Publications by authors named "Virginie Bito"

56 Publications

Cardiac Function is Preserved in Adolescents With Well-Controlled Type 1 Diabetes and a Normal Physical Fitness: A Cross-sectional Study.

Can J Diabetes 2021 Jan 23. Epub 2021 Jan 23.

Faculty of Rehabilitation Sciences, Rehabilitation Research Centre, Hasselt University, Diepenbeek, Belgium; Faculty of Medicine and Life Sciences, Biomedical Research Centre, Hasselt University, Diepenbeek, Belgium; Jessa Hospital, Heart Centre Hasselt, Hasselt, Belgium.

Objectives: Cardiovascular diseases and exercise intolerance elevate mortality in type 1 diabetes (T1D). Left ventricular systolic and diastolic function are already affected in T1DM adolescents, displaying poor glycemic control (glycated hemoglobin [A1C]>7.5%) and exercise intolerance. We investigated to the extent to which left ventricular function is affected by disease severity/duration and whether this is related to exercise capacity.

Methods: Transthoracic echocardiography was performed in 19 T1DM adolescents (14.8±1.9 years old, A1C 7.4±0.9%) and 19 controls (14.4±1.3 years old, A1C 5.3±0.2%), matched for age and Tanner stage. Diastolic and systolic (ejection fraction [EF]) function were assessed. Cardiopulmonary exercise testing was used to evaluate exercise capacity, as measured by peak oxygen uptake (VO).

Results: VO and left ventricular systolic and diastolic function were similar in both groups. Within the T1D group, EF was negatively associated with disease duration (r=-0.79 corrected for age, standardized body mass index, glucose variability and VO; p=0.011). Regression analyses revealed that 37.6% of the variance in EF could be attributed to disease duration.

Conclusions: Although left ventricular systolic and diastolic function are preserved in T1D with adequate exercise capacity, disease duration negatively affects EF. The detrimental effects of T1D seem to be driven by disease duration, rather than by disease severity, at least during adolescence. Young T1D patients may, therefore, benefit from cardiovascular evaluation in order to detect cardiovascular abnormalities early in the disease course, and therefore, improve long-term cardiovascular health.
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http://dx.doi.org/10.1016/j.jcjd.2021.01.010DOI Listing
January 2021

Impact of Cardiac Resynchronization Therapy on Global and Cardiac Metabolism and Cardiac Mitochondrial Function.

J Card Fail 2021 Feb 24. Epub 2021 Feb 24.

Department of Cardiology, Ziekenhuis Oost-Limburg, Genk, Belgium; Department of Laboratory Medicine, KU Leuven, UZ Leuven, Leuven, Belgium; Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Diepenbeek, Belgium.

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http://dx.doi.org/10.1016/j.cardfail.2021.02.008DOI Listing
February 2021

Exercise capacity is related to attenuated responses in oxygen extraction and left ventricular longitudinal strain in asymptomatic type 2 diabetes patients.

Eur J Prev Cardiol 2020 Nov 20. Epub 2020 Nov 20.

Department of REVAL - Rehabilitation Research Centre, Faculty of Rehabilitation Sciences, Hasselt University, Belgium.

Aims: Type 2 diabetes mellitus (T2DM) is associated with reduced exercise capacity and cardiovascular diseases, both increasing morbidity and risk for premature death. As exercise intolerance often relates to cardiac dysfunction, it remains to be elucidated to what extent such an interplay occurs in T2DM patients without overt cardiovascular diseases. Design: Cross-sectional study, NCT03299790.

Methods And Results: Fifty-three T2DM patients underwent exercise echocardiography (semi-supine bicycle) with combined ergospirometry. Cardiac output (CO), left ventricular longitudinal strain (LS), oxygen uptake (O2), and oxygen (O2) extraction were assessed simultaneously at rest, low-intensity exercise, and high-intensity exercise. Glycaemic control and lipid profile were assessed in the fasted state. Participants were assigned according to their exercise capacity being adequate or impaired (EXadequate: O2peak <80% and EXimpaired: O2peak ≥80% of predicted O2peak) to compare O2 extraction, CO, and LS at all stages. Thirty-eight participants (EXimpaired: n = 20 and EXadequate: n = 18) were included in the analyses. Groups were similar regarding HbA1c, age, and sex (P > 0.05). At rest, CO was similar in the EXimpaired group vs. EXadequate group (5.1 ± 1 L/min vs. 4.6 ± 1.4 L/min, P > 0.05) and increased equally during exercise. EXimpaired patients displayed a 30.7% smaller increase in O2 extraction during exercise compared to the EXadequate group (P = 0.016) which resulted in a lower O2 extraction at high-intensity exercise (12.5 ± 2.8 mL/dL vs. 15.3 ± 3.9 mL/dL, P = 0.012). Left ventricular longitudinal strain was similar at rest but increased significantly less in the EXimpaired vs. EXadequate patients (1.9 ± 2.5% vs. 5.9 ± 4.1%, P = 0.004).

Conclusions: In asymptomatic T2DM patients, an impaired exercise capacity is associated with an impaired response in oxygen extraction and myocardial deformation (LS).

Trial Registry: Effect of High-intensity Interval Training on Cardiac Function and Regulation of Glycemic Control in Diabetic Cardiomyopathy (https://clinicaltrials.gov/ct2/show/NCT03299790).
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http://dx.doi.org/10.1093/eurjpc/zwaa007DOI Listing
November 2020

Asymptomatic type 2 diabetes mellitus display a reduced myocardial deformation but adequate response during exercise.

Eur J Appl Physiol 2021 Mar 8;121(3):929-940. Epub 2021 Jan 8.

REVAL-Rehabilitation Research Centre, Faculty of Rehabilitation Sciences, Hasselt University, Agoralaan, Building A, 3590, Diepenbeek, Belgium.

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 ventricular LS was assessed at rest and at peak exercise. Peak oxygen uptake (V̇O) and workload (W) were similar between groups (p > 0.05). Diastolic (E, e', 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.
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http://dx.doi.org/10.1007/s00421-020-04557-5DOI Listing
March 2021

The Impact of Advanced Glycation End-Products (AGEs) on Proliferation and Apoptosis of Primary Stem Cells: A Systematic Review.

Stem Cells Int 2020 14;2020:8886612. Epub 2020 Nov 14.

Biomedical (BIOMED) Research Institute, Hasselt University, Agoralaan Building C, 3590 Diepenbeek, Belgium.

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.
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http://dx.doi.org/10.1155/2020/8886612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685833PMC
November 2020

Glycolaldehyde-Derived High-Molecular-Weight Advanced Glycation End-Products Induce Cardiac Dysfunction through Structural and Functional Remodeling of Cardiomyocytes.

Cell Physiol Biochem 2020 Aug;54(5):809-824

Biomedical Research Institute, Hasselt University, Hasselt, Belgium,

Background/aims: High-molecular-weight advanced glycation end-products (HMW-AGEs) are abundantly present in our Western diet. There is growing evidence reporting that HMW-AGEs contribute to the development of cardiovascular dysfunction in vivo, next to the well-known low-molecular-weight AGEs. The goal of our study is to assess the ultrastructure and function of cardiomyocytes after chronic exposure to HMW-AGEs. A better understanding of underlying mechanisms is essential to create new opportunities for further research on the specific role of HMW-AGEs in the development and progression of cardiovascular diseases.

Methods: Adult male rats were randomly assigned to daily intraperitoneal injection for six weeks with either HMW-AGEs (20 mg/kg/day) or a control solution. Hemodynamic measurements were performed at sacrifice. Single cardiomyocytes from the left ventricle were obtained by enzymatic dissociation through retrograde perfusion of the aorta. Unloaded cell shortening, time to peak and time to 50% relaxation were measured during field stimulation and normalized to diastolic length. L-type Ca current density (I) and steady-state inactivation of I were measured during whole-cell ruptured patch clamp. Myofilament functional properties were measured in membrane-permeabilized cardiomyocytes. Ultrastructural examination of cardiac tissue was performed using electron microscopy.

Results: Rats injected with HMW-AGEs displayed in vivo cardiac dysfunction, characterized by significant changes in left ventricular peak rate pressure rise and decline accompanied with an increased heart mass. Single cardiomyocytes isolated from the left ventricle revealed concentric hypertrophy, indicated by the increase in cellular width. Unloaded fractional cell shortening was significantly reduced in cells derived from the HMW-AGEs group and was associated with slower kinetics. Peak L-type Ca current density was significantly decreased in the HMW-AGEs group.
L-type Ca channel availability was significantly shifted towards more negative potentials after HMW-AGEs injection. The impact of HMW-AGEs on myofilament function was measured in membrane-permeabilized cardiomyocytes showing a reduction in passive force, maximal Ca activated force and rate of force development. Ultrastructural examination of cardiac tissue demonstrated adverse structural remodeling in HMW-AGEs group characterized by a disruption of the cyto-architecture, a decreased mitochondrial density and altered mitochondrial function.

Conclusion: Our data indicate that HMW-AGEs induce structural and functional cellular remodeling via a different working mechanism as the well-known LMW-AGEs. Results of our research open the door for new strategies targeting HMW-AGEs to improve cardiac outcome.
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http://dx.doi.org/10.33594/000000271DOI Listing
August 2020

Glycolaldehyde-modified proteins cause adverse functional and structural aortic remodeling leading to cardiac pressure overload.

Sci Rep 2020 07 22;10(1):12220. Epub 2020 Jul 22.

Biomedical Research Institute (BIOMED), Hasselt University, Martelarenlaan 42, 3500, Hasselt, Belgium.

Growing evidence supports the role of advanced glycation end products (AGEs) in the development of diabetic vascular complications and cardiovascular diseases (CVDs). We have shown that high-molecular-weight AGEs (HMW-AGEs), present in our Western diet, impair cardiac function. Whether HMW-AGEs affect vascular function remains unknown. In this study, we aimed to investigate the impact of chronic HMW-AGEs exposure on vascular function and structure. Adult male Sprague Dawley rats were daily injected with HMW-AGEs or control solution for 6 weeks. HMW-AGEs animals showed intracardiac pressure overload, characterized by increased systolic and mean pressures. The contraction response to PE was increased in aortic rings from the HMW-AGEs group. Relaxation in response to ACh, but not SNP, was impaired by HMW-AGEs. This was associated with reduced plasma cyclic GMP levels. SOD restored ACh-induced relaxation of HMW-AGEs animals to control levels, accompanied by a reduced half-maximal effective dose (EC). Finally, collagen deposition and intima-media thickness of the aortic vessel wall were increased with HMW-AGEs. Our data demonstrate that chronic HMW-AGEs exposure causes adverse vascular remodelling. This is characterised by disturbed vasomotor function due to increased oxidative stress and structural changes in the aorta, suggesting an important contribution of HMW-AGEs in the development of CVDs.
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http://dx.doi.org/10.1038/s41598-020-68974-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7376068PMC
July 2020

Differentiation of Human Cardiac Atrial Appendage Stem Cells into Adult Cardiomyocytes: A Role for the Wnt Pathway?

Int J Mol Sci 2020 May 30;21(11). Epub 2020 May 30.

UHasselt, Faculty of Medicine and Life Sciences, Martelarenlaan 42, 3500 Hasselt, Belgium.

Human cardiac stem cells isolated from atrial appendages based on aldehyde dehydrogenase activity (CASCs) can be expanded in vitro and differentiate into mature cardiomyocytes. In this study, we assess whether Wnt activation stimulates human CASC proliferation, whereas Wnt inhibition induces cardiac maturation. CASCs were cultured as described before. Conventional PCR confirmed the presence of the Frizzled receptors. Small-molecule inhibitors (IWP2, C59, XAV939, and IWR1-endo) and activator (CHIR99021) of the Wnt/β -catenin signaling pathway were applied, and the effect on β-catenin and target genes for proliferation and differentiation was assessed by Western blot and RT-qPCR. CASCs express multiple early cardiac differentiation markers and are committed toward myocardial differentiation. They express several Frizzled receptors, suggesting a role for Wnt signaling in clonogenicity, proliferation, and differentiation. Wnt activation increases total and active β-catenin levels. However, this does not affect CASC proliferation or clonogenicity. Wnt inhibition upregulated early cardiac markers but could not induce mature myocardial differentiation. When CASCs are committed toward myocardial differentiation, the Wnt pathway is active and can be modulated. However, despite its role in cardiogenesis and myocardial differentiation of pluripotent stem-cell populations, our data indicate that Wnt signaling has limited effects on CASC clonogenicity, proliferation, and differentiation.
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http://dx.doi.org/10.3390/ijms21113931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312541PMC
May 2020

Acute exposure to glycated proteins reduces cardiomyocyte contractile capacity.

Exp Physiol 2019 07 4;104(7):997-1003. Epub 2019 May 4.

Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium.

New Findings: What is the central question of this study? Does acute exposure to high molecular weight advanced glycation end products (HMW-AGEs) alter cardiomyocyte contractile function? What is the main finding and its importance? Ventricular cardiomyocytes display reduced Ca influx, resulting in reduced contractile capacity, after acute exposure to HMW-AGEs, independent of activation of their receptor. Given that HMW-AGEs are abundantly present in our Western diet, a better understanding of underlying mechanisms, especially in patients already displaying altered cardiac function, should be gained for these compounds.

Abstract: Sustained elevated levels of high molecular weight advanced glycation end products (HMW-AGEs) are known to promote cardiac dysfunction. Recent data suggest that acutely elevated levels of AGEs occur in situations of increased oxidative stress. Whether this increase might have detrimental effects on cardiac function remains unknown. In this study, we investigated whether acute exposure to HMW-AGEs affects cardiomyocyte function via activation of their receptor (RAGE) signalling pathway. Single cardiomyocytes from the left ventricle of adult male rats were obtained by enzymatic dissociation through retrograde perfusion of the aorta. Functional experiments were performed in cardiomyocytes pre-incubated with or without an anti-RAGE antibody. Unloaded cell shortening and L-type Ca current amplitude were evaluated in the presence or absence of HMW-AGEs (200 μg ml ). Expression of RAGE, c-Jun N-terminal kinase (JNK) and phosphorylated JNK (pJNK) were assessed by western blot. Experiments were performed at room temperature. After 4 min application of HMW-AGEs, unloaded cell shortening was significantly reduced. This impaired contractile function was related to reduced Ca influx. These alterations were also observed in cardiomyocytes pre-incubated with anti-RAGE antibody. Our study demonstrates that acute exposure to elevated levels of HMW-AGEs leads to direct and irreversible cardiomyocyte dysfunction, independent of RAGE activation.
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http://dx.doi.org/10.1113/EP087127DOI Listing
July 2019

High intensity training improves cardiac function in healthy rats.

Sci Rep 2019 04 4;9(1):5612. Epub 2019 Apr 4.

Biomedical Research Institute, Hasselt University, Hasselt, Belgium.

Exercise training is a low cost and safe approach for reducing the risk of cardiovascular disease development. Currently, moderate-intensity training (MIT) is the most preferred exercise type. However, high-intensity interval training (HIIT) is gaining interest especially among athletes and healthy individuals. In this study, we examined cardiac remodeling resulting from MIT and HIIT in healthy rats. Healthy male Sprague-Dawley rats were randomly assigned to MIT or HIIT for 13 weeks. Animals kept sedentary (SED) were used as control. Cardiac function was evaluated with echocardiography and hemodynamic measurements. Heart tissue was stained for capillary density and fibrosis. After 13 weeks of training, only HIIT induced beneficial cardiac hypertrophy. Overall global cardiac parameters (such as ejection fraction, cardiac output and volumes) were improved similarly between both training modalities. At tissue level, collagen content was significantly and similarly reduced in both exercise groups. Finally, only HIIT increased significantly capillary density. Our data indicate that even if very different in design, HIIT and MIT appear to be equally effective in improving cardiac function in healthy rats. Furthermore, HIIT provides additional benefits through improved capillary density and should therefore be considered as a preferred training modality for athletes and for patients.
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http://dx.doi.org/10.1038/s41598-019-42023-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6449502PMC
April 2019

Effect of Exercise Intervention on Cardiac Function in Type 2 Diabetes Mellitus: A Systematic Review.

Sports Med 2019 Feb;49(2):255-268

BIOMED-Biomedical Research Centre, Faculty of Medicine and Life Sciences, Hasselt University, Agoralaan building C, 3590, Diepenbeek, Belgium.

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.
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http://dx.doi.org/10.1007/s40279-018-1003-4DOI Listing
February 2019

Western diet given to healthy rats mimics the human phenotype of diabetic cardiomyopathy.

J Nutr Biochem 2018 11 21;61:140-146. Epub 2018 Aug 21.

Biomedical Research Institute, Hasselt University, Belgium. Electronic address:

Diabetes mellitus (DM) is a major problem worldwide. Within this patient group, cardiovascular diseases are the biggest cause of morbidity and mortality. Diabetic cardiomyopathy (DCM) is defined as diabetes-associated structural and functional changes in the myocardium, not directly attributable to other confounding factors such as coronary artery disease or hypertension. Pathophysiology of DCM remains unclear due to a lack of adequate animal models reflecting the current pandemic of diabetes, associated with a high increased sugar intake and the 'Western' lifestyle. The aim of this study was to develop an animal model mimicking this 'Western' lifestyle causing a human-like phenotype of DCM. Twenty-four Sprague-Dawley rats were randomly assigned into a normal or a 'Western' diet group for 18 weeks. Glucose and insulin levels were measured with an OGTT. Heart function was assessed by echocardiography and hemodynamic measurements in vivo. Cardiac fibrosis and inflammation were investigated in vitro. 'Western' diet given to healthy rats for 18 weeks induced hyperglycemia together with increased AGEs levels, insulin levels and hypertriglyceridemia. Heart function was altered with increased end-diastolic pressure, left ventricle hypertrophy. Changes in vivo were associated with increased collagen deposition and increased PAI-1 levels in the heart. High-sugar diet or 'Western' diet causes T2DM and the hallmarks of DCM in rats, reflecting the phenotype of the disease seen in patients. Using this new model of T2DM with DCM might open new insight in understanding the pathophysiology of DCM and on a long term, test targeted therapies for T2DM with DCM patients.
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http://dx.doi.org/10.1016/j.jnutbio.2018.08.002DOI Listing
November 2018

Pyridoxamine improves survival and limits cardiac dysfunction after MI.

Sci Rep 2017 11 22;7(1):16010. Epub 2017 Nov 22.

Biomedical Research Institute (BIOMED), Hasselt University, Martelarenlaan 42, 3500, Hasselt, Belgium.

Advanced glycation end products (AGEs) play a key role in the progression of heart failure. Whether treatments limiting AGEs formation would prevent adverse left ventricular remodeling after myocardial infarction (MI) remain unknown. We investigated whether pyridoxamine (PM) could limit adverse cardiac outcome in MI. Rats were divided into MI, MI + PM and Sham. Echocardiography and hemodynamic parameters were used to assess cardiac function 8 weeks post-surgery. Total interstitial collagen, collagen I and collagen III were quantified using Sirius Red and polarized light microscopy. PM improved survival following LAD occlusion. Pre-treatment with PM significantly decreased the plasma AGEs levels. MI rats treated with PM displayed reduced left ventricular end-diastolic pressure and tau compared to untreated MI rats. Deformation parameters were also improved with PM. The preserved diastolic function was related to the reduced collagen content, in particular in the highly cross-linked collagen type I, mainly in the peri-infarct region, although not via TGF-β1 pathway. Our data indicate that PM treatment prevents the increase in AGEs levels and reduces collagen levels in a rat model of MI, resulting in an improved cardiac phenotype. As such, therapies targeting formation of AGEs might be beneficial in the prevention and/or treatment of maladaptive remodeling following MI.
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http://dx.doi.org/10.1038/s41598-017-16255-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5700185PMC
November 2017

Advanced glycation end products (AGEs) and cardiovascular dysfunction: focus on high molecular weight AGEs.

Amino Acids 2017 09 14;49(9):1535-1541. Epub 2017 Jul 14.

Biomedical Research Institute (BIOMED), Hasselt University, Martelarenlaan 42, 3500, Hasselt, Belgium.

Advanced glycation end products (AGEs) are a group of proteins and lipids becoming glycated and oxidized after persistent contact with reducing sugars or short-chain aldehydes with amino group and/or high degree of oxidative stress. The accumulation of AGEs in the body is a natural process that occurs with senescence, when the turnover rate of proteins is reduced. However, increased circulating AGEs have been described to arise at early lifetime and are associated with adverse outcome and survival, in particular in settings of cardiovascular diseases. AGEs contribute to the development of cardiac dysfunction by two major mechanisms: cross-linking of proteins or binding to their cell surface receptor. Recently, growing evidence shows that high-molecular weight AGEs (HMW-AGEs) might be as important as the characterized low-molecular weight AGEs (LMW-AGEs). Here, we point out the targets of AGEs in the heart and the mechanisms that lead to heart failure with focus on the difference between LMW-AGEs and the less characterized HMW-AGEs. As such, this review is a compilation of relevant papers in the form of a useful resource tool for researchers who want to further investigate the role of HMW-AGEs on cardiac disorders and need a solid base to start on this specific topic.
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http://dx.doi.org/10.1007/s00726-017-2464-8DOI Listing
September 2017

Reduced mitochondrial respiration in the ischemic as well as in the remote nonischemic region in postmyocardial infarction remodeling.

Am J Physiol Heart Circ Physiol 2016 11 9;311(5):H1075-H1090. Epub 2016 Sep 9.

Division of Experimental Cardiology, KU Leuven, University of Leuven, Leuven, Belgium.

Scarring and remodeling of the left ventricle (LV) after myocardial infarction (MI) results in ischemic cardiomyopathy with reduced contractile function. Regional differences related to persisting ischemia may exist. We investigated the hypothesis that mitochondrial function and structure is altered in the myocardium adjacent to MI with reduced perfusion (MI) and less so in the remote, nonischemic myocardium (MI). We used a pig model of chronic coronary stenosis and MI (n = 13). Functional and perfusion MR imaging 6 wk after intervention showed reduced ejection fraction and increased global wall stress compared with sham-operated animals (Sham; n = 14). Regional strain in MI was reduced with reduced contractile reserve; in MI strain was also reduced but responsive to dobutamine and perfusion was normal compared with Sham. Capillary density was unchanged. Cardiac myocytes isolated from both regions had reduced basal and maximal oxygen consumption rate, as well as through complex I and II, but complex IV activity was unchanged. Reduced respiration was not associated with detectable reduction of mitochondrial density. There was no significant change in AMPK or glucose transporter expression levels, but glycogen content was significantly increased in both MI and MI Glycogen accumulation was predominantly perinuclear; mitochondria in this area were smaller but only in MI where also subsarcolemmal mitochondria were smaller. In conclusion, after MI reduction of mitochondrial respiration and glycogen accumulation occur in all LV regions suggesting that reduced perfusion does not lead to additional specific changes and that increased hemodynamic load is the major driver for changes in mitochondrial function.
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http://dx.doi.org/10.1152/ajpheart.00945.2015DOI Listing
November 2016

From Bone Marrow to Cardiac Atrial Appendage Stem Cells for Cardiac Repair: A Review.

Curr Med Chem 2016 ;23(23):2421-38

Jessa Ziekenhuis vwz Department of Cardiothoracic and Vascular Surgery, Hasselt, Belgium.

Traditionally the heart is considered a terminally differentiated organ. However, at the beginning of this century increased mitotic activity was reported in ischemic and idiopathic dilated cardiomyopathy hearts, compared to healthy controls, underscoring the potential of regeneration after injury. Due to the presence of adult stem cells in bone marrow and their purported ability to differentiate into other cell lineages, this cell population was soon estimated to be the most suited candidate for cardiac regeneration. Clinical trials with autologous bone marrow-derived mononuclear cells, using either an intracoronary or direct intramyocardial injection approach consistently showed only minor improvement in global left ventricular ejection fraction. This was explained by their limited cardiomyogenic differentiation potential. To obtain more convincing improvement in cardiac function, based on true myocardial regeneration, the focus of research has shifted towards resident cardiac progenitor cells. Several isolation procedures have been described: the c-kit surface marker was the first to be used, however experimental research has clearly shown that c-kit+ cells only marginally contribute to regeneration post myocardial infarction. Sphere formation was used to isolate the so-called cardiosphere derived cells (CDC), and also in this cell population cardiomyogenic differentiation is a rare event. Recently a new type of stem cells derived from atrial tissue (cardiac atrial stem cells - CASCs) was identified, based on the presence of the enzyme aldehyde dehydrogenase (ALDH). Those cells significantly improve both regional and global LV ejection fraction, based on substantial engraftment and consistent differentiation into mature cardiomyocytes (98%).
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http://dx.doi.org/10.2174/0929867323666160525114735DOI Listing
February 2017

Cross-linking versus RAGE: How do high molecular weight advanced glycation products induce cardiac dysfunction?

Int J Cardiol 2016 May 18;210:100-8. Epub 2016 Feb 18.

Biomedical Research Institute (BIOMED), Hasselt University, Martelarenlaan 42, BE 3500 Hasselt, Belgium. Electronic address:

Background: Several clinical and experimental studies have demonstrated that advanced glycation end products (AGEs) are associated with adverse cardiac outcome. Growing evidence shows that high molecular weight AGEs (HMW-AGEs) might be as important as the characterized low molecular weight AGEs. To date, the role of HMW-AGEs in the pathogenesis of cardiac remodeling remains unknown. In this study, we investigated whether HMW-AGEs are involved in cardiac dysfunction.

Methods: Healthy rats were daily ip injected with 20mg/kg BSA-derived HMW-AGEs or, as a control, unmodified BSA, during 6 weeks. Cardiac function was assessed with echocardiography. Plasma levels of glucose, AGEs and soluble RAGE (sRAGE) were measured. AGEs, RAGE and lysyl oxidase (LOX) expression were determined by western blot.

Results: After 6 weeks, animals displayed a sustained increase in circulating total AGEs without hyperglycemia. HMW-AGEs injections induced cardiac dysfunction characterized by wall hypertrophy, increased heart sphericity, reduced strain and strain rate with preserved ejection fraction. Plasma sRAGE levels were significantly higher compared to control and correlated significantly with decreased strain. RAGE expression, TNF-α and IL-6 remained unchanged. Finally, HMW-AGEs induced prominent cardiac fibrosis associated with an increased LOX expression.

Conclusion: Our data demonstrate that rather than via a specific activation of RAGE, the deleterious effects of HMW-AGEs are likely mediated via an increased collagen cross-linking responsible for the observed cardiac stiffness. Additionally, we show that in the setting of elevated HMW-AGEs, increased sRAGE levels are markers of altered cardiac function.
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http://dx.doi.org/10.1016/j.ijcard.2016.02.095DOI Listing
May 2016

Cardiac atrial appendage stem cells engraft and differentiate into cardiomyocytes in vivo: A new tool for cardiac repair after MI.

Int J Cardiol 2015 Dec 1;201:10-9. Epub 2015 Aug 1.

Faculty of Medicine and Life Sciences, Hasselt University, Hasselt, Belgium; Department of Cardiothoracic Surgery, Jessa Hospital, Hasselt, Belgium. Electronic address:

Background: This study assessed whether autologous transplantation of cardiac atrial appendage stem cells (CASCs) preserves cardiac function after myocardial infarction (MI) in a minipig model.

Methods And Results: CASCs were isolated from right atrial appendages of Göttingen minipigs based on high aldehyde dehydrogenase activity and expanded. MI was induced by a 2h snare ligation of the left anterior descending coronary artery. Upon reperfusion, CASCs were intramyocardially injected under NOGA guidance (MI-CASC, n=10). Non-transplanted pigs (MI, n=8) received sham treatment. 3D electromechanical mapping (EMM) and cardiac MRI were performed to assess left ventricular (LV) function. MI pigs developed LV dilatation at 2 months (2M), while in the MI-CASC group volumes remained stable. Global LV ejection fraction decreased by 16 ± 8% in MI animals vs 3 ± 10% in MI-CASC animals and regional wall thickening in border areas was better preserved in the MI-CASC group. EMM showed decreased viability and wall motion in the LV for both groups POST-MI, whereas at 2M these parameters only improved in the MI-CASC. Substantial cell retention was accompanied by cardiomyogenic differentiation in 98±1% of the transplanted CASCs, which functionally integrated. Second harmonic generation microscopy confirmed the formation of mature sarcomeres in transplanted CASCs. Absence of cardiac arrhythmias indicated the safety of CASC transplantation.

Conclusion: CASCs preserve cardiac function by extensive engraftment and cardiomyogenic differentiation. Our data indicate the enormous potential of CASCs in myocardial repair.
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http://dx.doi.org/10.1016/j.ijcard.2015.07.066DOI Listing
December 2015

On the interpretation of second harmonic generation intensity profiles of striated muscle.

J Biomed Opt 2015 Aug;20(8):86010

Hasselt University, Biomedical Research Institute, Agoralaan Building C, Diepenbeek 3590, Belgium.

Recently, a supramolecular model was developed for predicting striated skeletal muscle intensity profiles obtained by label-free second harmonic generation (SHG) microscopy. This model allows for a quantitative determination of the length of the thick filament antiparallel range or M-band (M ), and results in M=0.12  μm for single-band intensity profiles when fixing the A-band length (A ) to A=1.6  μm , a value originating from electron microscopy (EM) observations. Using simulations and experimental data sets, we showed that the objective numerical aperture (NA) and the refractive index (RI) mismatch (Δn=n 2ω −n ω ) between the illumination wave (ω ) and the second harmonic wave (2ω ) severely affect the simulated sarcomere intensity profiles. Therefore, our recovered filament lengths did not match with those observed by EM. For an RI mismatch of Δn=0.02 and a moderate illumination NA of 0.8, analysis of single-band SHG intensity profiles with freely adjustable A- and M-band sizes yielded A=1.40±0.04  μm and M=0.07±0.05  μm for skeletal muscle. These lower than expected values were rationalized in terms of the myosin density distribution along the myosin thick filament axis. Our data provided new and practical insights for the application of the supramolecular model to study SHG intensity profiles in striated muscl
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http://dx.doi.org/10.1117/1.JBO.20.8.086010DOI Listing
August 2015

A systematic approach for assessing Ca²⁺ handling in cardiac myocytes.

Cold Spring Harb Protoc 2015 May 1;2015(5):431-3. Epub 2015 May 1.

Division of Experimental Cardiology, Department of Cardiovascular Sciences, KU Leuven, Belgium.

In cardiac myocytes, Ca(2+) release from the sarcoplasmic reticulum (SR) Ca(2+) store through the opening of ryanodine receptors (RyRs) is the major source of Ca(2+) for activation of myofilaments and contraction. Over the past 20 years, tools have become available to study this release process in detail, allowing new insights into the regulation of SR Ca(2+) release and RyR function. To assess these processes, we recommend and here review a systematic approach that evaluates the essential transport mechanisms and Ca(2+) fluxes in isolated single cardiac myocytes by using fluorescent Ca(2+) indicators and whole-cell recording of membrane voltage and ionic currents under voltage clamp. The approach includes an assessment of the L-type Ca(2+) current as a trigger for opening of RyRs and release of SR Ca(2+), of the SR Ca(2+) content, of intrinsic properties of RyRs, and of Ca(2+)-removal systems.
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http://dx.doi.org/10.1101/pdb.top066142DOI Listing
May 2015

Assessing Ca²⁺-removal pathways in cardiac myocytes.

Cold Spring Harb Protoc 2015 May 1;2015(5):498-503. Epub 2015 May 1.

Division of Experimental Cardiology, Department of Cardiovascular Sciences, KU Leuven, Belgium.

The decline of an intracellular calcium ([Ca(2+)]i) transient during a single excitation-contraction coupling (ECC) cycle reflects the combined activity of the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA) pump and the sarcolemmal Na(+)-Ca(2+) exchanger (NCX), along with minor contributions of the plasma membrane Ca(2+)-ATPase and mitochondrial Ca(2+) uniporter, in removing Ca(2+) from the cytosol. A traditional approach for assessing the individual components is to fit the decline of the [Ca(2+)]i transient evoked during electrical stimulation with an exponential. This reflects mostly the SERCA-dependent rate of uptake, which can be properly deduced after correcting for a component of NCX removal. As NCX function is an important determinant of the membrane potential as well as the Ca(2+) balance, we present here several detailed protocols for assessing NCX function. As the reversal potential and the amplitudes of the current are highly dependent on the prevailing concentrations of Na(+) and Ca(2+), we show how NCX function can be assessed under highly controlled conditions, with Ca(2+) and Na(+) clamped, as well as under more physiological conditions, with freely changing Ca(2+) and Na(+).
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http://dx.doi.org/10.1101/pdb.prot076992DOI Listing
May 2015

Measuring Ca²⁺ sparks in cardiac myocytes.

Cold Spring Harb Protoc 2015 May 1;2015(5):490-7. Epub 2015 May 1.

Division of Experimental Cardiology, Department of Cardiovascular Sciences, KU Leuven, Belgium.

This protocol describes the measurement of Ca(2+) sparks in intact myocytes by using a Ca(2+)-sensitive dye and imaging using laser scanning confocal microscopy. It takes advantage of spontaneous Ca(2+)-release events-sparks-using them as a measure of the activity of ryanodine receptors (RyRs). Two methodologies are described: One requires that cardiomyocytes be stimulated, preferably under voltage clamp by depolarizing pulses, until steady-state is reached, and then stimulation is stopped and Ca(2+) sparks are recorded. The second requires that cells be permeabilized and bathed in a solution to load the cell with Ca(2+) sufficient to elicit Ca(2+) sparks, but not Ca(2+) waves. These are then analyzed offline to quantify spark frequency and morphology. The advantages and disadvantages of each approach are discussed.
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http://dx.doi.org/10.1101/pdb.prot076984DOI Listing
May 2015

Measuring sarcoplasmic reticulum Ca2+ content, fractional release, and Ca2+ buffering in cardiac myocytes.

Cold Spring Harb Protoc 2015 Apr 1;2015(4):403-7. Epub 2015 Apr 1.

Division of Experimental Cardiology, Department of Cardiovascular Sciences, KU Leuven, Belgium.

Here, we describe a protocol for the reliable measurement of the amount of Ca(2+) in the sarcoplasmic reticulum (SR) Ca(2+) store of cardiac myocytes. The whole-cell patch-clamp method is used to provide controlled loading of the SR during conditioning depolarizing pulses, followed by rapid application of a high dose of caffeine to release all SR Ca(2+) and to prevent Ca(2+) reuptake by the SR. Simultaneous measurement of membrane currents records Ca(2+) extruded through the Na(+)-Ca(2+) exchanger. The integral of the caffeine-induced Na(+)-Ca(2+) exchange current is then used as a measure of the SR Ca(2+). Derived measurements include the Ca(2+) buffering capacity and measurement of fractional release as an indicator of coupling gain. Caveats, advantages, and disadvantages of this method and alternative methods are discussed.
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http://dx.doi.org/10.1101/pdb.prot076976DOI Listing
April 2015

Characterizing the trigger for sarcoplasmic reticulum Ca2+ release in cardiac myocytes.

Cold Spring Harb Protoc 2015 Apr 1;2015(4):398-402. Epub 2015 Apr 1.

Division of Experimental Cardiology, Department of Cardiovascular Sciences, KU Leuven, Belgium.

Here, we describe a method for characterizing the L-type Ca(2+) current, ICaL, which is a major trigger for Ca(2+) release from the sarcoplasmic reticulum (SR). The protocol includes measuring ICaL amplitude and voltage dependence and the elicited SR Ca(2+) release. The procedure for measuring ICaL activity is performed using solutions (internal and external) and voltage control such that other ionic currents are eliminated. The resultant relationship between the Ca(2+) current and the associated internal [Ca(2+)]i transient is a first approach for evaluating coupling gain. We discuss which parameters are most appropriate for this analysis and how an evaluation of gain needs to be further explored by measuring the SR Ca(2+) content.
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http://dx.doi.org/10.1101/pdb.prot076968DOI Listing
April 2015

Basic methods for monitoring intracellular Ca2+ in cardiac myocytes using Fluo-3.

Cold Spring Harb Protoc 2015 Apr 1;2015(4):392-7. Epub 2015 Apr 1.

Division of Experimental Cardiology, Department of Cardiovascular Sciences, KU Leuven, Belgium.

In cardiac myocytes, the physiological increase of intracellular calcium, the [Ca(2+)]i transient, elicited during excitation-contraction coupling typically reaches a peak amplitude of up to 1 µm, from a resting value of ∼100 nm, within 50-100 msec, depending on the species. Various conditions will affect the amplitude and rise time of the [Ca(2+)]i transient and, depending on the nature of the Ca(2+) signals under study, a variety of different probes are available for monitoring changes in intracellular Ca(2+). In this protocol, we focus on Fluo-3, which exists in the cytosol in its salt form K5Fluo-3. This form is practically nonfluorescent in the absence of Ca(2+), but the fluorescence increases dramatically on Ca(2+) binding. Although Fluo-3 is a single excitation-emission dye, it has a number of advantages for investigators, including an ideal dissociation constant (Kd) value and high quantum yield, meaning that it can be used at low concentrations that introduce minimal buffering. Here, we describe the basic setup and methodology for recording the global cytosolic [Ca(2+)]i transient with this probe during simultaneous patch-clamp and whole-cell recording of membrane voltage or of ionic currents under voltage clamp.
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http://dx.doi.org/10.1101/pdb.prot076950DOI Listing
April 2015

Exercise improves cardiac function and attenuates insulin resistance in Dahl salt-sensitive rats.

Int J Cardiol 2015 10;186:154-60. Epub 2015 Mar 10.

REVAL Rehabilitation Research Center, BIOMED Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Belgium.

Background: The development of heart failure (HF) secondary to hypertension is a complex process related to a series of physiological and molecular factors including glucose dysregulation. The overall objective of this study was to investigate whether exercise training could improve cardiac function and insulin resistance in a rat model of hypertensive HF.

Methods: Seven week old Dahl salt-sensitive rats received either 8% NaCl (n = 30) or 0.3% NaCl (n = 18) diet. After a 5-week diet, animals were randomly assigned to exercise training (treadmill running at 18 m/min, 5% inclination for 60 min, 5 days/week) or kept sedentary for 6 additional weeks. 2D echocardiography was used to calculate left ventricular (LV) dimensions, volumes and global functional parameters. LV global deformation parameters were measured with speckle tracking echocardiography. Insulin resistance was assessed using 1h oral glucose tolerance testing.

Results: High salt diet led to cardiac hypertrophy and HF, characterized by increased wall thicknesses and LV volumes as well as reduced deformation parameters. In addition, high salt diet was associated with the development of insulin resistance. Exercise training improved cardiac function, reduced the extent of interstitial fibrosis and reduced insulin levels 60 min post-glucose administration.

Conclusions: Even if not fully reversed, exercise training in HF animals improved cardiac function and insulin resistance. Adjusted modalities of exercise training might offer new insights not only as a preventive strategy, but also as a treatment for HF patients.
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http://dx.doi.org/10.1016/j.ijcard.2015.03.094DOI Listing
March 2016

Melusin protects from cardiac rupture and improves functional remodelling after myocardial infarction.

Cardiovasc Res 2014 Jan 15;101(1):97-107. Epub 2013 Oct 15.

Department of Cardiology, University of Göttingen, Heart Research Center Göttingen, Göttingen, Germany.

Aims: Melusin is a muscle-specific chaperone protein whose expression is required for a compensatory hypertrophy response to pressure overload. Here, we evaluated the consequences of melusin overexpression in the setting of myocardial infarction (MI) using a comprehensive multicentre approach.

Methods And Results: Mice overexpressing melusin in the heart (TG) and wild-type controls (WT) were subjected to permanent LAD ligation and both the acute response (Day 3) and subsequent remodelling (2 weeks) were examined. Mortality in wild-type mice was significant between Days 3 and 7, primarily due to cardiac rupture, but melusin's overexpression strongly reduced mortality (43.2% in wild-type vs. 27.3% in melusin-TG, P = 0.005). At Day 3 after MI, a time point preceding the mortality peak, TG hearts had increased heat shock protein 70 expression, increased ERK1/2 signalling, reduced cardiomyocyte hyper-contractility and inflammatory cell infiltrates, and increased matricellular protein expression in the infarcted area. At 2 weeks after MI, melusin overexpression conferred a favourable adaptive remodelling characterized by reduced left ventricle dilatation and better preserved contractility in the presence of a comparable degree of hypertrophy. Adaptive remodelling in melusin TG mice was characterized by reduced apoptosis and fibrosis as well as increased cardiomyocyte contractility.

Conclusions: Consistent with its function as a chaperone protein, melusin overexpression exerts a dual protective action following MI reducing an array of maladaptive processes. In the early phase after MI, reduced inflammation and myocyte remodelling protect against cardiac rupture. Chronically, reduced myocyte loss and matrix remodelling, with preserved myocyte contractility, confer adaptive LV remodelling.
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http://dx.doi.org/10.1093/cvr/cvt235DOI Listing
January 2014

Selective modulation of coupled ryanodine receptors during microdomain activation of calcium/calmodulin-dependent kinase II in the dyadic cleft.

Circ Res 2013 Nov 30;113(11):1242-52. Epub 2013 Sep 30.

From the Laboratory of Experimental Cardiology, Department of Cardiovascular Sciences, KU Leuven, Belgium (E.D., V.B., I.L., G.A., K.R.S., N.M.); Biomedical Research Institute, University of Hasselt, Belgium (V.B.); Division of Cardiology, Medical University of Graz, Austria (G.A.); and Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom (N.M.).

Rationale: In ventricular myocytes of large mammals with low T-tubule density, a significant number of ryanodine receptors (RyRs) are not coupled to the sarcolemma; cardiac remodeling increases noncoupled RyRs.

Objective: Our aim was to test the hypothesis that coupled and noncoupled RyRs have distinct microdomain-dependent modulation.

Methods And Results: We studied single myocytes from pig left ventricle. The T-tubule network was analyzed in 3-dimension (3D) to measure distance to membrane of release sites. The rising phase of the Ca(2+) transient was correlated with proximity to the membrane (confocal imaging, whole-cell voltage-clamp, K5fluo-4 as Ca(2+) indicator). Ca(2+) sparks after stimulation were thus identified as resulting from coupled or noncoupled RyRs. We used high-frequency stimulation as a known activator of Ca(2+)/calmodulin-dependent kinase II. Spark frequency increased significantly more in coupled than in noncoupled RyRs. This specific modulation of coupled RyRs was abolished by the Ca(2+)/calmodulin-dependent kinase II blockers autocamtide-2-related inhibitory peptide and KN-93, but not by KN-92. Colocalization of Ca(2+)/calmodulin-dependent kinase II and RyR was not detectably different for coupled and noncoupled sites, but the F-actin disruptor cytochalasin D prevented the specific modulation of coupled RyRs. NADPH oxidase 2 inhibition by diphenyleneiodonium or apocynin, or global reactive oxygen species scavenging, also prevented coupled RyR modulation. During stimulated Ca(2+) transients, frequency-dependent increase of the rate of Ca(2+) rise was seen in coupled RyR regions only and abolished by autocamtide-2-related inhibitory peptide. After myocardial infarction, selective modulation of coupled RyR was lost.

Conclusions: Coupled RyRs have a distinct modulation by Ca(2+)/calmodulin-dependent kinase II and reactive oxygen species, dependent on an intact cytoskeleton and consistent with a local Ca(2+)/reactive oxygen species microdomain, and subject to modification with disease.
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http://dx.doi.org/10.1161/CIRCRESAHA.113.301896DOI Listing
November 2013

ACE-inhibition, but not weight reduction restores cardiomyocyte response to β-adrenergic stimulation in the metabolic syndrome.

BMC Cardiovasc Disord 2013 Jul 12;13:51. Epub 2013 Jul 12.

Department of Cardiovascular Sciences, Research Unit of Experimental Cardiac Surgery, KU Leuven, Herestraat 49, Leuven B-3000, Belgium.

Background: Diabetic cardiomyopathy is characterized by systolic and early diastolic ventricular dysfunction. In the metabolic syndrome (MS), ventricular stiffness is additionally increased in a later stage. It is unknown whether this is related to intrinsic cardiomyocyte dysfunction, extrinsic factors influencing cardiomyocyte contractility and/or cardiac function, or a combination of both. A first aim was to study cardiomyocyte contractility and Ca2+ handling in vitro in a mouse model of MS. A second aim was to investigate whether in vivo hypocaloric diet or ACE-inhibition (ACE-I) improved cardiomyocyte contractility in vitro, contractile reserve and Ca2+ handling.

Methods: This study was performed in LDL-receptor (LDLR-/-) and leptin-deficient (ob/ob), double knock-out mice (DKO), featuring obesity, type II diabetes, atherogenic dyslipidemia and hypertension. Single knock-out LDLR-/-, ob/ob and wild type mice were used as controls. Cellular contractility, Ca2+ handling and their response to in vivo treatment with diet or ACE-I were studied in isolated cardiomyocytes at baseline, during β-adrenergic stimulation or increased extracellular Ca2+, using field stimulation and patch-clamp.

Results: In untreated conditions, prolongation of contraction-relaxation cycle and altered Ca2+ handling are observed in MS. Response to increased extracellular Ca2+ and β-adrenergic stimulation is impaired and could not be rescued by weight loss. ACE-I restored impaired response to β-adrenergic stimulation in MS, but not the decreased response to increased extracellular Ca2+.

Conclusions: Cardiomyocyte contractility and β-adrenergic response are impaired in MS, due to alterations in cellular Ca2+ handling. ACE-I, but not weight loss, is able to restore cardiomyocyte response to β-adrenergic stimulation in MS.
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http://dx.doi.org/10.1186/1471-2261-13-51DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3729821PMC
July 2013