Multiscale modeling of calcium cycling in cardiac ventricular myocyte: macroscopic consequences of microscopic dyadic function.
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ABSTRACT:
SUBMITTER: Gaur N
PROVIDER: S-EPMC3123916 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Intracellular calcium (Ca2+) cycling dynamics in cardiac myocytes are spatiotemporally generated by stochastic events arising from a spatially distributed network of coupled Ca2+ release units that interact with an intertwined mitochondrial network. In this study, we developed a spatiotemporal ventricular myocyte model that integrates mitochondria-related Ca2+ cycling components into our previously developed ventricular myocyte model consisting of a three-dimensional Ca2+ release unit network. Mathematical formulations of mitochondrial membrane potential, mitochondrial Ca2+ cycling, mitochondrial permeability transition pore stochastic opening and closing, intracellular reactive oxygen species signaling, and oxidized Ca2+/calmodulin-dependent protein kinase II signaling were incorporated into the model. We then used the model to simulate the effects of mitochondrial depolarization on mitochondrial Ca2+ cycling, Ca2+ spark frequency, and Ca2+ amplitude, which agree well with experimental data. We also simulated the effects of the strength of mitochondrial Ca2+ uniporters and their spatial localization on intracellular Ca2+ cycling properties, which substantially affected diastolic and systolic Ca2+ levels in the mitochondria but exhibited only a small effect on sarcoplasmic reticulum and cytosolic Ca2+ levels under normal conditions. We show that mitochondrial depolarization can cause Ca2+ waves and Ca2+ alternans, which agrees with previous experimental observations. We propose that this new, to our knowledge, spatiotemporal ventricular myocyte model, incorporating properties of mitochondrial Ca2+ cycling and reactive-oxygen-species-dependent signaling, will be useful for investigating the effects of mitochondria on intracellular Ca2+ cycling and action potential dynamics in ventricular myocytes.
| S-EPMC6990377 | biostudies-literature
Project description:Cardiovascular disease is often related to defects of subcellular components in cardiac myocytes, specifically in the dyadic cleft, which include changes in cleft geometry and channel placement. Modeling of these pathological changes requires both spatially resolved cleft as well as whole cell level descriptions. We use a multiscale model to create dyadic structure-function relationships to explore the impact of molecular changes on whole cell electrophysiology and calcium cycling. This multiscale model incorporates stochastic simulation of individual L-type calcium channels and ryanodine receptor channels, spatially detailed concentration dynamics in dyadic clefts, rabbit membrane potential dynamics, and a system of partial differential equations for myoplasmic and lumenal free Ca2+ and Ca2+-binding molecules in the bulk of the cell. We found action potential duration, systolic, and diastolic [Ca2+] to respond most sensitively to changes in L-type calcium channel current. The ryanodine receptor channel cluster structure inside dyadic clefts was found to affect all biomarkers investigated. The shape of clusters observed in experiments by Jayasinghe et al. and channel density within the cluster (characterized by mean occupancy) showed the strongest correlation to the effects on biomarkers.
| S-EPMC6990380 | biostudies-literature
Project description:Electrophysiological changes promoting arrhythmias during acute regional ischemia/reperfusion are challenging to study in intact cardiac tissue because of complex 3-dimensional myocardial and vascular geometry. We characterized electrophysiological alterations and arrhythmias during regional ischemia/reperfusion in a simpler 2-dimensional geometry of cultured neonatal rat ventricular myocyte monolayers.Optical mapping of intracellular Ca (Ca(i)) and voltage was performed with the use of Rhod 2-AM and Rh-237, respectively. Regional ischemia was mimicked by covering the central portion of monolayer with a glass coverslip, and reperfusion was mimicked by removing the coverslip. Monolayers were stained with fluorescent antibodies to detect total and dephosphorylated connexin-43 at various time points. During coverslip ischemia, action potential duration shortened, Ca(i) transient duration was prolonged, and local conduction velocity (CV) slowed progressively, with loss of excitability after 10.6 +/- 3.6 minutes. CV slowing was accompanied by connexin-43 dephosphorylation. During ischemia, spontaneous reentry occurred in 5 of 11 monolayers, initiated by extrasystoles arising from the border zone or unidirectional conduction block of paced beats. On reperfusion, excitability recovered within 1.0 +/- 0.8 minutes, but CV remained depressed for 9.0 +/- 3.0 minutes, promoting reentry in the reperfused zone. As connexin-43 phosphorylation recovered in the reperfused zone, CV normalized, and arrhythmias resolved.Acute regional ischemia/reperfusion in neonatal rat ventricular myocyte monolayers recapitulates electrophysiological alterations and arrhythmias similar to those observed during acute coronary occlusion/reperfusion in intact hearts. During early reperfusion, slow recovery from connexin-43 dephosphorylation leads to persistent CV slowing, creating a highly arrhythmogenic substrate.
| S-EPMC2730415 | biostudies-literature
Project description:Mitochondria are vital organelles inside the cell and contribute to intracellular calcium (Ca2+) dynamics directly and indirectly via calcium exchange, ATP generation, and production of reactive oxygen species (ROS). Arrhythmogenic Ca2+ alternans in cardiac myocytes has been observed in experiments under abnormal mitochondrial depolarization. However, complex signaling pathways and Ca2+ cycling between mitochondria and cytosol make it difficult in experiments to reveal the underlying mechanisms of Ca2+ alternans under abnormal mitochondrial depolarization. In this study, we use a newly developed spatiotemporal ventricular myocyte computer model that integrates mitochondrial Ca2+ cycling and complex signaling pathways to investigate the mechanisms of Ca2+ alternans during mitochondrial depolarization. We find that elevation of ROS in response to mitochondrial depolarization plays a critical role in promoting Ca2+ alternans. Further examination reveals that the redox effect of ROS on ryanodine receptors and sarco/endoplasmic reticulum Ca2+-ATPase synergistically promote alternans. Upregulation of mitochondrial Ca2+ uniporter promotes Ca2+ alternans via Ca2+-dependent mitochondrial permeability transition pore opening. Due to their relatively slow kinetics, oxidized Ca2+/calmodulin-dependent protein kinase II activation and ATP do not play significant roles acutely in the genesis of Ca2+ alternans after mitochondrial depolarization, but their roles can be significant in the long term, mainly through their effects on sarco/endoplasmic reticulum Ca2+-ATPase activity. In conclusion, mitochondrial depolarization promotes Ca2+ alternans acutely via the redox effect of ROS and chronically by ATP reduction. It suppresses Ca2+ alternans chronically through oxidized Ca2+/calmodulin-dependent protein kinase II activation.
| S-EPMC7861552 | biostudies-literature
Project description:Calcium (Ca2+) plays a central role in the excitation and contraction of cardiac myocytes. Experiments have indicated that calcium release is stochastic and regulated locally suggesting the possibility of spatially heterogeneous calcium levels in the cells. This spatial heterogeneity might be important in mediating different signaling pathways. During more than 50 years of computational cell biology, the computational models have been advanced to incorporate more ionic currents, going from deterministic models to stochastic models. While periodic increases in cytoplasmic Ca2+ concentration drive cardiac contraction, aberrant Ca2+ release can underly cardiac arrhythmia. However, the study of the spatial role of calcium ions has been limited due to the computational expense of using a three-dimensional stochastic computational model. In this paper, we introduce a three-dimensional stochastic computational model for rat ventricular myocytes at the whole-cell level that incorporate detailed calcium dynamics, with (1) non-uniform release site placement, (2) non-uniform membrane ionic currents and membrane buffers, (3) stochastic calcium-leak dynamics and (4) non-junctional or rogue ryanodine receptors. The model simulates spark-induced spark activation and spark-induced Ca2+ wave initiation and propagation that occur under conditions of calcium overload at the closed-cell condition, but not when Ca2+ levels are normal. This is considered important since the presence of Ca2+ waves contribute to the activation of arrhythmogenic currents.
| S-EPMC8706945 | biostudies-literature
Project description:BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a severe inherited cardiac disorder caused by mutations predominantly in the ryanodine receptor (RyR2) gene. We sought to identify mutations in genes affecting cardiac calcium cycling in patients with CPVT and in less typical familial exercise-related ventricular arrhythmias. METHODS AND RESULTS: We recruited 33 consecutive patients with frequent ventricular premature complexes (VPCs) without structural heart disease and often history of syncope or sudden death in family. Sixteen of the patients featured a phenotype typical of CPVT. In 17 patients, VPCs emerged also at rest. Exercise stress test and echocardiography were performed to each patient and 232 family members. Familial background was evident in 42% of cases (n = 14). We sequenced all the coding exons of the RyR2, FKBP1B, ATP2A2 and SLC8A1 genes from the index patients. Single channel recordings of a mutant RyR2 were performed in planar lipid bilayers. Two novel RyR2 missense mutations (R1051P and S616L) and two RyR2 exon 3 deletions were identified, explaining 25% of the CPVT phenotypes. A rare variant (N3308S) with open probabilities similar to the wild type channels in vitro, was evident in a patient with resting VPCs. No disease-causing variants were detectable in the FKBP1B, ATP2A2 or SLC8A1 genes. CONCLUSION: We report two novel CPVT-causing RyR2 mutations and a novel RyR2 variant of uncertain clinical significance in a patient with abundant resting VPCs. Our data also strengthen the previous assumption that exon 3 deletions of RyR2 should screened for in CPVT and related phenotypes.
| S-EPMC2667497 | biostudies-literature
Project description:The relative importance of regulatory versus structural evolution for the evolution of different biological systems is a subject of controversy. The primacy of regulatory evolution in the diversification of morphological traits has been promoted by many evolutionary developmental biologists. For physiological traits, however, the role of regulatory evolution has received less attention or has been considered to be relatively unimportant. To address this issue for electrophysiological systems, we examined the importance of regulatory and structural evolution in the evolution of the electrophysiological function of cardiac myocytes in mammals. In particular, two related phenomena were studied: the change in action potential morphology in small mammals and the scaling of action potential duration across mammalian phylogeny. In general, the functional properties of the ion channels involved in ventricular action potential repolarization were found to be relatively invariant. In contrast, there were large changes in the expression levels of multiple ion channel and transporter genes. For the Kv2.1 and Kv4.2 potassium channel genes, which are primary determinants of the action potential morphology in small mammals, the functional properties of the proximal promoter regions were found to vary in concordance with species-dependent differences in mRNA expression, suggesting that evolution of cis-regulatory elements is the primary determinant of this trait. Scaling of action potential duration was found to be a complex phenomenon, involving changes in the expression of a large number of channels and transporters. In this case, it is concluded that regulatory evolution is the predominant mechanism by which the scaling is achieved.
| S-EPMC2585018 | biostudies-literature
Project description:AimsFibrosis is known to promote cardiac arrhythmias by disrupting myocardial structure. Given recent evidence that myofibroblasts form gap junctions with myocytes at least in co-cultures, we investigated whether myofibroblast-myocyte coupling can promote arrhythmia triggers, such as early afterdepolarizations (EADs), by directly influencing myocyte electrophysiology.Methods and resultsUsing the dynamic voltage clamp technique, patch-clamped adult rabbit ventricular myocytes were electrotonically coupled to one or multiple virtual fibroblasts or myofibroblasts programmed with eight combinations of capacitance, membrane resistance, resting membrane potential, and gap junction coupling resistance, spanning physiologically realistic ranges. Myocytes were exposed to oxidative (1 mmol/L H(2)O(2)) or ionic (2.7 mmol/L hypokalaemia) stress to induce bradycardia-dependent EADs. In the absence of myofibroblast-myocyte coupling, EADs developed during slow pacing (6 s), but were completely suppressed by faster pacing (1 s). However, in the presence of myofibroblast-myocyte coupling, EADs could no longer be suppressed by rapid pacing, especially when myofibroblast resting membrane potential was depolarized (-25 mV). Analysis of the myofibroblast-myocyte virtual gap junction currents revealed two components: an early transient-outward I(to)-like current and a late sustained current. Selective elimination of the I(to)-like component prevented EADs, whereas selective elimination of the late component did not.ConclusionCoupling of myocytes to myofibroblasts promotes EAD formation as a result of a mismatch in early vs. late repolarization reserve caused by the I(to)-like component of the gap junction current. These cellular and ionic mechanisms may contribute to the pro-arrhythmic risk in fibrotic hearts.
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Project description:Myocardial delivery of human c-kit+ cardiac interstitial cells (hCICs) and human mesenchymal stem cells (hMSCs), an emerging approach for treating the failing heart, has been limited by an incomplete understanding of the effects on host myocardium. This computational study aims to model hCIC and hMSC effects on electrophysiology and calcium cycling of healthy and diseased human cardiomyocytes (hCM), and reveals a possible cardiotherapeutic benefit independent of putative regeneration processes. First, we developed an original hCIC mathematical model with an electrical profile comprised of distinct experimentally identified ion currents. Next, we verified the model by confirming it is representative of published experiments on hCIC whole-cell electrophysiology and on hCIC co-cultures with rodent cardiomyocytes. We then used our model to compare electrophysiological effects of hCICs to other non-excitable cells, as well as clinically relevant hCIC-hMSC combination therapies and fused hCIC-hMSC CardioChimeras. Simulation of direct coupling of hCICs to healthy or failing hCMs through gap junctions led to greater increases in calcium cycling with lesser reductions in action potential duration (APD) compared with hMSCs. Combined coupling of hCICs and hMSCs to healthy or diseased hCMs led to intermediate effects on electrophysiology and calcium cycling compared to individually coupled hCICs or hMSCs. Fused hCIC-hMSC CardioChimeras decreased healthy and diseased hCM APD and calcium transient amplitude compared to individual or combined cell treatments. Finally, to provide a theoretical basis for optimizing cell-based therapies, we randomized populations of 2,500 models incorporating variable hMSC and hCIC interventions and simulated their effects on restoring diseased cardiomyocyte electrophysiology and calcium handling. The permutation simulation predicted the ability to correct abnormal properties of heart failure hCMs in fibrotic, but not non-fibrotic, myocardium. This permutation experiment also predicted paracrine signaling to be a necessary and sufficient mechanism for this correction, counteracting the fibrotic effects while also restoring arrhythmia-related metrics such as upstroke velocity and resting membrane potential. Altogether, our in silico findings suggest anti-fibrotic effects of paracrine signaling are critical to abrogating pathological cardiomyocyte electrophysiology and calcium cycling in fibrotic heart failure, and support further investigation of delivering an optimized cellular secretome as a potential strategy for improving heart failure therapy.
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Project description:Ventricular-arterial coupling plays a key role in the physiologic function of the cardiovascular system. We have previously described a hybrid lumped-finite element (FE) modeling framework of the systemic circulation that couples idealized FE models of the aorta and the left ventricle (LV). Here, we describe an extension of the lumped-FE modeling framework that couples patient-specific FE models of the left and right ventricles, aorta and the large pulmonary arteries in both the systemic and pulmonary circulations. Geometries of the FE models were reconstructed from magnetic resonance (MR) images acquired in a pediatric patient diagnosed with pulmonary arterial hypertension (PAH). The modeling framework was calibrated with pressure waveforms acquired in the heart and arteries by catheterization as well as ventricular volume and arterial diameter waveforms measured from MR images. The calibrated model hemodynamic results match well with the clinically-measured waveforms (volume and pressure) in the LV and right ventricle (RV) as well as with the clinically-measured waveforms (pressure and diameter) in the aorta and main pulmonary artery. The calibrated framework was then used to simulate three cases, namely, (1) an increase in collagen in the large pulmonary arteries, (2) a decrease in RV contractility, and (3) an increase in the total pulmonary arterial resistance, all characteristics of progressive PAH. The key finding from these simulations is that hemodynamics of the pulmonary vasculature and RV wall stress are more sensitive to vasoconstriction with a 10% of reduction in the lumen diameter of the distal vessels than a 67% increase in the proximal vessel's collagen mass.
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