Cardiac Electrical Propagation Research Articles

Effects of Regional Mitochondrial Depolarization on Electrical Propagation

Sudden cardiac death often involves arrhythmias triggered by metabolic stress. Loss of mitochondrial function is thought to contribute to the arrhythmogenic substrate, but how mitochondria contribute to uncoordinated electrical activity is poorly understood. It has been proposed that the formation of metabolic current sinks, caused by the nonuniform collapse of mitochondrial inner membrane potential (ΔΨm), contributes to re-entrant arrhythmias because ΔΨm depolarization is tightly coupled to the activation of sarcolemmal ATP-sensitive K(+) channels, hastening action potential repolarization and shortening the refractory period. Here, we use computational and experimental methods to investigate how ΔΨm instability can induce re-entrant arrhythmias. We develop the first tissue-level model of cardiac electrical propagation incorporating cellular electrophysiology, excitation-contraction coupling, mitochondrial energetics, and reactive oxygen species balance. Simulations show that re-entry and fibrillation can be initiated by regional ΔΨm loss because of the disparity of refractory periods inside and outside the metabolic sink. Computational results are compared with the effects of a metabolic sink generated experimentally by local perfusion of a mitochondrial uncoupler in a monolayer of cardiac myocytes. The results demonstrate that regional mitochondrial depolarization triggered by oxidative stress activates sarcolemmal ATP-sensitive K(+) currents to form a metabolic sink. Consequent shortening of the action potential inside, but not outside, the sink increases the propensity for re-entry. ΔΨm recovery during pacing can lead to novel mechanisms of ectopic activation. The findings highlight the importance of mitochondria as potential therapeutic targets for sudden death associated with cardiovascular disease.

Efficient simulation of cardiac electrical propagation using high-order finite elements II: Adaptive p-version

We present a computationally efficient method of simulating cardiac electrical propagation using an adaptive high-order finite element method to automatically concentrate computational effort where it is most needed in space on each time-step. We drive the adaptivity using a residual-based error indicator, and demonstrate using norms of the error that the indicator allows us to control it successfully.Our results using two-dimensional domains of varying complexity demonstrate that significant improvements in efficiency are possible over the standard linear FEM in our single-thread studies, and our preliminary three-dimensional results suggest that improvements are also possible in 3D. We do not work in parallel or investigate the challenges for adaptivity such as dynamic load-balancing which are associated with parallelisation. However, based upon recent work demonstrating that in some circumstances and with moderate processor counts parallel h-adaptive methods are efficient, and upon the claim that p-adaptivity will outperform h-adaptivity, we argue that p-adaptivity should be investigated for efficiency in parallel for simulation on moderate numbers of processors.

Principles of Cardiac Electric Propagation and Their Implications for Re-entrant Arrhythmias

The study of clinical electrophysiology essentially comprises examining how electric excitation develops and spreads through the millions of cells that constitute the heart. Given the enormous number of cells in a human heart, there is an extremely large number of possible ways that the heart can behave. We encounter rhythms across the spectrum from the organized and orderly behavior of sinus rhythm through repetitive continuous excitation (via reentry) in structurally defined circuits like atrial flutter and, finally, the complex, dynamic, and disorganized behavior of fibrillation. Despite these myriad possibilities, one can apply a basic understanding of the principles of propagation to predict how cardiac tissue will behave under varied circumstances and in response to various manipulations. In this article, we review the principles of propagation and how these can be used to understand reentry of all degrees of complexity. We use these principles to explain the mechanisms by which antiarrhythmic medications and ablation can terminate and prevent reentry. This article is not intended to be an exhaustive description of the physiology of cardiac propagation, rather, it is meant to capture the essence of propagation with sufficient detail to provide an intuitive feel for the interplay of the physiological features relevant to propagation. The figures and videos used in this article were created using a computational model of cardiac propagation (VisibleEP LLC, Colchester, VT). It is a hybrid between a physics-based and cellular automaton model. The model incorporates the fundamental features of propagation without modeling individual ion channels.1 The model manifests several relevant emergent properties, for example, electrotonic interactions, restitution of action potential duration, and conduction velocity as well as source–sink balance–dependent propagation. ### Cell Excitation A cell becomes excited when the balance of inward and outward currents passes a critical point after which inward currents exceed outward and an action potential ensues. …

Introduction to the Series on Computational Approaches to Cardiac Arrhythmias

Of all the cardiac arrhythmias seen in clinical practice, atrial fibrillation (AF) and ventricular tachycardia/fibrillation (VT/VF) are among the leading causes of morbidity and mortality in the developed world. AF is the most common sustained arrhythmia and is associated with an increased risk of stroke, heart failure, dementia, and death.1–3 In developed nations overall prevalence of AF is 0.9% and the number of people affected is projected to more than double over the next 2 decades.3,4 VT/VF is the most important immediate cause of sudden cardiac death (SCD). Incidence of SCD is estimated to be 4 to 5 million cases per year worldwide.5,6 Thus arrhythmias and SCD are among the most significant manifestations of cardiovascular diseases worldwide, but their underlying mechanisms remain elusive. Arrhythmogenic substrates may be established by ischemia, infarction, heart failure and genetic mutations, all of which may cause inflammation, extracellular matrix remodeling, interstitial fibrosis, fatty infiltration, and changes in the 3-dimensional cellular architecture of the working myocardium.7,8 Over the last 17 years, the study of the molecular genetic basis of monogenic cardiac rhythm disorders, together with characterization of functional expression and biophysical properties of mutant channels from patients with inheritable ion channel diseases, has significantly advanced our understanding of the molecular basis of cardiac arrhythmias.9 Yet, this clearly has not been sufficient. Despite such advances, predictable prevention of AF or VF is currently not possible and the development of effective antiarrhythmic pharmacological agents has been extremely difficult. Not all questions related to arrhythmia mechanisms are directly answerable by reductionist experiments such as DNA sequencing or patch clamping. There is a hierarchy of questions whose levels are determined by the generality of the answers sought. Thus the question of what a mutation in an ion …

Na + Channel I–II Loop Mediates Parallel Genetic and Phosphorylation-Dependent Gating Changes

In this issue of Circulation , Koval et al1 show that 2 arrhythmogenic human cardiac Na+ channel (hNaV1.5) variants mimic the altered channel gating effects induced by Ca2+-calmodulin–dependent protein kinase (CaMKII). They also show that phosphorylation of an adjacent CaMKII target site on NaV1.5 is enhanced in human heart failure (HF) samples and in the border zone of postinfarcted canine hearts. Article see p 2084 The cardiac Na+ channel, NaV1.5, is responsible for inward Na+ current ( I Na) that drives the cardiac action potential (AP) upstroke and electrical impulse propagation.2 Genetic variants of the SCN5A gene encoding NaV1.5 are associated with long QT syndrome-3 (LQTs; gain of function), Brugada syndrome (BRs; loss of function), conduction system disease, sudden infant death syndrome, sick sinus syndrome, and dilated cardiomyopathy.3,4 These inherited channelopathies have been tremendously important to our understanding of normal NaV1.5 function and arrhythmia mechanisms. However, acquired forms of altered NaV1.5 function attributable to posttranslational modification (eg, phosphorylation or oxidation) may have pathophysiological consequences during ischemia/reperfusion or HF and thus reach a larger patient population. Indeed, half of all HF deaths are sudden and presumed to be attributable to lethal ventricular arrhythmias.5,6 The pore forming α subunit (NaV1.5; ≈220 Kd predicted MW) has 4 homologous domains (I–IV) with 6 transmembrane segments each (S1–S6; Figure 1), is glycosylated, and has auxiliary regulatory β subunits (β1–β4; ≈30–35 Kd).7 The S5–S6 linker includes the P-loops or pore region, the 4 S4 segments serve as voltage sensors (involved in activation gating), whereas an IFM motif in the DIII–IV linker is important for fast inactivation gating. Importantly, NaV1.5 forms a macromolecular complex with interacting proteins that …

A NUMERICAL SIMULATION OF CARDIAC ELECTRIC ACTIVITY IN LV BASED ON MONO-DOMAIN MODEL

Heterogeneities of ionic current expression and electrophysiological characteristics exist within the mammalian ventricle wall and are assumed to be the result of regional differences in myocardial membrane ionic current densities. This work describes computational approaches of modeling the cardiac cellular excitability and electrical activity propagation in the spatially inhomogeneous ventricular tissue. A three-dimensional (3D) unsteady Rogers model with one gating variable has been considered for simulating the cardiac electrical activity. Based on the paradigm of domain decomposition a 3D finite element scheme has been developed and implemented using PETSc Library under MPI environment. The numerical simulations are carried out on IBM SP3 machine. The computational studies provide insight into the underlying mechanisms during the normal and pathological cardiac excitation.

Abstract 1514: RXP-E: A Connexin43-Binding Peptide that Prevents Action Potential Propagation Block

Gap junctions (GJ’s) provide a low resistance pathway for cardiac electrical propagation. The role of GJ regulation in arrhythmias is unclear, partly due to the limited availability of pharmacological tools. Recently, we showed that a peptide called “RXP-E” binds to the carboxyl terminal of connexin43 (Cx43) and prevents chemically-induced uncoupling in Cx43-expressing N2a cells. Here, we used pull-down experiments to show that RXP-E binds to adult cardiac Cx43. Patch-clamp studies revealed that RXP-E prevented heptanol-induced and acidification-induced uncoupling in pairs of neonatal rat ventricular myocytes (NRVM’s). Separately, RXP-E was concatenated to a cytoplasmic transduction peptide for translocation into the cytoplasm (construct CTP-RXP-E). The effect of RXP-E on action potential (AP) propagation was assessed by high resolution optical mapping in monolayers of NRVMs, containing approximately 20% of randomly distributed myofibroblasts. Conduction velocity (CV) was 164 ± 8mm/sec (avg±SEM; n=12; pacing frequency 2Hz) in untreated cells, and 158±10mm/sec, (n=6) and 180±7mm/sec (n=10) in monolayers treated with CTP-RXPE or a scrambled version of the peptide (CTP-Scr), respectively (pNS). Exposure of either untreated, or CTP-Scr-treated monolayers to heptanol caused propagation block. However, when heptanol (2 mmol/L) was added to the superfusate of monolayers loaded with CTP-RXP-E, AP propagation was maintained, albeit at a slower velocity (87±5mm/sec;n=4; P<0.001). Similarly, intracellular acidification (pHi=6.2) caused a loss of AP propagation in control or CTP-Scr monolayers; however, propagation was maintained in CTP-RXP-E treated cells, though at a slower rate (CV=93 ± 28mm/sec; n=4). Consistent with these results, patch clamp experiments revealed that RXP-E did not prevent heptanol-induced block of sodium or calcium currents, nor did it alter the voltage dependence or amplitude of Kir2.1/Kir2.3 currents. RXP-E is the first synthetic molecule known to: bind cardiac Cx43; prevent heptanol and acidification-induced uncoupling of cardiac GJ’s and preserve AP propagation among cardiac myocytes. RXP-E can be used to characterize the role of GJ’s in the function of multicellular systems, including the heart. This research has received full or partial funding support from the American Heart Association, AHA Founders Affiliate (Connecticut, Maine, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, Vermont).

RXP-E

Gap junctions provide a low-resistance pathway for cardiac electric propagation. The role of GJ regulation in arrhythmia is unclear, partly because of limited availability of pharmacological tools. Recently, we showed that a peptide called "RXP-E" binds to the carboxyl terminal of connexin43 and prevents chemically induced uncoupling in connexin43-expressing N2a cells. Here, pull-down experiments show RXP-E binding to adult cardiac connexin43. Patch-clamp studies revealed that RXP-E prevented heptanol-induced and acidification-induced uncoupling in pairs of neonatal rat ventricular myocytes. Separately, RXP-E was concatenated to a cytoplasmic transduction peptide (CTP) for cytoplasmic translocation (CTP-RXP-E). The effect of RXP-E on action potential propagation was assessed by high-resolution optical mapping in monolayers of neonatal rat ventricular myocytes, containing approximately 20% of randomly distributed myofibroblasts. In contrast to control experiments, when heptanol (2 mmol/L) was added to the superfusate of monolayers loaded with CTP-RXP-E, action potential propagation was maintained, albeit at a slower velocity. Similarly, intracellular acidification (pH(i) 6.2) caused a loss of action potential propagation in control monolayers; however, propagation was maintained in CTP-RXP-E-treated cells, although at a slower rate. Patch-clamp experiments revealed that RXP-E did not prevent heptanol-induced block of sodium currents, nor did it alter voltage dependence or amplitude of Kir2.1/Kir2.3 currents. RXP-E is the first synthetic molecule known to: (1) bind cardiac connexin43; (2) prevent heptanol and acidification-induced uncoupling of cardiac gap junctions; and (3) preserve action potential propagation among cardiac myocytes. RXP-E can be used to characterize the role of gap junctions in the function of multicellular systems, including the heart.

Crosstalk between theoretical and experimental studies for the understanding of cardiac electrical impulse propagation

The repetitive electrical impulse generated by the sinoatrial node spreads rapidly through the atrial tissue and the atrioventricular node to the ventricles. Endocardial spread in the Purkinje system and subsequent endocardial-toepicardial spread in the working myocardium assure the rapid and coordinated excitation and subsequent mechanical contraction of the ventricles. The process of electrical impulse propagation involves downstream excitation of resting excitable myocardium by local circuit current generated by excited upstream tissue. It is determined (i) by the upstroke of the cardiac action potential, as the electrical driving force; (ii) tissue architecture; (iii) the electrical resistance of the extracellular space; and (iv) parameters that affect resistance to intraand intercellular current flow, such as cell-to-cell coupling by gap junctions, cell size, and cell surface-to-volume ratio. The complexity of this process is not only represented by the large number of variables but also by the fact that the variables interact in a highly complex manner. The advancement of computer technology during the past decades has critically enhanced our ability to investigate this complexity using increasingly sophisticated algorithms and shown that understanding the mechanisms of impulse propagation requires theoretical modeling. In the field of cardiac impulse propagation, the high degree of agreement between theoretical and experimental studies has strengthened our understanding of cardiac impulse propagation significantly. Although theoretical studies are probably the only tool that can (i) make us understand the complexities of interaction between the multitude of variables affecting impulse propagation and (ii)

Cellular uncoupling can unmask dispersion of action potential duration in ventricular myocardium. A computer modeling study.

Although slow conduction is a requirement for the preparation of sustained reentry, it alone is not sufficient for the initiation of reentry. Additionally, unidirectional block and recovery of excitability distal to the site of block must occur. Thus, a comprehensive description of the electrophysiological determinants of reentry must explain both slow conduction and unidirectional block. Although there is a growing body of research exploring the influence of axial resistivity and anisotropy on slow conduction, somewhat less is known about the relation of axial resistivity to spatial dispersion of action potential duration, a condition favorable to the development of unidirectional block. We hypothesized that when cells are well coupled, local differences in intrinsic action potential duration are not evident and that, as axial resistivity increases, local variation in action potential duration becomes manifest. We tested this hypothesis in a numerical model of electrical propagation in a grid of resistively coupled ionic current sources simulating a sheet of ventricular myocardium. Spatial dispersion of intrinsic action potential duration was simulated by varying the magnitude of the fully activated slow inward conductance in Beeler-Reuter membrane ionic kinetics. By then altering coupling resistance, we showed that dispersion of manifest action potential duration is masked in the setting of normal low-resistance cellular coupling and unmasked by increased axial resistance. When nonuniform anisotropy was simulated, dramatic pacing-site-dependent changes in both the pattern of activation and dispersion of action potential duration were noted. These findings may be important in understanding the mechanism of reentrant tachycardia initiation in the border zone of chronic, healed myocardial infarctions where evidence suggests that abnormal cellular coupling is the predominant electrophysiological derangement. In this study, we have shown, using a detailed ionic current-based model of cardiac electrical propagation, that changes in axial resistivity can modulate how spatial dispersion of intrinsic action potential duration is manifest.