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Stem cell-based regenerative therapies hold great promises to treat a wide spectrum of diseases. However, stem cell engraftment and survival are still challenging due to an unfavorable transplantation environment. Advanced glycation end-products (AGEs) can contribute to the generation of these harmful conditions. AGEs are a heterogeneous group of glycated products, nonenzymatically formed when proteins and/or lipids become glycated and oxidized. Our typical Western diet as well as cigarettes contain high AGEs content. AGEs are also endogenously formed in our body and accumulate with senescence and in pathological situations. Whether AGEs have an impact on stem cell viability in regenerative medicine remains unclear, and research on the effect of AGEs on stem cell proliferation and apoptosis is still ongoing. Therefore, this systematic review provides a clear overview of the effects of glycated proteins on cell viability in various types of primary isolated stem cells used in regenerative medicine. Figures were created using images from Servier Medical Art Commons Attribution 3.0 Unported License (http://smart.servier.com). Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License. This work was supported by a Bijzonder onderzoeksfonds (BOF) grant from Hasselt University (grant number: 16NI05BOF). HB benefits from an aspirant PhD mandate (grant number: 1154120N) of the `Research Foundation-Flanders' (fonds voor wetenschappelijk onderzoek (FWO)). PG is also supported by the FWO (grant numbers: 12U7718N and 1502120N). Bito, V (corresponding author), Hasselt Univ, Biomed BIOMED Res Inst, Agoralaan Bldg C, B-3590 Diepenbeek, Belgium. virginie.bito@uhasselt.be

Background The effect of exercise on cardiac function/structure in type 2 diabetes mellitus (T2DM) with or without diabetic cardiomyopathy (DCM) is not yet completely understood. To date, results of studies have been controversial with variable outcomes due to the variety of exercise modalities. Objectives The aim of the present review was to examine the impact of exercise intervention, and different types of exercise, on cardiac function and structure in T2DM through a systematic literature review, combining both pre-clinical and clinical studies. Methods A systematic literature search was performed on PubMed, Web of Science, and PEDro to identify studies up to 2 April 2018. Articles were included when well-defined exercise protocols were provided, and cardiac function in T2DM patients or validated animal models was examined. Results In diabetic animals, improvements in both diastolic and systolic function through exercise therapy were mainly attributed to reduced collagen deposition. In T2DM patients, improvements were observed in diastolic function, but not consistently in systolic function, after endurance (and combined resistance) exercise training. Different exercise intervention modalities and exercise types seemed equally effective in improving cardiac structure and function. Conclusion Exercise training elicits significant improvements in diastolic function and beneficial remodeling in T2DM and DCM animal models, but not necessarily improvements in systolic function and left ventricular structure, regardless of exercise type. Therefore, exercise intervention should be a cornerstone in the treatment of T2DM patients not only to improve glycemic control but also to specifically enhance cardiac function. No sources of funding were used to assist in the preparation of this article. Funding was provided by BOF-scholarship from Hasselt University (Grant no. 15NI06-BOF).

Background. Several studies have shown that advanced glycation end products (AGEs) are associated with adverse cardiac outcome. In that context, growing evidence show that high molecular weight AGEs (HMW-AGEs) play a role as important as the well characterized low molecular weight AGEs (e.g. pentosidine and carboxymethyllysine), chronically but also possibly acutely. Objective. In this study, we investigated whether HMW-AGEs acutely alter Ca2+ homeostasis in cardiomyocytes. Methodology. Single cardiomyocytes from the left ventricle of adult male rats were obtained by enzymatic dissociation. Ionic currents were evaluated during whole cell patch-clamp in the presence or absence of HMW-AGEs (200 µg/ml) and normalized to cell capacitance. Data are expressed as mean ± SEM. Results. After 4 minutes HMW-AGEs application, peak ICaL measured at +10 mV significantly decreased (-5.2±0.6 pA/pF vs -7.8±1.1 pA/pF at baseline, ncells =10, p, Journal of International Society of Antioxidants in Nutrition & Health, Vol 3, No 2 (2016): Journal of ISANH Volume 3: Special Issue for Maillard Reaction & Glycation

Purpose: Left ventricular (LV) twist and untwist rate (UR) are known to be strongly related to LV systolic and diastolic function, respectively. Although these parameters are emerging as important tools to evaluate LV function, yet their assessment and physiological significance in small animals remain challenging. The study was designed to investigate how twist and UR, measured by speckle tracking imaging (STI), relate to LV function and extent of fibrosis in a rat model of chronic myocardial infarction (MI). Methods: 23 Sprague-Dawley rats were subjected to LAD ligation (MI; n=14) or sham surgery (SHAM; n=9). 2D echocardiography at baseline (BL), day 1, day 3 and 2 months post-surgery was used to calculate LV dimensions, volumes (EDV, ESV) and global functional parameters. STI was applied to measure circumferential strain (Scirc), twist and UR. LV fibrosis was estimated from Sirius Red staining at day 1, day 3 and 2 months post-surgery. Results: Progressive cardiac failure evaluated during 2 months was characterized by a gradual increase in EDV and ESV respectively (0.2±0.04 mL to 0.8±0.2mL, and 0.04±0.02mL to 0.5±0.1 from BL to 2 months post-surgery, p

1. The effect of ruthenium red on calcium and sodium currents was studied in guinea-pig isolated ventricular heart cells with the whole cell patch-clamp technique. 2. Ruthenium red very efficiently blocked the L-type calcium current in a dose-dependent manner. A significant block was observed for concentrations as low as 0.3 microM. Analysis of the dose-response curve with the logistic equation indicated an EC50 of 0.8 microM, a maximum inhibition of 85% reached at 5 microM, and a coefficient of 2.37. 3. There was no shift in the voltage-dependence of the Ca current activation, nor in that of its steady-state inactivation determined with a 1 s prepulse. However, removal of Ca current inactivation at positive voltage was considerably reduced in the presence of concentrations of ruthenium red above 1 microM. A slowing of the time-course of inactivation of the Ca current was also observed. 4. At 10 microM, a concentration generally used to block the sarcoplasmic Ca release channels or the mitochondrial Ca uptake, ruthenium red blocked 26.7+/-4.3% (n=8) of the sodium current, and slowed its inactivation time-course. No effect was observed on the voltage-dependence of the current activation or inactivation. The peak sodium current was also decreased at a 10 times lower concentration by 7.6+/-2.7% (n=3). 5. Thus, at concentrations used to assess intracellular Ca movements, ruthenium red induced in heart cells a significant block of both Ca and Na channels.

Chronically increased levels of high molecular weight advanced glycation end products (HMW-AGEs) are known to induce cardiovascular dysfunction. Whether an acute increase in HMW-AGE levels affects vascular function remains unknown. In this study, we examined whether acute exposure to HMW-AGEs disturbs aortic vasomotor function. Aortae were obtained from healthy male rats and were acutely pre-treated with HMW-AGEs in organ baths. Aortic relaxation responses to cumulative doses of acetylcholine (ACh), in the presence or absence of superoxide dismutase (SOD), were measured after precontraction with phenylephrine (PE). Furthermore, levels of 3-nitrotyrosine were evaluated on aortic paraffine sections. In our study, we show that acute exposure to HMW-AGEs significantly decreases the aortic relaxation response to ACh. SOD pre-treatment prevents acute HMW-AGEs-induced impairment by limiting superoxide formation. In conclusion, our data demonstrate that acute exposure to HMW-AGEs causes adverse vascular remodelling, characterised by disturbed vasomotor function due to increased oxidative stress. These results create opportunities for future research regarding the acute role of HMW-AGEs in cardiovascular dysfunction. This research was funded by a Bijzonder onderzoeksfonds (BOF) grant from Hasselt University, grant number: 16NI05BOF. We thank Jeanine Santermans for embedding the tissues in paraffin. The authors also thank Petra Bex for her skilful technical assistance. The graphical abstract was created using images from Biorender and ServierMedical Art Commons Attribution 3.0 Unported License (http: //smart.servier.com, accessed on 2 September 2022). Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License.

Background and purpose The development of myocardial fibrosis is a major complication of Type 2 diabetes mellitus (T2DM), impairing myocardial deformation and, therefore, cardiac performance. It remains to be established whether abnormalities in longitudinal strain (LS) exaggerate or only occur in well-controlled T2DM, when exposed to exercise and, therefore, cardiac stress. We therefore studied left ventricular LS at rest and during exercise in T2DM patients vs. healthy controls. Methods and results Exercise echocardiography was applied with combined breath-by-breath gas exchange analyses in asymptomatic, well-controlled (HbA1c: 6.9 ± 0.7%) T2DM patients (n = 36) and healthy controls (HC, n = 23). Left ventricu-lar LS was assessed at rest and at peak exercise. Peak oxygen uptake (V̇ O 2peak) and workload (W peak) were similar between groups (p > 0.05). Diastolic (E, e' s , E/e') and systolic function (left ventricular ejection fraction) were similar at rest and during exercise between groups (p > 0.05). LS (absolute values) was significantly lower at rest and during exercise in T2DM vs. HC (17.0 ± 2.9% vs. 19.8 ± 2% and 20.8 ± 4.0% vs. 23.3 ± 3.3%, respectively, p < 0.05). The response in myocardial deformation (the change in LS from rest up to peak exercise) was similar between groups (+ 3.8 ± 0.6% vs. + 3.6 ± 0.6%, in T2DM vs. HC, respectively, p > 0.05). Multiple regression revealed that HDL-cholesterol, fasted insulin levels and exercise tolerance accounted for 30.5% of the variance in response of myocardial deformation in the T2DM group (p = 0.002). Conclusion Myocardial deformation is reduced in well-controlled T2DM and despite adequate responses, such differences persist during exercise. Trial registration NCT03299790, initially released 09/12/2017.

Advanced glycation end products (AGEs) are compounds formed by irreversible glycation of proteins. Our research group has recently demonstrated that high-molecular-weight AGEs (HMW-AGEs) impair cardiac function in healthy rats. This project aims to examine the effect of HMW-AGEs on vascular function and to investigate ultrastructural abnormalities in cardiomyocytes. Therefore, male Sprague Dawley rats were daily intraperitoneally injected with either HMW-AGEs or a control solution for six weeks. Plasma AGEs levels and cardiac hemodynamic parameters were evaluated to validate this animal model. The relaxation responses to cumulative doses of acetylcholine (ACh) or sodium nitroprusside (SNP) were assessed in isolated rat aortic rings. Microscopy was performed to examine the ultrastructural cardiomyocyte organization. HMW-AGEs injections in rats significantly increased plasma AGEs levels and cardiac pressure. The vasorelaxation response to ACh but not to SNP was decreased in HMW-AGEs animals, indicating impaired endothelium-dependent relaxation. Interestingly, superoxide dismutase restored relaxation in aortic rings from HMW-AGEs animals, which indicates that HMW-AGEs disturb vascular function through superoxide formation. In addition, we show that HMW-AGEs cause ultrastructural remodeling in cardiomyocytes, characterized by an increase in cytoplasmic fraction and a reduction of mitochondrial area and number in cardiomyocytes. This research provides more insight into the role of HMW-AGEs in cardiovascular disease.

Myocardinfarct (MI) is wereldwijd de meest frequente oorzaak van hartfalen. Huidige therapieën kunnen het beschadigde cardiale weefsel niet herstellen en bijgevolg de verdere progressie naar hartfalen niet verhinderen. Onze onderzoeksgroep heeft recent een nieuwe cardiale stamcel, ‘cardiac atrial appendage stem cells’ (CASCs), ontdekt met een hogere in vitro differentiatiecapaciteit naar cardiomyocyten vergeleken met andere stamcellen. Zowel functionele verbetering in cardiale functie op orgaan- en celniveau, als differentiatie van CASCs na in vivo transplantatie moeten echter nog bevestigd worden voordat deze therapie in het ziekenhuis gebruikt kan worden. Daarnaast zijn de toepassingsmogelijkheden van deze stamcellen beperkt door de lage celretentie aangezien CASCs een beperkte mogelijkheid hebben om te overleven en prolifereren in de ischemische omgeving van het infarct. Dentale pulp stamcellen (DPSCs) hebben sterke paracriene en celbeschermende eigenschappen en werden daarom in deze studie gebruikt om de functionele eigenschappen van CASCs te stimuleren. Onze resultaten tonen aan dat CASCs transplantatie de cardiale functie na MI verbetert op orgaan- en celniveau ondanks de beperkte CASCs retentie. Daarnaast tonen wij aan dat stimulatie van CASCs met DPSCs de functionele eigenschappen van CASCs bevordert. Uit deze studie kunnen we concluderen dat CASCs transplantatie een effectieve therapie is na MI.

Cardiovascular disorders, such as diabetic cardiomyopathy (DCM), are the main cause of morbidity and mortality in type 2 diabetes patients. Exercise training can reduce the risk of cardiovascular disease, yet, it is not known which type of exercise training is most potent in reaching this goal. Therefore, a study was set up to verify whether high-intensity interval training (HIIT) is efficient as moderate-intensity interval training (MIT) in reducing the adverse effects occurring in DCM. 32 male Sprague-Dawley rats were randomly divided into 4 groups: sedentary control, sedentary diabetic, MIT diabetic and HIIT diabetic. T2DM was induced by a high-sugar diet for 18 weeks where after the rats performed treadmill running for 5 days/week for a period of 12 weeks. In the current study, we show exercise training leads to a reduction in the level of left ventricular fibrosis and hypertrophy, inflammation, end-diastolic pressure, body weight, plasma triglycerides, and free fatty acids. Both MIT and HIIT show promising results which could lead to the use of exercise training as a treatment and/or prevention method for DCM, thereby significantly reducing morbidity and mortality in the T2DM patient population. We conclude that only a slight difference in exercise-induced effects was observed between both training modalities. Therefore, more research is needed to further determine the advantages of both training modalities in the treatment or prevention of DCM.

Elektrische cardioversie (ECV) wordt vaak geopteerd als behandelingsoptie van paroxysmale of persistente voorkamerfibrillatie (VKF). Ondanks zijn hoge doeltreffendheid, komt herval van VKF vaak voor. Daarnaast kan onvoldoende zelfmanagement, door gebrek aan kennis over VKF, dit herval uitlokken of de detectie ervan uitstellen. Dit heeft als gevolg dat de patiënt een verhoogd risico heeft op het ontwikkelen van complicaties, zoals bijvoorbeeld een beroerte. Daarom veronderstellen wij dat het voorzien van educatie aan VKF patiënten die ECV als behandeling zullen krijgen hun kennis omtrent hun aandoening zal verhogen, wat vervolgens zal resulteren in een verbetering van hun zelfmanagement. Dit zou uiteindelijk kunnen leiden tot een snellere detectie van herval van VKF na een succesvolle ECV. De kennis van de patiënten omtrent VKF en ECV, alsook hun attitude en zelfmanagement activiteiten werden geëvalueerd aan de hand van vragenlijsten. Deze studie heeft aangetoond dat het informeren van VKF patiënten die ECV als behandeling krijgen hun kennis over VKF alsook hun zelfmanagement verhoogt. Desondanks werd herval van VKF niet sneller vastgesteld in de educatiegroep, aangezien zij niet geïnstrueerd werden om enkele keren per dag hun pols te monitoren. Meer studies zijn nodig om te achterhalen of educatie in combinatie met een duidelijk polsmeting protocol kunnen leiden tot een snellere detectie van herval in VKF na een succesvolle ECV.

Diabetic cardiomyopathy (DCM) is a devastating disease of the heart, which increases the risk of heart failure in individuals with diabetes mellitus (DM). DCM is characterized by structural and functional changes of the myocardium, which are attributable only to the presence of DM and not to confounding factors or diseases. To date, little is known about the pathophysiology of this disease and there is no specific treatment available. Therefore, a clinically relevant animal model, in which DCM is developed after induction of DM, is warranted. This study showed that the combination of a high fat diet and a low dose of streptozotocin is efficient to induce type 2 diabetes, a deteriorated left ventricular relaxation and an increased left ventricular pressure in a rat model. Moreover, rats which are fed only a high fat diet, will develop the insulin resistance syndrome. This nongenetic rat model has the additional advantage of being easy to induce and can be used in the future to unravel the molecular mechanisms of DCM.

AGEs zijn eiwitten of vetten die in vivo versuikerd worden. Enerzijds is er steeds meer bewijs dat AGEs mogelijk ook betrokken zijn in de ontwikkeling en vooruitgang van hart- en nierfalen. Anderzijds is het bekend dat vrouwen over het algemeen minder gevoelig zijn aan cardiovasculaire aandoeningen. De huidige studie had als doel om het effect van AGEs op de hart- en nierfunctie en om de geslachtsverschillen in hart- en nierfunctie te bestuderen als gevolg van verhoogde AGEs in het lichaam. Mannelijke en vrouwelijke Sprague-Dawley ratten werden dagelijks i.p geïnjecteerd met AGEs (20 mg/kg) of BSA met eenzelfde concentratie gedurende 6 weken.Injecties van AGEs gedurende 6 weken leidden tot hart dysfunctie. Hypertrofie werd bevestigd met een verhoogd hart gewicht-tibia lengteverhouding in beide geslachten. Totaal collageen was hoger in AGE-BSA geïnjecteerde dieren, waarbij het totaal collageen hoger was bij mannen dan bij vrouwen. Urine analyse toonde veranderingen in elektrolyt concentraties van AGE-BSA behandelde mannelijke dieren en fibrose was uitgesproken in de cortex. Deze studie toont aan dat AGE-BSA injecties aanleiding geven tot fibrose in zowel het hartweefsel als nierweefsel. Mannelijke ratten vertonen meer uitgesproken fibrose dan de vrouwtjes wat de duidelijke verslechtering in hartfunctie in vivo deels verklaart.