Browsing by Author "Sun, Liang"

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    A model of sarcolemmal calcium(2+) currents and cytosolic calcium(2+) transients in a rat ventricular cell
    (2000) Sun, Liang; Clark, John W., Jr.
    We have developed a mathematical model of the L-type Ca2+ current and cytosolic Ca2+ transient, which is based on data from whole-cell voltage clamp experiments on rat ventricular myocytes. Modified Goldman-Hodgkin-Katz (GHK) equations are provided to account for the different ion selectivity of the DHP-sensitive Ca2+ current channel. The decay of whole cell currents obtained by maintained depolarization is characterized by means of voltage and Ca2+-dependent inactivation embedded in a 5-state dynamic DHP channel model. To characterize a reduced amount of steady-state inactivation of DHP channel in the presence of [Ca 2+]o, a mechanism is used in the model whereby Ca 2+ also inhibits the voltage-dependent inactivation pathway. The 5-state DHP model is also used to simulate single-channel activity. Cytosolic Ca 2+ transients are studied as well. They derive mainly from secondary Calcium-Induced-Calcium-Release (CICR) from the Sarcoplasmic Reticulum (SR). We have developed a 4-state RyR-sensitive Ca2+ model that describes the kinetics of the release channel. This model provides close fitting of cytosolic Ca2+-transient data and mimics the high gain, graded Ca2+ release behavior of the channel. Overall, the model provides a quantitative description of the Ca2+ subsystem in the mammalian heart.
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    Modeling CICR in rat ventricular myocytes: voltage clamp studies
    (BioMed Central, 2010) Krishna, Abhilash; Sun, Liang; Valderrábano, Miguel; Palade, Philip T.; Clark, John W.
    Background: The past thirty-five years have seen an intense search for the molecular mechanisms underlying calcium-induced calcium-release (CICR) in cardiac myocytes, with voltage clamp (VC) studies being the leading tool employed. Several VC protocols including lowering of extracellular calcium to affect Ca2+ loading of the sarcoplasmic reticulum (SR), and administration of blockers caffeine and thapsigargin have been utilized to probe the phenomena surrounding SR Ca2+ release. Here, we develop a deterministic mathematical model of a rat ventricular myocyte under VC conditions, to better understand mechanisms underlying the response of an isolated cell to calcium perturbation. Motivation for the study was to pinpoint key control variables influencing CICR and examine the role of CICR in the context of a physiological control system regulating cytosolic Ca2+ concentration ([Ca2+] myo ). Methods: The cell model consists of an electrical-equivalent model for the cell membrane and a fluid-compartment model describing the flux of ionic species between the extracellular and several intracellular compartments (cell cytosol, SR and the dyadic coupling unit (DCU), in which resides the mechanistic basis of CICR). The DCU is described as a controller-actuator mechanism, internally stabilized by negative feedback control of the unit's two diametrically-opposed Ca2+ channels (trigger-channel and release-channel). It releases Ca2+ flux into the cyto-plasm and is in turn enclosed within a negative feedback loop involving the SERCA pump, regulating[Ca2+] myo . Results: Our model reproduces measured VC data published by several laboratories, and generates graded Ca2+ release at high Ca2+ gain in a homeostatically-controlled environment where [Ca2+] myo is precisely regulated. We elucidate the importance of the DCU elements in this process, particularly the role of the ryanodine receptor in controlling SR Ca2+ release, its activation by trigger Ca2+, and its refractory characteristics mediated by the luminal SR Ca2+ sensor. Proper functioning of the DCU, sodium-calcium exchangers and SERCA pump are important in achieving negative feedback control and hence Ca2+ homeostasis. Conclusions: We examine the role of the above Ca2+ regulating mechanisms in handling various types of induced disturbances in Ca2+ levels by quantifying cellular Ca2+ balance. Our model provides biophysically-based explanations of phenomena associated with CICR generating useful and testable hypotheses.
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    Motion-corrected treadmill nuclear angiography
    (2003) Sun, Liang; Clark, John W., Jr.
    First-pass radionuclide angiography (RNA) of the human heart is performed during peak treadmill exercise using a Multiwire Gamma Camera (MWGC) and an intravenous injection of ultra-short-lived radionuclide Tantalum-178. The study focuses on left ventricular function during treadmill exercise and the use of this technique in patients with coronary artery disease (CAD) is significant compared with other methods such as echocardiography. However, patient motion and resulting image blurring during treadmill exercise can significantly degrade resolution and introduce serious image distortion. To help eliminate the effects of patient motion, we have adopted an electro-magnetic motion tracking system that can monitor the movement of patient's left ventricle (LV), based on the real-time six-dimensional position and orientation of a sensor attached to the patient's back, and the location of LV in the patient's chest contour. This system implements a motion correction algorithm which significantly reduces the effects of motion artifact incurred in treadmill exercise RNA. The motion correction algorithm is evaluated using dynamic phantom simulations, where an external radioactive marker is attached to a volunteer, who exercises at several different Bruce levels on treadmill. Correction accuracy is assessed by calculating the root mean square (RMS) error of the locations of the maximum activity pixel (centroid) in corrected and uncorrected images. These initial test results using a dynamic phantom show that the motion artifacts can be removed. The algorithm was also evaluated on patients undergoing treadmill exercise RNA. In evaluating clinical data, one must be careful to select the correct lung background beat, and find the proper LV beats to form representative cycle, which yields reliable LV ejection fraction (EF) values. Motion-corrected images are superior with regard to the determination of ventricular wall motion and the calculation of regional ejection fraction images. In the uncorrected images, these are severely distorted and may result in an improper diagnosis. The success of motion-corrected treadmill research points to a revolutionary new approach to stress imaging, which can potentially benefit millions of patients entering the health care system with chest pain symptoms by improving the accuracy of diagnosis, as well as, the cost-effectiveness of front-line methods of detecting cardiac dysfunction.