Modeling ventricular repolarization: effects of transmural and apex-to-base heterogeneities in action potential durations

Heterogeneities in the densities of membrane ionic currents of myocytes cause regional variations in action potential duration (APD) at various intramural depths and along the apico-basal and circumferential directions in the left ventricle. This work extends our previous study of cartesian slabs to ventricular walls shaped as an ellipsoidal volume and including both transmural and apex-to-base APD heterogeneities. Our 3D simulation study investigates the combined effect on repolarization sequences and APD distributions of: (a) the intrinsic APD heterogeneity across the wall and along the apex-to-base direction, and (b) the electrotonic currents that modulate the APDs when myocytes are embedded in a ventricular wall with fiber rotation and orthotropic anisotropy. Our findings show that: (i) the transmural and apex-to-base heterogeneities have only a weak influence on the repolarization patterns on myocardial layers parallel to the epicardium; (ii) the patterns of APD distribution on the epicardial surface are mostly affected by the apex-to-base heterogeneities and do not reveal the APD transmural heterogeneity; (iii) the transmural heterogeneity is clearly discernible in both repolarization and APD patterns only on transmural sections; (iv) the apex-to-base heterogeneity is clearly discernible only in APD patterns on layers parallel to the epicardium. Thus, in our orthotropic ellipsoidal wall, the complex 3D electrotonic modulation of APDs does not fully mix the effects of the transmural and apex-to-base heterogeneity. The intrinsic spatial heterogeneity of the APDs is unmasked in the modulated APD patterns only in the appropriate transmural or intramural sections. These findings are independent of the stimulus location (epicardial, endocardial) and of Purkinje involvement.     

Effect of activation sequence on transmural patterns of repolarization and action potential duration in rabbit ventricular myocardium

Although transmural heterogeneity of action potential duration (APD) is established in single cells isolated from different tissue layers, the extent to which it produces transmural gradients of repolarization in electrotonically coupled ventricular myocardium remains controversial. The purpose of this study was to examine the relative contribution of intrinsic cellular gradients of APD and electrotonic influences to transmural repolarization in rabbit ventricular myocardium. Transmural optical mapping was performed in left ventricular wedge preparations from eight rabbits. Transmural patterns of activation, repolarization, and APD were recorded during endocardial and epicardial stimulation. Experimental results were compared with modeled data during variations in electrotonic coupling. A transmural gradient of APD was evident during endocardial stimulation, which reflected differences previously seen in isolated cells, with the longest APD at the endocardium and the shortest at the epicardium (endo: 165 ± 5 vs. epi: 147 ± 4 ms; P < 0.05). During epicardial stimulation, this gradient reversed (epi: 162 ± 4 vs. endo: 148 ± 6 ms; P < 0.05). In both activation sequences, transmural repolarization followed activation and APD shortened along the activation path such that significant transmural gradients of repolarization did not occur. This correlation between transmural activation time and APD was recapitulated in simulations and varied with changes in intercellular coupling, confirming that it is mediated by electrotonic current flow between cells. These data suggest that electrotonic influences are important in determining the transmural repolarization sequence in rabbit ventricular myocardium and that they are sufficient to overcome intrinsic differences in the electrophysiological properties of the cells across the ventricular wall.     

Calcium-activated chloride current contributes to action potential alternations in left ventricular hypertrophy rabbit

T-wave alternans, characterized by a beat-to-beat change in T-wave morphology, amplitude, and/or polarity on the ECG, often heralds the development of lethal ventricular arrhythmias in patients with left ventricular hypertrophy (LVH). The aim of our study was to examine the ionic basis for a beat-to-beat change in ventricular repolarization in the setting of LVH. Transmembrane action potentials (APs) from epicardium and endocardium were recorded simultaneously, together with transmural ECG and contraction force, in arterially perfused rabbit left ventricular wedge preparation. APs and Ca(2+)-activated chloride current (I(Cl,Ca)) were recorded from left ventricular myocytes isolated from normal rabbits and those with renovascular LVH using the standard microelectrode and whole cell patch-clamping techniques, respectively. In the LVH rabbits, a significant beat-to-beat change in endocardial AP duration (APD) created beat-to-beat alteration in transmural voltage gradient that manifested as T-wave alternans on the ECG. Interestingly, contraction force alternated in an opposite phase ("out of phase") with APD. In the single myocytes of LVH rabbits, a significant beat-to-beat change in APD was also observed in both left ventricular endocardial and epicardial myocytes at various pacing rates. APD alternans was suppressed by adding 1 microM ryanodine, 100 microM 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), and 100 microM 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid (SITS). The density of the Ca(2+)-activated chloride currents (I(Cl,Ca)) in left ventricular myocytes was significantly greater in the LVH rabbits than in the normal group. Our data indicate that abnormal intracellular Ca(2+) fluctuation may exert a strong feedback on the membrane I(Cl,Ca), leading to a beat-to-beat change in the net repolarizing current that manifests as T-wave alternans on the ECG.     

Modelling changes in transmural propagation and susceptibility to arrhythmia induced by volatile anaesthetics in ventricular tissue

Volatile anaesthetics such as halothane, isoflurane and sevoflurane inhibit membrane currents contributing to the ventricular action potential. Transmural variation in the extent of current blockade induces differential effects on action potential duration (APD) in the endocardium and epicardium which may be pro-arrhythmic. Biophysical modelling techniques were used to simulate the functional impact of anaesthetic-induced blockade of membrane currents on APD and effective refractory period (ERP) in rat endocardial and epicardial cell models. Additionally, the transmural conduction of excitation waves in 1-dimensional cell arrays, the tissue's vulnerability to arrhythmogenesis and dynamic behaviour of re-entrant excitation in 2-dimensional cell arrays were studied. Simulated anaesthetic exposure reduced APD and ERP in both epicardial and endocardial cell models. The reduction in APD was greater in endocardial than epicardial cells, reducing transmural APD dispersion consistent with experimental data. However, the transmural ERP dispersion was augmented. All three anaesthetics increased the width of the tissue's vulnerable window during which a premature stimulus could induce unidirectional conduction block but only halothane reduced the critical size of ventricular substrates necessary to initiate and sustain re-entrant excitation. All three anaesthetics accelerated the rate of re-entrant excitation waves, but only halothane prolonged the lifespan of re-entry. These data illustrate in silico, that modest changes in ion channel conductance abbreviate rat ventricular APD and ERP, reduce transmural APD dispersion, but augment transmural ERP dispersion. These changes collectively enhance the propensity for arrhythmia generation and provide a substrate for re-entry circuits with a longer half life than in control conditions.     

A mathematical model of action potential heterogeneity in adult rat left ventricular myocytes.

Mathematical models were developed to reconstruct the action potentials (AP) recorded in epicardial and endocardial myocytes isolated from the adult rat left ventricle. The main goal was to obtain additional insight into the ionic mechanisms responsible for the transmural AP heterogeneity. The simulation results support the hypothesis that the smaller density and the slower reactivation kinetics of the Ca(2+)-independent transient outward K(+) current (I(t)) in the endocardial myocytes can account for the longer action potential duration (APD), and more prominent rate dependence in that cell type. The larger density of the Na(+) current (I(Na)) in the endocardial myocytes results in a faster upstroke (dV/dt(max)). This, in addition to the smaller magnitude of I(t), is responsible for the larger peak overshoot of the simulated endocardial AP. The prolonged APD in the endocardial cell also leads to an enhanced amplitude of the sustained K(+) current (I(ss)), and a larger influx of Ca(2+) ions via the L-type Ca(2+) current (I(CaL)). The latter results in an increased sarcoplasmic reticulum (SR) load, which is mainly responsible for the higher peak systolic value of the Ca(2+) transient [Ca(2+)](i), and the resultant increase in the Na(+)-Ca(2+) exchanger (I(NaCa)) activity, associated with the simulated endocardial AP. In combination, these calculations provide novel, quantitative insights into the repolarization process and its naturally occurring transmural variations in the rat left ventricle.     

The canine virtual ventricular wall: a platform for dissecting pharmacological effects on propagation and arrhythmogenesis

We have constructed computational models of canine ventricular cells and tissues, ultimately combining detailed tissue architecture and heterogeneous transmural electrophysiology. The heterogeneity is introduced by modifying the Hund–Rudy canine cell model in order to reproduce experimentally reported electrophysiological properties of endocardial, midmyocardial (M) and epicardial cells. These models are validated against experimental data for individual ionic current and action potential characteristics, and their rate dependencies. 1D and 3D heterogeneous virtual tissues are constructed, with detailed tissue architecture (anisotropy and orthotropy, due to fibre orientation and sheet structure) of the left ventricular wall wedge extracted from a diffusion tensor imaging data set. The models are used to study the effects of tissue heterogeneity and class III drugs on transmural propagation and tissue vulnerability to re-entry.

We have determined relationships between the transmural dispersion of action potential duration (APD) and the vulnerable window in the 1D virtual ventricular wall, and demonstrated how changes in the transmural heterogeneity, and hence tissue vulnerability, can lead to generation of re-entry in the 3D ventricular wedge. Two class III drugs with opposite qualitative effects on transmural APD heterogeneity are considered: d-sotalol that increases transmural APD dispersion, and amiodarone that decreases it. Simulations with the 1D virtual ventricular wall show that under d-sotalol conditions the vulnerable window is substantially wider compared to amiodarone conditions, primarily in the epicardial region where unidirectional conduction block persists until the adjacent M cells are fully repolarised.

Further simulations with the 3D ventricular wedge have shown that ectopic stimulation of the epicardial region results in generation of sustained re-entry under d-sotalol conditions, but not under amiodarone conditions or in control. Again, APD increase in M cells was identified as the major contributor to tissue vulnerability—re-entry was initiated primarily due to ectopic excitation propagating around the unidirectional conduction block in the M cell region. This suggests an electrophysiological mechanism for the anti- and proarrhythmic effects of the class III drugs: the relative safety of amiodarone in comparison to d-sotalol can be explained by relatively low transmural APD dispersion, and hence, a narrow vulnerable window and low probability of re-entry in the tissue.     

Heterogeneous ventricular chamber response to hypokalemia and inward rectifier potassium channel blockade underlies bifurcated T wave in guinea pig

It was previously demonstrated that transmural electrophysiological heterogeneities can inscribe the ECG T wave. However, the bifurcated T wave caused by loss of inward rectifier potassium current (I(K1)) function is not fully explained by transmural heterogeneities. Since right ventricular (RV) guinea pig myocytes have significantly lower I(K1) than left ventricular (LV) myocytes, we hypothesized that the complex ECG can be inscribed by heterogeneous chamber-specific responses to hypokalemia and partial I(K1) blockade. Ratiometric optical action potentials were recorded from the epicardial surface of the RV and LV. BaCl(2) (10 micromol/l) was perfused to partially block I(K1) in isolated guinea pig whole heart preparations. BaCl(2) or hypokalemia alone significantly increased RV basal (RV(B)) action potential duration (APD) by approximately 30% above control compared with LV apical (LV(A)) APD (14%, P<0.05). In the presence of BaCl(2), 2 mmol/l extracellular potassium (hypokalemia) further increased RV(B) APD to a greater extent (31%) than LV(A) APD (19%, P<0.05) compared with BaCl(2) perfusion alone. Maximal dispersion between RV(B) and LV(A) APD increased by 105% (P<0.05), and the QT interval prolonged by 55% (P<0.05) during hypokalemia and BaCl(2). Hypokalemia and BaCl(2) produced an ECG with a double repolarization wave. The first wave (QT1) corresponded to selective depression of apical LV plateau potentials, while the second wave (QT2) corresponded to the latest repolarizing RV(B) myocytes. These data suggest that final repolarization is more sensitive to extracellular potassium changes in regions with reduced I(K1), particularly when I(K1) availability is reduced. Furthermore, underlying I(K1) heterogeneities can potentially contribute to the complex ECG during I(K1) loss of function and hypokalemia.     

Voltage noise influences action potential duration in cardiac myocytes

Stochastic gating of ion channels introduces noise to membrane currents in cardiac muscle cells (myocytes). Since membrane currents drive membrane potential, noise thereby influences action potential duration (APD) in myocytes. To assess the influence of noise on APD, membrane potential is in this study formulated as a stochastic process known as a diffusion process, which describes both the current-voltage relationship and voltage noise. In this framework, the response of APD voltage noise and the dependence of response on the shape of the current-voltage relationship can be characterized analytically. We find that in response to an increase in noise level, action potential in a canine ventricular myocytes is typically prolonged and that distribution of APDs becomes more skewed towards long APDs, which may lead to an increased frequency of early after-depolarization formation. This is a novel mechanism by which voltage noise may influence APD. The results are in good agreement with those obtained from more biophysically-detailed mathematical models, and increased voltage noise (due to gating noise) may partially underlie an increased incidence of early after-depolarizations in heart failure.     

Postnatal development has a marked effect on ventricular repolarization in mice

To better understand the mechanisms that underlie cardiac repolarization abnormalities in the immature heart, this study characterized and compared K(+) currents in mouse ventricular myocytes from day 1, day 7, day 20, and adult CD1 mice to determine the effects of postnatal development on ventricular repolarization. Current- and patch-clamp techniques were used to examine action potentials and the K(+) currents underlying repolarization in isolated myocytes. RT-PCR was used to quantify mRNA expression for the K(+) channels of interest. This study found that action potential duration (APD) decreased as age increased, with the shortest APDs observed in adult myocytes. This study also showed that K(+) currents and the mRNA relative abundance for the various K(+) channels were significantly greater in adult myocytes compared with day 1 myocytes. Examination of the individual components of total K(+) current revealed that the inward rectifier K(+) current (I(K1)) developed by day 7, both the Ca(2+)-independent transient outward current (I(to)) and the steady-state outward K(+) current (I(ss)) developed by day 20, and the ultrarapid delayed rectifier K(+) current (I(Kur)) did not fully develop until the mouse reached maturity. Interestingly, the increase in I(Kur) was not associated with a decrease in APD. Comparison of atrial and ventricular K(+) currents showed that I(to) and I(Kur) density were significantly greater in day 7, day 20, and adult myocytes compared with age-matched atrial cells. Overall, it appears that, in mouse ventricle, developmental changes in APD are likely attributable to increases in I(to), I(ss), and I(K1), whereas the role of I(Kur) during postnatal development appears to be less critical to APD.     

I(NaCa) contributes to electrical heterogeneity within the canine ventricle

This study examines the amplitude of sodium-calcium exchange current (I(NaCa)) in epicardial, midmyocardial, and endocardial canine ventricular myocytes. Whole cell currents were recorded at 37( degrees )C using standard or perforated-patch voltage-clamp techniques in the absence of potassium, calcium-activated chloride, and sodium-pump currents. I(NaCa) was triggered by release of calcium from the sarcoplasmic reticulum or by rapid removal of external sodium. I(NaCa) was large in midmyocardial myocytes and significantly smaller in endocardial myocytes, regardless of the method used to activate I(NaCa). I(NaCa) at -80 mV was -0.316 +/- 0. 013, -0.293 +/- 0.016, and -0.210 +/- 0.007 pC/pF, respectively, in midmyocardial, epicardial, and endocardial myocytes when activated by the calcium transient. When triggered by sodium removal, peak I(NaCa) was 0.74 +/- 0.04, 0.57 +/- 0.04, and 0.50 +/- 0.03 pA/pF, respectively, in midmyocardial, epicardial, and endocardial myocytes. Epicardial I(NaCa) was smaller than midmyocardial I(NaCa) when activated by removal of external sodium but was comparable to epicardial and midmyocardial I(NaCa) when activated by the normal calcium transient, implying possible transmural differences in excitation-contraction coupling. Our results suggest that I(NaCa) differences contribute to transmural electrical heterogeneity under normal and pathological states. A large midmyocardial I(NaCa) may contribute to the prolonged action potential of these cells as well as to the development of triggered activity under calcium-loading conditions.     

Coronary occlusion and reperfusion promote early afterdepolarizations and ventricular tachycardia in a canine tissue model of type 3 long QT syndrome

Although long QT syndrome (LQTS) and coronary occlusion-reperfusion (O/R) are arrhythmogenic, they affect ventricular action potential duration (APD) differently. In contrast to the prolonged APD in LQTS, ischemia abbreviates APD after a transient prolongation. Thus we hypothesized that the dynamic interactive effects of ischemia and LQTS on APD and its dispersion would affect ventricular arrhythmogenicity. We mapped transmural distribution of action potentials in 6 groups of 10 isolated wedges of canine ventricular walls: LQTS-O/R, LQTS only, and O/R only, with separate groups for pacing cycle lengths (PCL) of 1,000 and 2,000 ms. We created type 3 LQTS with anemone toxin (ATX) II followed >30 min later by arterial occlusion (40 min) and reperfusion (>100 min). Arterial occlusion initially (first 4 min) prolonged and then shortened APD. Early afterdepolarizations (EADs) occurred during the initial 4 min of occlusion in 4 of the 10 LQTS-O/R wedges at PCL of 2,000 ms but not in the other groups. Reperfusion restored APD in the O/R-only groups but caused APD to overshoot its original duration, indicating depressed repolarization reserve, in the LQTS-O/R group. Reperfusion increased the dispersion of APDs and initiated ventricular tachycardia-fibrillation in 7 of 10 and 6 of 10 LQTS-O/R wedges and in 2 of 10 and 1 of 10 O/R-only wedges at PCLs of 1,000 and 2,000 ms, respectively. The LQTS-only wedges exhibited neither EADs nor ventricular tachycardia. We conclude that coronary O/R increased the arrhythmogenicity of LQTS via cumulative prolongation of APD, increase in repolarization dispersion, and suppression of repolarization reserve.     

Intramural optical mapping of V(m) and Ca(i)2+ during long-duration ventricular fibrillation in canine hearts

Intramural gradients of intracellular Ca(2+) (Ca(i)(2+)) Ca(i)(2+) handling, Ca(i)(2+) oscillations, and Ca(i)(2+) transient (CaT) alternans may be important in long-duration ventricular fibrillation (LDVF). However, previous studies of Ca(i)(2+) handling have been limited to recordings from the heart surface during short-duration ventricular fibrillation. To examine whether abnormalities of intramural Ca(i)(2+) handling contribute to LDVF, we measured membrane voltage (V(m)) and Ca(i)(2+) during pacing and LDVF in six perfused canine hearts using five eight-fiber optrodes. Measurements were grouped into epicardial, midwall, and endocardial layers. We found that during pacing at 350-ms cycle length, CaT duration was slightly longer (by ?10%) in endocardial layers than in epicardial layers, whereas action potential duration (APD) exhibited no difference. Rapid pacing at 150-ms cycle length caused alternans in both APD (APD-ALT) and CaT amplitude (CaA-ALT) without significant transmural differences. For 93% of optrode recordings, CaA-ALT was transmurally concordant, whereas APD-ALT was either concordant (36%) or discordant (54%), suggesting that APD-ALT was not caused by CaA-ALT. During LDVF, V(m) and Ca(i)(2+) progressively desynchronized when not every action potential was followed by a CaT. Such desynchronization developed faster in the epicardium than in the other layers. In addition, CaT duration strongly increased (by ～240% at 5 min of LDVF), whereas APD shortened (by ～17%). CaT rises always followed V(m) upstrokes during pacing and LDVF. In conclusion, the fact that V(m) upstrokes always preceded CaTs indicates that spontaneous Ca(i)(2+) oscillations in the working myocardium were not likely the reason for LDVF maintenance. Strong V(m)-Ca(i)(2+) desynchronization and the occurrence of long CaTs during LDVF indicate severely impaired Ca(i)(2+) handling and may potentially contribute to LDVF maintenance.     

压力负荷性心衰小鼠左心室跨壁L-型钙电流的变化

为了观察正常和心衰时心内膜下和心外膜下心肌细胞L-型钙电流(ICa-L)的差别,我们采用主动脉弓狭窄的方法建立小鼠压力超负荷性心衰模型,采用全细胞膜片钳技术记录了正常、主动脉狭窄(band)及假手术对照(sham)组动物左心室游离壁内、外膜下心肌细胞的动作电位时程(action potential duration,APD)和ICa-L。结果显示:(1)与sham组同龄的正常小鼠左心室心内膜下细胞动作电位复极达90％的时程(APD90)为(38．2±6．44)ms,较心外膜下细胞的APD90(15.67±5.31)ms明显延长,二者的比值约为2．5:1;内膜下细胞和外膜下细胞ICa-L密度没有差异,峰电流密度分别为(-2.7±0.49)pA/pF和(-2.54±0．53)pA/pF;(2)Band组内、外膜下细胞的动作电位复极达50％的时程(APD50)、APD90均较sham组显著延长,尤以内膜下细胞延长突出,分别较sham组延长了400％和360％,内、外膜下细胞APD90的比值约为4.2:1;(3)与sham组相比, band组内膜下细胞ICa-L密度显著减小,在+10 mV～+40 mV的4个电压下分别降低了20．2％、21．4％、21.6％和25.7％(P< 0．01),但其激活电位、峰电位和翻转电位没有改变;band组外膜下细胞的ICa-L密度与同期sham组相比无明显变化;band组钙通道激活、失活及复活的动力学特征与sham组相比没有改变。以上结果提示,生理状态下小鼠左心室内、外膜下细胞ICa-L密度不存在明显差别,提示ICa-L与APD跨壁异质性的产生无关;心衰时左心室内、外膜下细胞APD明显延长,以内膜下细胞延长尤为突出,内膜下细胞ICa-L密度明显减少,而外膜下细胞ICa-L密度无明显改变,这种ICa-L的非同步变化在心衰时可能起到对抗APD延长、减少复极离散度的有益作用。     

Transmural left ventricular mechanics underlying torsional recoil during relaxation

Early relaxation in the cardiac cycle is characterized by rapid torsional recoil of the left ventricular (LV) wall. To elucidate the contribution of the transmural arrangement of the myofiber to relaxation, we determined the time course of three-dimensional fiber-sheet strains in the anterior wall of five adult mongrel dogs in vivo during early relaxation with biplane cineangiography (125 Hz) of implanted transmural markers. Fiber-sheet strains were found from transmural fiber and sheet orientations directly measured in the heart tissue. The strain time course was determined during early relaxation in the epicardial, midwall, and endocardial layers referenced to the end-diastolic configuration. During early relaxation, significant circumferential stretch, wall thinning, and in-plane and transverse shear were observed (P < 0.05). We also observed significant stretch along myofibers in the epicardial layers and sheet shortening and shear in the endocardial layers (P < 0.01). Importantly, predominant epicardial stretch along the fiber direction and endocardial sheet shortening occurred during isovolumic relaxation (P < 0.05). We conclude that the LV mechanics during early relaxation involves substantial deformation of fiber and sheet structures with significant transmural heterogeneity. Predominant epicardial stretch along myofibers during isovolumic relaxation appears to drive global torsional recoil to aid early diastolic filling.     

The contribution of ventricular apicobasal and transmural repolarization patterns to the development of the T wave body surface potentials in frogs (Rana temporaria) and pike (Esox lucius)

The study aimed at the simultaneous determination of the transmural and apicobasal differences in the repolarization timing and the comparison of the contributions of these two repolarization gradients to the development of the body surface T wave potentials in animals with the single heart ventricle (fishes and amphibians). Unipolar potentials were measured on the body surface, epicardium and in the intramural (subepicardial, Epi; midmyocardial; and subendocardial, Endo) ventricular layers of 9 pike and 8 frogs. Activation times, repolarization times and activation-recovery intervals were determined. A transmural gradient in repolarization durations in frogs (Endo>Epi, P<0.024) corresponds to the gradient in repolarization times. No significant transmural difference in repolarization duration is observed in pike that produces a repolarization sequence from Endo to Epi (Endo相似文献   

Effect of simulated I(to) on guinea pig and canine ventricular action potential morphology

The transient outward current (I(to)) is a major repolarizing current in the heart. Marked reduction of I(to) density occurs in heart failure and is accompanied by significant action potential duration (APD) prolongation. To understand the species-dependent role of I(to) in regulating the ventricular action potential morphology and duration, we introduced simulated I(to) conductance in guinea pig and canine endocardial ventricular myocytes using the dynamic clamp technique and perforated patch-clamp recordings. The effects of simulated I(to) in both types of cells were complex and biphasic, separated by a clear density threshold of approximately 40 pA/pF. Below this threshold, simulated I(to) resulted in a distinct phase 1 notch and had little effect on or moderately prolonged the APD. I(to) above the threshold resulted in all-or-none repolarization and precipitously reduced the APD. Qualitatively, these results agreed with our previous studies in canine ventricular cells using whole cell recordings. We conclude that 1) contrary to previous gene transfer studies involving the Kv4.3 current, the response of guinea pig ventricular myocytes to a fully inactivating I(to) is similar to that of canine ventricular cells and 2) in animals such as dogs that have a broad cardiac action potential, I(to) does not play a major role in setting the APD.     

Ventricular hypertrophy amplifies transmural repolarization dispersion and induces early afterdepolarization

The effects of left ventricular hypertrophy (LVH) on the generation of phase 2 early afterdepolarization (EAD) and transmural dispersion of repolarization (TDR) were assessed using arterially perfused rabbit ventricular wedge preparations. Transmembrane action potentials from epicardium, subendocardium, and endocardium were simultaneously recorded together with a transmural ECG. Transmural action potential duration (APD) was also mapped. LVH (renovascular hypertension model) produced significant prolongation in ventricular APD and QT interval. Preferential APD prolongation in subendocardium and endocardium was associated with a marked increase in TDR. Phase 2 EADs were generated from subendocardium or endocardium in all LVH rabbits (15 of 15) in the absence of APD prolonging agents at basic cycle lengths of 2,000-4,000 ms. Phase 2 EAD could produce "R on T" extrasystoles, initiating polymorphic ventricular tachycardia (VT). This study provides the first direct evidence from intracellular recordings that phase 2 EAD could be generated from rabbit intact hypertrophied LV wall in the absence of APD prolonging agents, resulting in R on T extrasystoles capable of initiating polymorphic VT under enhanced TDR.     

In silico risk assessment for drug-induction of cardiac arrhythmia

The main components of repolarization reserve for the ventricular action potential (AP) are the rapid (I_Kr) and slow (I_Ks) delayed outward K⁺ currents. While many drugs block I_Kr and cause life-threatening arrhythmias including torsades de pointes, the frequency of arrhythmias varies between different I_Kr-blockers. Different types of block of I_Kr cause distinct phenotypes of prolongation of action potential duration (APD), increase in transmural dispersion of repolarization (TDR) and, accordingly, occurrence of torsades de pointes. Therefore the assessment of a drug's proarrhythmic risk requires a method that provides quantitative and comprehensive comparison of the effects of different forms of I_Kr-blockade upon APDs and TDR. However, most currently available methods are not adapted to such an extensive comparison. Here, we introduce I_Kr–I_Ks two-dimensional maps of APD and TDR as a novel risk-assessment method. Taking the kinetics of I_Kr-blockade into account, APDs can be calculated upon a ventricular AP model which systematically alters the magnitudes of I_Kr and I_Ks. The calculated APDs are then plotted on a map where the x axis represents the conductance of I_Kr while the y axis represents that of I_Ks. TDR is simulated with models corresponding to APs in epicardial, midcardial and endocardial myocardium. These two-dimensional maps of APD and TDR successfully account for differences in the risk resulting from three distinct types of I_Kr-blockade which correspond to the effects of dofetilide, quinidine and vesnarinone. This method may be of use to assess the arrhythmogenic risk of various I_Kr-blockers.     

Transmural and apicobasal gradients in repolarization contribute to T-wave genesis in human surface ECG

The cellular basis of the T-wave morphology of surface ECG remains controversial in clinical cardiology. We examined the effect of action potential duration (APD) distribution on T-wave morphology using a realistic model of the human ventricle and torso. We developed a finite-element model of the ventricle consisting of ～26 million elements, including the conduction system, each implemented with the ion current model of cardiomyocytes. This model was embedded in a torso model with distinct organ structures to obtain the standard ECG leads. The APD distribution was changed in the transmural direction by locating the M cells in either the endocardial or epicardial region. We also introduced apicobasal gradients by modifying the ion channel parameters. Both the transmural gradient (with M cells on the endocardial side) and the apicobasal gradient produced positive T waves, although a very large gradient was required for the apicobasal gradient. By contrast, T waves obtained with the transmural gradient were highly symmetric and, therefore, did not represent the true physiological state. Only combination of the transmural and the moderate apicobasal gradients produced physiological T waves in surface ECG. Positive T waves in surface ECG mainly originated from the transmural distribution of APD with M cells on the endocardial side, although the apicobasal gradient was also required to attain the physiological waveform.     

Torsion of the human left ventricle: experimental analysis and computational modeling

We set a twofold investigation: we assess left ventricular (LV) rotation and twist in the human heart through 3D-echocardiographic speckle tracking, and use representative experimental data as benchmark with respect to numerical results obtained by solving our mechanical model of the LV. We aim at new insight into the relationships between myocardial contraction patterns and the overall behavior at the scale of the whole organ. It is concluded that torsional rotation is sensitive to transmural gradients of contractility which is assumed linearly related to action potential duration (APD). Pressure-volume loops and other basic strain measures are not affected by these gradients. Therefore, realistic torsional behavior of human LV may indeed correspond to the electrophysiological and functional differences between endocardial and epicardial cells recently observed in non-failing hearts. Future investigations need now to integrate the mechanical model proposed here with minimal models of human ventricular APD to drive excitation-contraction coupling transmurally.