Effect of AP morphology on BVR.

<p><b>A.</b> Overlay of 30 APs (top panel) and Poincaré plot of corresponding APDs (bottom panel) for the control myocyte, without alterations in ion currents, simulated with deterministic I_CaL, I_K1, I_Kur, and I_To and stochastic gating of the remaining 9 currents. APs with the shortest and longest duration are shown in black, others in grey. Average APD and STV are indicated below the APs. <b>B.</b> Similar to panel A for a triangular AP morphology obtained by reducing I_K1 and I_To (by 70% and 60%, respectively) and increasing I_Kur (by 275%). <b>C.</b> Similar to panels A and B for a square AP morphology obtained by increasing I_K1 and I_Kur (by 20% each) and decreasing I_CaL and I_To (by 75% and 20%), respectively.</p

Mechanisms underlying increased BVR under LQT1 conditions with SR Ca²⁺ overload.

<p><b>A.</b> STV vs. APD relationship under control (open symbols) or LQT1 conditions (filled symbols) in individual canine ventricular myocytes (left panel). Right panel shows the parameters of the non-linear fit of the STV vs. APD relationship under control or LQT1 conditions (solid and dashed lines in left panel, respectively), or under LQT2 conditions (from <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003202#pcbi-1003202-g008" target="_blank"><b>Figure 8</b></a>). <b>B.</b> Consecutive APDs (top panel) and Ca²⁺-transient amplitudes (middle panel) during simulated application of 1.0 µmol/L isoproterenol (ISO) at a 500-ms CL in the deterministic model. Membrane potential and intracellular [Ca²⁺] for the beats indicated by the black vertical boxes are shown in the bottom panel. APD (in ms) is indicated below each beat and a Poincaré plot is shown on the right. Simulations were performed with 100% I_Ks inhibition to simulate LQT1 conditions and with 10% inhibition of I_NaK, resulting in increased [Na⁺]_i and reduced Ca²⁺ extrusion via I_NaCa, to promote Ca²⁺-handling abnormalities. <b>C.</b> Similar to panel B for the stochastic model with a single domain. <b>D.</b> Similar to panel B for the stochastic model divided into four identical domains connected via Ca²⁺-diffusion terms with time constant τ = 20 ms.</p

BVR in simulated LQT syndrome types 1–3 in the absence or presence of βARS.

<p><b>A.</b> Overlay of 30 consecutive APs in the absence (−βARS) or presence (+βARS) of β-adrenergic receptor stimulation under control conditions (top-left panel) or simulated LQT1 (top-right panel), LQT2 (bottom-left panel), or LQT3 (bottom-right panel) at 1000-ms CL. Shortest and longest APs are shown in black, intermediate APs in grey. A Poincaré plot of the 30 APDs is shown below. <b>B.</b> Quantification of BVR in LQT1-3 at CL of 500, 1000, or 2000 ms in the absence or presence of βARS. HMR indicates simulation of the I_Ks blocker HMR1556 (simulated LQT1), Dof simulation of the I_Kr blocking drug dofetilide (LQT2) and ATXII indicates simulations with enhanced persistent I_Na (LQT3). βARS reduces BVR significantly in LQT2 and LQT3, but not in LQT1, consistent with experimental results <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003202#pcbi.1003202-Johnson1" target="_blank">[8]</a>.</p

Role of APD in the observed increase in BVR under simulated LQT2 conditions.

<p><b>A.</b> Overlay of 30 consecutive APs in the model using control conditions, simulated LQT2, simulated LQT2 with deterministic I_Kr, or simulated LQT2 with reduced APD due to injection of a deterministic stimulus current. Shortest and longest APs are shown in black, intermediate APs in grey. APD, STV, and Poincaré plots are shown below each overlay. <b>B.</b> STV vs. APD relationship under control conditions (left panel) or LQT2 conditions (right panel) in individual canine ventricular myocytes (filled symbols) or individual model cells (open symbols; based on whole-cell conductances drawn from a Gaussian distribution, as in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003202#pcbi-1003202-g003" target="_blank"><b>Figure 3A</b></a>). Data were fit with a monoexponential function (lines). <b>C.</b> Parameters of the monoexponential fits of panel B under control and LQT2 conditions in experiments (grey bars) and model (white bars). The model shows a quantitatively similar STV vs. APD relationship as experiments, and this relationship is not different between control and LQT2 conditions.</p

Role of APD and stochastic gating in BVR reverse rate dependence.

<p><b>A.</b> Magnitude of channel gating stochastics (assessed by Std(I_m) for 50 beats) over time for CL of 350–4000 ms using the fully stochastic model under control conditions. <b>B.</b> Rate dependence of total magnitude of I_m fluctuations (given by area under Std(I_m) curve). <b>C.</b> STV rate dependence in the fully stochastic model during fixed-CL pacing (solid line) or fixed-DI pacing (dash-dotted line), or in the deterministic model during fixed-CL pacing with a CL-independent stochastic term (see <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003202#s2" target="_blank">Results</a>, section “BVR rate dependence”) added to I_m (dashed line). CL-independent stochastic behavior results in a blunted STV rate dependence. <b>D.</b> STV vs. APD relationship at CLs of 500 ms (dark grey symbols), 1000 ms (white symbols), or 2000 ms (light grey symbols). APD was varied through injection of a deterministic stimulus current between −0.1 and 0.1 pA/pF for the duration of the AP.</p

Contribution of channel density of stochastic ion currents to BVR and its rate dependence.

<p><b>A.</b> STV magnitude induced by stochastic channel gating of individual currents in an otherwise deterministic model or stochastic channel gating of all 13 currents/fluxes combined (right-most bars) at CL of 500 ms, 1000 ms, or 2000 ms. Top panel shows 5-fold reduction in channel density (with 5-fold increase in single-channel conductance), middle panel shows channel density based on estimates from experimental data (Section 2.5 in the Supplemental Information), and bottom panel shows 5-fold increase in channel density with reduced single-channel conductance. <b>B.</b> Rate dependence of average APD (left), STV (middle) and LTV (right) in experiments (symbols) and model (lines) with stochastic gating of all 13 targets combined at 100% channel density.</p

Contribution of currents to BVR determined via linear regression of 200 unique virtual myocytes.

<p><b>A.</b> Relative changes in the maximal conductance (G_x) of the 13 currents/fluxes (lanes correspond to the column pairs in panel B) for 100 (out of 200) trials (left panel) and corresponding changes in outputs (APD, STV and LTV) during steady-state pacing at CL = 1000 ms (right panel). Middle panel shows the coefficients that indicate the contribution of each current to every output measure as determined via linear regression. <b>B.</b> Bar plot of the magnitude of the coefficients from panel A regarding their impact on APD (white bars) or STV (shaded bars). I_Kr and I_Na have a large impact on both APD and BVR, consistent with the results from <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003202#pcbi-1003202-g002" target="_blank"><b>Figure 2</b></a>. In addition, I_NaK also strongly affects STV. LTV showed similar pattern as STV and is not shown for clarity.</p