Ultrastructure and cardiac impulse propagation: scaling up from microscopic to macroscopic conduction.

The standard conception of cardiac conduction is based on the cable theory of nerve conduction, which treats cardiac tissue as a continuous syncytium described by the Hodgkin-Huxley equations. However, cardiac tissue is composed of discretized cells with microscopic and macroscopic heterogeneities and discontinuities, such as subcellular localizations of sodium channels and connexins. In addition to this, there are heterogeneities in the distribution of sympathetic and parasympathetic nerves, which powerfully regulate impulse propagation.

Curvature-mediated source and sink effects on the genesis of premature ventricular complexes in long QT syndrome.

Premature ventricular complexes (PVCs) are spontaneous excitations occurring in the ventricles of the heart that are associated with ventricular arrhythmias and sudden cardiac death. Under long QT conditions, PVCs can be mediated by repolarization gradient (RG) and early afterdepolarizations (EADs), yet the effects of heterogeneities or geometry of the RG or EAD regions on PVC genesis remain incompletely understood. In this study, we use computer simulation to systematically investigate the effects of the curvature of the RG border region on PVC genesis under long QT conditions.

Intracellular ion accumulation in the genesis of complex action potential dynamics under cardiac diseases.

Intracellular ions, including sodium (Na^{+}), calcium (Ca^{2+}), and potassium (K^{+}), etc., accumulate slowly after a change of the state of the heart, such as a change of the heart rate. The goal of this study is to understand the roles of slow ion accumulation in the genesis of cardiac memory and complex action-potential duration (APD) dynamics that can lead to lethal cardiac arrhythmias.

Dissecting the roles of calcium cycling and its coupling with voltage in the genesis of early afterdepolarizations in cardiac myocyte models.

Early afterdepolarizations (EADs) are abnormal depolarizations during the plateau phase of the action potential, which are known to be associated with lethal arrhythmias in the heart. There are two major hypotheses for EAD genesis based on experimental observations, i.e.

Bistable spiral wave dynamics in electrically excitable media.

We show that a positive feedback loop between sodium current inactivation and wave-front ramp-up speed causes a saddle-node bifurcation to result in bistable planar and spiral waves in electrically excitable media, in which both slow and fast waves are triggered by different stimulation protocols. Moreover, the two types of spiral wave conduction may interact to give rise to more complex spiral wave dynamics. The transitions between different spiral wave behaviors via saddle-node bifurcation can be a candidate mechanism for transitions widely seen in cardiac arrhythmias and neural diseases.

Phase 2 Re-Entry Without I: Role of Sodium Channel Kinetics in Brugada Syndrome Arrhythmias.

Background: In Brugada syndrome (BrS), phase 2 re-excitation/re-entry (P2R) induced by the transient outward potassium current (I) is a proposed arrhythmia mechanism; yet, the most common genetic defects are loss-of-function sodium channel mutations.

Objectives: The authors used computer simulations to investigate how sodium channel dysfunction affects P2R-mediated arrhythmogenesis in the presence and absence of I.

Methods: Computer simulations were carried out in 1-dimensional cables and 2-dimensional tissue using guinea pig and human ventricular action potential models.

Heterogeneous cardiac sympathetic innervation gradients promote arrhythmogenesis in murine dilated cardiomyopathy.

Ventricular arrhythmias (VAs) in heart failure are enhanced by sympathoexcitation. However, radiotracer studies of catecholamine uptake in failing human hearts demonstrate a proclivity for VAs in patients with reduced cardiac sympathetic innervation. We hypothesized that this counterintuitive finding is explained by heterogeneous loss of sympathetic nerves in the failing heart.

Fibroblasts in heart scar tissue directly regulate cardiac excitability and arrhythmogenesis.

After heart injury, dead heart muscle is replaced by scar tissue. Fibroblasts can electrically couple with myocytes, and changes in fibroblast membrane potential can lead to myocyte excitability, which suggests that fibroblast-myocyte coupling in scar tissue may be responsible for arrhythmogenesis. However, the physiologic relevance of electrical coupling of myocytes and fibroblasts and its impact on cardiac excitability in vivo have never been demonstrated.

Myofibroblast senescence promotes arrhythmogenic remodeling in the aged infarcted rabbit heart.

Progressive tissue remodeling after myocardial infarction (MI) promotes cardiac arrhythmias. This process is well studied in young animals, but little is known about pro-arrhythmic changes in aged animals. Senescent cells accumulate with age and accelerate age-associated diseases.

Bifurcations to transient and oscillatory excitations in inhomogeneous excitable media: Insights into arrhythmogenesis in long QT syndrome.

Ventricular arrhythmias are the leading cause of sudden cardiac death. Understanding the mechanisms of arrhythmia initiation is important for developing effective therapeutics for prevention. Arrhythmias can be induced via premature external stimuli or occur spontaneously via dynamical instabilities.

Cardiac Alternans: From Bedside to Bench and Back.

Cardiac alternans arises from dynamical instabilities in the electrical and calcium cycling systems of the heart, and often precedes ventricular arrhythmias and sudden cardiac death. In this review, we integrate clinical observations with theory and experiment to paint a holistic portrait of cardiac alternans: the underlying mechanisms, arrhythmic manifestations and electrocardiographic signatures. We first summarize the cellular and tissue mechanisms of alternans that have been demonstrated both theoretically and experimentally, including 3 voltage-driven and 2 calcium-driven alternans mechanisms.

Synchronization of spatially discordant voltage and calcium alternans in cardiac tissue.

The heart is an excitable medium which is excited by membrane potential depolarization and propagation. Membrane potential depolarization brings in calcium (Ca) through the Ca channels to trigger intracellular Ca release for contraction of the heart. Ca also affects voltage via Ca-dependent ionic currents, and thus, voltage and Ca are bidirectionally coupled.

Bistable nerve conduction.

It has been demonstrated experimentally that slow and fast conduction waves with distinct conduction velocities can occur in the same nerve system depending on the strength or the form of the stimulus, which give rise to two modes of nerve functions. However, the mechanisms remain to be elucidated. In this study, we use computer simulations of the cable equation with modified Hodgkin-Huxley kinetics and analytical solutions of a simplified model to show that stimulus-dependent slow and fast waves recapitulating the experimental observations can occur in the cable, which are the two stable conduction states of a bistable conduction behavior.

Kramers Rate Theory of Pacemaker Dynamics in Noisy Excitable Media.

Rhythmic activities, which are usually driven by pacemakers, are common in biological systems. In noisy excitable media, pacemakers are self-organized firing clusters, but the underlying dynamics remains to be elucidated. Here we develop a Kramers rate theory of coupled cells to describe the firing properties of pacemakers and their dependence on coupling strength and system size and dimension.

R-on-T and the initiation of reentry revisited: Integrating old and new concepts.

Initiation of reentry requires 2 factors: (1) a triggering event, most commonly focal excitations such as premature ventricular complexes (PVCs); and (2) a vulnerable substrate with regional dispersion of refractoriness and/or excitability, such as occurs during the T wave of the electrocardiogram when some areas of the ventricle have repolarized and recovered excitability but others have not. When the R wave of a PVC coincides in time with the T wave of the previous beat, this timing can lead to unidirectional block and initiation of reentry, known as the R-on-T phenomenon. Classically, the PVC triggering reentry has been viewed as arising focally from 1 region and propagating into another region whose recovery is delayed, resulting in unidirectional conduction block and reentry initiation.

Mechanisms of Arrhythmogenicity of Hypertrophic Cardiomyopathy-Associated Troponin T () Variant I79N.

Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiovascular disease and often results in cardiac remodeling and an increased incidence of sudden cardiac arrest (SCA) and death, especially in youth and young adults. Among thousands of different variants found in HCM patients, variants of (cardiac troponin T-TNNT2) are linked to increased risk of ventricular arrhythmogenesis and sudden death despite causing little to no cardiac hypertrophy. Therefore, studying the effect of variants on cardiac propensity for arrhythmogenesis can pave the way for characterizing HCM in susceptible patients before sudden cardiac arrest occurs.

Why Is Only Type 1 Electrocardiogram Diagnostic of Brugada Syndrome? Mechanistic Insights From Computer Modeling.

Background: Three types of characteristic ST-segment elevation are associated with Brugada syndrome but only type 1 is diagnostic. Why only type 1 ECG is diagnostic remains unanswered.

Methods: Computer simulations were performed in single cells, 1-dimensional cables, and 2-dimensional tissues to investigate the effects of the peak and late components of the transient outward potassium current (I), sodium current, and L-type calcium current (I) as well as other potassium currents on the genesis of ECG morphologies and phase 2 reentry (P2R).

Mitochondrial Contributions in the Genesis of Delayed Afterdepolarizations in Ventricular Myocytes.

Mitochondria fulfill the cell's energy demand and affect the intracellular calcium (Ca) dynamics direct Ca exchange, the redox effect of reactive oxygen species (ROS) on Ca handling proteins, and other signaling pathways. Recent experimental evidence indicates that mitochondrial depolarization promotes arrhythmogenic delayed afterdepolarizations (DADs) in cardiac myocytes. However, the nonlinear interactions among the Ca signaling pathways, ROS, and oxidized Ca/calmodulin-dependent protein kinase II (CaMKII) pathways make it difficult to reveal the mechanisms.

Life and death saddles in the heart.

Saddle points are responsible for threshold phenomena of many biological systems. In the heart, saddle points determine the normal excitability and conduction, but are also responsible for certain abnormal action potential behaviors associated with lethal arrhythmias. We investigate the dynamical mechanisms for the genesis of lethal extra heartbeats in heterogeneous cardiac tissue under two diseased conditions.

Mechanisms of phase-3 early afterdepolarizations and triggered activities in ventricular myocyte models.

Early afterdepolarizations (EADs) are abnormal depolarizations during the repolarizing phase of the action potential, which are associated with cardiac arrhythmogenesis. EADs are classified into phase-2 and phase-3 EADs. Phase-2 EADs occur during phase 2 of the action potential, with takeoff potentials typically above -40 mV.

Activation of TRPC (Transient Receptor Potential Canonical) Channel Currents in Iron Overloaded Cardiac Myocytes.

Background: Arrhythmias and heart failure are common cardiac complications leading to substantial morbidity and mortality in patients with hemochromatosis, yet mechanistic insights remain incomplete. We investigated the effects of iron (Fe) on electrophysiological properties and intracellular Ca (Ca) handling in mouse left ventricular cardiomyocytes.

Methods: Cardiomyocytes were isolated from the left ventricle of mouse hearts and were superfused with Fe/8-hydroxyquinoline complex (5-100 μM).