Browse
Submit Data
Databases
API
Help

Dataset Information

19 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Myofilament Ca2+ sensitization causes susceptibility to cardiac arrhythmia in mice.

ABSTRACT: In human cardiomyopathy, anatomical abnormalities such as hypertrophy and fibrosis contribute to the risk of ventricular arrhythmias and sudden death. Here we have shown that increased myofilament Ca2+ sensitivity, also a common feature in both inherited and acquired human cardiomyopathies, created arrhythmia susceptibility in mice, even in the absence of anatomical abnormalities. In mice expressing troponin T mutants that cause hypertrophic cardiomyopathy in humans, the risk of developing ventricular tachycardia was directly proportional to the degree of Ca2+ sensitization caused by the troponin T mutation. Arrhythmia susceptibility was reproduced with the Ca2+-sensitizing agent EMD 57033 and prevented by myofilament Ca2+ desensitization with blebbistatin. Ca2+ sensitization markedly changed the shape of ventricular action potentials, resulting in shorter effective refractory periods, greater beat-to-beat variability of action potential durations, and increased dispersion of ventricular conduction velocities at fast heart rates. Together these effects created an arrhythmogenic substrate. Thus, myofilament Ca2+ sensitization represents a heretofore unrecognized arrhythmia mechanism. The protective effect of blebbistatin provides what we believe to be the first direct evidence that reduction of Ca2+ sensitivity in myofilaments is antiarrhythmic and might be beneficial to individuals with hypertrophic cardiomyopathy.

SUBMITTER: Baudenbacher F

PROVIDER: S-EPMC2582931 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Increased myofilament Ca2+-sensitivity and arrhythmia susceptibility.

Project description:Increased myofilament Ca(2+) sensitivity is a common attribute of many inherited and acquired cardiomyopathies that are associated with cardiac arrhythmias. Accumulating evidence supports the concept that increased myofilament Ca(2+) sensitivity is an independent risk factor for arrhythmias. This review describes and discusses potential underlying molecular and cellular mechanisms how myofilament Ca(2+) sensitivity affects cardiac excitation and leads to the generation of arrhythmias. Emphasized are downstream effects of increased myofilament Ca(2+) sensitivity: altered Ca(2+) buffering/handling, impaired energy metabolism and increased mechanical stretch, and how they may contribute to arrhythmogenesis.

| S-EPMC2854218 | biostudies-other

Myofilament Ca sensitization increases cytosolic Ca binding affinity, alters intracellular Ca homeostasis, and causes pause-dependent Ca-triggered arrhythmia.

Project description:RationaleCa binding to the troponin complex represents a major portion of cytosolic Ca buffering. Troponin mutations that increase myofilament Ca sensitivity are associated with familial hypertrophic cardiomyopathy and confer a high risk for sudden death. In mice, Ca sensitization causes ventricular arrhythmias, but the underlying mechanisms remain unclear.ObjectiveTo test the hypothesis that myofilament Ca sensitization increases cytosolic Ca buffering and to determine the resulting arrhythmogenic changes in Ca homeostasis in the intact mouse heart.Methods and resultsUsing cardiomyocytes isolated from mice expressing troponin T (TnT) mutants (TnT-I79N, TnT-F110I, TnT-R278C), we found that increasing myofilament Ca sensitivity produced a proportional increase in cytosolic Ca binding. The underlying cause was an increase in the cytosolic Ca binding affinity, whereas maximal Ca binding capacity was unchanged. The effect was sufficiently large to alter Ca handling in intact mouse hearts at physiological heart rates, resulting in increased end-diastolic [Ca] at fast pacing rates, and enhanced sarcoplasmic reticulum Ca content and release after pauses. Accordingly, action potential (AP) regulation was altered, with postpause action potential prolongation, afterdepolarizations, and triggered activity. Acute Ca sensitization with EMD 57033 mimicked the effects of Ca-sensitizing TnT mutants and produced pause-dependent ventricular ectopy and sustained ventricular tachycardia after acute myocardial infarction.ConclusionsMyofilament Ca sensitization increases cytosolic Ca binding affinity. A major proarrhythmic consequence is a pause-dependent potentiation of Ca release, action potential prolongation, and triggered activity. Increased cytosolic Ca binding represents a novel mechanism of pause-dependent arrhythmia that may be relevant for inherited and acquired cardiomyopathies.

| S-EPMC3393041 | biostudies-literature

Enhancement of ?-catenin/T-cell factor 4 signaling causes susceptibility to cardiac arrhythmia by suppressing NaV1.5 expression in mice.

Project description:BACKGROUND:?-Catenin/T-cell factor 4 (TCF4) signaling is enhanced in ischemic heart disease in which ventricular tachycardia (VT)/ventricular fibrillation occurs frequently. How this signaling links to arrhythmogenesis remains unclear. OBJECTIVE:The purpose of this study was to investigate the role of ?-catenin gain of function in the development of arrhythmia. METHODS:A mouse model with a conditional deletion of CTNNB1 exon 3 resulting in cardiac exon 3-deleted and stabilized ?-catenin (?-cat?E3) was used to determine the role of ?-catenin gain of function in the regulation of cardiac rhythm. RESULTS:Western blotting showed ?-cat?E3 expression and significantly decreased NaV1.5 protein in CTNNB1 E3-/- and CTNNB1 E3+/- mouse hearts. Real-time qRT-PCR revealed significantly decreased NaV1.5 messenger RNA with no changes in Na+ channel ?1 to ?4 expression in these hearts. Immunofluorescence revealed accumulation of ?-cat?E3 in the nuclei of CTNNB1 E3-/- cardiomyocytes. Immunohistochemistry demonstrated nuclear localization of ?-catenin in cardiomyocytes, which was associated with significantly decreased NaV1.5 messenger RNA in human ischemic hearts. Immunoprecipitation revealed that ?-cat?E3 interacted with TCF4 in CTNNB1 E3-/- cardiomyocytes. Whole-cell recordings showed that Na+ currents and depolarization and amplitude of action potentials were significantly decreased in CTNNB1 E3-/- ventricular myocytes. Electrocardiographic recordings demonstrated that in mice with cardiac CTNNB1 E3-/-, the QRS complex was prolonged and VT was induced by the Na+ channel blocker flecainide. However, cardiac function, as determined by echocardiography and heart/body weight ratios, remained unchanged. CONCLUSION:Enhancement of ?-catenin/TCF4 signaling led to the prolongation of the QRS complex and increase in susceptibility to VT by suppression of NaV1.5 expression and Na+ channel activity in mice.

| S-EPMC7027965 | biostudies-literature

Structural and functional impact of troponin C-mediated Ca2+ sensitization on myofilament lattice spacing and cross-bridge mechanics in mouse cardiac muscle.

Project description:Acto-myosin cross-bridge kinetics are important for beat-to-beat regulation of cardiac contractility; however, physiological and pathophysiological mechanisms for regulation of contractile kinetics are incompletely understood. Here we explored whether thin filament-mediated Ca2+ sensitization influences cross-bridge kinetics in permeabilized, osmotically compressed cardiac muscle preparations. We used a murine model of hypertrophic cardiomyopathy (HCM) harboring a cardiac troponin C (cTnC) Ca2+-sensitizing mutation, Ala8Val in the regulatory N-domain. We also treated wild-type murine muscle with bepridil, a cTnC-targeting Ca2+ sensitizer. Our findings suggest that both methods of increasing myofilament Ca2+ sensitivity increase cross-bridge cycling rate measured by the rate of tension redevelopment (kTR); force per cross-bridge was also enhanced as measured by sinusoidal stiffness and I1,1/I1,0 ratio from X-ray diffraction. Computational modeling suggests that Ca2+ sensitization through this cTnC mutation or bepridil accelerates kTR primarily by promoting faster cross-bridge detachment. To elucidate if myofilament structural rearrangements are associated with changes in kTR, we used small angle X-ray diffraction to simultaneously measure myofilament lattice spacing and isometric force during steady-state Ca2+ activations. Within in vivo lattice dimensions, lattice spacing and steady-state isometric force increased significantly at submaximal activation. We conclude that the cTnC N-domain controls force by modulating both the number and rate of cycling cross-bridges, and that the both methods of Ca2+ sensitization may act through stabilization of cTnC's D-helix. Furthermore, we propose that the transient expansion of the myofilament lattice during Ca2+ activation may be an additional factor that could increase the rate of cross-bridge cycling in cardiac muscle. These findings may have implications for the pathophysiology of HCM.

| S-EPMC6282743 | biostudies-literature

Removal of Abnormal Myofilament O-GlcNAcylation Restores Ca2+ Sensitivity in Diabetic Cardiac Muscle.

Project description:Contractile dysfunction and increased deposition of O-linked β-N-acetyl-d-glucosamine (O-GlcNAc) in cardiac proteins are a hallmark of the diabetic heart. However, whether and how this posttranslational alteration contributes to lower cardiac function remains unclear. Using a refined β-elimination/Michael addition with tandem mass tags (TMT)-labeling proteomic technique, we show that CpOGA, a bacterial analog of O-GlcNAcase (OGA) that cleaves O-GlcNAc in vivo, removes site-specific O-GlcNAcylation from myofilaments, restoring Ca(2+) sensitivity in streptozotocin (STZ) diabetic cardiac muscles. We report that in control rat hearts, O-GlcNAc and O-GlcNAc transferase (OGT) are mainly localized at the Z-line, whereas OGA is at the A-band. Conversely, in diabetic hearts O-GlcNAc levels are increased and OGT and OGA delocalized. Consistent changes were found in human diabetic hearts. STZ diabetic hearts display increased physical interactions of OGA with α-actin, tropomyosin, and myosin light chain 1, along with reduced OGT and increased OGA activities. Our study is the first to reveal that specific removal of O-GlcNAcylation restores myofilament response to Ca(2+) in diabetic hearts and that altered O-GlcNAcylation is due to the subcellular redistribution of OGT and OGA rather than to changes in their overall activities. Thus, preventing sarcomeric OGT and OGA displacement represents a new possible strategy for treating diabetic cardiomyopathy.

| S-EPMC4587639 | biostudies-literature

CYP2J2 overexpression protects against arrhythmia susceptibility in cardiac hypertrophy.

Project description:Maladaptive cardiac hypertrophy predisposes one to arrhythmia and sudden death. Cytochrome P450 (CYP)-derived epoxyeicosatrienoic acids (EETs) promote anti-inflammatory and antiapoptotic mechanisms, and are involved in the regulation of cardiac Ca(2+)-, K(+)- and Na(+)-channels. To test the hypothesis that enhanced cardiac EET biosynthesis counteracts hypertrophy-induced electrical remodeling, male transgenic mice with cardiomyocyte-specific overexpression of the human epoxygenase CYP2J2 (CYP2J2-TG) and wildtype littermates (WT) were subjected to chronic pressure overload (transverse aortic constriction, TAC) or ?-adrenergic stimulation (isoproterenol infusion, ISO). TAC caused progressive mortality that was higher in WT (42% over 8 weeks after TAC), compared to CYP2J2-TG mice (6%). In vivo electrophysiological studies, 4 weeks after TAC, revealed high ventricular tachyarrhythmia inducibility in WT (47% of the stimulation protocols), but not in CYP2J2-TG mice (0%). CYP2J2 overexpression also enhanced ventricular refractoriness and protected against TAC-induced QRS prolongation and delocalization of left ventricular connexin-43. ISO for 14 days induced high vulnerability for atrial fibrillation in WT mice (54%) that was reduced in CYP-TG mice (17%). CYP2J2 overexpression also protected against ISO-induced reduction of atrial refractoriness and development of atrial fibrosis. In contrast to these profound effects on electrical remodeling, CYP2J2 overexpression only moderately reduced TAC-induced cardiac hypertrophy and did not affect the hypertrophic response to ?-adrenergic stimulation. These results demonstrate that enhanced cardiac EET biosynthesis protects against electrical remodeling, ventricular tachyarrhythmia, and atrial fibrillation susceptibility during maladaptive cardiac hypertrophy.

| S-EPMC3758319 | biostudies-literature

Epac2 mediates cardiac ?1-adrenergic-dependent sarcoplasmic reticulum Ca2+ leak and arrhythmia.

Project description:?-Adrenergic receptor (?-AR) activation can provoke cardiac arrhythmias mediated by cAMP-dependent alterations of Ca(2+) signaling. However, cAMP can activate both protein kinase A and an exchange protein directly activated by cAMP (Epac), but their functional interaction is unclear. In heart, selective Epac activation can induce potentially arrhythmogenic sarcoplasmic reticulum (SR) Ca(2+) release that involves Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) effects on the ryanodine receptor (RyR).We tested whether physiological ?-AR activation causes Epac-mediated SR Ca(2+) leak and arrhythmias and whether it requires Epac1 versus Epac2, ?(1)-AR versus ?(2)-AR, and CaMKII?-dependent phosphorylation of RyR2-S2814. We used knockout (KO) mice for Epac1, Epac2, or both. All KOs exhibited unaltered basal cardiac function, Ca(2+) handling, and hypertrophy in response to pressure overload. However, SR Ca(2+) leak induced by the specific Epac activator 8-CPT in wild-type mice was abolished in Epac2-KO and double-KO mice but was unaltered in Epac1-KO mice. ?-AR-induced arrhythmias were also less inducible in Epac2-KO versus wild-type mice. ?-AR activation with protein kinase A inhibition mimicked 8-CPT effects on SR Ca(2+) leak and was prevented by blockade of ?(1)-AR but not ?(2)-AR. CaMKII inhibition (KN93) and genetic ablation of either CaMKII? or CaMKII phosphorylation on RyR2-S2814 prevented 8-CPT-induced SR Ca(2+) leak.?(1)-AR activates Epac2 to induce SR Ca(2+) leak via CaMKII?-dependent phosphorylation of RyR2-S2814. This pathway contributes to ?-AR-induced arrhythmias and reduced cardiac function.

| S-EPMC3690126 | biostudies-literature

Distinct circadian mechanisms govern cardiac rhythms and susceptibility to arrhythmia.

Project description:Electrical activity in the heart exhibits 24-hour rhythmicity, and potentially fatal arrhythmias are more likely to occur at specific times of day. Here, we demonstrate that circadian clocks within the brain and heart set daily rhythms in sinoatrial (SA) and atrioventricular (AV) node activity, and impose a time-of-day dependent susceptibility to ventricular arrhythmia. Critically, the balance of circadian inputs from the autonomic nervous system and cardiomyocyte clock to the SA and AV nodes differ, and this renders the cardiac conduction system sensitive to decoupling during abrupt shifts in behavioural routine and sleep-wake timing. Our findings reveal a functional segregation of circadian control across the heart's conduction system and inherent susceptibility to arrhythmia.

| S-EPMC8087694 | biostudies-literature

Leaky Ca2+ release channel/ryanodine receptor 2 causes seizures and sudden cardiac death in mice.

Project description:The Ca2+ release channel ryanodine receptor 2 (RyR2) is required for excitation-contraction coupling in the heart and is also present in the brain. Mutations in RyR2 have been linked to exercise-induced sudden cardiac death (catecholaminergic polymorphic ventricular tachycardia [CPVT]). CPVT-associated RyR2 mutations result in "leaky" RyR2 channels due to the decreased binding of the calstabin2 (FKBP12.6) subunit, which stabilizes the closed state of the channel. We found that mice heterozygous for the R2474S mutation in Ryr2 (Ryr2-R2474S mice) exhibited spontaneous generalized tonic-clonic seizures (which occurred in the absence of cardiac arrhythmias), exercise-induced ventricular arrhythmias, and sudden cardiac death. Treatment with a novel RyR2-specific compound (S107) that enhances the binding of calstabin2 to the mutant Ryr2-R2474S channel inhibited the channel leak and prevented cardiac arrhythmias and raised the seizure threshold. Thus, CPVT-associated mutant leaky Ryr2-R2474S channels in the brain can cause seizures in mice, independent of cardiac arrhythmias. Based on these data, we propose that CPVT is a combined neurocardiac disorder in which leaky RyR2 channels in the brain cause epilepsy, and the same leaky channels in the heart cause exercise-induced sudden cardiac death.

| S-EPMC2381750 | biostudies-literature

Methylmercury Poisoning Induces Cardiac Electrical Remodeling and Increases Arrhythmia Susceptibility and Mortality.

Project description:This study aims to investigate the cardiac electrical remodeling associated with intoxication by methylmercury (MeHg). We evaluated the chronic effects of MeHg on in vivo electrocardiograms and on ex vivo action potentials and depolarizing (ICa-L) and repolarizing (Ito) currents. The acute effect of MeHg was evaluated on HEK293 cells expressing human ERG, Kv4.3 and KCNQ1/KCNE1 channels. Chronic MeHg treatment increased QTc and Tpeak-Tend interval duration, prolonged action potential duration and decreased amplitude of Ito and ICa-L. In addition, heterologously expressed IhKv4.3, IhERG or IhKCNQ1/KCNE1 decreased after acute exposure to MeHg at subnanomolar range. The introduction of the in vitro effects of MeHg in a computer model of human ventricular action potentials triggered early afterdepolarizations and arrhythmia. In conclusion, cardiac electrical remodeling induced by MeHg poisoning is related to the reduction of Ito and ICa-L. The acute effect of MeHg on hKv4.3; hERG and hKCNQ1/KCNE1 currents and their transposition to in silico models show an association between MeHg intoxication and acquired Long QT Syndrome in humans. MeHg can exert its high toxicity either after chronic or acute exposure to concentrations as low as picomolar.

| S-EPMC7279040 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data