Role of CaMKII in post acidosis arrhythmias: A simulation study using a human myocyte model

Lascano, Elena C.; Said, Matilde; Vittone, Leticia; Mattiazzi, Alicia; Mundiña‐Weilenmann, Cecilia; Negroni, Jorge A.

doi:10.1016/j.yjmcc.2013.04.018

Cited by 29 publications

(47 citation statements)

References 63 publications

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“…• The sliding velocity of the equivalent crossbridge along the thin filament has to be increased by a factor of To this end, we follow the approach of Lascano et al [19] and adapt the equations governing calcium liberation by the sarcoplasmic reticulum. In our previous published paper [6], we were still using the original electrophysiological model of ten Tusscher and Panfilov model.…”

Section: Whole Cell Modelmentioning

confidence: 99%

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Multiscale model of the human cardiovascular system: Description of heart failure and comparison of contractility indices

Kosta

Negroni

Lascano

et al. 2017

Mathematical Biosciences

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A multiscale model of the cardiovascular system is presented. Hemodynamics is described by a lumped parameter model, while heart contraction is described at the cellular scale. An electrophysiological model and a mechanical model were coupled and adjusted so that the pressure and volume of both ventricles are linked to the force and length of a halfsarcomere. Particular attention was paid to the extreme values of the sarcomere length, which must keep physiological values. This model is able to reproduce healthy behavior, preload variations experiments, and ventricular failure. It also allows to compare the relevance of standard cardiac contractility indices. This study shows that the theoretical gold standard for assessing cardiac contractility, namely the end-systolic elastance, is actually load-dependent and therefore not a reliable index of cardiac contractility.

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Section: Whole Cell Modelmentioning

confidence: 99%

“…As explained in the previous section, some parameter values were adapted (see Table A.1) and some equations were modified [19]. From equation (7), it is easy to understand that systolic pressure, which is related to the maximum active force generated in the sarcomeres, can be increased by increasing the ventricular wall thickness.…”

Section: Parameter Adjustmentmentioning

confidence: 99%

Multiscale model of the human cardiovascular system: Description of heart failure and comparison of contractility indices

Kosta

Negroni

Lascano

et al. 2017

Mathematical Biosciences

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“…Under normal circumstances (PH=7.15), fPH=1; in the case of acidosis (PH=6.7), the values of f0, n, PK are shown in table 2 [7] . In addition, currents effected by PH include: ICaL, Ito, Irel, Iup, inward rectifier potassium current (IK1), and sodium calcium exchange current (INCX), sodium potassium exchange pump current (INaK) [7] .…”

Section: Acidotic Modelmentioning

confidence: 99%

“…It is well known that DADs are associated with increased sarcoplasmic reticulum (SR) Ca 2+ load [4,7] . However, CaMKII can regulate Ca 2+ channels and Ca 2+ receptors [4,7] .…”

Section: Cellular Simulationmentioning

confidence: 99%

Calcium Calmodulin Dependent Protein Kinase II (CaMKII) Contribute to Arrhythmias after Acidosis:A Simulation Study

Huanling

Wang

Bai

et al. 2016

2016 Computing in Cardiology Conference (CinC)

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“…In another computational study, Dai et al41 showed that CaMKII overexpression facilitates early afterdepolarization (EAD) by prolonging the deactivation of the I Na,L , and combination with β‐adrenergic activation further increases EAD risk. Modeling studies also suggested that CaMKII activation–mediated SR Ca 2+ overload and increased cytosolic Na + elicit post‐acidosis arrhythmias in human myocytes 42. To examine the role of oxidation‐dependent CaMKII activation in regulating cardiac cell excitability following myocardial infarction, Christensen et al43 developed a mathematical model of CaMKII activity, which, for the first time, includes both oxidative and autophosphorylation activation pathways.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial‐Mediated Oxidative Ca ²⁺ /Calmodulin‐Dependent Kinase II Activation Induces Early Afterdepolarizations in Guinea Pig Cardiomyocytes: An In Silico Study

Yang

Erñst

Song

et al. 2018

JAHA

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BackgroundOxidative stress–mediated Ca2+/calmodulin‐dependent protein kinase II (CaMKII) phosphorylation of cardiac ion channels has emerged as a critical contributor to arrhythmogenesis in cardiac pathology. However, the link between mitochondrial‐derived reactive oxygen species (mdROS) and increased CaMKII activity in the context of cardiac arrhythmias has not been fully elucidated and is difficult to establish experimentally.Methods and ResultsWe hypothesize that pathological mdROS can cause erratic action potentials through the oxidation‐dependent CaMKII activation pathway. We further propose that CaMKII‐dependent phosphorylation of sarcolemmal slow Na+ channels alone is sufficient to elicit early afterdepolarizations. To test the hypotheses, we expanded our well‐established guinea pig cardiomyocyte excitation‐contraction coupling, mitochondrial energetics, and ROS‐induced‐ROS‐release model by incorporating oxidative CaMKII activation and CaMKII‐dependent Na+ channel phosphorylation in silico. Simulations show that mdROS mediated‐CaMKII activation elicits early afterdepolarizations by augmenting the late Na+ currents, which can be suppressed by blocking L‐type Ca2+ channels or Na+/Ca2+ exchangers. Interestingly, we found that oxidative CaMKII activation–induced early afterdepolarizations are sustained even after mdROS has returned to its physiological levels. Moreover, mitochondrial‐targeting antioxidant treatment can suppress the early afterdepolarizations, but only if given in an appropriate time window. Incorporating concurrent mdROS‐induced ryanodine receptors activation further exacerbates the proarrhythmogenic effect of oxidative CaMKII activation.ConclusionsWe conclude that oxidative CaMKII activation–dependent Na channel phosphorylation is a critical pathway in mitochondria‐mediated cardiac arrhythmogenesis.

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Role of CaMKII in post acidosis arrhythmias: A simulation study using a human myocyte model

Cited by 29 publications

References 63 publications

Multiscale model of the human cardiovascular system: Description of heart failure and comparison of contractility indices

Multiscale model of the human cardiovascular system: Description of heart failure and comparison of contractility indices

Calcium Calmodulin Dependent Protein Kinase II (CaMKII) Contribute to Arrhythmias after Acidosis:A Simulation Study

Mitochondrial‐Mediated Oxidative Ca ²⁺ /Calmodulin‐Dependent Kinase II Activation Induces Early Afterdepolarizations in Guinea Pig Cardiomyocytes: An In Silico Study

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Role of CaMKII in post acidosis arrhythmias: A simulation study using a human myocyte model

Cited by 29 publications

References 63 publications

Multiscale model of the human cardiovascular system: Description of heart failure and comparison of contractility indices

Multiscale model of the human cardiovascular system: Description of heart failure and comparison of contractility indices

Calcium Calmodulin Dependent Protein Kinase II (CaMKII) Contribute to Arrhythmias after Acidosis:A Simulation Study

Mitochondrial‐Mediated Oxidative Ca 2+ /Calmodulin‐Dependent Kinase II Activation Induces Early Afterdepolarizations in Guinea Pig Cardiomyocytes: An In Silico Study

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Mitochondrial‐Mediated Oxidative Ca ²⁺ /Calmodulin‐Dependent Kinase II Activation Induces Early Afterdepolarizations in Guinea Pig Cardiomyocytes: An In Silico Study