bluuebunny/crossref_metadata_2025_split huggingface dataset:
Silent myocardial infarction in non-insulin dependent type 2 diabetes mellitus patients with low adherence to blood glucose monitoring
Authors: Viligorska K 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: None.

Background
Decompensated diabetic patients frequently suffer from ischemic complications including silent ST-elevation myocardial infarction (STEMI).

Purpose
Aim of this study was to define prognostic value of low adherence to self-monitoring of blood glucose (SMBG) in type 2 diabetes mellitus (T2DM) patients as risk factor that leads to silent STEMI.

Methods
The electronic search in Cochrane Library, Scopus, PubMed and Web of Science for the period of 2016-2018 systematic literature review concentrated on types of educational interventions administered before SMBG in type 2 diabetes mellitus patients who are not using insulin was conducted. 18 studies were eligible for inclusion. We included all randomized controlled trials on SMBG education in T2DM patients compared with standard care in adult patients. As a proof of self-efficacy after SMBG glycated hemoglobin (HbA1c) was chosen as primary endpoint. Study group: 12 (7 females, 5 male, age 56-85 years) T2DM patients with non-insulin dependent diabetes for &gt;5 years, low skills of SMBG that were admitted to surgery department with diabetic foot ulcers for the period of August 2019-September 2019 developed silent STEMI. Control group 10 (5 females, 5 males) T2DM patients that corresponded by age and study parameters, but did SMBG once a week via individual glucometers. Blood glucose, troponin I (cTnI) levels were registered. Statistical analysis:IBM SPSS Statistics v.23, RevMan5.

Results
During systematic review evidence indicated that a SMBG education was associated with more stress and lower rate in well-being and treatment satisfaction in comparison to a standard care (random-effects SMD: 0.45; 95% CI: 0.25-0.65; P &lt; 0.0001). Depending on type of SMBG record subgroup analysis indicated that SMBG skills depend on SMBG education delivery. Patients that did feet checking, SMBG at least once a week had lower risk of complications development (P&lt;0.05). STEMI development was associated with low SMBG in a form of checking only at visits to general practitioner (HR 1.15, 95% CI:1.04-1.13). Mean level of cTnI for study group patients was 0.045 ng/ml with no specific cardiac complaints.

Conclusions
There is a higher risk of silent ST-elevation myocardial infarction development in diabetic patients that have low SMBG skills) due to lacking information about importance of self-monitoring of blood glucose level as a predictor of cardiovascular complications.
Rictor is a central target of the molecular network of cardiac ProtectomiRs
Authors: Makkos A , Agg B , Varga ZV , Giricz Z , Gyongyosi M , Lukovic D , Schulz R , Bartekova M , Gorbe A , Ferdinandy P 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Research, Development and Innovation Office of Hungary (NKFIA; NVKP-16-1-2016-0017 National Heart Program and OTKA-FK 134751); MTA-SE System Pharmacology Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, H-1089 Budapest, Hungary
We have previously identified several cardiac microRNAs that are involved in cardioprotection and termed them as ProtectomiRs. mRNA targets of these ProtectomiRs may reveal new drug targets for cardioprotection.
Here we aimed to identify key molecular targets of ProtectomiRs and confirm their association with cardioprotection in a translational pig model of acute myocardial infarction.
Network theoretical approach was utilized to identify 882 potential target genes of 18 previously described protectomiRs. Rictor gene was the most central and it was ranked first in the protectomiR-target mRNA molecular network with the highest node degree of 5. Therefore, expression of Rictor and its targeting microRNAs were further validated in heart samples obtained from a translational pig model of acute myocardial infarction and cardioprotection induced by pre- or postconditioning. Three out of five Rictor-targeting pig homologue of rat ProtectomiRs showed significant upregulation in postconditioned but not in preconditioned pig hearts. Rictor was downregulated at the mRNA and protein level in ischemic postconditioning but not in ischemic preconditioning.
This is the first demonstration that Rictor is the central molecular target of ProtectomiRs and that decreased Rictor expression may regulate ischemic postconditioning-, but not preconditioning-induced acute cardioprotection. We conclude that Rictor is a potential novel drug target for acute cardioprotection.
Responsiveness of the widely used cardiomyocyte cell platforms to simulated ischemia/reperfusion
Authors: Kiss B , Onodi ZS , Makkos A , Pelyhe CS , Apati A , Varga N , Ree D , Ferdinandy P , Gorbe A , Varga Z 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Research, Development and Innovation Office of Hungary (NKFIA; NVKP-16-1-2016-0017 National Heart Program and OTKA-FK 134751)
MTA-SE System Pharmacology Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, H-1089 Budapest, Hungary
Ischemic heart disease is the leading cause of death worldwide; therefore, the development of cardioprotective therapies is currently a main focus of research. Cultured cell lines and primary cell cultures play an integral role in cardiovascular research. However, there are many limitations when using these models, including variations in proliferation capacity, uncontrolled stress during cell isolation, poor reproducibility and low translational value. The aim of our study was to test the responsiveness of the most widely used cardiomyocyte platforms to simulated ischemia/reperfusion injury (SI/R) considering the effect of differentiation protocols.
Human, rat and mouse cell lines as well as primary cell cultures were used for in vitro viability assay with or without widely used differentiation protocols. The cells were exposed to normoxic or simulated ischemia/reperfusion protocols: a simulated ischemic period of 6 hours was used for the primary and the differentiated cell cultures, while for the non-differentiated cells 16 hours of simulated ischemia followed by 2 hours of reperfusion was applied. The duration of simulated ischemia was determined from preliminary experiments. Viability of the cells was measured by calcein assay.
In non-differentiated human AC16 and rat H9C2 cardiac cell lines, cell viability was significantly reduced (50%) by 16h SI / 2h R in contrast, the viability of the mouse HL-1 cell line was not reduced by 16 h SI. In primary rat neonatal cardiac myocytes 6h SI / 2h R caused significant cell death (25%). In primary human iPSC-derived cardiac myocytes 6h SI / 2h R did not result significant injury (10%) whereas 16h did (37%). Responsiveness of different cell types to SI/R ranged between 40-100%.
We have shown that the responsiveness of primary cardiac cells and non-differentiated cardiac cell lines is significantly different to simulated ischemia / reperfusion. Differentiation protocols in cell lines markedly affects their response to simulated ischemia / reperfusion. Comparative analyses of different types of cardiomyocytes can provide a good basis for accurate design of in vitro cardioprotective test systems.
Left ventricular SGLT1 expression is upregulated in heart failure in humans and rat model
Authors: Sayour AA , Ruppert M , Olah A , Barta BA , Zsary E , Benke K , Horvath EM , Hartyanszky I , Merkely B , Radovits T 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Research, Development and Innovation Fund of Hungary;
Ministry of Human Capacities of Hungary

Introduction
Myocardial sodium-glucose cotransporter 1 (SGLT1) has been shown to contribute to cardiac pathological processes, whereas humans with functionally limited SGLT1 are at lower risk of developing heart failure (HF). The novel HF medications, SGLT2 inhibitors, non-selectively inhibit SGLT1 to different extent, therefore, characterization of its expression in disease conditions is relevant.

Purpose
To investigate left ventricular (LV) SGLT1 expression in humans with end-stage HF, and in a rat model of HF.

Methods
Myocardial LV samples were harvested from control subjects (Controls, n=9) undergoing valve surgery, and from patients with end-stage dilated cardiomyopathy (DCM, n=12) undergoing heart transplantation. The rat model of aorto-caval fistula (ACF, n=12) was used to induce HF with predominant LV dilation in rats during a course of 24 weeks; sham-operated animals served as controls (Sham-A, n=12). Echocardiography was used to assess LV structure and function prior to surgery in humans, as well as in rats at the end of the follow-up period. Western blotting was performed to characterize LV SGLT1 protein expression and to investigate the activity of the master regulators AMPK and ERK1/2. The extent of LV nitro-oxidative stress was quantified by immunohistochemistry (3-nitrotyrosine) in rats with HF.

Results
Both humans with DCM and rats with ACF-induced HF presented with severely dilated LVs compared to respective controls, whereas LV SGLT1 protein expression was significantly upregulated similarly by ~1.7-fold in both cases (both P&lt;0.01). These increases in SGLT1 expressions were accompanied by significant reductions in ERK1/2 activating phosphorylation (both P&lt;0.05), whereas AMPK activity was unaffected. In rats with HF, LV SGLT1 expression correlated significantly with the extent of myocardial nitro-oxidative stress (r=0.762, P=0.037).

Conclusions
LV SGLT1 expression is upregulated in HF in both humans and small animals, and ERK1/2 shows a concomitantly reduced activity. LV SGLT1 expression correlates with the extent of nitro-oxidative stress, suggesting a possible pathological role in HF. Whether SGLT2 inhibitors exert direct cardiac actions via inhibition of myocardial SGLT1 needs to be elucidated.
A novel translational stratification system for electrophysiological characterization: evaluating arrhythmia complexity from the lab to the clinic
Authors: Sanchez De La Nava AM , Gomez-Cid L , Fernandez-Santos ME , Arenal A , Atienza F , Fernandez-Aviles F 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: Public Institution(s). Main funding source(s): Instituto de Salud Carlos III
CIBERCV

Introduction
Cardiac arrhythmias can originate as a consequence of the proarrhythmic effects of some therapeutical regenerative products. In vitro studies have demonstrated different levels of electrophysiological complexity but these models usually lack of direct translation into the clinical practice.

Objective
To develop an arrhythmia complexity evaluation method that enables to characterize electrophysiological complexity in translational scenarios.
Methodology: To build a new evaluation method, frequency and rotor biomarkers from in vitro cell cultures presenting fibrillatory activity (N=15) were evaluated using optical mapping recordings (Rhod-2AM Ca2+ transient dye, 30-minute incubation, excited with green light). The patterns observed at in vitro level were analyzed and characterized by means of frequency and rotor biomarkers.
Next, we performed a forward translational study to evaluate these electrophysiological biomarkers at a clinical level. In 206 patients with atrial fibrillation (AF) with non-invasive body surface recordings using the Acorys system from Corify (67 electrodes, 4 second segments) (STRATIFY-AF study) were evaluated to analyze the same frequency and rotor biomarkers previously explored in vitro. Moreover, we build a complexity score that described from 0 to 1 the complexity at electrophysiological level, where 0 corresponded to simple scenarios and 1 to complex arrhythmic patterns. Patients were followed for 12 months to evaluate long term evolution.

Results
Complexity evaluation method identified the highest dominant frequency, median frequency and rotor time as the most important predictors for arrhythmia complexity definition. In vitro cultures results showed that samples presenting higher dominant frequency were also associated with small dominant frequency area extension and lower rotor time maintenance, i.e., with a high value of the complexity biomarker (Figure 1B). At clinical level, patients with high values of the complexity score were identified with Persistent AF patients showing complex patterns in whom AF recurred after ablation at 12 months (Figure 1D).

Conclusions
We developed a translational approach that enables to characterize arrhythmia complexity in different frameworks, which is crucial to evaluate potential undesirable effects of therapeutical regenerative products during the complete development and validation of the product.
Investigation of cardiotoxicity by dipeptidyl-peptidase-4 inhibitors in a human cardiomyocyte cell line as well as in samples from chronic heart failure patients
Authors: Voros I , Onodi ZS , Toth VE , Gergely T , Saghy E , Gorbe A , Kemeny A , Leszek P , Helyes ZS , Ferdinandy P , Varga ZV 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: Public grant(s) – EU funding. Main funding source(s): Horizon 2020 research and innovation programme, Ministry for Innovation and Technology

Background
Dipeptidyl-peptidase-4 (DPP4) inhibitors are relatively new therapeutic tools for type 2 diabetes. The SAVOR-TIMI-53 clinical trial has revealed an increased heart failure (HF)-associated hospitalization rate in saxagliptin treated patients. Although this critical side effect could limit the therapeutic use considerably, the mechanism by which DPP4 inhibitors damage the heart is still unclear.

Aims
We aimed to set up a relevant cellular platform to investigate mechanistically DPP4 inhibition, and the role of its potentially important neuropeptide substrates (e.g. Substance P and Neuropeptide Y). Moreover, we aim to determine the expression of DDP4 and its neuropeptide substrates in human and cellular samples.

Methods
Western blot, ELISA, and radioimmunoassay experiments were performed to investigate the expression of DPP4 and its neuropeptide substrates in human hearts and in AC16 cells. Viability measurements with calcein staining and scratch assay experiments were used to test the potentially toxic effect of DPP4 inhibitors. The localization of DPP4 mRNA was determined with RNA Scope in situ hybridization.

Results
Expression of DPP4 and NPY proteins decreased in interventricular septum samples of patients with HF compared to healthy controls. In human hearts DPP4 mRNA is detectable in cardiomyocytes, while other cell types (endothelial cells, fibroblasts, and macrophages) show negligible expression. AC16 human cardiomyocyte cell line expresses DPP4 enzyme. Treatment with various DPP4 inhibitors administered alone or in combination with neuropeptides don’t affect cellular survival; although, in scratch assay experiments treatments with neuropeptides decreased cell migration speed in the isolated neonatal rat cardiomyocyte-fibroblast co-culture. The migration speed reducing effect of NPY was revered by the administration of saxagliptin at the highest concentration of NPY.

Conclusions
Decreased activity of DPP4 may play a role in the pathomechanism of end-stage congestive heart failure. The DPP4 enzyme could be important as a compensating mechanism against the elevated sympathetic activity in HF and for the altered neuropeptide tone. Inhibition of DPP4 could decrease this adaptive mechanism thereby exacerbating myocardial damage.
Correlating electrical dysfunctions and structural remodeling in Arrhythmogenic Mouse Hearts by advanced optical methods
Authors: Giardini F , Olianti C , Biasci V , Arecchi G , Zaglia T , Mongillo M , Cerbai E , Zgierski-Johnston C , Kohl P , Sacconi L 
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 - No 952166 (REPAIR)
Regione Toscana - Bando Ricerca Salute 2018 - PERCARE project.
Severe remodeling processes may occur in the heart due to both genetic and non-genetic diseases. Structural remodeling, such as collagen deposition (fibrosis) and cellular misalignment, can affect electrical conduction at different orders of magnitude and, eventually, lead to arrhythmias. In this scenario, arrhythmogenic cardiomyopathy (ACM) is an inherited heart disease that involves ventricular dysfunction, arrhythmias, and localized replacement of contractile fibers with fibrofatty scar tissue. Unfortunately, nowadays, predicting the impact of fine structural alterations on the electrical dysfunction in entire organs is challenging, due to the inefficacy of standard imaging methods in performing high-resolution three-dimensional reconstructions in massive tissues.
In this work, we developed a new full-optical correlative approach to quantify and integrate the electrical dysfunctions with three-dimensional structural reconstructions of entire hearts, both in controls and in a mouse model of ACM. We combined optical mapping of the action potential propagation (APP) with advances in tissue clearing and light-sheet microscopy techniques. First, we employed an optical platform to map and analyze the APP in Langendorff-perfused hearts. Then, we optimized the SHIELD procedure for the clearing of cardiac tissue, thus converting the previously electrically characterized samples into well-preserved and fully-transparent specimens. A high-throughput light-sheet microscope has been developed following the mesoSPIM project: the conceived microscope allows the reconstruction of the whole mouse heart with a micrometric resolution allowing fine quantification of myocytes alignment and fibrosis deposition across the organ. Finally, we developed a software pipeline that employs high-resolution 3D images to analyze and co-register APP maps with the 3D anatomy, contractile fibers disarray, and fibrosis deposition on each heart.
We believe that this promising methodological framework will allow clarifying the involvement of fine structural alterations in the electrical dysfunctions, thus enabling a unified investigation of the structural causes that lead to electrical and mechanical alterations after the tissue remodeling.
Exploring the contribution of mechano-sensing to cardiomyopathy
Authors: Azad A , Jiang H , Hooper C , Davies B , Watkin H , Gehmlich K 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: Foundation. Main funding source(s): Medical Research Council (MR/V009540/1),
Wellcome Trust (201543/B/16/Z)
British Heart Foundation (FS/12/40/29712).
Hypertrophic cardiomyopathy (HCM) is an inherited cardiac condition associated with diastolic dysfunction and sudden cardiac death. Disease genes for HCM are traditionally coding for proteins involved in force generation. More recently, it has emerged that variants in genes coding for proteins involved in biomechanical stress-signalling can also cause HCM.
One such protein is filamin C, with proposed mechano-sensing functions in the heart. Within the protein, the immunoglobulin-like domain 20 (Ig20) may play a crucial role in mediating binding to muscle specific ligands. While the mechano-sensing functions of filamin C have been investigated well in skeletal muscle, the underlying cardiac disease mechanisms are not completely understood.

Aim
This work attempts to provide insights into the role of filamin C in cardiac mechano-sensing and dissect disease pathways leading to HCM in the presence of the FLNC variants in Ig20.

Methods
Using mass spectrometry, we aimed to provide a detailed analysis of the proteome of mice carrying the filamin C variant, using ventricular tissue samples from 14wk old homozygous mice. Samples were subject to molecular biology technical and underwent subcellular fractionation (n = 6 per genotype) and were investigated by label-free mass spectrometry.

Results
Utilising whole genome sequencing, a heterozygous FLNC missense variant in Ig20 was identified in a three-generation family affected by HCM. Mice carrying this variant recapitulate molecular features of HCM in the homozygous setting. Three proteins (FLNC, MYH7, MYOT) were found to be upregulated in the myofilament-enriched fraction. Up-regulations of key proteins were found to relocalise towards load-baring sites.

Conclusion
Our data indicate that changes in filamin C and its binding partners expression and localisation are involved in the pathogenesis of HCM in this mouse model.
Aspects of somatogenic asthenic syndrome in patients with high cardiovascular risk
Authors: Demikhov A , Demikhova N , Rudenko T , Orlovskiy A 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: None.

Aim
To study frequency and nature of psychopathological symptoms in various forms of somatogenic asthenic syndrome in patients with high cardiovascular risk (CVR).

Methods
The quantitative anamnestic analysis of medical history, the variational statistics, the probabilistic allocation of clinical signs with estimation of reliability of the results. Among the 199 persons with high CVR and non-psychotic mental disorders: 31 patients had somatogenic asthenic syndrome (SAS), stratified by clinical variants: asthenic (1n2=14); asthenic-anxious (2n2=8); asthenic-subdepressive (3n2=6) and dyssomniac (4n2=3).

Results
The frequency and kind of pathopsychological symptoms in young people with increased CVR and SAS was studied. Each variant of SAS in patients with high CVR has its features of symptomological structure. More, than in half of cases in asthenic variant of SAS in patients with high CVR, registered a headache, a feeling of heaviness in the head (63.4±12.8%), intolerance to loud sounds and bright lights (57.1±13.2%) and low mood (50.0±13.4%). Patients with high CVR and asthenic-anxious variant of SAS on the first place by the frequency of diagnosing was also weakness (87.5±11.7%), lack of vigor after a night's sleep (87.5±11.7%) and almost with the same frequency were registered fatigue (75.0±15.3%), memory impairment (62.5±17.1%), which in 1.5-3 times exceeded the average in patients with SAS by the frequency; anxiety, absentmindedness were diagnosed in 50.0±17.7% of cases in this subgroup. Prevailing (most common) psychopathological symptoms, significantly more represented than on the average in patients with high CVR and dyssomniac variant of SAS were (at 65-100%): absentmindedness, irritability, fatigue, weakness, anxiety.
Most common symptom in patients with high CVR and asthenic variant of SAS was a weakness - in (92.9±6.9)%, and the prevalence was significantly higher, than on the average in group of patients with SAS. There were fatigue (85.7±9.4%), tearfulness (85.7±9.4%), irritability (63.4±12.8%), difficulty falling asleep (57.1±13.2%), the prevalence of which significantly exceeded the average in patients with SAS (p&lt;0.05). In patients with high CVR and asthenic-anxious SAS on the first place by the frequency of diagnosis was also weakness (87.5±11.7%), lack of vigor after a night's sleep (87.5±11.7%) almost on the same frequency was registered fatigue (75.0±15.3%), memory impairment (62.5±17.1%), which in 1.5-3 times exceeded the average in patients with SAS by the frequency. Most common for patients with high CVR and asthenic-subdepressive variant of SAS were: dizziness (83.3±15.2), sleep disorders and restless sleep (66.7±19.2%), touchiness and anguish (66.7±19.2%).

Conclusions
Ranking of symptoms was made and the major syndromes, depending on the variant of SAS in patients with high CVR, were defined.