Eric Sobie - Academia.edu (original) (raw)
Papers by Eric Sobie
Drug Discovery Today: Disease Models, 2009
ABSTRACT
Circulation, Jan 20, 2015
nd d, OR OR OR; 5 Di Di Divi vi visi si sion on on o o of f f Ca Ca Card rd dio io iov v vasc sc ... more nd d, OR OR OR; 5 Di Di Divi vi visi si sion on on o o of f f Ca Ca Card rd dio io iov v vasc sc scul ul ular M Me e edic c cin in ine, e, e, D D Dep p pt t t of of of M M Me e edi di dicine e e, Un Un Univ iv iver e si si sity ty ty o o of f f Wi Wi Wisconsin, Mad d dis son, , W W WI, 6 6 Ph Ph Pharma macol lo ogy a a an nd d Sy yst t tems ms ms T T Th h her r rape e eut t tics, I I Ica ahn n n S S Schoo o ol of o o M M Medic c cin ne at at at M M Mount Sin in nai a , Ne N w Yo Y Y rk, NY NY NY, 7 Un Un Unit t t o o of Ex x xpe erime me ental al al R R Rhe e eu u umat t tolog gy, , , D Dep p par r rtm t t en n nt o of o M Me edic c cin ne,
Biophysical Journal, 2011
in HEK293 cells showed that it does not generate any current (n=6). We utilized recently publishe... more in HEK293 cells showed that it does not generate any current (n=6). We utilized recently published computational models of the human atrial and ventricular action potential (Abraham et al., J Mol Cell Cardiol. 2010 and Grandi, et al. J Mol Cell Cardiol. 2010) to determine the effect that T322M has on cardiac Action Potential Duration (APD) stimulated at 1 Hz. A 100% reduction of I Ks resulted in a prolonged APD in the atrial simulation but not the ventricular simulation. We incorporated a beta-adrenergic stimulation component into the ventricular model and found that reducing I Ks by 100% in the modified simulation increased APD. We further modified the ventricular action potential simulation to compromise 'repolarization reserve' by reducing the rapidly-activating delayed-rectifier K þ current or I Kr component. This modification exacerbated that effect that 100% block of I Ks had on ventricular APD. Based on these results we conclude that T322M prolongs the atrial APD in the absence of betaadrenergic stimulation, and prolongs the ventricular APD in the presence of beta-adrenergic stimulation and a compromised repolarization reserve.
Biophysical Journal, 2011
Biophysical Journal, 2009
hormones on QT interval in males versus females, we constructed ''male'' and ''female'' cell mode... more hormones on QT interval in males versus females, we constructed ''male'' and ''female'' cell models using Faber-Rudy model of the guinea pig myocyte. The female model incorporated physiological concentrations of 17b-estradiol and progesterone measured in the follicular and luteal phases of the menstrual cycle, and predicts changes in APD at different stages of the menstrual cycle that are consistent with clinically observed QT interval fluctuations. The male model was developed to reflect changes induced by physiology concentrations of Testosterone. The models suggest protective effects of testosterone and progesterone to prevent APD prolongation and reduce QT interval, while estrogen significantly increase QT and susceptibility to drug-induced arrhythmias.
The Journal of Physiology, 2005
Excitation-contraction coupling in the heart depends on the positive feedback process of Ca2+-ind... more Excitation-contraction coupling in the heart depends on the positive feedback process of Ca2+-induced Ca2+ release (CICR). While CICR provides for robust triggering of Ca2+ sparks, the mechanisms underlying their termination remain unknown. At present, it is unclear how a cluster of Ca2+ release channels (ryanodine receptors or RyRs) can be made to turn off when their activity is sustained by the Ca2+ release itself. We use a novel experimental approach to investigate indirectly this issue by exploring restitution of Ca2+ sparks. We exploit the fact that ryanodine can bind, nearly irreversibly, to an RyR subunit (monomer) and increase the open probability of the homotetrameric channel. By applying low concentrations of ryanodine to rat ventricular myocytes, we observe repeated activations of individual Ca2+ spark sites. Examination of these repetitive Ca2+ sparks reveals that spark amplitude recovers with a time constant of 91 ms whereas the sigmoidal recovery of triggering probability lags behind amplitude recovery by approximately 80 ms. We conclude that restitution of Ca2+ sparks depends on local refilling of SR stores after depletion and may also depend on another time-dependent process such as recovery from inactivation or a slow conformational change after rebinding of Ca2+ to SR regulatory proteins.
Developments in Cardiovascular Medicine, 2005
American journal of physiology. Heart and circulatory physiology, Jan 5, 2014
Population density approaches to modeling local control of Ca(2+) -induced Ca(2+) release in card... more Population density approaches to modeling local control of Ca(2+) -induced Ca(2+) release in cardiac myocytes can be used to construct minimal whole cell models that accurately represent heterogeneous local Ca(2+) signals. Unfortunately, the computational complexity of such "local/global" whole cell models scales with the number of Ca(2+) release unit (CaRU) states, which is a rapidly increasing function of the number of ryanodine receptors (RyRs) per CaRU. Here we present an alternative approach based on a Langevin description of the collective gating of RyRs coupled by local [Ca(2+)]. The computational efficiency of this approach no longer depends on the number of RyRs per CaRU. When the RyR model is minimal, Langevin equations may be replaced by a single Fokker-Planck equation, yielding an extremely compact and efficient local/global whole cell model that reproduces and helps interpret recent experiments that investigate Ca(2+) homeostasis in permeabilized ventricular m...
PloS one, 2014
The use of human stem cell-derived cardiomyocytes to study atrial biology and disease has been re... more The use of human stem cell-derived cardiomyocytes to study atrial biology and disease has been restricted by the lack of a reliable method for stem cell-derived atrial cell labeling and purification. The goal of this study was to generate an atrial-specific reporter construct to identify and purify human stem cell-derived atrial-like cardiomyocytes. We have created a bacterial artificial chromosome (BAC) reporter construct in which fluorescence is driven by expression of the atrial-specific gene sarcolipin (SLN). When purified using flow cytometry, cells with high fluorescence specifically express atrial genes and display functional calcium handling and electrophysiological properties consistent with atrial cardiomyocytes. Our data indicate that SLN can be used as a marker to successfully monitor and isolate hiPSC-derived atrial-like cardiomyocytes. These purified cells may find many applications, including in the study of atrial-specific pathologies and chamber-specific lineage dev...
The FASEB Journal, 2007
Sorcin is a Ca 2؉ binding protein implicated in the regulation of intracellular Ca 2؉ cycling and... more Sorcin is a Ca 2؉ binding protein implicated in the regulation of intracellular Ca 2؉ cycling and cardiac excitation-contraction coupling. Structural and human genetic studies suggest that a naturally occurring sequence variant encoding L112-sorcin disrupts an E-F hand Ca 2؉ binding domain and may be responsible for a heritable form of hypertension and hypertrophic heart disease. We generated transgenic mice overexpressing L112-sorcin in the heart and characterized the effects on Ca 2؉ regulation and cardiac function both in vivo and in dissociated cardiomyocytes. Hearts of sorcin F112L transgenic mice were mildly dilated but ventricular function was preserved and systemic blood pressure was normal. Sorcin F112L myocytes were smaller than control cells and displayed complex alterations in Ca 2؉ regulation and contractility, including a slowed inactivation of L-type Ca 2؉ current, enhanced Ca 2؉ spark width, duration, and frequency, and increased Na ؉ -Ca 2؉ exchange activity. In contrast, mice with cardiac-specific overexpression of wild-type sorcin displayed directionally opposite effects on L-type Ca 2؉ channel function and Ca 2؉ spark behavior. These data further define the role of sorcin in cardiac excitationcontraction coupling and highlight its negative regulation of SR calcium release. Our results also suggest that additional factors may be responsible for the development of cardiac hypertrophy and hypertension in humans expressing the L112-sorcin sequence variant.-Collis, L. P., Meyers, M. B., Zhang, J., Phoon, C. K. L., Sobie, E. A., Coetzee, W. A., Fishman, G. I. Expression of a sorcin missense mutation in the heart modulates excitation-contraction coupling. FASEB J. 21, 475-487 (2007)
Science, 2008
Classroom lectures by experts in combination with journal clubs and Web-based discussion forums h... more Classroom lectures by experts in combination with journal clubs and Web-based discussion forums help graduate students develop critical reasoning skills.
Progress in Biophysics and Molecular Biology, 2006
Ca(2+) efflux from the sarcoplasmic reticulum (SR) is routed primarily through SR Ca(2+) release ... more Ca(2+) efflux from the sarcoplasmic reticulum (SR) is routed primarily through SR Ca(2+) release channels (ryanodine receptors, RyRs). When clusters of RyRs are activated by trigger Ca(2+) influx through L-type Ca(2+) channels (dihydropyridine receptors, DHPR), Ca(2+) sparks are observed. Close spatial coupling between DHPRs and RyR clusters and the relative insensitivity of RyRs to be triggered by Ca(2+) together ensure the stability of this positive-feedback system of Ca(2+) amplification. Despite evidence from single channel RyR gating experiments that phosphorylation of RyRs by protein kinase A (PKA) or calcium-calmodulin dependent protein kinase II (CAMK II) causes an increase in the sensitivity of the RyR to be triggered by [Ca(2+)](i) there is little clear evidence to date showing an increase in Ca(2+) spark rate. Indeed, there is some evidence that the SR Ca(2+) content may be decreased in hyperadrenergic disease states. The question is whether or not these observations are compatible with each other and with the development of arrhythmogenic extrasystoles that can occur under these conditions. Furthermore, the appearance of an increase in the SR Ca(2+) "leak" under these conditions is perplexing. These and related complexities are analyzed and discussed in this report. Using simple mathematical modeling discussed in the context of recent experimental findings, a possible resolution to this paradox is proposed. The resolution depends upon two features of SR function that have not been confirmed directly but are broadly consistent with several lines of indirect evidence: (1) the existence of unclustered or "rogue" RyRs that may respond differently to local [Ca(2+)](i) in diastole and during the [Ca(2+)](i) transient; and (2) a decrease in cooperative or coupled gating between clustered RyRs in response to physiologic phosphorylation or hyper-phosphorylation of RyRs in disease states such as heart failure. Taken together, these two features may provide a framework that allows for an improved understanding of cardiac Ca(2+) signaling.
Proceedings of the National Academy of Sciences, 2006
Heart muscle is characterized by a regular array of proteins and structures that form a repeating... more Heart muscle is characterized by a regular array of proteins and structures that form a repeating functional unit identified as the sarcomere. This regular structure enables tight coupling between electrical activity and Ca(2+) signaling. In heart failure, multiple cellular defects develop, including reduced contractility, altered Ca(2+) signaling, and arrhythmias; however, the underlying causes of these defects are not well understood. Here, in ventricular myocytes from spontaneously hypertensive rats that develop heart failure, we identify fundamental changes in Ca(2+) signaling that are related to restructuring of the spatial organization of the cells. Myocytes display both a reduced ability to trigger sarcoplasmic reticulum Ca(2+) release and increased spatial dispersion of the transverse tubules (TTs). Remodeled TTs in cells from failing hearts no longer exist in the regularly organized structures found in normal heart cells, instead moving within the sarcomere away from the Z-line structures and leaving behind the sarcoplasmic reticulum Ca(2+) release channels, the ryanodine receptors (RyRs). These orphaned RyRs appear to be responsible for the dyssynchronous Ca(2+) sparks that have been linked to blunted contractility and, probably, Ca(2+)-dependent arrhythmias in diverse models of heart failure. We conclude that the increased spatial dispersion of the TTs and orphaned RyRs lead to the loss of local control and Ca(2+) instability in heart failure.
PLoS Computational Biology, 2010
A major challenge in computational biology is constraining free parameters in mathematical models... more A major challenge in computational biology is constraining free parameters in mathematical models. Adjusting a parameter to make a given model output more realistic sometimes has unexpected and undesirable effects on other model behaviors.
PLoS Computational Biology, 2014
Reverse rate dependence is a problematic property of antiarrhythmic drugs that prolong the cardia... more Reverse rate dependence is a problematic property of antiarrhythmic drugs that prolong the cardiac action potential (AP). The prolongation caused by reverse rate dependent agents is greater at slow heart rates, resulting in both reduced arrhythmia suppression at fast rates and increased arrhythmia risk at slow rates. The opposite property, forward rate dependence, would theoretically overcome these parallel problems, yet forward rate dependent (FRD) antiarrhythmics remain elusive. Moreover, there is evidence that reverse rate dependence is an intrinsic property of perturbations to the AP. We have addressed the possibility of forward rate dependence by performing a comprehensive analysis of 13 ventricular myocyte models. By simulating populations of myocytes with varying properties and analyzing population results statistically, we simultaneously predicted the rate-dependent effects of changes in multiple model parameters. An average of 40 parameters were tested in each model, and effects on AP duration were assessed at slow (0.2 Hz) and fast (2 Hz) rates. The analysis identified a variety of FRD ionic current perturbations and generated specific predictions regarding their mechanisms. For instance, an increase in L-type calcium current is FRD when this is accompanied by indirect, ratedependent changes in slow delayed rectifier potassium current. A comparison of predictions across models identified inward rectifier potassium current and the sodium-potassium pump as the two targets most likely to produce FRD AP prolongation. Finally, a statistical analysis of results from the 13 models demonstrated that models displaying minimal ratedependent changes in AP shape have little capacity for FRD perturbations, whereas models with large shape changes have considerable FRD potential. This can explain differences between species and between ventricular cell types. Overall, this study provides new insights, both specific and general, into the determinants of AP duration rate dependence, and illustrates a strategy for the design of potentially beneficial antiarrhythmic drugs.
![Research paper thumbnail of Local Ca2+ Signaling and EC Coupling in Heart: Ca2+ Sparks and the Regulation of the [Ca2+]i Transient](https://attachments.academia-assets.com/56867367/thumbnails/1.jpg)
](Journal of Molecular and Cellular Cardiology, 2002
34, 941À À950. The elementary event of Ca 2 release in heart is the Ca 2 spark. It occurs at a lo... more 34, 941À À950. The elementary event of Ca 2 release in heart is the Ca 2 spark. It occurs at a low rate during diastole, activated only by the low cytosolic [Ca 2 ] i . Synchronized activation of many sparks is due to the high local [Ca 2 ] i in the region surrounding the sarcoplasmic reticulum (SR) Ca 2 release channels and is responsible for the systolic [Ca 2 ] i transient. The biophysical basis of this calcium signaling is discussed. Attention is placed on the local organization of the ryanodine receptors (SR Ca 2 release channels, RyRs) and the other proteins that underlie and modulate excitationÀ Àcontraction (EC) coupling. A brief review of speci®c elements that regulate SR Ca 2 release (including SR lumenal Ca 2 and coupled gating of RyRs) is presented. Finally integrative calcium signaling in heart is presented in the context of normal heart function and heart failure.
Journal of Clinical Investigation, 2003
Journal of Cardiovascular Electrophysiology, 2006
Ca 2+ Release Restitution. New information has recently been obtained along two essentially paral... more Ca 2+ Release Restitution. New information has recently been obtained along two essentially parallel lines of research: investigations into the fundamental mechanisms of Ca 2+ -induced Ca 2+ release (CICR) in heart cells, and analyses of the factors that control the development of unstable rhythms such as repolariza-tion alternans. These lines of research are starting to converge such that we can begin to understand unstable and potentially arrhythmogenic cardiac dynamics in terms of the underlying mechanisms governing not only membrane depolarization and repolarization but also the complex bidirectional interactions between electrical and Ca 2+ signaling in heart cells. In this brief review, we discuss the progress that has recently been made in understanding the factors that control the beat-to-beat regulation of cardiac Ca 2+ release and attempt to place these results within a larger context. In particular, we discuss factors that may contribute to unstable Ca 2+ release and speculate about how instability in CICR may contribute to the development of arrhythmias under pathological conditions.
International Journal of Bifurcation and Chaos, 2003
Intracellular cardiac Ca 2+ handling involves interactions of numerous distinct cellular and macr... more Intracellular cardiac Ca 2+ handling involves interactions of numerous distinct cellular and macromolecular structures. Such interactions coordinate the complicated behaviors of individual processes into spatial and temporal coherent patterns of Ca 2+ sparks, oscillations and traveling waves. ...
Drug Discovery Today: Disease Models, 2009
ABSTRACT
Circulation, Jan 20, 2015
nd d, OR OR OR; 5 Di Di Divi vi visi si sion on on o o of f f Ca Ca Card rd dio io iov v vasc sc ... more nd d, OR OR OR; 5 Di Di Divi vi visi si sion on on o o of f f Ca Ca Card rd dio io iov v vasc sc scul ul ular M Me e edic c cin in ine, e, e, D D Dep p pt t t of of of M M Me e edi di dicine e e, Un Un Univ iv iver e si si sity ty ty o o of f f Wi Wi Wisconsin, Mad d dis son, , W W WI, 6 6 Ph Ph Pharma macol lo ogy a a an nd d Sy yst t tems ms ms T T Th h her r rape e eut t tics, I I Ica ahn n n S S Schoo o ol of o o M M Medic c cin ne at at at M M Mount Sin in nai a , Ne N w Yo Y Y rk, NY NY NY, 7 Un Un Unit t t o o of Ex x xpe erime me ental al al R R Rhe e eu u umat t tolog gy, , , D Dep p par r rtm t t en n nt o of o M Me edic c cin ne,
Biophysical Journal, 2011
in HEK293 cells showed that it does not generate any current (n=6). We utilized recently publishe... more in HEK293 cells showed that it does not generate any current (n=6). We utilized recently published computational models of the human atrial and ventricular action potential (Abraham et al., J Mol Cell Cardiol. 2010 and Grandi, et al. J Mol Cell Cardiol. 2010) to determine the effect that T322M has on cardiac Action Potential Duration (APD) stimulated at 1 Hz. A 100% reduction of I Ks resulted in a prolonged APD in the atrial simulation but not the ventricular simulation. We incorporated a beta-adrenergic stimulation component into the ventricular model and found that reducing I Ks by 100% in the modified simulation increased APD. We further modified the ventricular action potential simulation to compromise 'repolarization reserve' by reducing the rapidly-activating delayed-rectifier K þ current or I Kr component. This modification exacerbated that effect that 100% block of I Ks had on ventricular APD. Based on these results we conclude that T322M prolongs the atrial APD in the absence of betaadrenergic stimulation, and prolongs the ventricular APD in the presence of beta-adrenergic stimulation and a compromised repolarization reserve.
Biophysical Journal, 2011
Biophysical Journal, 2009
hormones on QT interval in males versus females, we constructed ''male'' and ''female'' cell mode... more hormones on QT interval in males versus females, we constructed ''male'' and ''female'' cell models using Faber-Rudy model of the guinea pig myocyte. The female model incorporated physiological concentrations of 17b-estradiol and progesterone measured in the follicular and luteal phases of the menstrual cycle, and predicts changes in APD at different stages of the menstrual cycle that are consistent with clinically observed QT interval fluctuations. The male model was developed to reflect changes induced by physiology concentrations of Testosterone. The models suggest protective effects of testosterone and progesterone to prevent APD prolongation and reduce QT interval, while estrogen significantly increase QT and susceptibility to drug-induced arrhythmias.
The Journal of Physiology, 2005
Excitation-contraction coupling in the heart depends on the positive feedback process of Ca2+-ind... more Excitation-contraction coupling in the heart depends on the positive feedback process of Ca2+-induced Ca2+ release (CICR). While CICR provides for robust triggering of Ca2+ sparks, the mechanisms underlying their termination remain unknown. At present, it is unclear how a cluster of Ca2+ release channels (ryanodine receptors or RyRs) can be made to turn off when their activity is sustained by the Ca2+ release itself. We use a novel experimental approach to investigate indirectly this issue by exploring restitution of Ca2+ sparks. We exploit the fact that ryanodine can bind, nearly irreversibly, to an RyR subunit (monomer) and increase the open probability of the homotetrameric channel. By applying low concentrations of ryanodine to rat ventricular myocytes, we observe repeated activations of individual Ca2+ spark sites. Examination of these repetitive Ca2+ sparks reveals that spark amplitude recovers with a time constant of 91 ms whereas the sigmoidal recovery of triggering probability lags behind amplitude recovery by approximately 80 ms. We conclude that restitution of Ca2+ sparks depends on local refilling of SR stores after depletion and may also depend on another time-dependent process such as recovery from inactivation or a slow conformational change after rebinding of Ca2+ to SR regulatory proteins.
Developments in Cardiovascular Medicine, 2005
American journal of physiology. Heart and circulatory physiology, Jan 5, 2014
Population density approaches to modeling local control of Ca(2+) -induced Ca(2+) release in card... more Population density approaches to modeling local control of Ca(2+) -induced Ca(2+) release in cardiac myocytes can be used to construct minimal whole cell models that accurately represent heterogeneous local Ca(2+) signals. Unfortunately, the computational complexity of such "local/global" whole cell models scales with the number of Ca(2+) release unit (CaRU) states, which is a rapidly increasing function of the number of ryanodine receptors (RyRs) per CaRU. Here we present an alternative approach based on a Langevin description of the collective gating of RyRs coupled by local [Ca(2+)]. The computational efficiency of this approach no longer depends on the number of RyRs per CaRU. When the RyR model is minimal, Langevin equations may be replaced by a single Fokker-Planck equation, yielding an extremely compact and efficient local/global whole cell model that reproduces and helps interpret recent experiments that investigate Ca(2+) homeostasis in permeabilized ventricular m...
PloS one, 2014
The use of human stem cell-derived cardiomyocytes to study atrial biology and disease has been re... more The use of human stem cell-derived cardiomyocytes to study atrial biology and disease has been restricted by the lack of a reliable method for stem cell-derived atrial cell labeling and purification. The goal of this study was to generate an atrial-specific reporter construct to identify and purify human stem cell-derived atrial-like cardiomyocytes. We have created a bacterial artificial chromosome (BAC) reporter construct in which fluorescence is driven by expression of the atrial-specific gene sarcolipin (SLN). When purified using flow cytometry, cells with high fluorescence specifically express atrial genes and display functional calcium handling and electrophysiological properties consistent with atrial cardiomyocytes. Our data indicate that SLN can be used as a marker to successfully monitor and isolate hiPSC-derived atrial-like cardiomyocytes. These purified cells may find many applications, including in the study of atrial-specific pathologies and chamber-specific lineage dev...
The FASEB Journal, 2007
Sorcin is a Ca 2؉ binding protein implicated in the regulation of intracellular Ca 2؉ cycling and... more Sorcin is a Ca 2؉ binding protein implicated in the regulation of intracellular Ca 2؉ cycling and cardiac excitation-contraction coupling. Structural and human genetic studies suggest that a naturally occurring sequence variant encoding L112-sorcin disrupts an E-F hand Ca 2؉ binding domain and may be responsible for a heritable form of hypertension and hypertrophic heart disease. We generated transgenic mice overexpressing L112-sorcin in the heart and characterized the effects on Ca 2؉ regulation and cardiac function both in vivo and in dissociated cardiomyocytes. Hearts of sorcin F112L transgenic mice were mildly dilated but ventricular function was preserved and systemic blood pressure was normal. Sorcin F112L myocytes were smaller than control cells and displayed complex alterations in Ca 2؉ regulation and contractility, including a slowed inactivation of L-type Ca 2؉ current, enhanced Ca 2؉ spark width, duration, and frequency, and increased Na ؉ -Ca 2؉ exchange activity. In contrast, mice with cardiac-specific overexpression of wild-type sorcin displayed directionally opposite effects on L-type Ca 2؉ channel function and Ca 2؉ spark behavior. These data further define the role of sorcin in cardiac excitationcontraction coupling and highlight its negative regulation of SR calcium release. Our results also suggest that additional factors may be responsible for the development of cardiac hypertrophy and hypertension in humans expressing the L112-sorcin sequence variant.-Collis, L. P., Meyers, M. B., Zhang, J., Phoon, C. K. L., Sobie, E. A., Coetzee, W. A., Fishman, G. I. Expression of a sorcin missense mutation in the heart modulates excitation-contraction coupling. FASEB J. 21, 475-487 (2007)
Science, 2008
Classroom lectures by experts in combination with journal clubs and Web-based discussion forums h... more Classroom lectures by experts in combination with journal clubs and Web-based discussion forums help graduate students develop critical reasoning skills.
Progress in Biophysics and Molecular Biology, 2006
Ca(2+) efflux from the sarcoplasmic reticulum (SR) is routed primarily through SR Ca(2+) release ... more Ca(2+) efflux from the sarcoplasmic reticulum (SR) is routed primarily through SR Ca(2+) release channels (ryanodine receptors, RyRs). When clusters of RyRs are activated by trigger Ca(2+) influx through L-type Ca(2+) channels (dihydropyridine receptors, DHPR), Ca(2+) sparks are observed. Close spatial coupling between DHPRs and RyR clusters and the relative insensitivity of RyRs to be triggered by Ca(2+) together ensure the stability of this positive-feedback system of Ca(2+) amplification. Despite evidence from single channel RyR gating experiments that phosphorylation of RyRs by protein kinase A (PKA) or calcium-calmodulin dependent protein kinase II (CAMK II) causes an increase in the sensitivity of the RyR to be triggered by [Ca(2+)](i) there is little clear evidence to date showing an increase in Ca(2+) spark rate. Indeed, there is some evidence that the SR Ca(2+) content may be decreased in hyperadrenergic disease states. The question is whether or not these observations are compatible with each other and with the development of arrhythmogenic extrasystoles that can occur under these conditions. Furthermore, the appearance of an increase in the SR Ca(2+) "leak" under these conditions is perplexing. These and related complexities are analyzed and discussed in this report. Using simple mathematical modeling discussed in the context of recent experimental findings, a possible resolution to this paradox is proposed. The resolution depends upon two features of SR function that have not been confirmed directly but are broadly consistent with several lines of indirect evidence: (1) the existence of unclustered or "rogue" RyRs that may respond differently to local [Ca(2+)](i) in diastole and during the [Ca(2+)](i) transient; and (2) a decrease in cooperative or coupled gating between clustered RyRs in response to physiologic phosphorylation or hyper-phosphorylation of RyRs in disease states such as heart failure. Taken together, these two features may provide a framework that allows for an improved understanding of cardiac Ca(2+) signaling.
Proceedings of the National Academy of Sciences, 2006
Heart muscle is characterized by a regular array of proteins and structures that form a repeating... more Heart muscle is characterized by a regular array of proteins and structures that form a repeating functional unit identified as the sarcomere. This regular structure enables tight coupling between electrical activity and Ca(2+) signaling. In heart failure, multiple cellular defects develop, including reduced contractility, altered Ca(2+) signaling, and arrhythmias; however, the underlying causes of these defects are not well understood. Here, in ventricular myocytes from spontaneously hypertensive rats that develop heart failure, we identify fundamental changes in Ca(2+) signaling that are related to restructuring of the spatial organization of the cells. Myocytes display both a reduced ability to trigger sarcoplasmic reticulum Ca(2+) release and increased spatial dispersion of the transverse tubules (TTs). Remodeled TTs in cells from failing hearts no longer exist in the regularly organized structures found in normal heart cells, instead moving within the sarcomere away from the Z-line structures and leaving behind the sarcoplasmic reticulum Ca(2+) release channels, the ryanodine receptors (RyRs). These orphaned RyRs appear to be responsible for the dyssynchronous Ca(2+) sparks that have been linked to blunted contractility and, probably, Ca(2+)-dependent arrhythmias in diverse models of heart failure. We conclude that the increased spatial dispersion of the TTs and orphaned RyRs lead to the loss of local control and Ca(2+) instability in heart failure.
PLoS Computational Biology, 2010
A major challenge in computational biology is constraining free parameters in mathematical models... more A major challenge in computational biology is constraining free parameters in mathematical models. Adjusting a parameter to make a given model output more realistic sometimes has unexpected and undesirable effects on other model behaviors.
PLoS Computational Biology, 2014
Reverse rate dependence is a problematic property of antiarrhythmic drugs that prolong the cardia... more Reverse rate dependence is a problematic property of antiarrhythmic drugs that prolong the cardiac action potential (AP). The prolongation caused by reverse rate dependent agents is greater at slow heart rates, resulting in both reduced arrhythmia suppression at fast rates and increased arrhythmia risk at slow rates. The opposite property, forward rate dependence, would theoretically overcome these parallel problems, yet forward rate dependent (FRD) antiarrhythmics remain elusive. Moreover, there is evidence that reverse rate dependence is an intrinsic property of perturbations to the AP. We have addressed the possibility of forward rate dependence by performing a comprehensive analysis of 13 ventricular myocyte models. By simulating populations of myocytes with varying properties and analyzing population results statistically, we simultaneously predicted the rate-dependent effects of changes in multiple model parameters. An average of 40 parameters were tested in each model, and effects on AP duration were assessed at slow (0.2 Hz) and fast (2 Hz) rates. The analysis identified a variety of FRD ionic current perturbations and generated specific predictions regarding their mechanisms. For instance, an increase in L-type calcium current is FRD when this is accompanied by indirect, ratedependent changes in slow delayed rectifier potassium current. A comparison of predictions across models identified inward rectifier potassium current and the sodium-potassium pump as the two targets most likely to produce FRD AP prolongation. Finally, a statistical analysis of results from the 13 models demonstrated that models displaying minimal ratedependent changes in AP shape have little capacity for FRD perturbations, whereas models with large shape changes have considerable FRD potential. This can explain differences between species and between ventricular cell types. Overall, this study provides new insights, both specific and general, into the determinants of AP duration rate dependence, and illustrates a strategy for the design of potentially beneficial antiarrhythmic drugs.
Journal of Molecular and Cellular Cardiology, 2002
34, 941À À950. The elementary event of Ca 2 release in heart is the Ca 2 spark. It occurs at a lo... more 34, 941À À950. The elementary event of Ca 2 release in heart is the Ca 2 spark. It occurs at a low rate during diastole, activated only by the low cytosolic [Ca 2 ] i . Synchronized activation of many sparks is due to the high local [Ca 2 ] i in the region surrounding the sarcoplasmic reticulum (SR) Ca 2 release channels and is responsible for the systolic [Ca 2 ] i transient. The biophysical basis of this calcium signaling is discussed. Attention is placed on the local organization of the ryanodine receptors (SR Ca 2 release channels, RyRs) and the other proteins that underlie and modulate excitationÀ Àcontraction (EC) coupling. A brief review of speci®c elements that regulate SR Ca 2 release (including SR lumenal Ca 2 and coupled gating of RyRs) is presented. Finally integrative calcium signaling in heart is presented in the context of normal heart function and heart failure.
Journal of Clinical Investigation, 2003
Journal of Cardiovascular Electrophysiology, 2006
Ca 2+ Release Restitution. New information has recently been obtained along two essentially paral... more Ca 2+ Release Restitution. New information has recently been obtained along two essentially parallel lines of research: investigations into the fundamental mechanisms of Ca 2+ -induced Ca 2+ release (CICR) in heart cells, and analyses of the factors that control the development of unstable rhythms such as repolariza-tion alternans. These lines of research are starting to converge such that we can begin to understand unstable and potentially arrhythmogenic cardiac dynamics in terms of the underlying mechanisms governing not only membrane depolarization and repolarization but also the complex bidirectional interactions between electrical and Ca 2+ signaling in heart cells. In this brief review, we discuss the progress that has recently been made in understanding the factors that control the beat-to-beat regulation of cardiac Ca 2+ release and attempt to place these results within a larger context. In particular, we discuss factors that may contribute to unstable Ca 2+ release and speculate about how instability in CICR may contribute to the development of arrhythmias under pathological conditions.
International Journal of Bifurcation and Chaos, 2003
Intracellular cardiac Ca 2+ handling involves interactions of numerous distinct cellular and macr... more Intracellular cardiac Ca 2+ handling involves interactions of numerous distinct cellular and macromolecular structures. Such interactions coordinate the complicated behaviors of individual processes into spatial and temporal coherent patterns of Ca 2+ sparks, oscillations and traveling waves. ...