Models of stretch-activated ventricular arrhythmias.

One of the most important components of mechanoelectric coupling is stretch-activated channels, sarcolemmal channels that open upon mechanical stimuli. Uncovering the mechanisms by which stretch-activated channels contribute to ventricular arrhythmogenesis under a variety of pathologic conditions is hampered by the lack of experimental methodologies that can record the 3-dimensional electromechanical activity simultaneously at high spatiotemporal resolution. Computer modeling provides such an opportunity.

Integrative computational models of cardiac arrhythmias -- simulating the structurally realistic heart.

Simulation of cardiac electrical function, and specifically, simulation aimed at understanding the mechanisms of cardiac rhythm disorders, represents an example of a successful integrative multiscale modeling approach, uncovering emergent behavior at the successive scales in the hierarchy of structural complexity. The goal of this article is to present a review of the integrative multiscale models of realistic ventricular structure used in the quest to understand and treat ventricular arrhythmias. It concludes with the new advances in image-based modeling of the heart and the promise it holds for the development of individualized models of ventricular function in health and disease.

Models of cardiac electromechanics based on individual hearts imaging data: image-based electromechanical models of the heart.

Current multi-scale computational models of ventricular electromechanics describe the full process of cardiac contraction on both the micro- and macro- scales including: the depolarization of cardiac cells, the release of calcium from intracellular stores, tension generation by cardiac myofilaments, and mechanical contraction of the whole heart. Such models are used to reveal basic mechanisms of cardiac contraction as well as the mechanisms of cardiac dysfunction in disease conditions. In this paper, we present a methodology to construct finite element electromechanical models of ventricular contraction with anatomically accurate ventricular geometry based on magnetic resonance and diffusion tensor magnetic resonance imaging of the heart.

Image-based models of cardiac structure in health and disease.

Computational approaches to investigating the electromechanics of healthy and diseased hearts are becoming essential for the comprehensive understanding of cardiac function. In this article, we first present a brief review of existing image-based computational models of cardiac structure. We then provide a detailed explanation of a processing pipeline which we have recently developed for constructing realistic computational models of the heart from high resolution structural and diffusion tensor (DT) magnetic resonance (MR) images acquired ex vivo.

Rate-dependent action potential alternans in human heart failure implicates abnormal intracellular calcium handling.

Background: Alternans in action potential voltage (APV-ALT) at heart rates <110 bpm is a novel index to predict ventricular arrhythmias. However, the rate dependency of APV-ALT and its mechanisms in failing versus nonfailing human myocardium are poorly understood. It is hypothesized that APV-ALT in human heart failure (HF) reflects abnormal calcium handling.

Tunnel propagation following defibrillation with ICD shocks: hidden postshock activations in the left ventricular wall underlie isoelectric window.

Background: After near-defibrillation threshold (DFT) shocks from an implantable cardioverter-defibrillator (ICD), the first postshock activation that leads to defibrillation failure arises focally after an isoelectric window (IW). The mechanisms underlying the IW remain incompletely understood.

Objective: The goal of this study was to provide mechanistic insight into the origins of postshock activations and IW after ICD shocks, and to link shock outcome to the preshock state of the ventricles.

Mechanisms for initiation of reentry in acute regional ischemia phase 1B.

Background: During phase 1B of acute regional ischemia, the subepicardial and subendocardial layers coupled to the inexcitable midmyocardium remain viable.

Objective: The purpose of this study was to examine how the degree of hyperkalemia in the surviving layers, the lateral width of border zone between the normal tissue and the central ischemic zone, and the degree of cellular uncoupling between the surviving layers and the midmyocardium contribute to initiation of reentry.

Methods: Simulations were conducted on the state-of-the-art model of rabbit ventricles with realistic representation of the spatial distribution of the ischemic insult.

In the spotlight: cardiovascular engineering.

This paper discusses about the electromechanical effect of rabbit ventricals and abnormalities caused by asynchronous electrical activation in perfusion and pump function. These applications are of paramount importance to therapies that employ pacing of the heart, and particularly cardiac resynchronization therapy (CRT).

Comparative analysis of three different modalities for characterization of the seismocardiogram.

We introduce and compare three different modalities to study seismocardiogram (SCG) and its correlation with cardiac events. We used an accelerometer attached to the subject sternum to get a reference measure. Cardiac events were then approximately identified using echocardiography.

Mechanisms of mechanically induced spontaneous arrhythmias in acute regional ischemia.

Rationale: Although ventricular premature beats (VPBs) during acute regional ischemia have been linked to mechanical stretch of ischemic tissue, whether and how ischemia-induced mechanical dysfunction can induce VPBs and facilitate their degradation into reentrant arrhythmias has not been yet addressed.

Objective: This study used a novel multiscale electromechanical model of the rabbit ventricles to investigate the origin of and the substrate for spontaneous arrhythmias arising from ischemia-induced electrophysiological and mechanical changes.

Methods And Results: Two stages of ischemia were simulated.

Electrotonic coupling between human atrial myocytes and fibroblasts alters myocyte excitability and repolarization.

Atrial fibrosis has been implicated in the development and maintenance of atrial arrhythmias, and is characterized by expansion of the extracellular matrix and an increased number of fibroblasts (Fbs). Electrotonic coupling between atrial myocytes and Fbs may contribute to the formation of an arrhythmogenic substrate. However, the role of these cell-cell interactions in the function of both normal and diseased atria remains poorly understood.

K+ current changes account for the rate dependence of the action potential in the human atrial myocyte.

Ongoing investigation of the electrophysiology and pathophysiology of the human atria requires an accurate representation of the membrane dynamics of the human atrial myocyte. However, existing models of the human atrial myocyte action potential do not accurately reproduce experimental observations with respect to the kinetics of key repolarizing currents or rate dependence of the action potential and fail to properly enforce charge conservation, an essential characteristic in any model of the cardiac membrane. In addition, recent advances in experimental methods have resulted in new data regarding the kinetics of repolarizing currents in the human atria.

Towards predictive modelling of the electrophysiology of the heart.

The simulation of cardiac electrical function is an example of a successful integrative multiscale modelling approach that is directly relevant to human disease. Today we stand at the threshold of a new era, in which anatomically detailed, tomographically reconstructed models are being developed that integrate from the ion channel to the electromechanical interactions in the intact heart. Such models hold high promise for interpretation of clinical and physiological measurements, for improving the basic understanding of the mechanisms of dysfunction in disease, such as arrhythmias, myocardial ischaemia and heart failure, and for the development and performance optimization of medical devices.

Automatically generated, anatomically accurate meshes for cardiac electrophysiology problems.

Significant advancements in imaging technology and the dramatic increase in computer power over the last few years broke the ground for the construction of anatomically realistic models of the heart at an unprecedented level of detail. To effectively make use of high-resolution imaging datasets for modeling purposes, the imaged objects have to be discretized. This procedure is trivial for structured grids.

Mathematical simulations of ligand-gated and cell-type specific effects on the action potential of human atrium.

In the mammalian heart, myocytes and fibroblasts can communicate via gap junction, or connexin-mediated current flow. Some of the effects of this electrotonic coupling on the action potential waveform of the human ventricular myocyte have been analyzed in detail. The present study employs a recently developed mathematical model of the human atrial myocyte to investigate the consequences of this heterogeneous cell-cell interaction on the action potential of the human atrium.

Image-based models of cardiac structure with applications in arrhythmia and defibrillation studies.

The objective of this article is to present a set of methods for constructing realistic computational models of cardiac structure from high-resolution structural and diffusion tensor magnetic resonance images and to demonstrate the applicability of the models in simulation studies. The structural image is segmented to identify various regions such as normal myocardium, ventricles, and infarct. A finite element mesh is generated from the processed structural data, and fiber orientations are assigned to the elements.

Action potential dynamics explain arrhythmic vulnerability in human heart failure: a clinical and modeling study implicating abnormal calcium handling.

Objectives: The purpose of this study was to determine whether abnormalities of calcium cycling explain ventricular action potential (AP) oscillations and cause electrocardiogram T-wave alternans (TWA).

Background: Mechanisms explaining why heart failure patients are at risk for malignant ventricular arrhythmias (ventricular tachycardia [VT]/ventricular fibrillation [VF]) are unclear. We studied whether oscillations in human ventricular AP explain TWA and predict VT/VF, and used computer modeling to suggest potential cellular mechanisms.

Systems approach to understanding electromechanical activity in the human heart: a national heart, lung, and blood institute workshop summary.

The National Heart, Lung, and Blood Institute (NHLBI) convened a workshop of cardiologists, cardiac electrophysiologists, cell biophysicists, and computational modelers on August 20 and 21, 2007, in Washington, DC, to advise the NHLBI on new research directions needed to develop integrative approaches to elucidate human cardiac function. The workshop strove to identify limitations in the use of data from nonhuman animal species for elucidation of human electromechanical function/activity and to identify what specific information on ion channel kinetics, calcium handling, and dynamic changes in the intracellular/extracellular milieu is needed from human cardiac tissues to develop more robust computational models of human cardiac electromechanical activity. This article summarizes the workshop discussions and recommendations on the following topics: (1) limitations of animal models and differences from human electrophysiology, (2) modeling ion channel structure/function in the context of whole-cell electrophysiology, (3) excitation-contraction coupling and regulatory pathways, (4) whole-heart simulations of human electromechanical activity, and (5) what human data are currently needed and how to obtain them.

Polarity reversal lowers activation time during diastolic field stimulation of the rabbit ventricles: insights into mechanisms.

To fully characterize the mechanisms of defibrillation, it is necessary to understand the response, within the three-dimensional (3D) volume of the ventricles, to shocks given in diastole. Studies that have examined diastolic responses conducted measurements on the epicardium or on a transmural surface of the left ventricular (LV) wall only. The goal of this study was to use optical imaging experiments and 3D bidomain simulations, including a model of optical mapping, to ascertain the shock-induced virtual electrode and activation patterns throughout the rabbit ventricles following diastolic shocks.

From mitochondrial ion channels to arrhythmias in the heart: computational techniques to bridge the spatio-temporal scales.

Computer simulations of electrical behaviour in the whole ventricles have become commonplace during the last few years. The goals of this article are (i) to review the techniques that are currently employed to model cardiac electrical activity in the heart, discussing the strengths and weaknesses of the various approaches, and (ii) to implement a novel modelling approach, based on physiological reasoning, that lifts some of the restrictions imposed by current state-of-the-art ionic models. To illustrate the latter approach, the present study uses a recently developed ionic model of the ventricular myocyte that incorporates an excitation-contraction coupling and mitochondrial energetics model.

Reentry in survived subepicardium coupled to depolarized and inexcitable midmyocardium: insights into arrhythmogenesis in ischemia phase 1B.

Background: Delayed ventricular arrhythmias during acute myocardial ischemia (1B arrhythmias) are associated with an increase in tissue impedance and are most likely sustained in a thin subepicardial layer.

Objective: The goal of this study was to test the hypothesis that heterogeneous uncoupling between depolarized midmyocardium and surviving subepicardium results in heterogeneous refractoriness in the latter, providing the reentry substrate after a premature beat.

Methods: A 3-dimensional bidomain slab was constructed comprising a normal subepicardial layer coupled to a slightly depolarized (-80 to -60 mV) but inexcitable midmyocardium.

The role of mechanoelectric feedback in vulnerability to electric shock.

Experimental and clinical studies have shown that ventricular dilatation is associated with increased arrhythmogenesis and elevated defibrillation threshold; however, the underlying mechanisms remain poorly understood. The goal of the present study was to test the hypothesis that (1) stretch-activated channel (SAC) recruitment and (2) geometrical deformations in organ shape and fiber architecture lead to increased arrhythmogenesis by electric shocks following acute ventricular dilatation. To elucidate the contribution of these two factors, the study employed, for the first time, a combined electro-mechanical simulation approach.

Tunnel propagation of postshock activations as a hypothesis for fibrillation induction and isoelectric window.

Comprehensive understanding of the ventricular response to shocks is the approach most likely to succeed in reducing defibrillation threshold. We propose a new theory of shock-induced arrhythmogenesis that unifies all known aspects of the response of the heart to monophasic (MS) and biphasic (BS) shocks. The central hypothesis is that submerged "tunnel" propagation of postshock activations through shock-induced intramural excitable areas underlies fibrillation induction and the existence of isoelectric window.