By James N.Weiss, MichaelNivala, AlanGarfinkel and ZhilinQu
Edited by RaimondWinslow
Multiscale behaviors. A, Stochastic protein behavior. Single-channel recording of an L-type Ca channel from a cardiac myocyte, during successive volta...Show More
Multiscale behaviors. A, Stochastic protein behavior. Single-channel recording of an L-type Ca channel from a cardiac myocyte, during successive voltage-clamp pulses from −40 to 0 mV, showing different behaviors on each sweep. Downward deflections indicate channel openings. B, Regular cell behavior. Integrated behavior of stochastic ion channel network creates a dependably regular AP and Ca transient from beat-to-beat. C, Pathological tissue behavior. In addition to coordinating the normal heart beat, wave propagation at the tissue level also permits reentry which can cause life-threatening arrhythmias.Show Less
By James N.Weiss, MichaelNivala, AlanGarfinkel and ZhilinQu
Edited by RaimondWinslow
Modeling the cardiac couplon network. A, Schematic of a cardiac couplon, formed by L-type Ca channels (LTCC) in the T-tubular membrane and RyRs in the...Show More
Modeling the cardiac couplon network. A, Schematic of a cardiac couplon, formed by L-type Ca channels (LTCC) in the T-tubular membrane and RyRs in the apposed junctional SR (JSR). Extracellular Ca entering through LTCC triggers RyRs to open, releasing SR Ca into the diadic space (DS) and myoplasm (MYO) to activate the myofilaments (MF). Ca is then pumped back into the nonjunctional SR (NSR) by a Ca pump (SERCA2a) or extruded from the cell via Na/Ca exchange (NCX). B, Spatially distributed 2D model of the couplon network. See text. J, Ca fluxes between compartments. (Illustration credit: Ben Smith/Cosmocyte.)Show Less
By James N.Weiss, MichaelNivala, AlanGarfinkel and ZhilinQu
Edited by RaimondWinslow
A, Graded Ca release. SR Ca release flux (black) tracks the amplitude of the L-type Ca current (red) during voltage clamps to different membrane volta...Show More
A, Graded Ca release. SR Ca release flux (black) tracks the amplitude of the L-type Ca current (red) during voltage clamps to different membrane voltages (Vm) in a rabbit ventricular myocyte, reproduced by the couplon network model (right). Reproduced from Altamirano and Bers24 with permission from the American Heart Association. B, Voltage-dependent EC coupling gain. Left, EC coupling gain, defined as the ratio of SR Ca release to the L-type Ca current amplitude, is higher at less-depolarized voltages in experimental data from rabbit ventricular myocytes. Reproduced from Altamirano and Bers24 with permission from the American Heart Association. Right, The steep decline in gain is reproduced better in the couplon network model, when the couplons are coupled (solid symbols) than when uncoupled (open symbols). C, Steep SR fractional release–load relationship. Left, The fraction of SR Ca released increases steeply as the SR load increases in a rabbit ventricular myocyte. Reproduced from Shannon et al22 with permission from Elsevier. Right, The steepness is more accurately reproduced by the couplon network model (right) when the couplons are coupled (solid symbols) than when uncoupled (open symbols). D, Ca alternans. During rapid pacing with a fixed AP waveform (black), the Ca transient (red) alternates between large and small on successive beats in a patch-clamped rabbit ventricular myocyte (top), reproduced by the couplon network model (bottom panels). Second panel shows alternans of the global Ca transient and SR Ca content during pacing with a fixed-voltage waveform. Third and fourth panels show 2 representative couplons in the network, exhibiting irregular activations instead of alternans. Fifth and sixth panels show the spatial patterns of Ca release from couplons during alternans on 4 successive beats. Note that when the 2 small beats or 2 large beats are compared to each other, the spatial patterns differ, indicating the macroscopic alternans is not accompanied by microscopic alternans. Reproduced from Rovetti et al8 with permission from the American Heart Association.Show Less
By James N.Weiss, MichaelNivala, AlanGarfinkel and ZhilinQu
Edited by RaimondWinslow
Ryanodine receptor properties. A, Ryanodine receptor macromolecular complex. The cardiac ryanodine receptor (RyR2) is a tetramer that forms a macromol...Show More
Ryanodine receptor properties. A, Ryanodine receptor macromolecular complex. The cardiac ryanodine receptor (RyR2) is a tetramer that forms a macromolecular complex with multiple interacting partners, including anchoring proteins (mAKAP plus others not shown), protein kinases and phosphatases (PKA, CaMKII, PP1, PP2a), and other additional accessory regulatory proteins (FKBP12.6, triadin, junction, calsequestrin, CSQ). B, Couplon refractoriness. Time course of SR refilling (solid line) vs couplon recovery from inactivation (dashed line), from Brochet et al.18 C, Simple four-state RyR model, from Stern,23 without SR luminal Ca regulation.Show Less
By James N.Weiss, MichaelNivala, AlanGarfinkel and ZhilinQu
Edited by RaimondWinslow
Ca alternans. A, Ca alternans attributable to CICR waves on alternate beats, elicited by successive voltage-clamp pulses from −40 to −20 mV in a ventr...Show More
Ca alternans. A, Ca alternans attributable to CICR waves on alternate beats, elicited by successive voltage-clamp pulses from −40 to −20 mV in a ventricular myocyte (top; reproduced from Diaz et al6 with permission from the American Heart Association) and the couplon network model (bottom). Line scans with spatial position vertically and time horizontally are shown. Note that the Ca waves initiate at different locations on the first and third beats. B, Dissociation between SR Ca release and load during alternans. When heart rate was decreased (left panels), Ca alternans resolved in a patch-clamped rabbit ventricular myocyte (top left; reproduced from Picht et al31 with permission from the American Heart Association) and the 3 R model (bottom left; reproduced from Rovetti et al8 with permission from the American Heart Association). Left panels show that SR load (diastolic [Ca]SR) was lower during regular beating than during alternans, even though the SR depletion was larger than during the small Ca transient.Show Less
By James N.Weiss, MichaelNivala, AlanGarfinkel and ZhilinQu
Edited by RaimondWinslow
Ca signaling hierarchy in the couplon network. A, Ca quarks (q), sparks (s), macrosparks (ms), aborted wave (aw), and full wave (fw) shown as labeled...Show More
Ca signaling hierarchy in the couplon network. A, Ca quarks (q), sparks (s), macrosparks (ms), aborted wave (aw), and full wave (fw) shown as labeled in line scans of cytoplasmic [Ca] along a line through the center of the couplon network array (100× 20 μm) vs time. Cytoplasmic free [Ca] is indicated by height and color scale. Right, SR Ca load was higher to promote the full wave, which started as a spark in the upper corner (asterisk) and propagated downward (arrow) by CICR through the full length of the couplon array. B, Snapshot of Ca rotors (r) in a couplon array (100×20 μm) at high SR Ca load. Figure-eight spiral wave reentry causing a double rotor is shown at left, with a single spiral wave rotor at right.Show Less
By James N.Weiss, MichaelNivala, AlanGarfinkel and ZhilinQu
Edited by RaimondWinslow
Electrical restitution and alternans. A, APD and CV restitution curves. As DI decreases, APD shortens and CV slows. B, Positive and negative Cai-APD c...Show More
Electrical restitution and alternans. A, APD and CV restitution curves. As DI decreases, APD shortens and CV slows. B, Positive and negative Cai-APD coupling. See text. C, Arrhythmogenic spatially discordant APD alternans. In region a, APD alternans has a long-short pattern, whereas region b has a short–long pattern, separated by a nodal line without alternans. If a PVC (*) occurs in the short APD region, it can block as it propagates across the nodal line into in the long APD region, while propagating laterally until the long APD region recovers, initiating figure-eight reentry.Show Less
By James N.Weiss, MichaelNivala, AlanGarfinkel and ZhilinQu
Edited by RaimondWinslow
Properties of DADs. A, Sub- and suprathreshold DADs. Depending on the size and rate of rise of the Ca transient during the Ca wave(s), and the diastol...Show More
Properties of DADs. A, Sub- and suprathreshold DADs. Depending on the size and rate of rise of the Ca transient during the Ca wave(s), and the diastolic Ca-voltage coupling gain, a DAD can remain below or above the threshold to trigger an AP. B, DAD–repolarization interaction. DADs recorded from a paced isolated rabbit ventricular myocyte before (black traces) and after (red traces) exposure to isoproterenol. Depending on the timing, subthreshold DADs can cause APD prolongation (top) and frank EADs (bottom). Data kindly provided by Lai-Hua Xie, PhD.Show Less
