Restitution Curve Research Articles

Electrophysiology of Heart Failure Using a Rabbit Model: From the Failing Myocyte to Ventricular Fibrillation.

Heart failure is a leading cause of death, yet its underlying electrophysiological (EP) mechanisms are not well understood. In this study, we use a multiscale approach to analyze a model of heart failure and connect its results to features of the electrocardiogram (ECG). The heart failure model is derived by modifying a previously validated electrophysiology model for a healthy rabbit heart. Specifically, in accordance with the heart failure literature, we modified the cell EP by changing both membrane currents and calcium handling. At the tissue level, we modeled the increased gap junction lateralization and lower conduction velocity due to downregulation of Connexin 43. At the biventricular level, we reduced the apex-to-base and transmural gradients of action potential duration (APD). The failing cell model was first validated by reproducing the longer action potential, slower and lower calcium transient, and earlier alternans characteristic of heart failure EP. Subsequently, we compared the electrical wave propagation in one dimensional cables of healthy and failing cells. The validated cell model was then used to simulate the EP of heart failure in an anatomically accurate biventricular rabbit model. As pacing cycle length decreases, both the normal and failing heart develop T-wave alternans, but only the failing heart shows QRS alternans (although moderate) at rapid pacing. Moreover, T-wave alternans is significantly more pronounced in the failing heart. At rapid pacing, APD maps show areas of conduction block in the failing heart. Finally, accelerated pacing initiated wave reentry and breakup in the failing heart. Further, the onset of VF was not observed with an upregulation of SERCA, a potential drug therapy, using the same protocol. The changes introduced at the cell and tissue level have increased the failing heart’s susceptibility to dynamic instabilities and arrhythmias under rapid pacing. However, the observed increase in arrhythmogenic potential is not due to a steepening of the restitution curve (not present in our model), but rather to a novel blocking mechanism.

A Mathematical Model of Neonatal Rat Atrial Monolayers with Constitutively Active Acetylcholine-Mediated K+ Current.

Atrial fibrillation (AF) is the most frequent form of arrhythmia occurring in the industrialized world. Because of its complex nature, each identified form of AF requires specialized treatment. Thus, an in-depth understanding of the bases of these arrhythmias is essential for therapeutic development. A variety of experimental studies aimed at understanding the mechanisms of AF are performed using primary cultures of neonatal rat atrial cardiomyocytes (NRAMs). Previously, we have shown that the distinct advantage of NRAM cultures is that they allow standardized, systematic, robust re-entry induction in the presence of a constitutively-active acetylcholine-mediated K+ current (IKACh-c). Experimental studies dedicated to mechanistic explorations of AF, using these cultures, often use computer models for detailed electrophysiological investigations. However, currently, no mathematical model for NRAMs is available. Therefore, in the present study we propose the first model for the action potential (AP) of a NRAM with constitutively-active acetylcholine-mediated K+ current (IKACh-c). The descriptions of the ionic currents were based on patch-clamp data obtained from neonatal rats. Our monolayer model closely mimics the action potential duration (APD) restitution and conduction velocity (CV) restitution curves presented in our previous in vitro studies. In addition, the model reproduces the experimentally observed dynamics of spiral wave rotation, in the absence and in the presence of drug interventions, and in the presence of localized myofibroblast heterogeneities.

Biophysical Modeling Predicts Ventricular Tachycardia Inducibility and Circuit Morphology: A Combined Clinical Validation and Computer Modeling Approach.

Computational modeling of cardiac arrhythmogenesis and arrhythmia maintenance has made a significant contribution to the understanding of the underlying mechanisms of arrhythmia. We hypothesized that a cardiac model using personalized electro-anatomical parameters could define the underlying ventricular tachycardia (VT) substrate and predict reentrant VT circuits. We used a combined modeling and clinical approach in order to validate the concept. Non-contact electroanatomic mapping studies were performed in 7 patients (5 ischemics, 2 non-ischemics). Three ischemic cardiomyopathy patients underwent a clinical VT stimulation study. Anatomical information was obtained from cardiac magnetic resonance imaging (CMR) including high-resolution scar imaging. A simplified biophysical mono-domain action potential model personalized with the patients' anatomical and electrical information was used to perform in silico VT stimulation studies for comparison. The personalized in silico VT stimulations were able to predict VT inducibility as well as the macroscopic characteristics of the VT circuits in patients who had clinical VT stimulation studies. The patients with positive clinical VT stimulation studies had wider distribution of action potential duration restitution curve (APD-RC) slopes and APDs than the patient with a negative VT stimulation study. The exit points of reentrant VT circuits encompassed a higher percentage of the maximum APD-RC slope compared to the scar and non-scar areas, 32%, 4%, and 0.2%, respectively. VT stimulation studies can be simulated in silico using a personalized biophysical cardiac model. Myocardial spatial heterogeneity of APD restitution properties and conductivity may help predict the location of crucial entry/exit points of reentrant VT circuits.

136-01: Repolarization Changes From Remodelling Explain Why Persistent Atrial Fibrillation Responds Less Well To Pulmonary Vein Isolation

Introduction: It is not clear why persistent (AF) is less trigger dependent than paroxysmal AF and responds less well to pulmonary vein isolation (PVI). We hypothesized that structural remodelling may flatten left atrial APD restitution, reducing the ability of a trigger to cause APD oscillations in persistent AF patients. Methods: Monophasic action potentials (MAP) were recorded in 47 patients (61 ± 9 years, LA 44 ± 6mm, 52% persistent AF) near the PV antra during pacing. We plotted MAP duration restitution cycle length (CL) dependence of APD90, i.e. the time from monophasic action potential (MAP) upstroke to 90% repolarization, as a restitution curve, and calculated its maximum slope. ERP was defined routinely. Both factors were related to LA size to assess structural remodelling. Results: Dynamic ERP tracked APD in remodelled human LA (Fig A; p < 0.05). Fig B shows an AF trigger engaging steep APD restitution (C) to initiate AF. Fig D shows that APD restitution slope correlated negatively with LA diameter (p < 0.05). Compared to patients with paroxysmal AF, those with persistent AF (remodelled atria) had shorter APD90 (236 ± 35 vs 284 ± 46ms, p < 0.01), flatter APD restitution (0.67 ± 0.2 vs 1.5 ± 0.4, p < 0.001) and shorter ERP (204 ± 28 vs 241 ± 38ms, p = 0.01).

Personalized Models of Human Atrial Electrophysiology Derived From Endocardial Electrograms.

Computational models represent a novel framework for understanding the mechanisms behind atrial fibrillation (AF) and offer a pathway for personalizing and optimizing treatment. The characterization of local electrophysiological properties across the atria during procedures remains a challenge. The aim of this work is to characterize the regional properties of the human atrium from multielectrode catheter measurements. We propose a novel method that characterizes regional electrophysiology properties by fitting parameters of an ionic model to conduction velocity and effective refractory period restitution curves obtained by a s1-s2 pacing protocol applied through a multielectrode catheter. Using an in-silico dataset we demonstrate that the fitting method can constrain parameters with a mean error of 21.9 ± 16.1% and can replicate conduction velocity and effective refractory curves not used in the original fitting with a relative error of 4.4 ± 6.9%. We demonstrate this parameter estimation approach on five clinical datasets recorded from AF patients. Recordings and parametrization took approx. 5 and 6 min, respectively. Models fitted restitution curves with an error of ~ 5% and identify a unique parameter set. Tissue properties were predicted using a two-dimensional atrial tissue sheet model. Spiral wave stability in each case was predicted using tissue simulations, identifying distinct stable (2/5), meandering and breaking up (2/5), and unstable self-terminating (1/5) spiral tip patterns for different cases. We have developed and demonstrated a robust and rapid approach for personalizing local ionic models from a clinically tractable.

Local Heterogeneous Electrical Restitution Properties of Rabbit Atria.

This study aims to characterize the regional variability in rate-adaptation in the atria. Action potential (AP) responses to pulses with uniform as well as pseudo-random non-uniform pacing intervals were recorded from rabbit sino-atrial node, right and left atrial pectinate as well as pulmonary vein antrum tissue preparations using conventional intracellular glass microelectrodes. Steady-state restitution curves were reconstructed for various AP waveform metrics. We observed significant variability between the four regions under basal pacing representing the rabbit resting heart rate as well as regional variability in rate-adaptation to increased pacing frequencies. Right-left atrial restitution differences were further confirmed using the non-uniform pacing protocol, with significant differences in AP amplitude, duration (APD) as well as maximum phase 0 depolarization rate restitution curves in response to an identical sequence of non-uniform pacing intervals. In addition, we report regional differences in alternans of AP waveform metrics, over a wide range of pacing frequencies and not simply prior to 1:1 entrainment being lost. We also observed an increase in APD90 along the conduction pathway from the left atrium to pulmonary vein junction. Our results identified significant regional differences in electrical restitution in the rabbit atria and suggest their dependency on both baseline AP morphology and local intrinsic differences in rate-adaptation. We propose that the atrial heterogeneity in rate-adaptation could contribute to arrhythmogenesis and the greater susceptibility of pulmonary vein myocardial sleeves to ectopic foci and reentrant activity.

Protection against ventricular fibrillation via cholinergic receptor stimulation and the generation of nitric oxide.

Key points Animal studies suggest an anti‐fibrillatory action of the vagus nerve on the ventricle, although the exact mechanism is controversial.Using a Langendorff perfused rat heart, we show that the acetylcholine analogue carbamylcholine raises ventricular fibrillation threshold (VFT) and flattens the electrical restitution curve.The anti‐fibrillatory action of carbamylcholine was prevented by the nicotinic receptor antagonist mecamylamine, inhibitors of neuronal nitric oxide synthase (nNOS) and soluble guanylyl cyclase (sGC), and can be mimicked by the nitric oxide (NO) donor sodium nitroprusside.Carbamylcholine increased NO metabolite content in the coronary effluent and this was prevented by mecamylamine.The anti‐fibrillatory action of both carbamylcholine and sodium nitroprusside was ultimately dependent on muscarinic receptor stimulation as all effects were blocked by atropine.These data demonstrate a protective effect of carbamylcholine on VFT that depends upon both muscarinic and nicotinic receptor stimulation, where the generation of NO is likely to be via a neuronal nNOS–sGC dependent pathway. Implantable cardiac vagal nerve stimulators are a promising treatment for ventricular arrhythmia in patients with heart failure. Animal studies suggest the anti‐fibrillatory effect may be nitric oxide (NO) dependent, although the exact site of action is controversial. We investigated whether a stable analogue of acetylcholine could raise ventricular fibrillation threshold (VFT), and whether this was dependent on NO generation and/or muscarinic/nicotinic receptor stimulation. VFT was determined in Langendorff perfused rat hearts by burst pacing until sustained VF was induced. Carbamylcholine (CCh, 200 nmol l–1, n = 9) significantly (P < 0.05) reduced heart rate from 292 ± 8 to 224 ± 6 b.p.m. Independent of this heart rate change, CCh caused a significant increase in VFT (control 1.5 ± 0.3 mA, CCh 2.4 ± 0.4 mA, wash 1.1 ± 0.2 mA) and flattened the restitution curve (n = 6) derived from optically mapped action potentials. The effect of CCh on VFT was abolished by a muscarinic (atropine, 0.1 μmol l−1, n = 6) or a nicotinic receptor antagonist (mecamylamine, 10 μmol l−1, n = 6). CCh significantly increased NOx content in coronary effluent (n = 8), but not in the presence of mecamylamine (n = 8). The neuronal nitric oxide synthase inhibitor AAAN (N‐(4S)‐4‐amino‐5‐[aminoethyl]aminopentyl‐N′‐nitroguanidine; 10 μmol l−1, n = 6) or soluble guanylate cyclase (sGC) inhibitor ODQ (1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one; 10 μmol l−1, n = 6) prevented the rise in VFT with CCh. The NO donor sodium nitrprusside (10 μmol l–1, n = 8) mimicked the action of CCh on VFT, an effect that was also blocked by atropine (n = 10). These data demonstrate a protective effect of CCh on VFT that depends upon both muscarinic and nicotinic receptor stimulation, where the generation of NO is likely to be via a neuronal nNOS/sGC‐dependent pathway.

Transient Outward Potassium Current and its Arrhythmogenic Dynamics in Cardiac Myocytes

The transient outward K+ current (Ito) is a main contributor to repolarization during the cardiac action potential in cardiac myocytes, which may play important roles in arrhythmogenesis in cardiac diseases including ischemia, Brugada syndrome, and heart failure. Previous experimental and computer modeling studies have shown that Ito can cause complex action potential dynamics (alternans and chaos), which can potentiate phase-2 reentry. However, the underlying mechanisms are not well understood. In this study, we carried out computer simulations and developed simplified mathematical models (iterated maps) to reveal the mechanisms of Ito-induced complex action potential dynamics. We showed that: 1) Ito induces short-term cardiac memory via its interactions with a slowly activating K+ current (IKs) and the L-type Ca2+ current (ICa,L), which promotes alternans during the physiological heart rate. This can be a candidate mechanism for T-wave alternans widely seen in patients with Brugada syndrome; 2) Ito gives rise to two different types of non-monotonic restitution curves. In the presence of rapidly recovering Ito, as the diastolic interval increases, the action potential duration is short at short diastolic intervals (DIs), increases sharply at a certain range of DIs, and saturates at large DIs. In the presence of slowly recovering Ito, the action potential duration is normal at short DIs, decreases sharply at a certain range of DIs, and becomes short at large DIs. These restitution curves along with short-term memory induced by Ito can give rise to complex action potential dynamics and chaos. In conclusion, using both computer simulation and simplified mathematical models, we can pinpoint the underlying mechanisms for the complex arrhythmogenic action potential dynamics induced by Ito.

In Vivo and In Silico Investigation Into Mechanisms of Frequency Dependence of Repolarization Alternans in Human Ventricular Cardiomyocytes.

Repolarization alternans (RA) are associated with arrhythmogenesis. Animal studies have revealed potential mechanisms, but human-focused studies are needed. RA generation and frequency dependence may be determined by cell-to-cell variability in protein expression, which is regulated by genetic and external factors. To characterize in vivo RA in human and to investigate in silico using human models, the ionic mechanisms underlying the frequency-dependent differences in RA behavior identified in vivo. In vivo electrograms were acquired at 240 sites covering the epicardium of 41 patients at 6 cycle lengths (600-350 ms). In silico investigations were conducted using a population of biophysically detailed human models incorporating variability in protein expression and calibrated using in vivo recordings. Both in silico and in vivo, 2 types of RA were identified, with Fork- and Eye-type restitution curves, based on RA persistence or disappearance, respectively, at fast pacing rates. In silico simulations show that RA are strongly correlated with fluctuations in sarcoplasmic reticulum calcium, because of strong release and weak reuptake. Large L-type calcium current conductance is responsible for RA disappearance at fast frequencies in Eye-type (30% larger in Eye-type versus Fork-type; P<0.01), because of sarcoplasmic reticulum Ca(2+) ATPase pump potentiation caused by frequency-induced increase in intracellular calcium. Large Na(+)/Ca(2+) exchanger current is the main driver in translating Ca(2+) fluctuations into RA. In human in vivo and in silico, 2 types of RA are identified, with RA persistence/disappearance as frequency increases. In silico, L-type calcium current and Na(+)/Ca(2+) exchanger current determine RA human cell-to-cell differences through intracellular and sarcoplasmic reticulum calcium regulation.

Supernormal Conduction and Suppression of Spatially Discordant Alternans of Cardiac Action Potentials.

Spatially discordant alternans (DA) of action potential durations (APD) is thought to be more pro-arrhythmic than concordant alternans. Super normal conduction (SNC) has been reported to suppress formation of DA. An increase in conduction velocity (CV) as activation rate increases, i.e., a negative CV restitution, is widely considered as hallmark of SNC. Our aim in this study is to show that it is not an increase in CV for faster rates that prevents formation of DA, rather, it is the ratio of the CV for the short relative to the long activation that is critical in DA suppression. To illustrate this subtlety, we simulated this phenomenon using two approaches; (1) by using the standard, i.e., S1S2 protocol to quantify restitution and disabling the slow inactivation gate j of the sodium current (INa), and (2) by using the dynamic, i.e., S1S1 protocol for quantification of restitution and increasing INa at different cycle lengths (CL). Even though both approaches produced similar CV restitution curves, DA was suppressed only during the first approach, where the CV of the short of the long-short action potential (AP) pattern was selectively increased. These results show that negative CV restitution, which is considered characteristic of SNC, per se, is not causal in suppressing DA, rather, the critical factor is a change in the ratio of the velocities of the short and the long APs.

Inducibility of human atrial fibrillation in an in silico model reflecting local acetylcholine distribution and concentration.

Vagal nerve activity has been known to play a crucial role in the induction and maintenance of atrial fibrillation (AF). However, it is unclear how the distribution and concentration of local acetylcholine (ACh) promotes AF. In this study, we investigated the effect of the spatial distribution and concentration of ACh on fibrillation patterns in an in silico human atrial model. A human atrial action potential model with an ACh-dependent K+ current (IKAch) was used to examine the effect of vagal activation. A simulation of cardiac wave dynamics was performed in a realistic 3D model of the atrium. A model of the ganglionated plexus (GP) and nerve was developed based on the "octopus hypothesis". The pattern of cardiac wave dynamics was examined by applying vagal activation to the GP areas or randomly. AF inducibility in the octopus hypothesis-based GP and nerve model was tested. The effect of the ACh concentration level was also examined. In the single cell simulation, an increase in the ACh concentration shortened APD90 and increased the maximal slope of the restitution curve. In the 3D simulation, a random distribution of vagal activation promoted wavebreaks while ACh secretion limited to the GP areas did not induce a noticeable change in wave dynamics. The octopus hypothesis-based model of the GP and nerve exhibited AF inducibility at higher ACh concentrations. In conclusion, a 3D in silico model of the GP and parasympathetic nerve based on the octopus model exhibited higher AF inducibility with higher ACh concentrations.

Simultaneous conduction mapping and intracellular membrane potential recording in isolated atria.

We describe a novel approach for simultaneously determining regional differences in action potential (AP) morphology and tissue electrophysiological properties in isolated atria. The epicardial surface of rat atrial preparations was placed in contact with a multi-electrode array (9 × 10 silver chloride electrodes, 0.1 mm diameter and 0.1 mm pitch). A glass microelectrode (100 MΩ) was simultaneously inserted into the endocardial surface to record intracellular AP from either of 2 regions (A, B) during pacing from 2 opposite corners of the tissue. AP duration at 80% of repolarisation and its restitution curve was significantly different only in region A (p < 0.01) when AP was initiated at different stimulation sites. Alternans in AP duration and AP amplitude, and in conduction velocity were observed during 2 separate arrhythmic episodes. This approach of combining microelectrode array and intracellular membrane potential recording may provide new insights into arrhythmogenic mechanisms in animal models of cardiovascular disease.

The roles of pacing interval and pacing strength in ventricular fibrillation induced by rapid pacing with 1 : 1 capture.

IntroductionThe roles of pacing interval (PI) and pacing strength (PS) in ventricular fibrillation (VF) induced by rapid pacing with 1 : 1 capture remain unclear.Material and methodsEpicardial unipolar electrograms (UEs) were simultaneously recorded using contact mapping in 11 swine. Activation-recovery interval (ARI) restitution was constructed at 4 sites, i.e. the apex and base of the left and right ventricles, respectively. A steady state pacing (SSP) protocol was performed to induce VF. The longest PI and the lowest PS for inducing VF were recorded. Statistical correlation analysis was performed to determine the relationship between local ARI restitution properties and PI and PS for VF induction.ResultsForty restitution curves were constructed from 11 SSP procedures. The maximal slope (Smax) of the ARI restitution curve of the right ventricular apex was positively correlated with the PI for VF induction (r = 0.761, p < 0.05). Spatial dispersions of ARI and Smax were negatively correlated with the PS for VF induction (r = –0.626 and r = –0.722, respectively, both p < 0.05).ConclusionsVentricular fibrillation can be induced by rapid ventricular pacing with 1 : 1 capture. The PI for VF induction was related to the Smax of the ARI restitution curve of the right ventricular apex, while PS for VF induction was associated with the spatial dispersions of ARI and its restitution property.

Receptor for Advanced Glycation End Products Suppressed Arrhythmia by Reducing Infarct Size and Fibrosis in Ischemia Reperfusion Rat Model

Background and Objectives: The role of the receptor for advanced glycation end products (RAGE) blockers in the arrhythmogenic effect after myocardial infarction remains unclear. In this study, we evaluated the anti-arrhythmogenic effects of RAGE in an ischemia reperfusion (IR) model. Subject and Methods: IR was performed by ligation of the left anterior descending artery for 1 h in 8-week-old male Sprague-Dawley rats. A RAGE-siRNA polyplex combined with a polyethyleneiminemodified with deoxycholic acid (PEI-DA) was delivered to the heart. Rats were randomly divided into the following four groups: 1) control (sham operation, n=10), 2) IR (IR only, n=11), 3) IR+siRAGE (IR and RAGE-siRNA injection, n=10), and 4) IR+scRNA (IR and scrambled siRNA injection, n=9). Results: In the IR group, 6 (55%) of 11 rats died suddenly at 46 ± 14 min after acute myocardial infarction. However, no rats died in the control or IR+siRAGE groups. The IR+siRAGE group showed a better survival rate than the IR group (p=0.03). IR+siRAGE prevented arrhythmia (10% vs. 50%, p=0.02) compared with IR only. In Langendorff-perfused rat hearts, the IR+siRAGE group showed decreased action potential duration (121 ± 10, vs. 162 ± 60 ms, p=0.001), maximum slope of the action potential duration restitution curve (0.34 ± 0.09 vs. 1.14 ± 0.26, p<0.001), and inducible ventricular tachycardia (0% vs. 71%, p=0.01) compared to the IR group. However, these protective effects were not observed in the IR+scRNA group. The IR+siRAGE group showed significantly reduced infarct size and fibrosis compared to the IR group. Conclusion: RAGE-siRNA polyplexes combined with polyethyleneimine-modified with deoxycholic acid suppressed arrhythmia by reducing infarct size and fibrosis in a rat IR model.

Sympathetic denervation of heart and kidney induces similar effects on ventricular electrophysiological properties.

We aimed to investigate whether sympathetic denervation of the heart and kidney had similar effects on ventricular effective refractory period (ERP) and action potential duration (APD) restitution properties in a canine model. Twenty-four anaesthetised open-chest dogs (17-20 kg) were assigned to a sham operation group (n=8), a cardiac sympathetic denervation group (CSD, n=8) or a renal sympathetic denervation group (RSD, n=8). CSD was performed by ablating the caudal half of the LSG and T2-T4 thoracic sympathetic ganglia, while RSD was performed by ablating four sites on the adventitial surface of each renal artery. The ventricular electrophysiological properties were determined at four time points: baseline, 0 min, 30 min, and 60 min after interventions. The results showed that, when compared to the control group at the time point of 60 min after interventions, both CSD and RSD significantly reduced heart rate, prolonged the QT interval and ventricular ERP and APD, decreased the ERP dispersion and the slopes of APD restitution curves, and suppressed the APD alternans without affecting blood pressure and corrected QT interval. However, there were no significant differences in these parameters between CSD and RSD groups at the same time point. This study showed that sympathetic denervation of the heart and kidney induced similar electrophysiological effects in ventricles.

Representing variability and transmural differences in a model of human heart failure.

During heart failure (HF) at the cellular level, the electrophysiological properties of single myocytes get remodeled, which can trigger the occurrence of ventricular arrhythmias that could be manifested in many forms such as early afterdepolarizations (EADs) and alternans (ALTs). In this paper, based on experimentally observed human HF data, specific ionic and exchanger current strengths are modified from a recently developed human ventricular cell model: the O'Hara-Virág-Varró-Rudy (OVVR) model. A new transmural HF-OVVR model is developed that incorporates HF changes and variability of the observed remodeling. This new heterogeneous HF-OVVR model is able to replicate many of the failing action potential (AP) properties and the dynamics of both [Ca(2+)]i and [Na(+)]i in accordance with experimental data. Moreover, it is able to generate EADs for different cell types and exhibits ALTs at modest pacing rate for transmural cell types. We have assessed the HF-OVVR model through the examination of the AP duration and the major ionic currents' rate dependence in single myocytes. The evaluation of the model comes from utilizing the steady-state (S-S) and S1-S2 restitution curves and from probing the accommodation of the HF-OVVR model to an abrupt change in cycle length. In addition, we have investigated the effect of chosen currents on the AP properties, such as blocking the slow sodium current to shorten the AP duration and suppress the EADs, and have found good agreement with experimental observations. This study should help elucidate arrhythmogenic mechanisms at the cellular level and predict unseen properties under HF conditions. In addition, this AP cell model might be useful for modeling and simulating HF at the tissue and organ levels.

The Relationship Between Cardiac Vulnerability and Restitution Properties of the Ventricular Activation Recovery Interval

The restitution of the action potential duration (APD) is an important contributor to ventricular fibrillation (VF) initiation by a single critically timed ectopic beat. We hypothesized that a steep slope of the activation recovery interval restitution curve was related to the upper limit of vulnerability (ULV). Fifty-four consecutive patients with implantable cardioverter defibrillators (ICDs) implanted between April 2012 and July 2013 were included. At the implantation, pacing from the right ventricular (RV) coil to an indifferent electrode inserted in the ICD pocket was performed, and the unipolar electrograms from the RV coil were simultaneously recorded. We assessed the standard restitution by introducing extra-stimuli, while measuring the activation recovery interval (ARI). Our protocol for the vulnerability test consisted of delivering three 15 J shocks on the T-peak and within ±20 milliseconds of it. If VF was not induced by that procedure, a ULV of ≤15 J was defined. The relationship between the ULV and maximum slope of the restitution curve was analyzed. A restitution curve could finally be obtained in a total of 40 patients. The background characteristics were similar between the two groups. The maximum slope of the restitution curve was steeper in the ULV > 15 J group than ULV ≤ 15 J group (1.55 ± 0.45 vs. 0.91 ± 0.64, P < 0.05). A maximum slope exceeding 1.0 was the optimal point for discriminating patients with a ULV > 15 J from a ULV ≤ 15 J (sensitivity 61.5% and specificity 96.3%). The maximum slope of the restitution curve was significantly related to the ULV. High defibrillation threshold patients could be detected by the ARI dynamics.

0298 : Action potential shortening in the pig right ventricular outflow tract epicardium

The right ventricular outflow tract (RVOT) has a distinct embryological origin from the rest of the right ventricle (RV) and is a frequent origin for idiopathic and disease-related arrhythmias. We hypothesised that heterogeneous action potential duration (APD) across the right ventricle (RV) may contribute to RVOT arrhythmia generation. Pigs were anesthetized and monophasic action potentials (MAPs) recorded in sinus rhythm from the epicardium of the RV free wall and RVOT. The RV was isolated and perfused via both right and left anterior coronary arteries. The preparation was paced (1-5Hz) and the electrical activity optically mapped (di-4-ANEPPS, 10μM) on both epicardial (EPI) and endocardial (ENDO) surfaces. The expression of potassium channels was assessed by RT-PCR. In vivo, MAP durations measured at 20% and 80% repolarization were both significantly shorter in the RVOT than in the RV free wall EPI (P<0.05). Similar APD variations were observed ex vivo as RVOT APD20 and APD80 were decreased by 29% and 15% respectively compared to free wall (P<0.01). Interestingly, no APD difference was observed on the ENDO resulting in a larger transmural APD difference in the RVOT than in the RV free wall. The RVOT EPI APD80 shortening was preserved over a range of stimulation frequencies leading to a downward shift of the restitution curve and a significant decrease of its slope (P<0.05). In accordance with these results, expression level of mRNA coding for Kv4.3 (Ito) and Kv11.1 (IKr) were upregulated in the RVOT compared to the RV free wall epicardium (P<0.01) while no difference was found for Kv7.1 (IKs) or Kv4.2 (Ito). Moreover, no variation in K+ channel expression was observed across the RV endocardium. Action potentials are shorter in the RVOT than elsewhere in the RV EPI. This electrophysiological signature was mirrored by regional variations in specific K+ channels. The resulting APD dispersion may facilitate RV re-entrant arrhythmias in the context of a RVOT ectopy.

Cardiac contraction induces discordant alternans and localized block.

In this paper we use a simplified model of cardiac excitation-contraction coupling to study the effect of tissue deformation on the dynamics of alternans, i.e., alternations in the duration of the cardiac action potential, that occur at fast pacing rates and are known to be proarrhythmic. We show that small stretch-activated currents can produce large effects and cause a transition from in-phase to off-phase alternations (i.e., from concordant to discordant alternans) and to conduction blocks. We demonstrate numerically and analytically that this effect is the result of a generic change in the slope of the conduction velocity restitution curve due to electromechanical coupling. Thus, excitation-contraction coupling can potentially play a relevant role in the transition to reentry and fibrillation.

Modulation of Action Potential Alternans by IKs in Myocardial Infarction

Background: Patients with post myocardial infarction (MI) have increased incidence of ventricular arrhythmias. The slowly activating K+ channels (IKs) has been reported to be downregulated consistently but in different degrees in the post-MI hearts. The role of downregulation of IKs in arrhythmogenesis in post MI remains to be defined.Hypothesis: We hypothesize that significant suppression of IKs in post MI impairs the rate-dependent and Ca2+-dependent augmentation of repolarization reserve resulting in increased alternans and thereby arrhythmias.Methods: We evaluated the effect of IKs on alternans in post MI using transgenic rabbit model of Long QT Type 1 (LQT1) lacking IKs. LQT1 and littermate control (LMC) rabbits underwent MI procedures and optical mapping was performed to record Vm and Ca2+ simultaneously from the 3 week post-MI hearts (n=9 LQT1-MI, 4 LQT-MI Sham, 10 LMC-MI, 9 LMC-Sham hearts).Results: The dispersion of APD was enhanced in LQT1-MI compared to LQT1-Sham and LMC-MI (αAPDmax-min = 28±4 ms vs. 20±3 ms and 27±6 ms). APD alternans was more pronounced in LQT1-MI, accompanied with large amplitude Ca2+ alternans, and often spatially discordant (see traces and restitution curves in panel A&B). Spatially discordant alternans in LQT1-MI was highly dynamic, preceded by sudden appearance of Ca2+ nodal lines near the MI border zone (panel C, dark lines), associated with high VF induction (n=9/9 LQT1-MI vs. 1/4 LQT1-sham and 7/10 LMC-MI).Conclusion: Our results demonstrate the importance of IKs as a repolarization reserve in MI and that significant downregulation of IKs may promote spatially discordant Ca2+ and APD alternans and VF induction.