The heart of the matter.
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| Mesh representation of the ventricles of the heart |
Ventricular relaxation occurs as intracellular calcium drops to resting levels. Under low calcium conditions, contraction is inhibited by the troponin/tropomyosin complex. However, experimental evidence has long suggested that some degree of actin-myosin interaction is possible even in the absence of calcium. Under calcium-free conditions, as many as 5% of actin binding sites are occupied by myosin, according to some estimates made from solution studies of purified myofilament components. Despite abundant in vitro evidence for calcium-independent activation (CIA), its relevance to in vivo cardiac function is not clear. Striated muscle preparations can produce small amounts of actin-myosin-based force under low calcium conditions, especially near physiological temperatures. This suggests that residual actin-myosin cross bridges resist diastolic filling, adding to the resistance provided by other structures such as collagen and titin. However, distinguishing the contributions of these various factors is technically challenging, and cross bridge-based diastolic stiffness remains controversial.
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| Schematic diagram of model components and states [1]. |
In their recent study, Dr. Yasser Aboelkassem and his colleagues investigate CIA using computational analysis by adding a structurally motivated representation of this phenomenon to an existing myofilament model, which allowed predictions of CIA-dependent muscle behavior. The researchers found that a certain amount of CIA was essential for the model to reproduce reported effects of nonfunctional troponin C on myofilament force generation. Consequently, those data enabled estimation of ΔGCIA, the energy barrier for activating a thin filament regulatory unit in the absence of calcium. Using this estimate of ΔGCIA as a point of reference (∼7 kJ mol−1), they examined its impact on various aspects of muscle function through additional simulations. CIA decreases the Hill coefficient of steady-state force while increasing myofilament calcium sensitivity. At the same time, CIA has minimal effect on the rate of force redevelopment after slack/restretch. Simulations of twitch tension show that the presence of CIA increases peak tension while profoundly delaying relaxation. We tested the model’s ability to represent perturbations to the calcium regulatory mechanism by analyzing twitch records measured in transgenic mice expressing a cardiac troponin I mutation (R145G). The effects of the mutation on twitch dynamics were fully reproduced by a single parameter change, namely lowering ΔGCIA by 2.3 kJ mol−1 relative to its wild-type value. The analyses of Dr. Aboelkassem's and his team suggest that CIA is present in cardiac muscle under normal conditions and that its modulation by gene mutations or other factors can alter both systolic and diastolic function.
[1] Aboelkassem, Yasser, et al. "Contributions of Ca 2+-Independent Thin Filament Activation to Cardiac Muscle Function." Biophysical journal 109.10 (2015): 2101-2112.
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Dr. Yasser Aboelkassem obtained his BSc. in Aerospace Engineering from Cairo University, Egypt and received his master's degree in Mechanical Engineering from a joint program between Concordia-McGill University, Montreal, Canada. After graduation, Dr. Aboelkassem moved to Virginia Tech where he obtained a Master in Applied Mathematics degree and a Ph.D. in Engineering Science and Mechanics in 2012. He did his first postdoctoral training working in cardiac mechanics at the department of Biomedical Engineering at Yale University. Currently, he is a postdoc research associate with Natalia Trayanova at the Institute of Computational Medicine, Johns Hopkins University.
Dr. Aboelkassem has published 16 first-author papers and co-authored 6 papers in peer-reviewed international journals. His current research focus is the multiscale modelling of cardiac thin filament activation.
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