Developing a Better Understanding of Heart Failure at the Cellular Level
Modeling Calcium Dynamics in Ventricular Myocytes with Realistic Transverse Tubules/em> What is known as cardiac remodeling (or ventricular remodeling) is not a good thing; it implies that there is a decline in the function of the heart. It happens in response to injuries to the heart, typically from heart attacks or such conditions as chronic high blood pressure (and other causes that result in increased pressure or volume overload). The current consensus is that this compensatory and adaptive process to injury causes histopathological and structural changes that lead to a decline in the function of the heart (enlarged heart and congestive heart failure). Z-disc defects are central to such pathological processes, resulting in the progression of malignant congestive heart failure.
Disorganization of the architecture of uniquely developed membrane organelles (transverse tubules [t-tubules], junctional sarcoplasmic reticulum, dyads) located in the vicinity of Z-discs in ventricular myocytes are known to play a major role in dynamically controlling subcellular calcium (Ca2+) levels, which in turn regulates cardiac contraction and other cellular functions. An accurate understanding of the complex pathology, including abnormal excitation-contraction (E-C) coupling in cardiomyocytes, is key to developing better models which will improve prevention and treatment. Cardiomyocytes comprise the muscle cells of the heart; coordinated contractions of these cells propel blood out of the upper and lower chambers of the heart (atria and ventricles) on to the blood vessels in the rest of the body. T-tubules, deep folds in the plasma membrane, are found only in skeletal and cardiac muscle cells; they play a critical role in excitation-contraction coupling. Experimental measurements of ionic currents, local Ca2+ gradients and cell geometry under normal and pathological conditions are underway.
In collaboration with Dr. Masahiko Hoshijima, NBCR researchers have investigated the Ca2+ dynamics in rodent ventricular myocytes with pharmacologically disabled sarcoplasmic reticulum by employing two numerical methods (finite element method and meshless method) [Yu , et al. 2011]. The simulations indicate that cytosolic Ca2+ levels are tightly regulated by the t-tubule ultra-structure and Ca2+ flux via the sarcolemma. Key challenges going forward include: extending the current geometric model towards a more realistic model containing a whole cell t-tubule network, including dyadic cleft topology and L-type Ca2+ channel clustering along the sarcolemma; modeling sarcoplasmic reticulum Ca2+ release and uptake.
References: Yu Z, Yao G, Hoshijima M, Michailova A, and Holst M, Multi-Scale Modeling of Calcium Dynamics in Ventricular Myocytes with Realistic Transverse Tubules. IEEE TBME Letters, Special Issue on “MultiScale Modeling and Analysis for Computational Biology and Medicine”, 2011. 58(10):2947-51.
NBCR Researchers: Michael J. Holst (Core Lead - Multiscale and Multiphysics Simulations Tools with Applications to Biomedical Systems), Zeyun Yu (Core Co-lead) Guangming Yao, Anushka P. Michailova (Core Co-lead), Masahiko Hoshijima (Collaborative Project Lead)
Figure 1 (a) Multiple t-tubule geometry and its surrounding box domain. (b) The model in (a) is placed at various locations at a distance d from the cell membrane.
Figure 2 3-D views of the Ca2+ concentrations at the Ca2+ peak when the model in Figure 1 is placed 8µM (left), 2µM (middle), and 0µM (right) away from the cell membrane.