Karin R Sipido

University of Leuven, Louvain, Flemish, Belgium

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Publications (141)849.79 Total impact

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    ABSTRACT: Postconditioning and cyclosporine A prevent mitochondrial permeability transition pore opening providing cardioprotection during ischemia/reperfusion. Whether microvascular obstruction is affected by these interventions is largely unknown. Pigs subjected to coronary occlusion for 1 h followed by 3 h of reperfusion were assigned to control (n = 8), postconditioning (n = 9) or cyclosporine A intravenous infusion 10-15 min before the end of ischemia (n = 8). Postconditioning was induced by 8 cycles of repeated 30-s balloon inflation and deflation. After 3 h of reperfusion magnetic resonance imaging, triphenyltetrazolium chloride/Evans blue staining and histopathology were performed. Microvascular obstruction (MVO, percentage of gadolinium-hyperenhanced area) was measured early (3 min) and late (12 min) after contrast injection. Infarct size with double staining was smaller in cyclosporine (46.2 ± 3.1 %, P = 0.016) and postconditioning pigs (47.6 ± 3.9 %, P = 0.008) versus controls (53.8 ± 4.1 %). Late MVO was significantly reduced by cyclosporine (13.9 ± 9.6 %, P = 0.047) but not postconditioning (23.6 ± 11.7 %, P = 0.66) when compared with controls (32.0 ± 16.9 %). Myocardial blood flow in the late MVO was improved with cyclosporine versus controls (0.30 ± 0.06 vs 0.21 ± 0.03 ml/g/min, P = 0.002) and was inversely correlated with late-MVO extent (R (2) = 0.93, P < 0.0001). Deterioration of left ventricular ejection fraction (LVEF) between baseline and 3 h of reperfusion was smaller with cyclosporine (-7.9 ± 2.4 %, P = 0.008) but not postconditioning (-12.0 ± 5.5 %, P = 0.22) when compared with controls (-16.4 ± 5.5 %). In the three groups, infarct size (β = -0.69, P < 0.001) and late MVO (β = -0.33, P = 0.02) were independent predictors of LVEF deterioration following ischemia/reperfusion (R (2) = 0.73, P < 0.001). Despite both cyclosporine A and postconditioning reduce infarct size, only cyclosporine A infusion had a beneficial effect on microvascular damage and was associated with better preserved LV function when compared with controls.
  • Cardiovascular Research 11/2014; DOI:10.1093/cvr/cvu238 · 5.81 Impact Factor
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    Cardiovascular Research 01/2014; 101(1):1-3. DOI:10.1093/cvr/cvt272 · 5.81 Impact Factor
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    ABSTRACT: Differentiation of cardiac fibroblasts (Fb) into myofibroblasts (MyoFb) is responsible for connective tissue buildup in myocardial remodeling. We examined MyoFb differentiation and reversibility.Methods and ResultsAdult rat cardiac Fb were cultured on a plastic substratum providing mechanical stress, with conditions to obtain different levels of Fb differentiation. Fb spontaneously differentiated to proliferating MyoFb (p-MyoFb) with stress fiber formation decorated with alpha-smooth muscle actin (α-SMA). Transforming growth factor-β1 (TGF-β1) promoted differentiation into α-SMA positive MyoFb showing near absence of proliferation i.e. non-p-MyoFb. SD-208, a TGF-β-receptor-I kinase blocker, inhibited p-MyoFb differentiation as shown by stress fiber absence, low α-SMA expression, and high proliferation levels. Fb seeded in collagen matrices induced no contraction, whereas p-MyoFb and non-p-MyoFb induced 2.5- and 4-fold contraction. Fb produced little collagen but high levels of IL-10. Non-p-MyoFb had high collagen production and high MCP-1 and TIMP-1 levels. Transcriptome analysis indicated differential activation of gene networks related to differentiation of MyoFb (e.g. paxilin, PAK) and reduced proliferation of non-p-MyoFb (e.g. cyclins and cell cycle regulation). Dedifferentiation of p-MyoFb with stress fiber de-polymerization, but not of non-p-MyoFb, was induced by SD-208 despite maintained stress. Stress fiber de-polymerization could also be induced by mechanical strain release in p-MyoFb and non-p-MyoFb (2 day culture in unrestrained 3-D collagen matrices). Only p-MyoFb showed true dedifferentiation after long-term 3-D culture. Fb, p-MyoFb and non-p-MyoFb have a distinct gene expression, ultrastructural and functional profile. Both reduction in mechanical strain and TGF-β-receptor-I kinase inhibition can reverse p-MyoFb differentiation but not of non-p-MyoFb.
    Cardiovascular Research 12/2013; DOI:10.1093/cvr/cvt338 · 5.81 Impact Factor
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    ABSTRACT: 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 multicenter approach.Methods and ResultsMice 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 day 3 and 7, primarily due to cardiac rupture, but melusin 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 HSP70 expression, increased ERK1/2 signalling, reduced cardiomyocyte hyper-contractility and reduced inflammatory cell infiltrates and increased matricellular protein expression in the infarcted area.At 2 weeks after MI melusin overexpression conferred a favorable adaptive remodelling characterized by reduced left ventricle dilatation and better preserved contractility in 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. Consistent with its function as 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.
    Cardiovascular Research 10/2013; DOI:10.1093/cvr/cvt235 · 5.81 Impact Factor
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    ABSTRACT: Rationale: In ventricular myocytes of large mammals with low T-tubule (TT) density, a significant number of ryanodine receptors (RyR) are not coupled to the sarcolemma; cardiac remodeling increases non-coupled RyR. Objective: To test the hypothesis that coupled and non-coupled RyRs have distinct microdomain-dependent modulation. Methods and Results: We studied single myocytes from pig left ventricle. The TT network was analyzed in 3-D 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 following stimulation were thus identified as resulting from coupled or non-coupled RyRs. We used high frequency stimulation as a known activator of CaMKII. Spark frequency increased significantly more in coupled than in non-coupled RyRs. This specific modulation of coupled RyRs was abolished by the CaMKII-blockers AIP and KN-93, but not by KN-92. Colocalization of CaMKII and RyR was not detectably different for coupled and non-coupled sites but the F-actin disruptor cytochalasin D prevented the specific modulation of coupled RyRs. NOX2 inhibition by DPI or apocynin, or global ROS 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 AIP. After myocardial infarction, selective modulation of coupled RyR was lost. Conclusions: Coupled RyRs have a distinct modulation by CaMKII and ROS, dependent on an intact cytoskeleton and consistent with a local Ca(2+)/ROS microdomain, and subject to modification with disease.
    Circulation Research 09/2013; 113(11). DOI:10.1161/CIRCRESAHA.113.301896 · 11.09 Impact Factor
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    ABSTRACT: 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. 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 beta-adrenergic stimulation or increased extracellular Ca2+, using field stimulation and patch-clamp. In untreated conditions, prolongation of contraction-relaxation cycle and altered Ca2+ handling are observed in MS. Response to increased extracellular Ca2+ and beta-adrenergic stimulation is impaired and could not be rescued by weight loss. ACE-I restored impaired response to beta-adrenergic stimulation in MS, but not the decreased response to increased extracellular Ca2+. Cardiomyocyte contractility and beta-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 beta-adrenergic stimulation in MS.
    BMC Cardiovascular Disorders 07/2013; 13(1):51. DOI:10.1186/1471-2261-13-51 · 1.50 Impact Factor
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    ABSTRACT: Rationale: Synchronized release of Ca(2+) into the cytosol during each cardiac cycle determines cardiomyocyte contraction. Objective: We investigated synchrony of cytosolic [Ca(2+)] decay during diastole and the impact of cardiac remodeling. Methods and Results: Local cytosolic [Ca(2+)] transients (1 µm intervals) were recorded in murine, porcine and human ventricular single cardiomyocytes. We identified intracellular regions of slow (slowCaR) and fast (fastCaR) [Ca(2+)] decay based on the local time constants of decay (TAUlocal). The standard deviation of TAUlocal (SDTAU) as a measure of dyssynchrony was not related to the amplitude or the timing of local Ca(2+) release. Stimulation of SERCA with forskolin or istaroxime accelerated, its inhibition with cyclopiazonic acid slowed TAUlocal significantly more in slowCaR, thus altering the relationship between SDTAU and global [Ca(2+)] decay (TAUglobal). NCX-inhibitor SEA0400 prolonged TAUlocal similarly in slowCaR and fastCaR. FastCaR were associated with increased mitochondrial density and were more sensitive to the mitochondrial Ca(2+) uniporter blocker Ru360. Variation in TAUlocal was higher in pig and human cardiomyocytes and higher with increased stimulation frequency (2 Hz). TAUlocal correlated with local sarcomere relengthening. In mice with myocardial hypertrophy following trans-aortic constriction (TAC), in pigs with chronic myocardial ischemia and in end-stage human heart failure, variation in TAUlocal was increased and related to cardiomyocyte hypertrophy and increased mitochondrial density. Conclusions: In cardiomyocytes, cytosolic [Ca(2+)] decay is regulated locally and related to local sarcomere relengthening. Dyssynchronous intracellular [Ca(2+)] decay in cardiac remodeling and end-stage heart failure suggests a novel mechanism of cellular contractile dysfunction.
    Circulation Research 07/2013; 113(5). DOI:10.1161/CIRCRESAHA.113.300895 · 11.09 Impact Factor
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    ABSTRACT: INTRODUCTION: There is convincing experimental evidence that cellular action potential duration (APD) alternans is arrhythmogenic but its relationship with body surface microvolt T-wave alternans (MTWA) remains unclear. We investigated the relationship between MTWA and APD alternans induced by alternating cycle length (CL) pacing in a pig model. METHODS: In 10 pigs, catheters in the right atrium (RA) and right (RV) and left ventricle (LV) allowed pacing and recording of monophasic action potentials (MAP). During RA pacing at stable 500-ms CL, LV was paced at alternating CL (505 ms and 495 ms). Changing the alternating LV (A-LV) pacing delay changes the size of the region with alternating ventricular activation. Spectral analysis of intracardiac MAP was correlated with body surface MTWA. In a similar setup (during alternating pacing in RV and LV), we investigated concordant versus discordant APD alternans. RESULTS: Pacing the LV with subtle alternating cycle lengths at short A-LV delay leads to broad QRS (97 ± 10 ms), body surface MTWA (mean Valt 4.2 ± 1.8 µV), and positive RR-interval alternans. At longer A-LV delay, not resulting in QRS widening (68 ± 5 ms), body surface RR alternans was absent but MTWA remained detectable and was even more pronounced (8.7 ± 5.1 µV, P < 0.01). During both concordant and discordant pacing MTWA was present. The precordial leads were better for detecting discordant APD alternans (8.0 ± 2.9 µV and 12.8 ± 4.52 µV, P = 0.02). CONCLUSION: MTWA is a potent technique to detect subtle and isolated intracardiac APD alternans that is artificially induced by alternating pacing. In the same model, discordant activation alternans can only be discriminated from concordant when using a quantifying approach of MTWA analysis.
    Pacing and Clinical Electrophysiology 04/2013; 36(8). DOI:10.1111/pace.12139 · 1.75 Impact Factor
  • Karin R Sipido, Heping Cheng
    Cardiovascular Research 04/2013; DOI:10.1093/cvr/cvt077 · 5.81 Impact Factor
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    ABSTRACT: BACKGROUND: -L-type calcium channel (LTCC) and Na(+)/Ca(2+) exchanger (NCX) have been implicated in repolarization-dependent arrhythmias, but also modulate calcium and contractility. While LTCC inhibition is negative inotropic, NCX inhibition has the opposite effect. Combined block may therefore offer an advantage for hemodynamics and antiarrhythmic efficiency, particularly in diseased hearts. In a model of proarrhythmia, the dog with chronic atrioventricular block (CAVB), we investigated if combined inhibition of NCX and LTCC with SEA-0400 is effective against dofetilide-induced Torsade de Pointes arrhythmias (TdP), while maintaining calcium homeostasis and hemodynamics. METHODS AND RESULTS: -Left ventricular pressure (LVP) and ECG were monitored during infusion of SEA-0400 and verapamil in anesthetized dogs. Different doses were tested against dofetilide-induced TdP in CAVB dogs. In ventricular myocytes, effects of SEA-0400 were tested on action potentials (AP), calcium transients, and early afterdepolarizations (EAD). In cardiomyocytes, SEA-0400 (1 μM) blocked 66±3% of outward NCX, 50±2% of inward NCX, and 33±9% of LTCC current. SEA-0400 had no effect on systolic calcium, but slowed relaxation despite AP shortening, and increased diastolic calcium. SEA-0400 stabilized dofetilide-induced lability of repolarization and suppressed EADs. In vivo, SEA-0400 (0.4 and 0.8 mg/kg) had no effect on LVP, and suppressed dofetilide-induced TdPs dose-dependently. Verapamil (0.3 mg/kg) also inhibited TdP, but caused a 15±8% drop of LVP. A lower dose of verapamil without effects on LVP (0.06 mg/kg) was not anti-arrhythmic. CONCLUSIONS: -In CAVB dogs, SEA-0400 treatment is effective against TdP. Unlike specific inhibition of LTCC, combined NCX and LTCC inhibition has no negative effects on cardiac hemodynamics.
    Circulation Arrhythmia and Electrophysiology 03/2013; 6(2). DOI:10.1161/CIRCEP.113.000322 · 5.95 Impact Factor
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    ABSTRACT: AIMS: Oxidative stress can modulate nitric oxide (NO) signalling pathways. Both pathways have been shown to be involved in the pathophysiology of atrial fibrillation (AF), but data are conflicting. We aimed to characterize the NO-pathway and its relation to oxidative stress in persistent AF in a sheep model.METHODS AND RESULTS: Persistent AF was induced by rapid atrial pacing for a mean of 136.5 ± 21.7 days. Non-stimulated sheep served as controls. Nicotine adenine dinucleotide phosphate (NADPH) oxidase-stimulated superoxide production was significantly increased in the AF group (+51.3 ± 23.2%, P < 0.01). Although there were no changes in mRNA expression of the different NADPH oxidase subunits, the increased activity was associated with markedly increased protein expression of the NADPH oxidase activator, Rac1 (+26 ± 4.6%, P < 0.05). No differences were seen in superoxide dismutase activity, but glutathione peroxidase activity was lower in the AF group. There was a marked accumulation of 3-nitrotyrosine, a biomarker for peroxynitrite, in atrial tissue of AF animals, as demonstrated by immunohistochemical staining and dot blot analysis (+15.6 ± 1.8%, P < 0.05). Expression of atrial NOS3 mRNA was 24.9 ± 4.4% lower in the AF group vs. control (P < 0.05), while NOS1 and 2 were unchanged. Immunoblot analysis revealed no changes in protein expression. Nitrite/nitrate levels were significantly lower during AF (-24.8 ± 5.8%, P < 0.05).CONCLUSION: In a sheep model of persistent AF, NOS3 transcript levels are attenuated and circulating NOx levels decreased. Persistent AF is associated with increased oxidative stress, probably resulting from increased NADPH oxidase activity, without major changes in anti-oxidant capacity of the atrial tissue.
    Europace 02/2013; DOI:10.1093/europace/eut012 · 3.05 Impact Factor
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    ABSTRACT: Connexin-43 (Cx43), a predominant cardiac connexin, forms gap junctions (GJs) that facilitate electrical cell-cell coupling and unapposed/nonjunctional hemichannels that provide a pathway for the exchange of ions and metabolites between cytoplasm and extracellular milieu. Uncontrolled opening of hemichannels in the plasma membrane may be deleterious for the myocardium and blocking hemichannels may confer cardioprotection by preventing ionic imbalance, cell swelling and loss of critical metabolites. Currently, all known hemichannel inhibitors also block GJ channels, thereby disturbing electrical cell-cell communication. Here we aimed to characterize a nonapeptide, called Gap19, derived from the cytoplasmic loop (CL) of Cx43 as a hemichannel blocker and examined its effect on hemichannel currents in cardiomyocytes and its influence in cardiac outcome after ischemia/reperfusion. We report that Gap 19 inhibits Cx43 hemichannels without blocking GJ channels or Cx40/pannexin-1 hemichannels. Hemichannel inhibition is due to the binding of Gap19 to the C-terminus (CT) thereby preventing intramolecular CT-CL interactions. The peptide inhibited Cx43 hemichannel unitary currents in both HeLa cells exogenously expressing Cx43 and acutely isolated pig ventricular cardiomyocytes. Treatment with Gap19 prevented metabolic inhibition-enhanced hemichannel openings, protected cardiomyocytes against volume overload and cell death following ischemia/reperfusion in vitro and modestly decreased the infarct size after myocardial ischemia/reperfusion in mice in vivo. We conclude that preventing Cx43 hemichannel opening with Gap19 confers limited protective effects against myocardial ischemia/reperfusion injury.
    Archiv für Kreislaufforschung 01/2013; 108(1):309. DOI:10.1007/s00395-012-0309-x · 5.96 Impact Factor
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    ABSTRACT: The Na(+)/Ca(2+) exchanger (NCX) is a key regulator of intracellular Ca(2+) in cardiac myocytes, predominantly contributing to Ca(2+) removal during the diastolic relaxation process but also modulating excitation-contraction coupling. NCX is preferentially located in the T-tubules and can be close to or within the dyad, where L-type Ca(2+) channels face ryanodine receptors (RyRs), the Ca(2+) release channels of the sarcoplasmic reticulum. However, especially in larger animals, not all RyRs are in dyads or adjacent to T-tubules, and a substantial fraction of Ca(2+) release from the sarcoplasmic reticulum thus occurs at distance from NCX. This chapter deals with the functional consequences of NCX location and how NCX can modulate diastolic and systolic Ca(2+) events. The loss of T-tubules and the effects on RyR function and NCX modulation are explored, as well as quantitative measurement of local Ca(2+) gradients at the level of the dyadic space.
    Advances in Experimental Medicine and Biology 01/2013; 961:375-83. DOI:10.1007/978-1-4614-4756-6_32 · 2.01 Impact Factor
  • Circulation Arrhythmia and Electrophysiology 01/2013; · 5.42 Impact Factor
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    ABSTRACT: Connexin mimetic peptides (CxMPs), such as Gap26 and Gap27, are known as inhibitors of gap junction channels but evidence is accruing that these peptides also inhibit unapposed/non-junctional hemichannels (HCs) residing in the plasma membrane. We used voltage clamp studies to investigate the effect of Gap26/27 at the single channel level. Such an approach allows unequivocal identification of HC currents by their single channel conductance that is typically ~220 pS for Cx43. In HeLa cells stably transfected with Cx43 (HeLa-Cx43), Gap26/27 peptides inhibited Cx43 HC unitary currents over minutes and increased the voltage threshold for HC opening. By contrast, an elevation of intracellular calcium ([Ca(2+)](i)) to 200-500 nM potentiated the unitary HC current activity and lowered the voltage threshold for HC opening. Interestingly, Gap26/27 inhibited the Ca(2+)-potentiated HC currents and prevented lowering of the voltage threshold for HC opening. Experiments on isolated pig ventricular cardiomyocytes, which display strong endogenous Cx43 expression, demonstrated voltage-activated unitary currents with biophysical properties of Cx43 HCs that were inhibited by small interfering RNA targeting Cx43. As observed in HeLa-Cx43 cells, HC current activity in ventricular cardiomyocytes was potentiated by [Ca(2+)](i) elevation to 500 nM and was inhibited by Gap26/27. Our results indicate that under pathological conditions, when [Ca(2+)](i) is elevated, Cx43 HC opening is promoted in cardiomyocytes and CxMPs counteract this effect.
    Archiv für Kreislaufforschung 11/2012; 107(6):304. DOI:10.1007/s00395-012-0304-2 · 5.96 Impact Factor
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    ABSTRACT: BACKGROUND: The calcium-dependent signaling molecules calcineurin and calcium/calmodulin-dependent protein kinase II (CaMKII) both have been linked to decompensated hypertrophy and arrhythmias. CaMKII is also believed to be involved in acute modulation of ion channels. OBJECTIVE: The purpose of this study was to determine the role of calcineurin and CaMKII in a dog model of compensated hypertrophy and a long QT phenotype. METHODS: AV block was created in dogs to induce ventricular remodeling, including enhanced susceptibility to dofetilide-induced torsades de pointes arrhythmias. Dogs were treated with cyclosporin A for 3 weeks, which reduced calcineurin activity, as determined by mRNA expression levels of regulator of calcineurin 1 exon 4, but which was unable to prevent structural, contractile, or electrical remodeling and arrhythmias. Biopsies were taken before and at 2 or 9 weeks after AV block. Western blots were performed against phosphorylated and total CaMKII, phospholamban, Akt, and histone deacetylase 4 (HDAC4). RESULTS: Chronic AV block showed an increase in Akt, CaMKII and phospholamban phosphorylation levels, but HDAC4 phosphorylation remained unaltered. Dofetilide induced torsades de pointes in vivo and early afterdepolarizations in cardiomyocytes, and increased [Ca(2+)](i) and CaMKII autophosphorylation. Both W-7 and KN-93 treatment counteracted this. CONCLUSION: The calcineurin pathway seems not to be involved in long-term cardiac remodeling of the chronic AV block dog. Although CaMKII is chronically activated, this does not translate to HDAC4 phosphorylation. However, acute CaMKII overactivation is able to initiate arrhythmias based on triggered activity.
    Heart rhythm: the official journal of the Heart Rhythm Society 07/2012; 9(11). DOI:10.1016/j.hrthm.2012.07.023 · 4.56 Impact Factor
  • Karin R Sipido, Frans Van de Werf
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    ABSTRACT: Will the new EU research funding programme Horizon 2020 provide what is needed?
    European Heart Journal 07/2012; 33(13):1540-1. · 14.72 Impact Factor
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    ABSTRACT: Background. Reducing the open probability of the ryanodine receptor (RyR) has been proposed to have beneficial effects in heart failure. We investigated whether conditional FKBP12.6 overexpression at the time of myocardial infarction (MI) could improve cardiac remodeling and cell Ca2+ handling. Methods. Wild-type (WT) mice and mice overexpressing FKBP12.6 (Tg) were studied on average 7.5±0.2 weeks after MI and compared to sham for in vivo, myocyte function and remodeling. Results. At baseline, unloaded cell shortening in Tg was not different from WT. [Ca2+]i transient amplitude was similar but SR Ca2+ content was larger in Tg, suggesting reduced fractional release. Spontaneous spark frequency was similar despite the increased SR Ca2+ content, consistent with reduced RyR Po in Tg. After MI, LV dilation and myocyte hypertrophy were present in both groups, but more pronounced in Tg. Cell shortening amplitude was unchanged with MI in WT, but increased in Tg MI. Amplitude of the [Ca2+]i transient was not affected by MI in either genotype, but time to peak was increased; this was most pronounced in Tg. SR Ca2+ content and NCX function were not affected by MI. Spontaneous spark frequency was increased significantly after MI in Tg, and larger than in WT (at 4 Hz: 2.6±0.4 sparks/100μm/s in Tg MI vs. 1.6±0.2 sparks/100μm/s in WT MI, P<0.05). Conclusions. FKPB12.6 overexpression can effectively reduce RyR open probability with maintained cardiomyocyte contraction. However, this approach appears insufficient to prevent and reduce post-MI remodeling indicating that additional pathways may need to be targeted.
    Experimental physiology 06/2012; 98(1). DOI:10.1113/expphysiol.2011.064089 · 2.87 Impact Factor

Publication Stats

4k Citations
849.79 Total Impact Points


  • 1995–2014
    • University of Leuven
      • Division of Experimental Cardiology
      Louvain, Flemish, Belgium
  • 2003–2013
    • Catholic University of Louvain
      Лувен-ла-Нев, Walloon, Belgium
  • 2007
    • Universiteit Utrecht
      • Division of Heart and Lungs
      Utrecht, Provincie Utrecht, Netherlands
  • 1992
    • Johns Hopkins University
      • Department of Medicine
      Baltimore, Maryland, United States