Role of spatial dispersion of repolarization in inherited and acquired sudden cardiac death syndromes

This review examines the role of spatial electrical heterogeneity within the ventricular myocardium on the function of the heart in health and disease. The cellular basis for transmural dispersion of repolarization (TDR) is reviewed, and the hypothesis that amplification of spatial dispersion of repolarization underlies the development of life-threatening ventricular arrhythmias associated with inherited ion channelopathies is evaluated. The role of TDR in long QT, short QT, and Brugada syndromes, as well as catecholaminergic polymorphic ventricular tachycardia (VT), is critically examined. In long QT syndrome, amplification of TDR is often secondary to preferential prolongation of the action potential duration (APD) of M cells; in Brugada syndrome, however, it is thought to be due to selective abbreviation of the APD of the right ventricular epicardium. Preferential abbreviation of APD of the endocardium or epicardium appears to be responsible for the amplification of TDR in short QT syndrome. In catecholaminergic polymorphic VT, reversal of the direction of activation of the ventricular wall is responsible for the increase in TDR. In conclusion, long QT, short QT, Brugada, and catecholaminergic polymorphic VT syndromes are pathologies with very different phenotypes and etiologies, but they share a common final pathway in causing sudden cardiac death.     

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.     

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.     

Ventricular tachycardia in the absence of structural heart disease

In up to 10% of patients who present with ventricular tachycardia (VT), obvious structural heart disease is not identified. In such patients, causes of ventricular arrhythmia include right ventricular outflow tract (RVOT) VT, extrasystoles, idiopathic left ventricular tachycardia (ILVT), idiopathic propranolol-sensitive VT (IPVT), catecholaminergic polymorphic VT (CPVT), Brugada syndrome, and long QT syndrome (LQTS). RVOT VT, ILVT, and IPVT are referred to as idiopathic VT and generally do not have a familial basis. RVOT VT and ILVT are monomorphic, whereas IPVT may be monomorphic or polymorphic. The idiopathic VTs are classified by the ventricle of origin, the response to pharmacologic agents, catecholamine dependence, and the specific morphologic features of the arrhythmia. CPVT, Brugada syndrome, and LQTS are inherited ion channelopathies. CPVT may present as bidirectional VT, polymorphic VT, or catecholaminergic ventricular fibrillation. Syncope and sudden death in Brugada syndrome are usually due to polymorphic VT. The characteristic arrhythmia of LQTS is torsades de pointes. Overall, patients with idiopathic VT have a better prognosis than do patients with ventricular arrhythmias and structural heart disease. Initial treatment approach is pharmacologic and radiofrequency ablation is curative in most patients. However, radiofrequency ablation is not useful in the management of inherited ion channelopathies. Prognosis for patients with VT secondary to ion channelopathies is variable. High-risk patients (recurrent syncope and sudden cardiac death survivors) with inherited ion channelopathies benefit from implantable cardioverter-defibrillator placement. This paper reviews the mechanism, clinical presentation, and management of VT in the absence of structural heart disease.     

Functional and transmural modulation of M cell behavior in canine ventricular wall

Previous studies have demonstrated a discrete population of midmyocardial (M) cells in the ventricular myocardium having excessive action potential duration (APD) prolongation during long activation cycle lengths (CL) and under the influence of APD-prolonging agents. However, M cells have not been found in other studies. Existing explanations for the discrepancies appear inadequate. We hypothesized that instead of being a discrete group, M cell behavior is functional and conditionally expressed. We mapped APDs on the cut-exposed transmural surfaces of arterially perfused ventricular wedges from 26 dogs during Na+ current modification with anemone toxin II (ATX-II). Compared with the endocardium, APDs were not statistically different in the parallel layer having the longest mean APD (APDL) and were significantly shorter in the epicardium in the 26 wedges before ATX-II. ATX-II (> or =5 nmol/l) prolonged APD heterogeneously (midmyocardium > endocardium > epicardium). The differences increased at longer CLs. ATX-II (20.0 nmol/l) shifted the APD(L) layer to 32 +/- 6.2% (6 wedges, CL: 4,000 ms) of the transmural thickness from the (sub)endocardium (8.6 +/- 7.2%, 26 wedges, ATX-II free). We detected the presence of M cell behavior (significantly longer APDs in the APDL layer than in the endocardium and epicardium, P < or = 0.04, CL: 4,000 ms) in the 18 wedges having > or =5 nmol/l ATX-II but not (P >0.36) in the other 18 wedges having < or =2.5 nmol/l ATX-II. Both the position of the APDL layer and presence of M cell-like behavior were modulated by ATX-II. The dynamic spatial modulation indicates that M cell behavior is functional and only becomes manifest under suitable conditions.     

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.     

Shock-induced arrhythmogenesis is enhanced by 2,3-butanedione monoxime compared with cytochalasin D

Investigation of the mechanisms of arrhythmia genesis and maintenance has benefited from the use of optical mapping techniques that employ excitation-contraction uncouplers. We investigated the effects of the excitation-contraction uncouplers 2,3-butanedione monoxime (BDM) and cytochalasin D (Cyto D) on the induction and maintenance of arrhythmia by electric shocks. Electrical activity was optically mapped from anterior epicardium of rabbit hearts (n = 9) during shocks (-100 V, 8 ms) applied from a ventricular lead at various phases of action potential duration (APD). Restitution curves were obtained using S1-S2 protocol and measurement of APD values at 70% of repolarization. Compared with Cyto D, BDM significantly shortened APD at 90% of repolarization, although no significant difference in dispersion of repolarization was observed. Wavelength was also shortened with BDM. In general, shock-induced arrhythmias with BDM and Cyto D were ventricular tachycardic in nature. With respect to shock-induced sustained arrhythmias, the vulnerable window was wider and the incidence was higher with BDM than with Cyto D. There was also a difference in the morphology of ventricular tachycardia (VT) between the two agents. The arrhythmias with BDM usually resembled monomorphic VT, especially those that lasted >30 s. In contrast, arrhythmias with Cyto D more resembled polymorphic VT. However, the average number of phase singularities increased under Cyto D vs. BDM, whereas no significant difference in the dominant frequency of shock-induced sustained arrhythmia was observed. BDM reduced the slope of the restitution curve compared with Cyto D, but duration of arrhythmia under BDM was significantly increased compared with Cyto D. In conclusion, BDM increased arrhythmia genesis and maintenance relative to Cyto D.     

Apoptosis in severe, compensated pressure overload predominates in nonmyocytes and is related to the hypertrophy but not function

It is widely held that myocyte apoptosis in left ventricular hypertrophy (LVH) contributes to left ventricle (LV) dysfunction and heart failure. The main goal of this investigation was to determine if there is a statistical relationship among LV hypertrophy, apoptosis and LV function, and importantly whether the apoptosis occurs in myocytes or nonmyocytes in the heart. We used both rat and canine models of severe LVH induced by chronic thoracic aortic banding with resultant LV-aortic pressure gradients 145-155 mmHg and increases in LV/body weight of 58 and 70%. These models also provided the ability to examine transmural apoptosis in LVH. In both models, the overwhelming majority (88%) of apoptotic cells were nonmyocytes. The regressions for apoptosis vs. LVH were stronger for nonmyocytes than myocytes and also stronger in the subendocardium than the subepicardium. Importantly, LV systolic and diastolic wall stresses were normal, indicating that the apoptosis could not be attributed to LV stretch or heart failure. In addition, there was no relationship between the extent of apoptosis and LV ejection fraction, which actually increased (P < 0.05), in the face of elevated LV systolic pressure, indicating that greater apoptosis did not result in a decrease in LV function. Thus, in response to chronic, severe pressure overload, LVH in the absence of LV dilation, and elevated LV wall stress, apoptosis occurred predominantly in nonmyocytes in the myocardial interstitium, more in the subendocardium than the subepicardium. The extent of apoptosis was linearly related to the amount of LV hypertrophy, but not to LV function.     

Effects of ectopic pacing on repolarization of the chicken left ventricle

Effects of ectopic pacing on left ventricular repolarization were studied in six anesthetized open-chest chickens. In each animal, unipolar electrograms were acquired from as many as 98 sites with 14 plunge needles (seven transmural locations between epicardium and endocardium in each needle). Activation-recovery intervals (ARIs), corrected to the cycle length, were used for estimating repolarization. At baseline, the nonuniform ARI distribution in the left ventricle resulted in the apicobasal differences being greater than the transmural gradient. Nonuniform ARI prolongation caused by ectopic pacing resulted in decreasing the transmural repolarization gradient and increasing the differences in the apex-to-base direction. The basal, but not apical transmural differences contributed to the total left ventricular transmural gradient. The total left ventricular apicobasal gradient was contributed by the apicobasal differences in mid-myocardial and subendocardial layers more than in subepicardial ones. Thus, in in situ chicken hearts, the transmural and apicobasal ARI gradients exist within the left ventricle with the shortest ARIs in the basal subepicardium and the longest ARIs in the subendocardium of the apical and middle parts of the left ventricle. Apicobasal compared to transmural heterogeneity of local repolarization properties contributes more to the total left ventricular repolarization gradient.     

Strain-based estimation of time-dependent transmural myocardial architecture in the ovine heart

Left ventricular myofibers are connected by an extensive extracellular collagen matrix to form myolaminar sheets. Histological cardiac tissue studies have previously observed a pleated transmural distribution of sheets in the ovine heart, alternating sign of the sheet angle from epicardium to endocardium. The present study investigated temporal variations in myocardial fiber and sheet architecture during the cardiac cycle. End-diastolic histological measurements made at subepicardium, midwall, and subendocardium at an anterior-basal and a lateral-equatorial region of the ovine heart, combined with transmural myocardial Lagrangian strains, showed that the sheet angle but not the fiber angle varied temporally throughout the cardiac cycle. The magnitude of the sheet angle decreased during systole at all transmural depths at the anterior-basal site and at midwall and subendocardium depths at the lateral-equatorial site, making the sheets more parallel to the radial axis. These results support a previously suggested accordion-like wall-thickening mechanism of the myocardial sheets.     

Chemical ablation of the Purkinje system causes early termination and activation rate slowing of long-duration ventricular fibrillation in dogs

Endocardial mapping has suggested that Purkinje fibers may play a role in the maintenance of long-duration ventricular fibrillation (LDVF). To determine the influence of Purkinje fibers on LDVF, we chemically ablated the Purkinje system with Lugol solution and recorded endocardial and transmural activation during LDVF. Dog hearts were isolated and perfused, and the ventricular endocardium was exposed and treated with Lugol solution (n = 6) or normal Tyrode solution as a control (n = 6). The left anterior papillary muscle endocardium was mapped with a 504-electrode (21 x 24) plaque with electrodes spaced 1 mm apart. Transmural activation was recorded with a six-electrode plunge needle on each side of the plaque. Ventricular fibrillation (VF) was induced, and perfusion was halted. LDVF spontaneously terminated sooner in Lugol-ablated hearts than in control hearts (4.9 +/- 1.5 vs. 9.2 +/- 3.2 min, P = 0.01). After termination of VF, both the control and Lugol hearts were typically excitable, but only short episodes of VF could be reinduced. Endocardial activation rates were similar during the first 2 min of LDVF for Lugol-ablated and control hearts but were significantly slower in Lugol hearts by 3 min. In control hearts, the endocardium activated more rapidly than the epicardium after 4 min of LDVF with wave fronts propagating most often from the endocardium to epicardium. No difference in transmural activation rate or wave front direction was observed in Lugol hearts. Ablation of the subendocardium hastens VF spontaneous termination and alters VF activation sequences, suggesting that Purkinje fibers are important in the maintenance of LDVF.     

Sex-based transmural differences in cardiac repolarization and ionic-current properties in canine left ventricles

The female sex is associated with longer electrocardiographic QT intervals and increased proarrhythmic risks of QT-prolonging drugs. This study examined the hypothesis that sex differences in repolarization may be associated with differential transmural ion-current distribution. Whole cell patch-clamp and current-clamp were used to study ionic currents and action potentials (APs) in isolated canine left ventricular cells from epicardium, midmyocardium, and endocardium. No sex differences in AP duration (APD) were found in cells from epicardium versus endocardium. In midmyocardium, APD was significantly longer in female dogs (e.g., at 1 Hz, female vs. male: 288 +/- 21 vs. 237 +/- 8 ms; P < 0.05), resulting in greater transmural APD heterogeneity in females. No sex differences in inward rectifier K+ current (I(K1)) were observed. Transient outward K+ current (I(to)) densities in epicardium and midmyocardium also showed no sex differences. In endocardium, female dogs had significantly smaller I(to) (e.g., at +30 mV, female vs. male: 2.5 +/- 0.2 vs. 3.5 +/- 0.3 pA/pF; P < 0.05). Rapid delayed-rectifier K+ current (I(Kr)) density and activation voltage-dependence showed no sex differences. Female dogs had significantly larger slow delayed-rectifier K+ current (I(Ks)) in epicardium and endocardium (e.g., at +40 mV; tail densities, female vs. male; epicardium: 1.3 +/- 0.1 vs. 0.8 +/- 0.1 pA/pF; P < 0.001; endocardium: 1.2 +/- 0.1 vs. 0.7 +/- 0.1 pA/pF; P < 0.05), but there were no sex differences in midmyocardial I(Ks). Female dogs had larger L-type Ca2+ current (I(Ca,L)) densities in all layers than male dogs (e.g., at -20 mV, female vs. male, epicardium: -4.2 +/- 0.4 vs. -3.2 +/- 0.2 pA/pF; midmyocardium: -4.5 +/- 0.5 vs. -3.3 +/- 0.3 pA/pF; endocarium: -4.5 +/- 0.4 vs. -3.2 +/- 0.3 pA/pF; P < 0.05 for each). We conclude that there are sex-based transmural differences in ionic currents that may underlie sex differences in transmural cardiac repolarization.     

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.     

The characteristics of action potential and nonselec-tive cation current of cardiomyocytes in rabbit superior vena cava

As a special focus in initiating and maintaining atrial fibrillation (AF), cardiomyocytes in superior vena cava (SVC) have distinctive electrophysiological characters. In this study, we found that comparing with the right atrial (RA) cardiomyoctyes, the SVC cardiomyoctyes had longer APD90 at the different basic cycle lengths; the conduction block could be observed on both RA and SVC cardiomyoctyes. A few of SVC cardiomyoctyes showed slow response action potentials with automatic activity and some others showed early afterdepolarization (EAD) spontaneously. Further more, we found that there are nonselective cation current (INs) in both SVC and RA cardiomyocytes. The peak density of INs in SVC cardiomyocytes was smaller than that in RA cardiomyocytes. Removal of extracellular divalent cation and glucose could increase INs in SVC cardiomyocytes. The agonist or the antagonist of INs may in-crease or decrease APD. To sum up, some SVC cardiomyocytes possess the ability of spontaneous activity; the difference of transmembrane action potentials between SVC and RA cardiomyocytes is partly because of the different density of INs between them; the agonist or the antagonist of INs can in-crease or decrease APD leading to the enhancement or reduction of EAD genesis in SVC cardiomyo-cytes. INs in rabbit myocytes is fairly similar to TRPC3 current in electrophysiological property, which might play an important role in the mechanisms of AF.     

Targeting the late component of the cardiac L-type Ca2+ current to suppress early afterdepolarizations

Early afterdepolarizations (EADs) associated with prolongation of the cardiac action potential (AP) can create heterogeneity of repolarization and premature extrasystoles, triggering focal and reentrant arrhythmias. Because the L-type Ca²⁺ current (I_Ca,L) plays a key role in both AP prolongation and EAD formation, L-type Ca²⁺ channels (LTCCs) represent a promising therapeutic target to normalize AP duration (APD) and suppress EADs and their arrhythmogenic consequences. We used the dynamic-clamp technique to systematically explore how the biophysical properties of LTCCs could be modified to normalize APD and suppress EADs without impairing excitation–contraction coupling. Isolated rabbit ventricular myocytes were first exposed to H₂O₂ or moderate hypokalemia to induce EADs, after which their endogenous I_Ca,L was replaced by a virtual I_Ca,L with tunable parameters, in dynamic-clamp mode. We probed the sensitivity of EADs to changes in the (a) amplitude of the noninactivating pedestal current; (b) slope of voltage-dependent activation; (c) slope of voltage-dependent inactivation; (d) time constant of voltage-dependent activation; and (e) time constant of voltage-dependent inactivation. We found that reducing the amplitude of the noninactivating pedestal component of I_Ca,L effectively suppressed both H₂O₂- and hypokalemia-induced EADs and restored APD. These results, together with our previous work, demonstrate the potential of this hybrid experimental–computational approach to guide drug discovery or gene therapy strategies by identifying and targeting selective properties of LTCC.     

Beat-to-beat repolarization variability in ventricular myocytes and its suppression by electrical coupling

Single ventricular myocytes paced at a constant rate and held at a constant temperature exhibit beat-to-beat variations in action potential duration (APD). In this study we sought to quantify this variability, assess its mechanism, and determine its responsiveness to electrotonic interactions with another myocyte. Interbeat APD(90) (90% repolarization) of single cells was normally distributed. We thus quantified APD(90) variability as the coefficient of variability, CV = (SD/mean APD(90)) x 100. The mean +/- SD of the CV in normal solution was 2.3 +/- 0.9 (132 cells). Extracellular TTX (13 microM) and intracellular EGTA (14 mM) both significantly reduced the CV by 44 and 26%, respectively. When applied in combination the CV fell by 54%. In contrast, inhibition of the rapid delayed rectifier current with L-691,121 (100 nM) increased the CV by 300%. The CV was also significantly reduced by 35% when two normal myocytes were electrically connected with a junctional resistance (R(j)) of 100 MOmega. Electrical coupling (R(j) = 100 MOmega) of a normal myocyte to one producing early afterdepolarization (EAD) completely blocked EAD formation. These results indicate that beat-to-beat APD variability is likely mediated by stochastic behavior of ion channels and that electrotonic interactions act to limit temporal dispersion of refractoriness, a major contributor to arrhythmogenesis.     

Steeper restitution slopes across right ventricular endocardium in patients with cardiomyopathy at high risk of ventricular arrhythmias

Steep action potential duration (APD) restitution slopes (>1) and spatial APD restitution heterogeneity provide the substrate for ventricular fibrillation in computational models and experimental studies. Their relationship to ventricular arrhythmia vulnerability in human cardiomyopathy has not been defined. Patients with cardiomyopathy [left ventricular (LV) ejection fraction <40%] and no history of ventricular arrhythmias underwent risk stratification with programmed electrical stimulation or T wave alternans (TWA). Low-risk patients (n = 10) had no inducible ventricular tachycardia (VT) or negative TWA, while high-risk patients (n = 8) had inducible VT or positive TWA. Activation recovery interval (ARI) restitution slopes were measured simultaneously from 10 right ventricular (RV) endocardial sites during an S1-S2 pacing protocol. ARI restitution slope heterogeneity was defined as the coefficient of variation of slopes. Mean ARI restitution slope was significantly steeper in the high-risk group compared with the low-risk group [1.16 (SD 0.31) vs. 0.59 (SD 0.19), P = 0.0002]. The proportion of endocardial recording sites with a slope >1 was significantly larger in the high-risk patients [47% (SD 35) vs. 13% (SD 21), P = 0.022]. Spatial heterogeneity of ARI restitution slopes was similar between the two groups [29% (SD 16) vs. 39% (SD 34), P = 0.48]. There was an inverse linear relationship between the ARI restitution slope and the minimum diastolic interval (P < 0.001). In cardiomyopathic patients at high risk of ventricular arrhythmias, ARI restitution slopes along the RV endocardium are steeper, but restitution slope heterogeneity is similar compared with those at low risk. Steeper ARI restitution slopes may increase the propensity for ventricular arrhythmias in patients with impaired left ventricular function.     

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.     

Transmural distribution of iron in the hypoxic and reoxygenated rabbit left ventricular myocardium

Transmural distribution of low molecular weight iron (LMWI), total iron, and protein carbonyls (PC) was investigated in the perfused rabbit heart under aerobic conditions, and after 60 min hypoxia followed or not by 3 min reoxygenation. In the aerobic perfused hearts, LMWI, total iron and PC did not show significant transmural differences. Hypoxia increased LMWI and PC levels, which were significantly higher in the subendocardium than in the subepicardium; further significant changes were not observed after reoxygenation. Total iron showed no transmural difference and was not significantly affected by both hypoxia and reoxygenation. Free iron was undetectable in the myocardial effluent of all experimental groups. Thus, hypoxia favors myocardial iron decompartmentalisation and oxidative stress, which are significantly greater in the inner than in the outer ventricular layers. Such findings may add further insight into the problem of the vulnerability of the mammalian subendocardium to injury induced by oxygen deprivation.     

Effects of transmural electrical heterogeneities and electrotonic interactions on the dispersion of cardiac repolarization and action potential duration: A simulation study

It has been shown in the literature that myocytes isolated from the ventricular walls at various intramural depths have different action potential durations (APDs). When these myocytes are embedded in the ventricular wall, their inhomogeneous properties affect the sequence of repolarization and the actual distribution of the APDs in the entire wall. In this article, we implement a mathematical model to simulate the combined effect of (a) the non-homogeneous intrinsic membrane properties (in particular the non-homogeneous APDs) and (b) the electrotonic currents that modulate the APDs when the myocytes are embedded in the ventricular myocardium. In particular, we study the effect of (a) and (b) on the excitation and repolarization sequences and on the distribution of APDs in the ventricles. We implement a Monodomain tissue representation that includes orthotropic anisotropy, transmural fiber rotation and homogeneous or heterogeneous transmural intrinsic membrane properties, modeled according to the phase I Luo-Rudy membrane ionic model. Three-dimensional simulations are performed in a cartesian slab with a parallel finite element solver employing structured isoparametric trilinear finite elements in space and a semi-implicit adaptive method in time. Simulations of excitation and repolarization sequences elicited by epicardial or endocardial pacing show that in a homogeneous slab the repolarization pathways approximately follow the activation sequence. Conversely, in the heterogeneous cases considered in this study, we observed two repolarization wavefronts that started from the epi and the endocardial faces respectively and collided in the thickness of the wall and in one case an additional repolarization wave starting from an intramural site. Introducing the heterogeneities along the transmural epi-endocardial direction affected both the repolarization sequence and the APD dispersion, but these effects were clearly discernible only in transmural planes. By contrast, in planes parallel to epi- and endocardium the APD distribution remained remarkably similar to that observed in the homogeneous model. Therefore, the patterns of the repolarization sequence and APD dispersion on the epicardial surface (or any other intramural surface parallel to it) do not reveal the uniform transmural heterogeneity.