 2020 Research and Innovation Programme, grant agreement no. 739593
New National Excellence Program of the Ministry of Human Capacities (ÚNKP-21-3-II)

Introduction
Heart failure with preserved ejection fraction (HFpEF) is characterized by diastolic dysfunction, left ventricular hypertrophy, left atrial enlargement and increased serum levels of NT-pro-BNP. HFpEF accounts for 50% of heart failure cases, and typically develops in patients with metabolic comorbidities. Non-alcoholic fatty liver disease and subsequent steatohepatitis (NAFLD, NASH) is the most common chronic liver disease developing due to obesity. Although clinical/epidemiological data exists in humans showing that NASH may lead to cardiac dysfunction per se, experimental data in this regard is lacking.

Purpose
We aimed to evaluate whether NASH is an independent factor of cardiac dysfunction and to investigate the age-dependent effects of NASH on cardiac function.

Methods
Middle aged (10 months old) and aged (24 months old) C57Bl/6J mice were fed either control diet or Choline Deficient (CDAA) diet over a period of eight weeks. Young (2 months old) mice were used as a control. Before termination, echocardiography was performed. Upon termination, organs were isolated for further analysis.

Results
CDAA diet lead to the development of NASH in both age groups, without inducing weight gain, allowing us to investigate the direct effects of NASH on cardiac function. Left ventricular end-diastolic volume (EDV) was increased in aged animals, compared to young and middle aged animals, suggesting increased ventricular pressure. Aged animals were characterized by increased posterior wall thickness (PWT) during diastole and by increased LV mass, indicating left ventricular hypertrophy. Assessment of ejection fraction showed an age-dependent decline. Pulse wave and tissue Doppler measurements showed no difference in E/e’ ratio between the groups. However, strain analysis showed that diastolic dysfunction developed only in aged mice due to NASH.

Conclusion
We conclude that there were no observed changes in cardiac diastolic function due to NASH when using standard echocardiographic evaluation; however, the more sensitive method of strain analysis with 2D speckle tracking was able to show evidence of diastolic dysfunction due to NASH in aging animals.
Identification of novel N-terminal splice variants in the DCM-associated gene RBM20
Authors: Gaertner A , Brodehl A , Sielemann K , Knoll R , Gummert J , Milting H 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: Foundation. Main funding source(s): Erich und Hanna Klessmann Foundation

Introduction
Mutations in human RBM20, encoding the RNA binding protein 20, cause dilated cardiomyopathy (DCM). Within the nucleus RBM20 partially colocalies with other splicing factors. Sequencing of the cardiac transcriptome of a RBM20-deficient rat model revealed RBM20-dependent regulation of myocardial alternative splicing. We identified several carriers of RBM20 mutations.
In the literature, it is postulated that in myocardial tissue only one cardiac form of RBM20 with transcription start in exon 2 is expressed. However, it remains unclear why in the heart this alternative start codon is used. Furthermore, the function of putative different transcripts is unknown.

Methods
We analyzed human myocardial cDNA by 5’RACE to identify novel 5’-terminal RBM20 transcripts using gene specific primers within exon 2. Furthermore, we performed RNA-Seq analysis to detect different RBM20 transcripts directly in the human heart.

Results
By 5’RACE we could identify additional RBM20 exons localized within the first intron. The usage of two of these exons (internal exons, IE1 and IE2) instead of exon 1 results in transcripts with translation starting in the second exon. The usage of the third alternative internal exon (IE3) might result in a protein differing from full length and cardiac RBM20. Furthermore, we identified transcripts using an alternative exon, which is localized upstream of exon 1. In addition, a transcript comprising exon 1 and 2 of RBM20 was also detected by 5’ RACE. Using RNA-Seq we verified the expression of the transcripts containing exon 1, IE1 and IE2 in the human heart, respectively.

Conclusions
Here, we present first data on different N-terminal RBM20 transcripts in the human myocardium. In contrast to previous assumptions we identified different splicing forms of RBM20 with unknown functional impact in the human heart. As RBM20 is a DCM-associated gene, the function of the different RBM20 splicing variants might be interesting with respect to cardiomyopathies.
Extracellular stiffness as a determinant of cardiac dysfunction in duchenne muscular distrophy: a study on human iPSC derived cardiomyocytes
Authors: Giammarino L , Santini L , Palandri C , Musumeci M , Langione M , Pioner JM , Ferrantini C , Coppini R , Cerbai E , Poggesi C 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: Foundation. Main funding source(s): Fondazione Intesa San Paolo

Introduction
Duchenne muscular dystrophy (DMD) is a genetic disorder characterized by progressive degeneration of striated muscles; in addition to skeletal muscle impairment, DMD is also characterized by progressive myocardial disfunction. The low translational value of animal models and the low availability of human samples make DMD hard to investigate; induced pluripotent stem cells (iPSCs) represent a novel tool to model this disease, preserving the genetic heritage of the patient, including the pathogenic mutation causing dystrophy.

Aim
Our aim is to characterize cardiomyocytes differentiated from iPSCs (iPSC-CMs) derived from healthy donors (CTRL) and DMD patients, to identify the pathophysiological mechanisms of DMD-related cardiomyopathy.

Materials and Methods
Cardiomyocytes are differentiated from IPSCs obtained by reprogramming isolated mononucleated blood cells from healthy donors and DMD patients. IPSC-CMs are cultured until day 60, 75 or 90 post-differentiation after plating on nanostructured substrates with two different stiffness levels: PEG-substrates, with lower rigidity, mimicking healthy extracellular tissue, and DEG-substrates, with greater rigidity, that mimic the presence of myocardial fibrosis. Through imaging techniques, we evaluated calcium handling and action potentials (AP) on DMD and CTRL iPSC-CMs by using specific fluorescent dyes for Ca2+ (CAL630) and membrane voltage (Fluovolt). Cells were stimulated at different pacing rates.

Results
The calcium transient amplitude of CTRL-iPSC-CMs became larger during maturation. This adaptation did not occur in DMD lines, showing a deficit calcium release due to poor maturation of the sarcoplasmic reticulum (SR). AP duration was shorter in the DMD line at d75 but at d90 we observed no differences when compared with the CTRL line. CTRL iPSC-CMs showed a marked ability to adapt to different substrate stiffnesses. Indeed, the calcium transient amplitude was larger and its kinetics faster when cells were grown on the rigid DEG substrates rather than on PEG plates. In the DMD line, however, no differences were observed between the substrates.

Conclusions
Our results highlight a scarce ability of DMD iPSC-CM to adapt to different substrate stiffness, resulting in mechanical and electrical impairment, especially in the presence of stiffer substrates. This might explain why cardiac impairment is usually absent in the early stages of DMD, when cardiac structural changes are still absent. However, the electrophysiological and mechanical impairment of DMD hearts may precipitate rapidly when extracellular stiffness starts to increase due to development of cardiac fibrosis.
Topographical Mapping of the cardiac autonomic innervation for selective cardiac neuromodulation in pigs and rabbits using MicroCT
Authors: Kronsteiner B , Zopf L , Heimel P , Oberoi G , Kramer A-M , Slezak P , Reissig L , Geyer S , Weninger WJ , Podesser BK , Kiss A , Moscato F 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: Public grant(s) – EU funding. Main funding source(s): Horizon 2020- EU H2020-EU.1.2.2. - FET Proactive
"NeuHeart" Nr. 824071

Background & Introduction
In recent years, Vagus Nerve Stimulation (VNS) has proved to be a potential therapeutic approach for the treatment of cardiovascular diseases, such as Heart Failure or atrial fibrillation [1]. However, the lack of specific anatomical knowledge of the cervical VN [2, 3] and thus, of the cardiac autonomic innervation aggravates the side effects of unselective cervical VNS.

Purpose
The goal of this study was to investigate the cardiac vagus nerve branches for selective cardiac VNS stimulation using micro-computed tomography (µCT) and 3D renderings.

Methods
Vagus nerve specimens (n= 11 pig nerves, n= 5 rabbit nerves) were harvested from the nodose ganglion down to the cardiac branches in domestic pigs and New Zealand White rabbits on both sides, and the cardiac autonomic innervation was mapped µCT and 3D renderings.

Results
Our results provide anatomical and topographical key features on the cervical and cardiac autonomic innervation including course of the cardiac branch, cardiac branching patterns, fascicle number, and size of the autonomic nerves. We also compared these aforementioned anatomical parameters between pigs and rabbits and highlighted key anatomical differences among individuals within pigs. In pigs, the cardiac branches were partly composed of both nerves even when they branched off the VN whereas in rabbits, the two nerves were completely separated and the cardiac branch was solely parasympathetic. Finally, we generated a 3D model of various parts of the VN specimen and compared them to images of the native nerves taken during VN dissection surgery.

Conclusions
Here we present an imaging approach to map the anatomy and topography of the cardiac Vagus Nerve for selective stimulation of cardiac VN branches. We also characterized the morphology of the VN, the sympathetic trunk (ST), and the cardiac branch (CB) at the level of the cardiac branching point to highlight the complex interplay between the nerves. Our data provide one possible reason for unwanted side effects of cervical VNS. However, future studies are required to broaden the knowledge in this specific research field of selective cardiac VNS.
MicroRNA biomarkers of platelet function
Authors: Gutmann C , Barwari T , Schulte C , Singh B , Theofilatos K , Joshi A , Zampetaki A , Chan M , Armstrong P , Kiechl S , Willeit J , Warner T , Mayr M 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: Foundation. Main funding source(s): British Heart Foundation (BHF), VASCage (Centre for Promoting Vascular Health in the Ageing Community) of the Austrian Research Promotion Agency FFG (COMET program - Competence Centers for Excellent Technologies)

Introduction
Antiplatelet therapy (APT) leads to reduced morbidity and mortality in patients with cardiovascular disease but some still have thrombotic events. Tailoring APT to platelet function is currently limited by a lack of suitable platelet function tests. It has been previously shown that different circulating microRNAs (miRNAs) are derived from platelets and their measurement could provide new markers of platelet reactivity.

Purpose
To compare the release of different platelet miRNAs in response to different platelet agonists.

Methods
Measurements of platelet function were performed by light transmission aggregometry (LTA) in participants of the 2015 follow-up of the Bruneck study (n=338), using the following agonists: arachidonic acid (1mM), adenosine diphosphate (5µM, 20µM), collagen (0.4 µg/ml, 4 µg/ml, 10µg/ml), TRAP-6 amide (25µM) and U46619 (10µM). LTA platelet releasates were then used for RT-qPCR measurements of five platelet-enriched miRNAs (miR-21, miR-126, miR-150, miR-197, miR-223). Platelet-poor plasma (PPP) served as negative control.

Results
Platelet activation led to aggregation and extracellular release of miRNAs, with aspirin users (n=155) showing significantly lower miRNA release than non-aspirin users (n=183). Agonist responsiveness differed among miRNAs, with miR-21 being hyperresponsive to arachidonic acid and miR-150 being hyperresponsive to adenosine diphosphate, whilst release of miR-126, miR-197 and miR-223 was strongest to collagen (10µg/ml). In non-aspirin users, inflammation markers such as granulocyte counts or C-reactive protein correlated positively with platelet-derived miRNAs measured in PPP, whilst they correlated negatively with platelet-derived miRNAs measured in releasates. These effects were absent in aspirin users.

Conclusions
MiRNAs released from activated platelets can be reliably detected in PPP and platelet releasates. Preferential release of miRNAs in response to specific agonists suggests a selective release mechanism. Elevated PPP levels and decreased releasate levels of platelet-derived miRNAs in inflammatory environments suggest platelet exhaustion ex vivo due to platelet pre-activation.