@article {doi:10.1161/CIRCRESAHA.123.322588,
	title = {Stretch Harmonizes Sarcomere Strain Across the Cardiomyocyte},
	journal = {Circulation Research},
	year = {2023},
	month = {07/2023},
	publisher = {American Heart Association},
	abstract = {BACKGROUND:Increasing cardiomyocyte contraction during myocardial stretch serves as the basis for the Frank-Starling mechanism in the heart. However, it remains unclear how this phenomenon occurs regionally within cardiomyocytes, at the level of individual sarcomeres. We investigated sarcomere contractile synchrony and how intersarcomere dynamics contribute to increasing contractility during cell lengthening.METHODS:Sarcomere strain and Ca2+\&nbsp;were simultaneously recorded in isolated left ventricular cardiomyocytes during 1 Hz field stimulation at 37\&thinsp;\&deg;C, at resting length and following stepwise stretch.RESULTS:We observed that in unstretched rat cardiomyocytes, differential sarcomere deformation occurred during each beat. Specifically, while most sarcomeres shortened during the stimulus, \&asymp;10\% to 20\% of sarcomeres were stretched or remained stationary. This nonuniform strain was not traced to regional Ca2+\&nbsp;disparities but rather shorter resting lengths and lower force production in systolically stretched sarcomeres. Lengthening of the cell recruited additional shortening sarcomeres, which increased contractile efficiency as less negative, wasted work was performed by stretched sarcomeres. Given the known role of titin in setting sarcomere dimensions, we next hypothesized that modulating titin expression would alter intersarcomere dynamics. Indeed, in cardiomyocytes from mice with titin haploinsufficiency, we observed greater variability in resting sarcomere length, lower recruitment of shortening sarcomeres, and impaired work performance during cell lengthening.CONCLUSIONS:Graded sarcomere recruitment directs cardiomyocyte work performance, and harmonization of sarcomere strain increases contractility during cell stretch. By setting sarcomere dimensions, titin controls sarcomere recruitment, and its lowered expression in haploinsufficiency mutations impairs cardiomyocyte contractility.},
	url = {https://www.ahajournals.org/doi/abs/10.1161/CIRCRESAHA.123.322588},
	author = {Li, Jia and Sundnes, Joakim and Hou, Yufeng and Laasmaa, Martin and Ruud, Marianne and Unger, Andreas and Terje R. {Kolstad} and Frisk, Michael and Per A. {Norseng} and Yang, Limin and Ingunn E. {Setterberg} and Estela S. {Alves} and Kalakoutis, Michaeljohn and Ole M. {Sejersted} and Johanna T. {Lanner} and Wolfgang A. {Linke} and Ida G. {Lunde} and Pieter P. {de Tombe} and William E. {Louch}}
}
@article {Simula.simula.3028,
	title = {Calcium Signaling in Developing Cardiomyocytes: Implications for Model Systems and Disease},
	journal = {The Journal of Physiology},
	volume = {593},
	year = {2015},
	month = {03/2015},
	pages = {1047-1063},
	publisher = {John Wiley and Sons},
	abstract = {Adult cardiomyocytes exhibit complex Ca2+ homeostasis, enabling tight control of contraction and relaxation. This intricate regulatory system develops gradually, with progressive maturation of specialized structures and increasing capacity of Ca2+ sources and sinks. In this review, we outline current understanding of these developmental processes, and draw parallels to pathophysiological conditions where cardiomyocytes exhibit a striking regression to an immature state of Ca2+ homeostasis. We further highlight the importance of understanding developmental physiology when employing immature cardiomyocyte models such as neonatal cell culture and stem cells.},
	doi = {10.1113/jphysiol.2014.274712},
	url = {http://onlinelibrary.wiley.com/doi/10.1113/jphysiol.2014.274712/abstract},
	author = {William E. {Louch} and Koivum{\"a}ki, Jussi and Tavi, Pasi}
}
@article {23371,
	title = {A computational pipeline for quantification of mouse myocardial stiffness parameters},
	journal = {Computers in Biology and Medicine},
	volume = {53},
	year = {2014},
	pages = {65{\textendash}75},
	publisher = {Comput. Biol. Med.},
	abstract = {The mouse is an important model for theoretical-experimental cardiac research, and biophysically based whole organ models of the mouse heart are now within reach. However, the passive material properties of mouse myocardium have not been much studied. We present an experimental setup and associated computational pipeline to quantify these stiffness properties. A mouse heart was excised and the left ventricle experimentally inflated from 0 to 1.44kPa in eleven steps, and the resulting deformation was estimated by echocardiography and speckle tracking. An in silico counterpart to this experiment was built using finite element methods and data on ventricular tissue microstructure from diffusion tensor {MRI}. This model assumed a hyperelastic, transversely isotropic material law to describe the force-deformation relationship, and was simulated for many parameter scenarios, covering the relevant range of parameter space. To identify well-fitting parameter scenarios, we compared experimental and simulated outcomes across the whole range of pressures, based partly on gross phenotypes (volume, elastic energy, and short- and long-axis diameter), and partly on node positions in the geometrical mesh. This identified a narrow region of experimentally compatible values of the material parameters. Estimation turned out to be more precise when based on changes in gross phenotypes, compared to the prevailing practice of using displacements of the material points. We conclude that the presented experimental setup and computational pipeline is a viable method that deserves wider application.},
	issn = {1879-0534},
	doi = {10.1016/j.compbiomed.2014.07.013},
	author = {Nordb{\o}, Oyvind and Lamata, Pablo and Land, Sander and Steven A {Niederer} and Jan M. {Aronsen} and William E. {Louch} and Sjaastad, Ivar and Martens, Harald and Arne B. {Gjuvsland} and T{\o}ndel, Kristin and Torp, Hans and Lohezic, Maelene and Jurgen E. {Schneider} and Espen W. {Remme} and Nicolas P. {Smith} and Stig W. {Omholt}}
}
@article {Simula.simula.2258,
	title = {Variable T-Tubule Organization and Ca2+ Homeostasis Across the Atria},
	journal = {Heart and Circulatory Physiology},
	volume = {307},
	number = {4},
	year = {2014},
	month = {August},
	pages = {H609-H620},
	publisher = { },
	abstract = {Rationale: Although t-tubules have traditionally been thought to be absent in atrial cardiomyocytes, recent studies suggest that t-tubules exist in the atria of large mammals. However, it is unclear whether regional differences in t-tubule organization exist, which define cardiomyocyte function across the atria. Objective: We sought to investigate regional t-tubule density in pig and rat atria, and the consequences for cardiomyocyte Ca2+ homeostasis. Methods and Results: In contrast to previous reports that t-tubules are absent in rat atria, we observed t- tubules in approximately one third of rat atrial cardiomyocytes, both in tissue cryosections and in isolated cardiomyocytes. In a minority (\approx10\%) of atrial cardiomyocytes, the t-tubular network was well organized, with a transverse structure resembling that of ventricular cardiomyocytes. In both rat and pig atrial tissue, we observed higher t-tubule density in the epicardium than endocardium. Consistent with high variability in the distribution of t-tubules and Ca2+ channels among cells, L-type Ca2+ current amplitude was also highly variable, and steeply dependent on capacitance and t-tubule density. Accordingly, Ca2+ transients showed great variability in Ca2+ release synchrony. Simultaneous imaging of the cell membrane and Ca2+ transients confirmed t-tubule functionality. Results from mathematical modeling indicated that a transmural gradient in t-tubule organization and Ca2+ release kinetics supports synchronization of contraction across the atrial wall, and may underlie transmural differences in refractory period. Conclusions: T-tubule density is highly variable across the atria. We propose that higher t-tubule density in cells localized in the epicardium promotes synchronization of contraction across the atrial wall.},
	author = {Frisk, Michael and Koivum{\"a}ki, Jussi and Per A. {Norseng} and Maleckar, Molly and Ole M. {Sejersted} and William E. {Louch}}
}
@article {Simula.simula.1794,
	title = {Slow Ca2+ Sparks De-Synchronize Ca2+ Release in Failing Cardiomyocytes: Evidence for Altered Configuration of Ca2+ Release Units?},
	journal = {Journal of Molecular and Cellular Cardiology},
	volume = {58},
	number = {1},
	year = {2013},
	pages = {41-52},
	author = {William E. {Louch} and Johan Elon {Hake} and Halvor K. {M{\o}rk} and Hougen, Karina and Skrbic, Biljana and Ursu, Daniel and T{\o}nnessen, Theis and Sjaastad, Ivar and Ole M. {Sejersted}}
}
@misc {Simula.simula.1724,
	title = {Altered Configurations of Ca2+ Release Units Cause Slowed Ca2+ Sparks in Failing Cardiomyocytes},
	year = {2012},
	month = {Nov},
	keywords = {Workshop},
	author = {Johan Elon {Hake} and Halvor K. {M{\o}rk} and Hougen, Karina and Sjaastad, Ivar and Ole M. {Sejersted} and William E. {Louch}}
}
@misc {Simula.simula.964,
	title = {A Stochastic Model of the Ryanodine Receptor Featuring Coupled Gating and Competitive Binding of Luminal and Cytosolic Ca2+ and Mg2+},
	year = {2011},
	author = {Johan Elon {Hake} and William E. {Louch} and Haugen, K. and Sjaastad, Ivar and Ole M. {Sejersted} and Andrew D. {McCulloch} and Anushka P. {Michailova} and Glenn T. {Lines}}
}
@article {Simula.simula.122,
	title = {Control of Ca2+ Release by Action Potential Configuration in Normal and Failing Murine Cardiomyocytes},
	journal = {Biophysical Journal},
	volume = {99},
	number = {5},
	year = {2010},
	month = {September},
	pages = {1377-1386},
	author = {William E. {Louch} and Johan Elon {Hake} and Guro Five {J{\o}lle} and Halvor K. {M{\o}rk} and Sjaastad, Ivar and Glenn T. {Lines} and Ole M. {Sejersted}}
}
@article {Lines.2006.1,
	title = {Contribution of the Na/Ca Exchanger to Rapid Ca Release in Cardiomyocytes},
	journal = {Biophysical Journal},
	volume = {91},
	number = {3},
	year = {2006},
	pages = {779-792},
	abstract = {Trigger Ca is considered to be the Ca current through the L-type Ca channel (LTCC) that causes release of Ca from the sarcoplasmic reticulum (SR). However, cell contraction also occurs in the absence of the LTCC current (ICa). In this paper we investigate the contribution of the Na/Ca -exchanger (NCX) to the trigger Ca. Experimental data from rat cardiomyocytes using confocal microscopy indicating that inhibition of reverse mode Na/Ca -exchange delays the Ca transient by 3-4 ms, served as a basis for the mathematical model. A detailed computational model of the dyadic cleft (fuzzy space) is presented where the diffusion of both Na and Ca is taken into account. Ionic channels are included at discrete locations, making it possible to study the effect of channel position and colocalization. The simulations indicate that if a Na channel is present in the fuzzy space, the NCX is able to bring enough Ca into the cell to affect the timing of release. However, this critically depends on channel placement and local diffusion properties. With fuzzy space diffusion in the order of 1\% compared to bulk diffusion, triggering through LTCC alone was 3-4 ms slower than with the presence of a Na channel and NCX.},
	author = {Glenn T. {Lines} and J{\o}rn Bodvar {Sande} and William E. {Louch} and Halvor K. {M{\o}rk} and Gr{\o}ttum, Per and Ole M. {Sejersted}}
}
