{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T19:14:20Z","timestamp":1778181260809,"version":"3.51.4"},"reference-count":134,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2023,8,17]],"date-time":"2023-08-17T00:00:00Z","timestamp":1692230400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Calcium (Ca2+) sparks are the elementary events of excitation\u2013contraction coupling, yet they are not explicitly represented in human ventricular myocyte models. A stochastic ventricular cardiomyocyte human model that adapts to intracellular Ca2+ ([Ca2+]i) dynamics, spark regulation, and frequency-dependent changes in the form of locally controlled Ca2+ release was developed. The 20,000 CRUs in this model are composed of 9 individual LCCs and 49 RyRs that function as couplons. The simulated action potential duration at 1 Hz steady-state pacing is ~0.280 s similar to human ventricular cell recordings. Rate-dependence experiments reveal that APD shortening mechanisms are largely contributed by the L-type calcium channel inactivation, RyR open fraction, and [Ca2+]myo concentrations. The dynamic slow-rapid-slow pacing protocol shows that RyR open probability during high pacing frequency (2.5 Hz) switches to an adapted \u201cnonconducting\u201d form of Ca2+-dependent transition state. The predicted force was also observed to be increased in high pacing, but the SR Ca2+ fractional release was lower due to the smaller difference between diastolic and systolic [Ca2+]SR. Restitution analysis through the S1S2 protocol and increased LCC Ca2+-dependent activation rate show that the duration of LCC opening helps modulate its effects on the APD restitution at different diastolic intervals. Ultimately, a longer duration of calcium sparks was observed in relation to the SR Ca2+ loading at high pacing rates. Overall, this study demonstrates the spontaneous Ca2+ release events and ion channel responses throughout various stimuli.<\/jats:p>","DOI":"10.3390\/biom13081259","type":"journal-article","created":{"date-parts":[[2023,8,17]],"date-time":"2023-08-17T10:15:48Z","timestamp":1692267348000},"page":"1259","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Local Control Model of a Human Ventricular Myocyte: An Exploration of Frequency-Dependent Changes and Calcium Sparks"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-2061-972X","authenticated-orcid":false,"given":"Jerome Anthony E.","family":"Alvarez","sequence":"first","affiliation":[{"name":"School of Systems Biology, George Mason University, Fairfax, VA 22030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3174-1007","authenticated-orcid":false,"given":"M. Saleet","family":"Jafri","sequence":"additional","affiliation":[{"name":"School of Systems Biology, George Mason University, Fairfax, VA 22030, USA"},{"name":"Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD 20201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aman","family":"Ullah","sequence":"additional","affiliation":[{"name":"School of Systems Biology, George Mason University, Fairfax, VA 22030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"H301","DOI":"10.1152\/ajpheart.1998.275.1.H301","article-title":"Ionic mechanisms underlying human atrial action potential properties: Insights from a mathematical model","volume":"275","author":"Courtemanche","year":"1998","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1161\/01.RES.82.1.63","article-title":"Mathematical Model of an Adult Human Atrial Cell","volume":"82","author":"Nygren","year":"1998","journal-title":"Circ. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.yjmcc.2009.09.019","article-title":"A novel computational model of the human ventricular action potential and Ca transient","volume":"48","author":"Grandi","year":"2010","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1942","DOI":"10.1016\/S0006-3495(94)80677-0","article-title":"Spatial non-uniformities in [Ca2+]i during excitation-contraction coupling in cardiac myocytes","volume":"67","author":"Cannell","year":"1994","journal-title":"Biophys. J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/S0006-3495(92)81615-6","article-title":"Theory of excitation-contraction coupling in cardiac muscle","volume":"63","author":"Stern","year":"1992","journal-title":"Biophys. J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1871","DOI":"10.1016\/S0006-3495(99)77030-X","article-title":"Modeling gain and gradedness of Ca2+ release in the functional unit of the cardiac diadic space","volume":"77","author":"Rice","year":"1999","journal-title":"Biophys. J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2918","DOI":"10.1016\/S0006-3495(02)75301-0","article-title":"An integrative model of the cardiac ventricular myocyte incorporating local control of Ca2+ release","volume":"83","author":"Greenstein","year":"2002","journal-title":"Biophys. J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/j.bpj.2015.06.017","article-title":"A human ventricular myocyte model with a refined representation of excitation-contraction coupling","volume":"109","author":"Himeno","year":"2015","journal-title":"Biophys. J."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1206","DOI":"10.1161\/01.RES.82.11.1206","article-title":"Simulation study of cellular electric properties in heart failure","volume":"82","author":"Priebe","year":"1998","journal-title":"Circ. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1501","DOI":"10.1161\/01.RES.68.6.1501","article-title":"A model of the ventricular cardiac action potential. Depolarization, repolarization, and their interaction","volume":"68","author":"Luo","year":"1991","journal-title":"Circ. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1161\/01.RES.74.6.1071","article-title":"A dynamic model of the cardiac ventricular action potential. I. Simulations of ionic currents and concentration changes","volume":"74","author":"Luo","year":"1994","journal-title":"Circ. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"114","DOI":"10.3389\/fphys.2012.00114","article-title":"Computational Modeling and Numerical Methods for Spatiotemporal Calcium Cycling in Ventricular Myocytes","volume":"3","author":"Nivala","year":"2012","journal-title":"Front. Physiol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Hoang-Trong, T.M., Ullah, A., Lederer, W.J., and Jafri, M.S. (2021). A Stochastic Spatiotemporal Model of Rat Ventricular Myocyte Calcium Dynamics Demonstrated Necessary Features for Calcium Wave Propagation. Membranes, 11.","DOI":"10.3390\/membranes11120989"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e48890","DOI":"10.7554\/eLife.48890","article-title":"Development, calibration, and validation of a novel human ventricular myocyte model in health, disease, and drug block","volume":"8","author":"Tomek","year":"2019","journal-title":"Elife"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.vascn.2016.05.016","article-title":"Human ex-vivo action potential model for pro-arrhythmia risk assessment","volume":"81","author":"Page","year":"2016","journal-title":"J. Pharmacol. Toxicol. Methods"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"O\u2019Hara, T., Vir\u00e1g, L., Varr\u00f3, A., and Rudy, Y. (2011). Simulation of the Undiseased Human Cardiac Ventricular Action Potential: Model Formulation and Experimental Validation. PLoS Comput. Biol., 7.","DOI":"10.1371\/journal.pcbi.1002061"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"6309","DOI":"10.1073\/pnas.0601533103","article-title":"Activation and repolarization of the normal human heart under complete physiological conditions","volume":"103","author":"Ramanathan","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1016\/S0006-3495(98)77832-4","article-title":"Cardiac Ca2+ dynamics: The roles of ryanodine receptor adaptation and sarcoplasmic reticulum load","volume":"74","author":"Jafri","year":"1998","journal-title":"Biophys. J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1016\/j.bpj.2011.07.021","article-title":"Dynamics of calcium sparks and calcium leak in the heart","volume":"101","author":"Williams","year":"2011","journal-title":"Biophys. J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"113a","DOI":"10.1016\/j.bpj.2018.11.638","article-title":"A Local-Control Model of the Guinea Pig Ventricular Myocyte Allows Understanding of Force-Interval Relations at the Calcium Spark Level","volume":"116","author":"Paudel","year":"2019","journal-title":"Biophys. J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"H1573","DOI":"10.1152\/ajpheart.00794.2003","article-title":"A model for human ventricular tissue","volume":"286","author":"Tusscher","year":"2004","journal-title":"Am. J. Physiol.-Heart Circ. Physiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2029","DOI":"10.1016\/j.bpj.2008.11.045","article-title":"A Thermodynamic Model of the Cardiac Sarcoplasmic\/Endoplasmic Ca2+ (SERCA) Pump","volume":"96","author":"Tran","year":"2009","journal-title":"Biophys. J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1111\/j.1469-7793.2000.00139.x","article-title":"A model of the L-type Ca2+ channel in rat ventricular myocytes: Ion selectivity and inactivation mechanisms","volume":"529","author":"Sun","year":"2000","journal-title":"J. Physiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1161\/CIRCRESAHA.112.274530","article-title":"Stimulated Emission Depletion Live-Cell Super-Resolution Imaging Shows Proliferative Remodeling of T-Tubule Membrane Structures After Myocardial Infarction","volume":"111","author":"Wagner","year":"2012","journal-title":"Circ. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"C1587","DOI":"10.1152\/ajpcell.1993.264.6.C1587","article-title":"Ratio of ryanodine to dihydropyridine receptors in cardiac and skeletal muscle and implications for E-C coupling","volume":"264","author":"Bers","year":"1993","journal-title":"Am. J. Physiol.-Cell Physiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1085\/jgp.27.1.37","article-title":"Potential, Impedance, and rectification in membranes","volume":"27","author":"Goldman","year":"1943","journal-title":"J. Gen. Physiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2300","DOI":"10.1021\/j100638a009","article-title":"Thermodynamics of electrolytes. II. Activity and osmotic coefficients for strong electrolytes with one or both ions univalent","volume":"77","author":"Pitzer","year":"1973","journal-title":"J. Phys. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1113\/jphysiol.1984.sp015374","article-title":"High selectivity of calcium channels in single dialysed heart cells of the guinea-pig","volume":"354","author":"Lee","year":"1984","journal-title":"J. Physiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1085\/jgp.88.3.293","article-title":"Calcium channel selectivity for divalent and monovalent cations. Voltage and concentration dependence of single channel current in ventricular heart cells","volume":"88","author":"Hess","year":"1986","journal-title":"J. Gen. Physiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1113\/jphysiol.1988.sp017326","article-title":"Properties of the transient outward current in rabbit atrial cells","volume":"405","author":"Clark","year":"1988","journal-title":"J. Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"H142","DOI":"10.1152\/ajpheart.1987.252.1.H142","article-title":"Two types of transient outward currents in adult human atrial cells","volume":"252","author":"Escande","year":"1987","journal-title":"Am. J. Physiol.-Heart Circ. Physiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1113\/jphysiol.1985.sp015856","article-title":"A transient outward current in isolated cells from the crista terminalis of rabbit heart","volume":"368","author":"Giles","year":"1985","journal-title":"J. Physiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"H1773","DOI":"10.1152\/ajpheart.1989.257.6.H1773","article-title":"Contributions of a transient outward current to repolarization in human atrium","volume":"257","author":"Shibata","year":"1989","journal-title":"Am. J. Physiol.-Heart Circ. Physiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"H1747","DOI":"10.1152\/ajpheart.1992.263.6.H1747","article-title":"Differences in rate dependence of transient outward current in rabbit and human atrium","volume":"263","author":"Fermini","year":"1992","journal-title":"Am. J. Physiol.-Heart Circ. Physiol."},{"key":"ref_35","unstructured":"Jafri, M.S., Hoang-Trong, T.M., and Williams, G.S.B. (2015). Method and System for Utilizing Markov Chain Monte Carlo Simulations. (US9009095B1), Google Patents."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1016\/j.cpc.2012.12.003","article-title":"Exploiting seeding of random number generators for efficient domain decomposition parallelization of dissipative particle dynamics","volume":"184","author":"Afshar","year":"2013","journal-title":"Comput. Phys. Commun."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Ullah, A., Hoang-Trong, M.T., Lederer, W.J., Winslow, R.L., and Jafri, M.S. (2022). Critical Requirements for the Initiation of a Cardiac Arrhythmia in Rat Ventricle: How Many Myocytes?. Cells, 11.","DOI":"10.3390\/cells11121878"},{"key":"ref_38","unstructured":"Smith, G.D. (2002). Computational Cell Biology, Springer."},{"key":"ref_39","unstructured":"Groff, J.R., DeRemigio, H., and Smith, G.D. (2009). Stochastic Methods in Neuroscience, Oxford Academic."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Hoang-Trong, M.T., Ullah, A., Lederer, W.J., and Jafri, M.S. (2021). Cardiac Alternans Occurs through the Synergy of Voltage- and Calcium-Dependent Mechanisms. Membranes, 11.","DOI":"10.3390\/membranes11100794"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1016\/j.yjmcc.2009.11.019","article-title":"The molecular basis of the steep force-calcium relation in heart muscle","volume":"48","author":"Sun","year":"2010","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1113\/jphysiol.2008.164707","article-title":"Calcium- and myosin-dependent changes in troponin structure during activation of heart muscle","volume":"587","author":"Sun","year":"2009","journal-title":"J. Physiol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"H98","DOI":"10.1152\/ajpheart.1999.276.1.H98","article-title":"TransmembraneI Ca contributes to rate-dependent changes of action potentials in human ventricular myocytes","volume":"276","author":"Li","year":"1999","journal-title":"Am. J. Physiol.-Heart Circ. Physiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1161\/01.CIR.93.1.168","article-title":"Regional Differences in Current Density and Rate-Dependent Properties of the Transient Outward Current in Subepicardial and Subendocardial Myocytes of Human Left Ventricle","volume":"93","author":"Beuckelmann","year":"1996","journal-title":"Circulation"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1016\/S0008-6363(98)00204-1","article-title":"Delayed rectifier potassium current in undiseased human ventricular myocytes","volume":"40","author":"Iost","year":"1998","journal-title":"Cardiovasc. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1016\/S0008-6363(00)00306-0","article-title":"The slow component of the delayed rectifier potassium current in undiseased human ventricular myocytes","volume":"49","author":"Iost","year":"2001","journal-title":"Cardiovasc. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1046\/j.0001-6772.2003.01223.x","article-title":"Reopening of L-type calcium channels in human ventricular myocytes during applied epicardial action potentials","volume":"180","author":"Magyar","year":"2004","journal-title":"Acta Physiol. Scand."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1522","DOI":"10.1529\/biophysj.106.088807","article-title":"Kinetic properties of the cardiac L-type Ca2+ channel and its role in myocyte electrophysiology: A theoretical investigation","volume":"92","author":"Faber","year":"2007","journal-title":"Biophys. J."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1085\/jgp.116.6.873","article-title":"Ryanodine receptor adaptation","volume":"116","author":"Fill","year":"2000","journal-title":"J. Gen. Physiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"479","DOI":"10.3389\/fphar.2020.00479","article-title":"Electrical Restitution and Its Modifications by Antiarrhythmic Drugs in Undiseased Human Ventricular Muscle","volume":"11","author":"Bitay","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1007\/s00395-009-0082-7","article-title":"Reverse rate-dependent changes are determined by baseline action potential duration in mammalian and human ventricular preparations","volume":"105","author":"Jost","year":"2010","journal-title":"Basic Res. Cardiol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"31624","DOI":"10.1074\/jbc.R112.349068","article-title":"Ryanodine receptors: Structure and function","volume":"287","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1038\/415198a","article-title":"Cardiac excitation\u2013contraction coupling","volume":"415","author":"Bers","year":"2002","journal-title":"Nature"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1016\/0002-8703(83)90002-9","article-title":"Amiodarone: Historical development and pharmacologic profile","volume":"106","author":"Singh","year":"1983","journal-title":"Am. Heart J."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1161\/01.CIR.86.3.955","article-title":"Cellular mechanisms of differential action potential duration restitution in canine ventricular muscle cells during single versus double premature stimuli","volume":"86","author":"Kobayashi","year":"1992","journal-title":"Circulation"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1093\/cvr\/27.6.946","article-title":"Effects of temperature on cycle length dependent changes and restitution of action potential duration in guinea pig ventricular muscle","volume":"27","author":"Tande","year":"1993","journal-title":"Cardiovasc. Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1085\/jgp.96.1.195","article-title":"Two components of cardiac delayed rectifier K+ current. Differential sensitivity to block by class III antiarrhythmic agents","volume":"96","author":"Sanguinetti","year":"1990","journal-title":"J. Gen. Physiol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1007\/BF00581319","article-title":"An analysis of the delayed outward current in single ventricular cells of the guinea-pig","volume":"410","author":"Matsuura","year":"1987","journal-title":"Pfl\u00fcgers Arch."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1097\/00005344-199205000-00022","article-title":"Contribution of delayed rectifier and inward rectifier to repolarization of the action potential: Pharmacologic separation","volume":"19","author":"Martin","year":"1992","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1113\/jphysiol.1988.sp017325","article-title":"Comparison of potassium currents in rabbit atrial and ventricular cells","volume":"405","author":"Giles","year":"1988","journal-title":"J. Physiol."},{"key":"ref_61","first-page":"553","article-title":"Two delayed rectifiers in guinea pig ventricular myocytes distinguished by tail current kinetics","volume":"264","author":"Chinn","year":"1993","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"e005914","DOI":"10.1161\/CIRCEP.117.005914","article-title":"Differential Expression and Remodeling of Transient Outward Potassium Currents in Human Left Ventricles","volume":"11","author":"Johnson","year":"2018","journal-title":"Circ. Arrhythmia Electrophysiol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1898","DOI":"10.1161\/01.CIR.99.14.1898","article-title":"Transient Outward Current, Ito1, Is Altered in Cardiac Memory","volume":"99","author":"Yu","year":"1999","journal-title":"Circulation"},{"key":"ref_64","unstructured":"Wei, X., Yohannan, S., and Richards, J.R. (2023). StatPearls, StatPearls Publishing."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2229","DOI":"10.1113\/JP272883","article-title":"Potassium currents in the heart: Functional roles in repolarization, arrhythmia and therapeutics","volume":"595","author":"Chiamvimonvat","year":"2017","journal-title":"J. Physiol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1161\/01.RES.77.1.140","article-title":"Two Components of the Delayed Rectifier K+ Current in Ventricular Myocytes of the Guinea Pig Type","volume":"77","author":"Zeng","year":"1995","journal-title":"Circ. Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1113\/jphysiol.1987.sp016654","article-title":"An intrinsic potential-dependent inactivation mechanism associated with calcium channels in guinea-pig myocytes","volume":"389","author":"Hadley","year":"1987","journal-title":"J. Physiol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1085\/jgp.102.6.1005","article-title":"Ca(2+)-dependent inactivation of cardiac L-type Ca2+ channels does not affect their voltage sensor","volume":"102","author":"Shirokov","year":"1993","journal-title":"J. Gen. Physiol."},{"key":"ref_69","first-page":"441","article-title":"Inactivation of L-type calcium channels in cardiomyocytes. Experimental and theoretical approaches","volume":"22","year":"2003","journal-title":"Gen. Physiol. Biophys."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1161\/res.90.1.14","article-title":"Calcium and Cardiac Rhythms","volume":"90","author":"Bers","year":"2002","journal-title":"Circ. Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1161\/01.RES.0000080932.98903.D8","article-title":"Role of sodium-calcium exchanger in modulating the action potential of ventricular myocytes from normal and failing hearts","volume":"93","author":"Armoundas","year":"2003","journal-title":"Circ. Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.cardiores.2003.09.022","article-title":"Quantification of the rat left ventricle force and Ca2+ frequency relationships: Similarities to dog and human","volume":"61","author":"Taylor","year":"2004","journal-title":"Cardiovasc. Res."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"205","DOI":"10.3389\/fphys.2018.00205","article-title":"Dynamic Action Potential Restitution Contributes to Mechanical Restitution in Right Ventricular Myocytes From Pulmonary Hypertensive Rats","volume":"9","author":"Hardy","year":"2018","journal-title":"Front. Physiol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/j.joa.2016.02.009","article-title":"Cardiac dynamics: Alternans and arrhythmogenesis","volume":"32","author":"Tse","year":"2016","journal-title":"J. Arrhythm."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.hrthm.2011.08.029","article-title":"Profile of L-type Ca2+ current and Na+\/Ca2+ exchange current during cardiac action potential in ventricular myocytes","volume":"9","author":"Banyasz","year":"2012","journal-title":"Heart Rhythm."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"H269","DOI":"10.1152\/ajpheart.1999.276.1.H269","article-title":"Cardiac electrical restitution properties and stability of reentrant spiral waves: A simulation study","volume":"276","author":"Qu","year":"1999","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1664","DOI":"10.1161\/01.CIR.102.14.1664","article-title":"Mechanisms of Discordant Alternans and Induction of Reentry in Simulated Cardiac Tissue","volume":"102","author":"Qu","year":"2000","journal-title":"Circulation"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1161\/CIRCRESAHA.112.265652","article-title":"Ryanodine Receptor Current Amplitude Controls Ca2+ Sparks in Cardiac Muscle","volume":"111","author":"Guo","year":"2012","journal-title":"Circ. Res."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1126\/science.8235594","article-title":"Calcium sparks: Elementary events underlying excitation-contraction coupling in heart muscle","volume":"262","author":"Cheng","year":"1993","journal-title":"Science"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1111\/j.1469-7793.1999.0173r.x","article-title":"The role of luminal Ca2+ in the generation of Ca2+ waves in rat ventricular myocytes","volume":"518","author":"Lukyanenko","year":"1999","journal-title":"J. Physiol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"H657","DOI":"10.1152\/ajpheart.1997.272.2.H657","article-title":"Effects of [Ca2+]i, SR Ca2+ load, and rest on Ca2+ spark frequency in ventricular myocytes","volume":"272","author":"Satoh","year":"1997","journal-title":"Am. J. Physiol.-Heart Circ. Physiol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1054\/ceca.2002.0272","article-title":"Calcium sparks in human ventricular cardiomyocytes from patients with terminal heart failure","volume":"31","author":"Lindner","year":"2002","journal-title":"Cell Calcium"},{"key":"ref_83","unstructured":"Usman, A., Gandhi, J., and Gupta, G. (2023). StatPearls, StatPearls Publishing."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1126\/science.87.2265.471","article-title":"Henry Pickering Bowditch, Physiologist","volume":"87","author":"Cannon","year":"1938","journal-title":"Science"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"H952","DOI":"10.1152\/ajpheart.2000.279.3.H952","article-title":"Ca2+ handling in isolated human atrial myocardium","volume":"279","author":"Maier","year":"2000","journal-title":"Am. J. Physiol.-Heart Circ. Physiol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1161\/01.RES.85.1.38","article-title":"Ca2+ handling and sarcoplasmic reticulum Ca2+ content in isolated failing and nonfailing human myocardium","volume":"85","author":"Pieske","year":"1999","journal-title":"Circ. Res."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1126\/science.8387229","article-title":"Ryanodine Receptor Adaptation: Control Mechanism of Ca2+-Induced Ca2+ Release in Heart","volume":"260","author":"Fill","year":"1993","journal-title":"Science"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1016\/S0006-3495(00)76596-9","article-title":"Potentiation of fractional sarcoplasmic reticulum calcium release by total and free intra-sarcoplasmic reticulum calcium concentration","volume":"78","author":"Shannon","year":"2000","journal-title":"Biophys. J."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1161\/CIRCRESAHA.117.310230","article-title":"Calcium and Excitation-Contraction Coupling in the Heart","volume":"121","author":"Eisner","year":"2017","journal-title":"Circ. Res."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"C1313","DOI":"10.1152\/ajpcell.1995.268.5.C1313","article-title":"Fractional SR Ca release is regulated by trigger Ca and SR Ca content in cardiac myocytes","volume":"268","author":"Bassani","year":"1995","journal-title":"Am. J. Physiol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1775","DOI":"10.1016\/S0006-3495(94)80652-6","article-title":"Intrinsic cytosolic calcium buffering properties of single rat cardiac myocytes","volume":"67","author":"Berlin","year":"1994","journal-title":"Biophys. J."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1410","DOI":"10.1161\/CIRCRESAHA.114.302505","article-title":"Optical Mapping of Sarcoplasmic Reticulum Ca2+ in the Intact Heart","volume":"114","author":"Wang","year":"2014","journal-title":"Circ. Res."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1021\/bi00349a033","article-title":"Kinetics of rapid Ca2+ release by sarcoplasmic reticulum. Effects of Ca2+, Mg2+, and adenine nucleotides","volume":"25","author":"Meissner","year":"1986","journal-title":"Biochemistry"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1113\/jphysiol.1974.sp010630","article-title":"Slow recovery from inactivation of inward currents in mammalian myocardial fibres","volume":"240","author":"Gettes","year":"1974","journal-title":"J. Physiol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1113\/jphysiol.1981.sp013675","article-title":"The effects of heart rate on the action potential of guinea-pig and human ventricular muscle","volume":"313","author":"Attwell","year":"1981","journal-title":"J. Physiol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"H448","DOI":"10.1152\/ajpheart.00898.2001","article-title":"Electrical refractory period restitution and spiral wave reentry in simulated cardiac tissue","volume":"283","author":"Xie","year":"2002","journal-title":"Am. J. Physiol.-Heart Circ. Physiol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1016\/j.pbiomolbio.2008.02.021","article-title":"Cardiac mechano-electric feedback and electrical restitution in humans","volume":"97","author":"Taggart","year":"2008","journal-title":"Prog. Biophys. Mol. Biol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1113\/expphysiol.2005.031070","article-title":"Whole heart action potential duration restitution properties in cardiac patients: A combined clinical and modelling study","volume":"91","author":"Nash","year":"2006","journal-title":"Exp. Physiol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.1152\/physrev.00030.2007","article-title":"Calcium Sparks","volume":"88","author":"Cheng","year":"2008","journal-title":"Physiol. Rev."},{"key":"ref_100","first-page":"203","article-title":"Calcium Sparks in the Heart: Dynamics and Regulation","volume":"6","author":"Ullah","year":"2015","journal-title":"Res. Rep. Biol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0008-6363(02)00248-1","article-title":"The failing human heart","volume":"54","author":"Alpert","year":"2002","journal-title":"Cardiovasc. Res."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1161\/01.RES.0000079967.11815.19","article-title":"Ca2+ Scraps: Local Depletions of Free [Ca2+] in Cardiac Sarcoplasmic Reticulum during Contractions Leave Substantial Ca2+ Reserve","volume":"93","author":"Shannon","year":"2003","journal-title":"Circ. Res."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1093\/cvr\/cvu158","article-title":"Direct measurements of SR free Ca reveal the mechanism underlying the transient effects of RyR potentiation under physiological conditions","volume":"103","author":"Greensmith","year":"2014","journal-title":"Cardiovasc. Res."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1093\/cvr\/27.4.542","article-title":"Preconditioning: State of the art myocardial protection","volume":"27","author":"Lawson","year":"1993","journal-title":"Cardiovasc. Res."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1161\/01.CIR.93.1.178","article-title":"Rapid Ventricular Pacing Produces Myocardial Protection by Nonischemic Activation of KATP+ Channels","volume":"93","author":"Koning","year":"1996","journal-title":"Circulation"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1136\/hrt.2003.025650","article-title":"Rapid right ventricular pacing is an alternative to adenosine in catheter interventional procedures for congenital heart disease","volume":"90","author":"Daehnert","year":"2004","journal-title":"Heart"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"e009038","DOI":"10.1161\/JAHA.118.009038","article-title":"Impact of Rapid Ventricular Pacing on Outcome After Transcatheter Aortic Valve Replacement","volume":"7","author":"Fefer","year":"2018","journal-title":"J. Am. Heart Assoc."},{"key":"ref_108","doi-asserted-by":"crossref","unstructured":"Grabert, J., Huber-Petersen, S., Lampmann, T., Eichhorn, L., Vatter, H., Coburn, M., Velten, M., and G\u00fcresir, E. (2021). Rapid Ventricular Pacing as a Safe Procedure for Clipping of Complex Ruptured and Unruptured Intracranial Aneurysms. J. Clin. Med., 10.","DOI":"10.3390\/jcm10225406"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"H2854","DOI":"10.1152\/ajpheart.01347.2006","article-title":"Regulation of Ca2+ and electrical alternans in cardiac myocytes: Role of CAMKII and repolarizing currents","volume":"292","author":"Livshitz","year":"2007","journal-title":"Am. J. Physiol.-Heart Circ. Physiol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"3168","DOI":"10.1161\/01.CIR.0000147231.69595.D3","article-title":"Rate dependence and regulation of action potential and calcium transient in a canine cardiac ventricular cell model","volume":"110","author":"Hund","year":"2004","journal-title":"Circulation"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"112a","DOI":"10.1016\/j.bpj.2013.11.683","article-title":"A small number of cells is sufficient to trigger a cardiac arrhythmia: Stochastic computational studies","volume":"106","author":"Ullah","year":"2014","journal-title":"Biophys. J."},{"key":"ref_112","doi-asserted-by":"crossref","unstructured":"Sutanto, H., and Heijman, J. (2022). Integrative Computational Modeling of Cardiomyocyte Calcium Handling and Cardiac Arrhythmias: Current Status and Future Challenges. Cells, 11.","DOI":"10.3390\/cells11071090"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"2533","DOI":"10.1529\/biophysj.105.067074","article-title":"Temperature dependence and thermodynamic properties of Ca2+ sparks in rat cardiomyocytes","volume":"89","author":"Fu","year":"2005","journal-title":"Biophys. J."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"H1023","DOI":"10.1152\/ajpheart.00785.2011","article-title":"Quantitative comparison of cardiac ventricular myocyte electrophysiology and response to drugs in human and nonhuman species","volume":"302","author":"Rudy","year":"2012","journal-title":"Am. J. Physiol.-Heart Circ. Physiol."},{"key":"ref_115","unstructured":"(2023, July 02). HDF-Group. Available online: http:\/\/www.hdfgroup.org\/HDF5\/."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1161\/01.RES.0000030180.06028.23","article-title":"Na+-Ca2+ exchange activity is localized in the T-tubules of rat ventricular myocytes","volume":"91","author":"Yang","year":"2002","journal-title":"Circ. Res."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/S0006-3495(02)75149-7","article-title":"Termination of Cardiac Ca2+ Sparks: An Investigative Mathematical Model of Calcium-Induced Calcium Release","volume":"83","author":"Sobie","year":"2002","journal-title":"Biophys. J."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/S0006-3495(98)77491-0","article-title":"A simple numerical model of calcium spark formation and detection in cardiac myocytes","volume":"75","author":"Smith","year":"1998","journal-title":"Biophys. J."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1529\/biophysj.107.119982","article-title":"Ryanodine receptor allosteric coupling and the dynamics of calcium sparks","volume":"95","author":"Groff","year":"2008","journal-title":"Biophys. J."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1038\/20079","article-title":"Calmodulin at the channel gate","volume":"399","author":"Ehlers","year":"1999","journal-title":"Nature"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"5135","DOI":"10.1073\/pnas.0807487106","article-title":"Crystal structure of dimeric cardiac L-type calcium channel regulatory domains bridged by Ca2+* calmodulins","volume":"106","author":"Fallon","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"30794","DOI":"10.1074\/jbc.M104959200","article-title":"Molecular basis of calmodulin tethering and Ca2+-dependent inactivation of L-type Ca2+ channels","volume":"276","author":"Pitt","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1126\/science.1093490","article-title":"Functional stoichiometry and local enrichment of calmodulin interacting with Ca2+ channels","volume":"304","author":"Mori","year":"2004","journal-title":"Science"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1113\/jphysiol.1952.sp004764","article-title":"A quantiative description of membrane current and its application to conduction and excitation in nerve","volume":"117","author":"Hodgkin","year":"1952","journal-title":"J. Physiol."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"H1378","DOI":"10.1152\/ajpheart.00185.2003","article-title":"Computer model of action potential of mouse ventricular myocytes","volume":"287","author":"Bondarenko","year":"2004","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1093\/cvr\/cvr143","article-title":"Recovery of cardiac calcium release is controlled by sarcoplasmic reticulum refilling and ryanodine receptor sensitivity","volume":"91","author":"Ramay","year":"2011","journal-title":"Cardiovasc. Res."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1161\/01.RES.78.4.689","article-title":"Evidence for Two Components of Delayed Rectifier K+ Current in Human Ventricular Myocytes","volume":"78","author":"Li","year":"1996","journal-title":"Circ. Res."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1056\/NEJMcp0706513","article-title":"Long-QT Syndrome","volume":"358","author":"Roden","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"1392","DOI":"10.1161\/CIRCULATIONAHA.105.550111","article-title":"Restricting Excessive Cardiac Action Potential and QT Prolongation","volume":"112","author":"Jost","year":"2005","journal-title":"Circulation"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1161\/01.CIR.0000044941.13346.74","article-title":"Effect of Adrenergic Stimulation on Action Potential Duration Restitution in Humans","volume":"107","author":"Taggart","year":"2003","journal-title":"Circulation"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"H782","DOI":"10.1152\/ajpheart.1983.244.6.H782","article-title":"Cycle length effect on restitution of action potential duration in dog cardiac fibers","volume":"244","author":"Elharrar","year":"1983","journal-title":"Am. J. Physiol.-Heart Circ. Physiol."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1113\/expphysiol.2012.065219","article-title":"Effects of ventricular pacing protocol on electrical restitution assessments in guinea-pig heart","volume":"97","author":"Osadchii","year":"2012","journal-title":"Exp. Physiol."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1093\/cvr\/cvx063","article-title":"Restitution slope is principally determined by steady-state action potential duration","volume":"113","author":"Shattock","year":"2017","journal-title":"Cardiovasc. Res."},{"key":"ref_134","first-page":"325","article-title":"Transient outward potassium current and repolarization of cardiac cells","volume":"182","author":"Coraboeuf","year":"1998","journal-title":"Bull. Acad. Natl. Med."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/13\/8\/1259\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:36:01Z","timestamp":1760128561000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/13\/8\/1259"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,17]]},"references-count":134,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2023,8]]}},"alternative-id":["biom13081259"],"URL":"https:\/\/doi.org\/10.3390\/biom13081259","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,17]]}}}