Mechanisms underlying enhanced cardiac excitation contraction coupling observed in the senescent sheep myocardium

Ageing related stiffening of the vascular system is believed to be in part responsible for a number of clinical outcomes including hypertension and heart failure. In the present study, we sought to determine whether there are alterations in cardiac excitation contraction coupling that may help compensate for the increased vessel stiffness. Experiments were performed on single cardiac myocytes isolated from young (18 months) and aged (>8 years) sheep. Intracellular Ca(2+) concentration, action potentials, L-type Ca(2+) currents and SR Ca(2+) content were measured at 23 degrees C. With ageing, cell capacitance increased by 26% indicating cellular hypertrophy. Action potential duration (APD90) (590 +/- 21 vs. 726 +/- 36 ms), Ca(2+) transient amplitude (112 +/- 15 vs. 202 +/- 25 nmol l(-1)) and fractional cell shortening (by 37%) also increased in the aged hearts (all values P < 0.05). The larger Ca(2+) transient amplitude observed under current clamp conditions was maintained under voltage clamp control; however, SR Ca(2+) content was identical. Both the peak L-type Ca(2+) current (2.8 +/- 0.3 vs. 4.9 +/- 0.5 pA pF(-1)) and integrated Ca(2+) entry (5.1 +/- 0.7 vs. 7.9 +/- 0.8 micromol l(-1), all P < 0.01) were greater in aged cells. In this study we show that in the ageing ovine myocardium, the amplitude of the systolic Ca(2+) transient is increased. The larger Ca(2+) transients cannot simply be explained by changes in APD and we suggest that the greater inward L-type Ca(2+) current provides a more effective trigger for calcium-induced-calcium release from the SR whilst maintaining a stable SR Ca(2+) content. These changes in cardiac excitation contraction coupling may help maintain cardiac output in the face of increased great vessel stiffness.     

The effect of oligomycin on the electrical activity of frog atrial muscle and the effect of variation of [Ca2+]0 concentration

The effect of oligomycin on electrical activity in frog atrial fibers has been studied using the current and voltage clamp double sucrose gap technique. Also, the accompanying contraction has been measured. Current clamp studies showed that oligomycin reduced both peak amplitude and duration of the action potential, and also the contractile force; the effect increasing with concentration. Recovery occurred following washout, but this also was dependent on concentration on inhibitor, with recovery not being achieved if concentration of inhibitor exceeded a given value. Voltage clamp demonstrated a marked reduction in the slow inward current amplitude and a negative shift of the reversal potentials. In addition, oligomycin induced a slight increase in the delayed outward current, this increase not occurring in the early repolarization phase of the action potential. In the presence of oligomycin with excess [Ca²⁺]₀ the action potential shortened, but its amplitude increased. Excess [Ca²⁺]₀ during inhibition also increased the slow inward current amplitude and shifted the reversal potential toward a more positive value. These results suggest that when the coupling of respiration with oxidative phosphorylation is inhibited the level of ATP in the sarcoplasm is decreased, leading to an increase in intracellular free Ca²⁺ concentration, thereby reducing the transmembrane Ca²⁺ concentration gradient. This decreases the Ca²⁺ driving force which is Ca-dependent and alters the action potential amplitude, together with the slow channel conductance (which is Ca²⁺ dependent) leading to a reduction of excitation-contraction coupling.     

The interrelationship of calcium-mediated action potentials and tension development in cat ventricular myocardium.

Studies of Ca-mediated action potentials and mechanical activity of cat papillary muscles and trabeculae partially depolarized and Na-inactivated by K-rich (13.7 mm) solution were performed. Variation in strength of muscle stimulation resulted in gradation of rate of rise, overshoot and duration of Ca-mediated action potentials, peak tension and time to peak tension. At constant stimulus strength the rate of rise, overshoot and duration of the Ca-mediated action potentials were markedly depressed when the frequency of stimulation was increased. Two/second was maximum driving frequency. Within this range the frequency: tension relationship was similar to, although less than, the control. When steady state peak tension was low the Ca inflow was high—as indicated by $\text{d}\text{V}\text{d}\text{t}{}_{\mathrm{<mtext>max</mtext>}}$, overshoot and plateau positivity—and action potential prolonged. Following frequency change, $\text{d}\text{V}\text{d}\text{t}{}_{\mathrm{<mtext>max</mtext>}}$ of the rising phase and overshoot decreased (increased) during the initial positive (negative) inotropic effect, and then tapered to steady-state by the end of the 1–2 min inotropic change. Hence, during staircase, as well as in steady state, the tension development was intimately interrelated to the Ca inflow, the underlying mechanism being discussed. Reducing [Ca]_o to 0.25 mm completely inhibited Ca-mediated excitation as well as contraction within 15–20 min. Inhibitors of the slow Ca inward current (Verapamil, D 600) similarly inhibited Ca-mediated action potentials, but left resting state excitation and contraction (1/min) essentially unaltered.     

Electrophysiologic study of the effects of aminophylline and metaproterenol on canine myocardium.

Aminophylline and beta-adrenergic agonists are widely used in the treatment of obstructive lung diseases. It has been suggested that combined aminophylline and beta-agonist therapy may promote the development of atrial and ventricular arrhythmias. The effects of these agents in combination on myocardial conduction and tissue refractoriness have not been documented. We evaluated the electrophysiologic effects of intravenous aminophylline and inhaled metaproterenol on canine myocardium. Aminophylline produced significant decreases from baseline in the AH interval (85 +/- 6.5 [SD] to 63 +/- 4.1 ms [p less than 0.02]), Wenckebach cycle length (WCL) (226 +/- 8.7 to 182 +/- 5.8 ms [p less than 0.02]), and ventricular effective refractory period (VERP) (166 +/- 6.0 to 148 +/- 4.9 ms [p less than 0.01]). Metaproterenol produced similar results, except metaproterenol significantly decreased the atrial effective refractory period (AERP) from 152 +/- 6.6 to 130 +/- 3.2 ms (p less than 0.02), an effect not seen with aminophylline alone. Metaproterenol also produced significantly greater reductions in AH interval and WCL, as well as a greater increase in heart rate than aminophylline did. When compared with aminophylline alone, combined metaproterenol and aminophylline therapy produced significantly greater reductions in the AH interval (63 +/- 4.1 versus 48 +/- 1.2 ms for combined therapy [p less than 0.01]), HV interval (32 +/- 1.2 versus 28 +/- 2.0 ms for combined therapy [p less than 0.02]), WCL (182 +/- 5.8 versus 150 +/- 7.1 ms for combined therapy [p less than 0.02]), and VERP (148 +/- 4.9 versus 132 +/- 2.0 ms for combined therapy [p less than 0.02]). We conclude that both aminophylline and metaproterenol significantly enhance AV nodal and His-Purkinje conduction. Metaproterenol produced significant changes in both atrial and ventricular tissue refractoriness. Metaproterenol produced significantly greater changes than aminophylline alone, and inhaled metaproterenol combined with intravenous aminophylline produced greater changes in AV nodal and His-Purkinje conduction and ventricular refractoriness than did aminophylline alone in a canine model.     

Electrophysiologic and mechanical effects of metabolic inhibition of high-energy phosphate production in cultured chick embryo ventricular cells

The early electrophysiological and mechanical effects of metabolic inhibition of high energy phosphate production were studied in cultured chick embryo heart cells. Selective inhibition of either glycolysis by 2-deoxyglucose in the presence of acetate or of oxidative phosphorylation by cyanide showed different effects. 2-deoxyglucose induced pronounced reduction in maximal diastolic potential and prolongation of excitation contraction delay, with only a moderate decrease of contractility and with only minimal changes in action potential duration. Cyanide, on the other hand, induced a profound negative inotropic effect and caused slowing of relaxation, shortening of action potential duration, a decrease in the upstroke of the action potential, and only a moderate decrease in the diastolic membrane potential. Exposure to 2-deoxyglucose and cyanide combined produced effects consistent with inhibition of both metabolic pathways. These observations are consistent with the hypothesis that these two metabolic pathways may have specific roles in fueling several energy-demanding functions of the myocardial cell.     

Electrophysiologic effects of Tween 80 in the myocardium and specialized conduction system of the canine heart

Amiodarone, a wide spectrum antiarrhythmic agent, has been associated with hypotensive reactions in man as well as in dogs after intravenous use. This hypotensive effect has been attributed to Tween 80, the diluent in the commercially available form of amiodarone. We studied the electrophysiologic effects of Tween 80 in the cardiac conduction system of the dog. Electrophysiologic studies were conducted in anesthetized adult dogs before and after the administration of 10 and 20 mg/kg of Tween 80, equivalent to the amount of diluent in 5 and 10 mg/kg respectively of commercial intravenous amiodarone. In addition to a drop of 60% in systolic blood pressure and 66% in diastolic blood pressure (p less than 0.005), 10 mg/kg of Tween 80 induced a decrease in heart rate (sinus cycle length increased from 523 +/- 57 msec to 662 +/- 27 msec, p less than 0.025), prolongation of sinus node recovery time (652 +/- 77 msec to 804 +/- 45 msec, p less than 0.05), depression of AV nodal function manifested by induction of Wenckebach at longer cycle length (from 208 +/- 18 msec to 266 +/- 14 msec, p less than 0.005), and increase in atrial ERP (from 138 +/- 7 msec to 176 +/- 14 msec, p less than 0.025) and FRP (from 180 +/- 14 msec to 209 +/- 12 msec, p less than 0.025). No further significant changes were observed after the second Tween 80 dose. The ventricular ERP increased significantly (from 168 +/- 18 msec to 20 +/- 16 msec, p less than 0.025) following the 20 mg/kg dose. It is demonstrated that Tween 80 is a potent depressant of the cardiac conduction system in the dog, capable of causing electrophysiologic changes similar to those produced by amiodarone in humans and dogs.     

阿魏酸钠与胺碘酮对家兔心室肌电生理作用的对比研究

目的 :研究阿魏酸钠对家兔心室肌复极及有效不应期 (ERP)的影响 ,探讨其抗心律失常的可能机制。方法 :16只家兔随机分为阿魏酸钠组与胺碘酮组 ,各组同步记录体表心电图 (ECG)及右室心内膜单相动作电位 (MAP) ,比较在窦性心律下 ,用药前及用药后窦性心动周长 (SCL)、QRS时限 (QRSD)、MAP振幅 (MAPA)、ERP及复极 90 %时程 (MAPD90 )的变化。结果 :阿魏酸钠发挥与胺碘酮一致的时间依赖性延长MAPD90 与ERP作用 ,但不改变ERP/MAPD90 比值 ,胺碘酮用药 15min ,ERP及MAPD90 分别由用药前的 (12 5 .0 0± 16 .2 6 )ms、(14 3.12± 15 .80 )ms延长为 (199.0 0± 2 1.6 2 )ms、(2 16 .88± 2 3.14 )ms(P <0 .0 1) ;阿魏酸钠用药 2 5min ,ERP及MAPD90 分别由用药前的 (12 2 .5 0± 8.13)ms、(14 0 .0 0± 6 .2 5 )ms延长为 (14 3.75± 6 .87)ms、(16 4 .38± 7.19)ms(P <0 .0 1)。结论 :经与胺碘酮比较 ,推测阿魏酸钠具有Ⅲ类抗心律失常药物的抗心律失常特性。     

Electrophysiological and pharmacological study of the inotropic effects of adrenaline,dopamine and tryptamine on frog atrial fibres

In order to investigate the action of the sympathetic amines adrenaline, dopamine and tryptamine, electrophysiological and pharmacological studies were undertaken on frog heart atrial fibres, using a double sucrose gap technique. Electrophysiological measurements, under voltage clamp conditions have shown that adrenaline, dopamine and tryptamine induce a large increase of the slow inward current (I_slow) and tension amplitudes. Dose-response relationships show a direct correlation between the increase in both I_slow and phasic tension, with a half-response dose (K_0·5) of 4 × 10^?7m for adrenaline, 2.5 × 10^?6m for dopamine and 4 × 10^?6m for tryptamine. These effects are inhibited by the β blocker agent propranolol, but a competitive inhibition was only observed in the case of adrenaline. While the typical effect of adrenaline is still present on catecholamine depleted preparations (previously treated with 6-hydroxydopamine), dopamine and tryptamine do not have an effect on those pretreated preparations. Results provide evidence for an adrenaline release mediated type of action of dopamine and tryptamine. Our work also suggests the presence of specific presynaptic dopamine and tryptamine receptors on sympathic nerve terminals in frog atrial fibres.     

Studies of sarcoplasmic reticulum function and contraction duration in young adult and aged rat myocardium

Kinetic measurements of Ca⁺² uptake in microsomal fractions from rat myocardium demonstrated significantly lower rates of oxalate-facilitated accumulation in preparations from aged (24 to 25 month) hearts as compared to those from young adult (6 to 8 month) hearts. The per cent decline in transport activity in microsomes from aged hearts varied with Ca²⁺ concentration decreasing from 57% at 0.33 μm Ca²⁺ to 24% at 1.21 μm Ca²⁺. Double-reciprocal plots of the dependence of the velocity of accumulation on Ca²⁺ concentration showed upward curvature in both age groups indicating the presence of multiple Ca²⁺ binding sites. Mechanical studies using muscles isolated from the same hearts used to prepare sarcoplasmic reticulum demonstrated prolonged contraction duration in aged myocardium in agreement with previous findings. The lower in vitro rates of Ca²⁺ accumulation in aged microsomes suggest a possible biochemical mechanism to account for the observed increase in the time-course of cardiac relaxation.     

银杏内酯A、B对豚鼠乳头肌细胞的电生理效应

目的：研究银杏内酯A、B（GA、GB）抗心肌缺血与抗心律失常的效应及其机制。方法：细胞内微电极方法记录乳头肌动作电位。灌流模拟缺血液造缺血模型以及在低钾台氏液中加入氯化铯灌流诱发延迟后除极（DAD）模型。观察GA、GB在生理、缺血状态下对乳头肌动作电位各项电生理参数以及DAD的影响。结果：生理条件下10^-6mol/LGA、GB使APD50分别缩短9．1％和6．2％；APD90分别缩短8．4％和5．9％。缺血状态下APD明显缩短、APA减小、RP及0期Vmax减小（P＜0．05－0．01）。GA、GB可延缓和减轻缺血引起的上述变化（P＜0．01），GA、GB可降低DADA的发生率（P＜0．01）。结论：银杏内酯A、B有缓解和改善心肌缺血作用，并可阻抑DAD的发生。     

D-600 blocks spontaneous discharge,excitability and contraction of cultured embryonic chick heart cells

Standard microelectrode techniques and a new microphotometric system were used to study the effects of D-600 on spontaneously beating or electrically driven cultured embryonic chick heart cells. The effects of the addition of 10^?6m D-600 to the superfusing solution were always first cessation of automaticity or triggered activity and then inhibition of excitability as measured by anodal-break excitation. Triggered and spontaneous activity faded during D-600 influence in a way similar to the damping of an inharmonic oscillation. Finally a stable membrane potential of about ?40 mV was reached. Simultaneous measurement of cell pulsation by photometric means showed that each excitation elicited a contraction, as long as the amplitude of spontaneous action potentials or of anodal-break excitations displayed overshoot of the zero line. Excitations of lower amplitude were not sufficient to trigger a measurable contraction. The inhibitory effects of D-600 could not be overcome by resting periods but were antagonized by membrane hyperpolarization. These findings indicate that reduction of the slow inward current by D-600 inhibits excitation and contraction in cultured embryonic chick heart cells.     

Calcium compartmentalization in cultured and adult myocardium: activation of a caffeine-sensitive component

Calcium (Ca) exchange was studied under various perfusion conditions in monolayer myocardial culture and in the interventricular septum of the rabbit. In cultured cells perfused in HEPES buffered medium or in 10 mM phosphate (Pi), pH less than 7.2, 10 mM caffeine produced no change in 45Ca uptake rate. By contrast, increase of pH to 7.35 in the presence of 10 mM Pi caused 45Ca uptake rate to increase by more than two-fold when caffeine was added. Control 45Ca uptake (prior to caffeine) was markedly increased in 10 mM Pi, pH = 7.35 as compared to the two other perfusion conditions in the cultured cells. The same sequence of response of 47Ca uptake rate to caffeine was found in the rabbit septum, i.e. no increased uptake under HEPES or Pi, pH less than 7.2 perfusion, but significant increase under 10 mM Pi, pH 7.35 with development of progressive contracture only in the last case. Two other conditions produced sensitivity (both in 47Ca uptake and contracture) to caffeine in the septum. Preperfusion with ouabain in HEPES buffer increased caffeine sensitivity proportional to ouabain concentration (5 X 10(-7) to 10(-5) M) as did preperfusion with vanadate at low concentration (1 to 3 X 10(-6) M). The results suggest that activation of Ca uptake by the sarcoplasmic reticulum (SR) is dependent upon a threshold of cellular Ca and that a stable contractile state is possible in the absence of SR activation in both cultured cells and adult ventricular tissue.     

A new cardiotonic agent,OPC-8212, elevates the myocardial oxygen consumption versus pressure-volume area (PVA) relation in a similar manner to catecholamines and calcium in canine hearts

Summary We studied the effect of a new positive inotropic agent, OPC-8212 (3,4-Dihydro-6-[4-(3,4-dimethoxybenzoyl)-l-piperazinyl]-2(1H)-quinolinone), on the relation between left ventricular oxygen consumption (VO₂) and pressure-volume area (PVA) in excised cross-circulated dog hearts. PVA represents the total mechanical energy generated by ventricular contraction. OPC-8212 increased the contractility index, Emax, by 59%±36% from 7.6±4.3 to 11.1±4.6 mmHg/(ml/100 g LV [leftventricle]). OPC-8212 elevated the VO₂-PVA relation without a significant change in its slope. Namely, OPC-8212 did not affect the mechanical efficiency of the contractile machinery from the PVA-dependent fraction of VO₂ to PVA, but increased the PVA-independent fraction of VO₂ which is related with non-mechanical processes of contraction. This effect suggested an increased energy expenditure for excitation-contraction coupling. These results associated with the enhanced contractile state by OPC-8212 were both qualitatively and quantitatively similar to those obtained with catecholamines and calcium in our previous study. This suggests that OPC-8212, catecholamines, and calcium have similar effects on intracellular Ca²⁺ concentration and enhanced ventricular contractility.Partly supported by a Grant-in-Aid (61480102) for Scientific Research from the Ministry of Education, Science, and Culture, and a Research Grant (60C-3) for Cardiovascular Diseases from the Ministry of Health and Welfare of Japan.     

Paired pulse pacing increases cardiac O2 consumption for activation without changing efficiency of contractile machinery in canine left ventricle

Summary The relation between cardiac O₂ consumption (Vo₂) and the total mechanical energy (TME) generated by contraction was studied under paired-pulse (PP) pacing and compared with that under single-pulse pacing at the same basic rate as PP pacing and at the double-pacing rate in ten excised cross-circulated canine left ventricles (LV). TME was assessed by the systolic pressure-volume (P–V) area (PVA) defined as the area bounded by the end-systolic and end-diastolic P–V curves and the systolic P–V trajectory. The Vo₂-PVA relation was linear under PP pacing as well as at control and double heart rates. PP pacing increased LV contractility index Emax from 6.3±3.3 (SD) to 18.0±8.6 mmHg/(ml/100 g) and elevated markedly the Vo₂-PVA relation by increasing the Vo₂-axis intercept (or PVA-independent Vo₂) from 0.62±0.11 to 1.13±0.35 J · beat^–1 · 100 g^–1. However, PP pacing did not change the slope of the Vo₂-PVA relation at 2.24±0.53 (dimensionless). The efficiency from PVA-dependent Vo₂ (total Vo₂-PVA-independent Vo₂) to PVA (= TME), calculated as the reciprocal of the slope of the Vo₂-PVA relation, was also constant at 47±11% regardless of PP pacing. These results are similar to previous results obtained by positive inotropic interventions with catecholamines and Ca²⁺. We conclude that PP pacing augments the PVA-independent Vo₂ for activation without affecting the efficiency of the contractile machinery to generate TME from the PVA-dependent Vo₂.     

Beneficial effects of iloprost in the stunned canine myocardium

The effect of the prostacyclin-mimetic, iloprost, on the reversibly damaged ("stunned") myocardium was studied in barbital-anesthetized, open-chest dogs subjected to 15 minutes of coronary artery occlusion and 3 hours of reperfusion. Regional myocardial segment shortening (%SS) was measured in the subendocardium of nonischemic and ischemic-reperfused areas by sonomicrometry. Iloprost was infused for 30 minutes beginning 15 minutes prior to occlusion (0.05 microgram/kg/min, ILO-LOW, or 0.1 microgram/kg/min, ILO-HIGH) or immediately prior to reperfusion (0.1 microgram/kg/min, ILO-REP). %SS in the ischemic-reperfused region recovered to 3% of pretreatment values in the control (saline-treated) group by 3 hours of reperfusion. In contrast, %SS in the iloprost-treated groups was significantly enhanced versus the control group at all times of reperfusion. At 3 hours of reperfusion, %SS recovered to 43% (ILO-LOW), 58% (ILO-HIGH), and 35% (ILO-REP) of pretreatment values. The beneficial effect on functional recovery was significantly greater when iloprost was administered before occlusion versus immediately prior to reperfusion. Thus, part of the salutory effects of iloprost appear to occur prior to and/or during ischemia. Iloprost did not improve collateral blood flow to the ischemic region or myocardial high energy phosphate content at 3 hours of reperfusion. While iloprost significantly decreased mean arterial pressure during ischemia and early reperfusion, the hypotensive action did not appear to play a role in the amelioration of postischemic dysfunction, as preocclusion treatment with an equihypotensive dose of sodium nitroprusside produced no significant effect on postischemic recovery beyond 5 minutes of reperfusion. Results of in vitro experiments indicated that iloprost had no effect on the xanthine oxidase free-radical generating system including lipid peroxidation. However, iloprost decreased the neutrophil-derived superoxide burst after chemotactic stimulation. This beneficial action may, in part, explain the efficacy of iloprost in enhancing postischemic function of the stunned myocardium.     

Excitation–contraction coupling in human heart failure examined by action potential clamp in rat cardiac myocytes

The effect of the loss of the notch in the human action potential (AP) during heart failure was examined by voltage clamping rat ventricular myocytes with human APs and recording intracellular Ca²⁺ with fluorescent dyes. Loss of the notch resulted in about a 50% reduction in the initial phase of the Ca²⁺ transient due to reduced ability of the l-type Ca²⁺ channel to trigger release. The failing human AP increased non-uniformity of cytosolic Ca²⁺, with some cellular regions failing to elicit Ca²⁺-induced Ca²⁺ release from the sarcoplasmic reticulum. In addition, there was an increase in the occurrence of late Ca²⁺ sparks. Monte-Carlo simulations of spark activation by l-type Ca²⁺ current supported the idea that the decreased synchrony of Ca²⁺ spark production associated with the loss of the notch could be explained by reduced Ca²⁺ influx from open Ca²⁺ channels. We conclude that the notch of the AP is critical for efficient and synchronous EC coupling and that the loss of the notch will reduce the SR Ca²⁺ release in heart failure, without changes in (for example) SR Ca²⁺-ATPase uptake.     

索他洛尔对离体猪右心室动作电位恢复特性的影响

目的评价索他洛尔对动作电位时限（APD）恢复特性的影响，以及索他洛尔抗心窀颤动（窒颤）作用是否与APD恢复特性有关。方法7只离体灌注猪的右心室，用微电极技术在基础状态、索他洛尔（1～10mg／L）灌注和洗脱（1h）时记录跨膜动作电位。在S1S2程序刺激和室颤期间，由动作电位复极90％时限（APD90）和舒张期构建APD恢复曲线。APD恢复最大斜半（Smax）由APD恢复曲线所扶得的资料计算。结果索他洛尔（5～10mg／L）延长APD90，减小S1S2起搏和窜颤的Smax，致使窀颤终止（n=2）、转化为室性心动过速（室速，n=3），室颤不能诱发（基础状态24．4％VS索他洛尔0％）以及室颤周期长度增加。结论索他洛尔延长APD90、减小APD恢复最大斜率而发挥抗室颤作用。     

Molecular and electrical characterization of the canine cardiac ventricular septum

Electrophysiological heterogeneity in the ventricular septum (VS) has been poorly addressed. In this study we investigated the electrophysiological and molecular composition of the VS in control sinus rhythm (SR) and chronic, complete atrio-ventricular block (CAVB) dogs. In the latter model, we anticipated that the increased inter-ventricular differences in action potential duration (APD; LV >RV) would accentuate the intrinsic heterogeneous composition of the VS. Steady-state mRNA levels of 10 important cardiac ion channels subunits as well as action potential (AP) characteristics (APD95, phase 1 amplitude (P1A), resting membrane potential) were measured in both sides of the VS excluding a small mid-myocardial strip (right: RVS, left: LVS). In SR, differences in steady-state mRNA between the two septal layers were observed for KChIP2 (approximately fivefold, P <0.01) and KCNQ1 (approximately twofold, P <0.05) with significantly higher levels of steady-state mRNA in the RVS compared to LVS. Correspondingly, shorter APDs and lower P1As (more spike and dome) were found in RVS, although the AP differences were subtle. This transseptal expression of KChIP2 and KCNQ1 corresponded with the observed differential expression levels in the right ventricle (RV) and left ventricular (LV) free wall, respectively. Electrical remodeling due to CAVB was also observed in the VS as was shown by approximately twofold lower levels in KCND3, KCNH2 and KCNQ1 mRNA (P <0.05) in the LVS compared to SR, thereby creating new or eliminating existing transseptal gradients. In parallel to changes in steady-state mRNA, CAVB resulted in a loss of the spike and dome morphology and longer APD95 (P <0.05) in the LVS. It is concluded that similar to other regions in the cardiac ventricles, the canine VS is molecularly and electrically heterogeneous. In the CAVB dog, this septal heterogeneity becomes accentuated as a result of electrical remodeling.