Catheter based simultaneous mapping of cardiac activation and motion: a review

Heart failure as a result of a variety of cardiac diseases is an ever growing, challenging condition that demands profound insight in the electrical and mechanical state of the myocardium. Assessment of cardiac function has largely relied on evaluation of cardiac motion by multiple imaging techniques. In recent years electrical properties have gained attention as heart failure could be improved by biventricular resynchronization therapy. In contrast to early belief, QRS widening as a result of left bundle branch block could not be identified as a surrogate for asynchronous contraction. The combined analysis of electrical and mechanical function is yet a largely experimental approach. Several mapping system are principally capable for this analysis, the most prominent being the NOGA-XP system. Electromechanical maps have concentrated on the local shortening of the reconstructed endocardial surface from end-diastole to end-systole. Temporal analysis of motion propagation, however, is a new aspect. The fundamental principles of percutaneous catheter based activation and motion assessment are reviewed. Related experimental setups are presented and their main findings discussed.     

Mathematical models for the study of electromechanical and mechanoelectrical coupling in the myocardium

Mathematical models have been developed to describe interactions of electrical, mechanical and chemical processes in cardiomyocytes. The models simulate wide range of experimental data on excitation-contraction coupling and, more importantly, on mechanoelectric feedback in heart muscle. The model results clearly show that mechano-dependence of intracellular calcium handling due to cooperative effects of contractile proteins activation plays a key role in cardiac mechanoelectric coupling. At the same time, mechanosensitive currents can also contribute to action potential responses to mechanical perturbations. Using this model to study the heterogeneous myocardium we have shown that temporal and functional electromechanical heterogeneity of coupled cardiomyocytes can essentially determine the myocardium contractility. Optimization of the electromechanical function of contractile system emerges from the fine coordination between the activation sequence of cardiomyocytes, their local electromechanical properties and the mechanical interaction during contraction.     

Mechanisms of electromechanical function disturbances in cardiomyocytes overloaded with calcium. The theoretical study

Arrhythmias and mechanical disturbances are simulated in a mathematical model of cardiomyocyte electromechanical activity. The simulated pattern is similar to that observed for acute heart failure associated with calcium overloading of myocardium cells. Special attention was paid to the calcium overloading resulting from the reduced Na+,K+ pump activity. In the framework of the model, it was shown that mechanical factors could promote arrhythmia initiation when the pump activity reduced. Different approaches to electrical and mechanical function restoration during acute heart failure associated with calcium overloading were suggested and analyzed in the model.     

Electromechanical analysis of infarct border zone in chronic myocardial infarction

To test the hypothesis that alterations in electrical activation sequence contribute to depressed systolic function in the infarct border zone, we examined the anatomic correlation of abnormal electromechanics and infarct geometry in the canine post-myocardial infarction (MI) heart, using a high-resolution MR-based cardiac electromechanical mapping technique. Three to eight weeks after an MI was created in six dogs, a 247-electrode epicardial sock was placed over the ventricular epicardium under thoracotomy. MI location and geometry were evaluated with delayed hyperenhancement MRI. Three-dimensional systolic strains in epicardial and endocardial layers were measured in five short-axis slices with motion-tracking MRI (displacement encoding with stimulated echoes). Epicardial electrical activation was determined from sock recordings immediately before and after the MR scans. The electrodes and MR images were spatially registered to create a total of 160 nodes per heart that contained mechanical, transmural infarct extent, and electrical data. The average depth of the infarct was 55% (SD 11), and the infarct covered 28% (SD 6) of the left ventricular mass. Significantly delayed activation (>mean + 2SD) was observed within the infarct zone. The strain map showed abnormal mechanics, including abnormal stretch and loss of the transmural gradient of radial, circumferential, and longitudinal strains, in the region extending far beyond the infarct zone. We conclude that the border zone is characterized by abnormal mechanics directly coupled with normal electrical depolarization. This indicates that impaired function in the border zone is not contributed by electrical factors but results from mechanical interaction between ischemic and normal myocardium.     

Electromechanical models of the ventricles

Computational modeling has traditionally played an important role in dissecting the mechanisms for cardiac dysfunction. Ventricular electromechanical models, likely the most sophisticated virtual organs to date, integrate detailed information across the spatial scales of cardiac electrophysiology and mechanics and are capable of capturing the emergent behavior and the interaction between electrical activation and mechanical contraction of the heart. The goal of this review is to provide an overview of the latest advancements in multiscale electromechanical modeling of the ventricles. We first detail the general framework of multiscale ventricular electromechanical modeling and describe the state of the art in computational techniques and experimental validation approaches. The powerful utility of ventricular electromechanical models in providing a better understanding of cardiac function is then demonstrated by reviewing the latest insights obtained by these models, focusing primarily on the mechanisms by which mechanoelectric coupling contributes to ventricular arrythmogenesis, the relationship between electrical activation and mechanical contraction in the normal heart, and the mechanisms of mechanical dyssynchrony and resynchronization in the failing heart. Computational modeling of cardiac electromechanics will continue to complement basic science research and clinical cardiology and holds promise to become an important clinical tool aiding the diagnosis and treatment of cardiac 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. The electromechanical model couples detailed representations of the cardiac cell membrane, cardiac myofilament dynamics, electrical impulse propagation, ventricular contraction, and circulation to simulate the electrical and mechanical activity of the ventricles. The utility of the model is demonstrated in an example simulation of contraction during sinus rhythm using a model of the normal canine ventricles.     

Cooperativity in mechano-calcium feedbacks in the myocardium: Some conceptual discrepancies and overcoming inconsistency within the framework of a mathematical model

Mechano-calcium feedbacks that provide fine tuning of electrical and calcium activation of the heart muscle to mechanical conditions of contractions are an important element of electromechanical coupling as a key mechanism of the autoregulation of the contractile activity of the myocardium. A large quantity of experimental and theoretical evidence supports the cooperative dependence of the calcium-troponin complex kinetics on the cross-bridge concentration as a principal mechanism that underlies the mechano-calcium feedback in the intact myocardium. At the same time, experiments performed using skinned myocardial preparations have demonstrated that mechanical conditions significantly affected only the calcium sensitivity of the Ca²⁺–force relationship rather than its Hill coefficient of cooperativity. These data make some investigators doubt the contribution of cooperativity to the mechano-calcium feedbacks. To overcome these arising discrepancies, we propose an improved conception of cooperativity that reveals the extent of intensity differently in the steady state and in transitional processes. The proposed conception enables us to reproduce and explain both the mechanodependence of calcium activation in the intact myocardium and the results with skinned muscle within the framework of a mathematical model.     

Mathematical Modeling of Mechanically Modulated Rhythm Disturbances in Homogeneous and Heterogeneous Myocardium with Attenuated Activity of Na<Superscript>+</Superscript>–K<Superscript>+</Superscript> Pump

A mathematical model of the cardiomyocyte electromechanical function is used to study contribution of mechanical factors to rhythm disturbances in the case of the cardiomyocyte calcium overload. Particular attention is paid to the overload caused by diminished activity of the sodium-potassium pump. It is shown in the framework of the model, where mechano-calcium feedback is accounted for that myocardium mechanics may significantly enhance arrhythmogenicity of the calcium overload. Specifically, a role of cross-bridge attachment/detachment processes, a role of mechanical conditions of myocardium contractions (length, load), and a role of myocardium viscosity in the case of simulated calcium overload have been revealed. Underlying mechanisms are analyzed. Several approaches are designed in the model and compared to each other for recovery of the valid myocardium electrical and mechanical performance in the case of the partially suppressed sodium-potassium pump.     

High resolution mechanical function in the intact porcine heart: mechanical effects of pacemaker location

The necessity to quantify the mechanical function with high spatial resolution stemmed from the advancement of myocardial salvaging techniques. Since these therapies are localized interventions, a whole field technique with high spatial resolution was needed to differentiate the normal, diseased, and treated myocardium. We developed a phase correlation algorithm for measuring myocardial displacement at high spatial resolution and to determine the regional mechanical function in the intact heart. Porcine hearts were exposed and high contrast microparticles were placed on the myocardium. A pressure transducer, inserted into the left ventricle, synchronized the pressure (LVP) with image acquisition using a charge-coupled device camera. The deformation of the myocardium was measured with a resolution of 0.58+/-0.04 mm. Within the region of interest (ROI), regional stroke work (RSW), defined as the integral of LVP with respect to regional area, was determined on average at 21 locations with a resolution of 27.1+/-2.7 mm2. To alter regional mechanical function, the heart was paced at three different locations around the ROI. Independent of the pacemaker location, RSW decreased in the ROI. In addition, a gradient of increasing RSW in the outward direction radiating from the pacemaker was observed in all pacing protocols. These data demonstrated the ability to determine regional whole field mechanical function with high spatial resolution, and the significant alterations induced by electrical pacing.     

Chronotropic and inotropic dependence of the myocardium in patients with rheumatic heart disease before and after amiodarone treatment

Characteristic features of the electromechanical coupling of the myocardium were studied in patients with heart failure caused by rheumatic heart disease. Experiments were performed on muscle trabeculae isolated from the right atrial auricle in the course of surgical correction of a valve defect. The trabeculae displayed two types of mechanical responses, recorded in the isometric mode, to the postrest test. In the type I response, the mechanical restitution had an ascending pattern, the interval between electrical stimuli increasing. In type II, the mechanical restitution pattern was descending. Amiodarone (1 μM) treatment of the myocardium with the type I response enhanced the postrest potentiation of the mechanical response of trabeculae by more than 30%, but it had no effect on the muscles with the type II response. All patients whose biopsy material displayed the type II response had long episodes of atrial fibrillation. It is conceivable that the observed differences in the rhythm inotropic dependence of the human myocardium in rheumatic heart disease reflect different degrees of cardiomyocyte remodeling. The direction of this process is determined by the range of adaptive changes in intracellular structures, primarily, the sarcoplasmic reticulum.     

Noninvasive three-dimensional electrocardiographic imaging of ventricular activation sequence

Imaging the myocardial activation sequence is critical for improved diagnosis and treatment of life-threatening cardiac arrhythmias. It is desirable to reveal the underlying cardiac electrical activity throughout the three-dimensional (3-D) myocardium (rather than just the endocardial or epicardial surface) from noninvasive body surface potential measurements. A new 3-D electrocardiographic imaging technique (3-DEIT) based on the boundary element method (BEM) and multiobjective nonlinear optimization has been applied to reconstruct the cardiac activation sequences from body surface potential maps. Ultrafast computerized tomography scanning was performed for subsequent construction of the torso and heart models. Experimental studies were then conducted, during left and right ventricular pacing, in which noninvasive assessment of ventricular activation sequence by means of 3-DEIT was performed simultaneously with 3-D intracardiac mapping (up to 200 intramural sites) using specially designed plunge-needle electrodes in closed-chest rabbits. Estimated activation sequences from 3-DEIT were in good agreement with those constructed from simultaneously recorded intracardiac electrograms in the same animals. Averaged over 100 paced beats (from a total of 10 pacing sites), total activation times were comparable (53.3 +/- 8.1 vs. 49.8 +/- 5.2 ms), the localization error of site of initiation of activation was 5.73 +/- 1.77 mm, and the relative error between the estimated and measured activation sequences was 0.32 +/- 0.06. The present experimental results demonstrate that the 3-D paced ventricular activation sequence can be reconstructed by using noninvasive multisite body surface electrocardiographic measurements and imaging of heart-torso geometry. This new 3-D electrocardiographic imaging modality has the potential to guide catheter-based ablative interventions for the treatment of life-threatening cardiac arrhythmias.     

Hybrid duplex: a novel method to study the contractile function of heterogeneous myocardium

In an earlier study, we experimentally mimicked the effects of mechanical interaction between different regions of the ventricular wall by allowing pairs of independently maintained cardiac muscle fibers to interact mechanically in series or in parallel. This simple physiological model of heterogeneous myocardium, which has been termed "duplex," has provided new insight into basic effects of cardiac electromechanical heterogeneity. Here, we present a novel "hybrid duplex," where one of the elements is an isolated cardiac muscle and the other a "virtual cardiac muscle." The virtual muscle is represented by a computational model of cardiomyocyte electromechanical activity. We present in detail the computer-based digital control system that governs the mechanical interaction between virtual and biological muscle, the software used for data analysis, and working implementations of the model. Advantages of the hybrid duplex method are discussed, and experimental recordings are presented for illustration and as proof of the principle.     

Multiparametric Optical Mapping of the Langendorff-perfused Rabbit Heart

Optical imaging and fluorescent probes have significantly advanced research methodology in the field of cardiac electrophysiology in ways that could not have been accomplished by other approaches¹. With the use of the calcium- and voltage-sensitive dyes, optical mapping allows measurement of transmembrane action potentials and calcium transients with high spatial resolution without the physical contact with the tissue. This makes measurements of the cardiac electrical activity possible under many conditions where the use of electrodes is inconvenient or impossible¹. For example, optical recordings provide accurate morphological changes of membrane potential during and immediately after stimulation and defibrillation, while conventional electrode techniques suffer from stimulus-induced artifacts during and after stimuli due to electrode polarization¹. The Langendorff-perfused rabbit heart is one of the most studied models of human heart physiology and pathophysiology. Many types of arrhythmias observed clinically could be recapitulated in the rabbit heart model. It was shown that wave patterns in the rabbit heart during ventricular arrhythmias, determined by effective size of the heart and the wavelength of reentry, are very similar to that in the human heart². It was also shown that critical aspects of excitation-contraction (EC) coupling in rabbit myocardium, such as the relative contribution of sarcoplasmic reticulum (SR), is very similar to human EC coupling³. Here we present the basic procedures of optical mapping experiments in Langendorff-perfused rabbit hearts, including the Langendorff perfusion system setup, the optical mapping systems setup, the isolation and cannulation of the heart, perfusion and dye-staining of the heart, excitation-contraction uncoupling, and collection of optical signals. These methods could be also applied to the heart from species other than rabbit with adjustments to flow rates, optics, solutions, etc.Two optical mapping systems are described. The panoramic mapping system is used to map the entire epicardium of the rabbit heart^4-7. This system provides a global view of the evolution of reentrant circuits during arrhythmogenesis and defibrillation, and has been used to study the mechanisms of arrhythmias and antiarrhythmia therapy^8,9. The dual mapping system is used to map the action potential (AP) and calcium transient (CaT) simultaneously from the same field of view^10-13. This approach has enhanced our understanding of the important role of calcium in the electrical alternans and the induction of arrhythmia^14-16.     

Mechanism of prolonged electromechanical delay in late activated myocardium during left bundle branch block

During left bundle branch block (LBBB), electromechanical delay (EMD), defined as time from regional electrical activation (REA) to onset shortening, is prolonged in the late-activated left ventricular lateral wall compared with the septum. This leads to greater mechanical relative to electrical dyssynchrony. The aim of this study was to determine the mechanism of the prolonged EMD. We investigated this phenomenon in an experimental LBBB dog model (n = 7), in patients (n = 9) with biventricular pacing devices, in an in vitro papillary muscle study (n = 6), and a mathematical simulation model. Pressures, myocardial deformation, and REA were assessed. In the dogs, there was a greater mechanical than electrical delay (82 ± 12 vs. 54 ± 8 ms, P = 0.002) due to prolonged EMD in the lateral wall vs. septum (39 ± 8 vs.11 ± 9 ms, P = 0.002). The prolonged EMD in later activated myocardium could not be explained by increased excitation-contraction coupling time or increased pressure at the time of REA but was strongly related to dP/dt at the time of REA (r = 0.88). Results in humans were consistent with experimental findings. The papillary muscle study and mathematical model showed that EMD was prolonged at higher dP/dt because it took longer for the segment to generate active force at a rate superior to the load rise, which is a requirement for shortening. We conclude that, during LBBB, prolonged EMD in late-activated myocardium is caused by a higher dP/dt at the time of activation, resulting in aggravated mechanical relative to electrical dyssynchrony. These findings suggest that LV contractility may modify mechanical dyssynchrony.     

A membrane bending model of outer hair cell electromotility

We propose a new mechanism for outer hair cell electromotility based on electrically induced localized changes in the curvature of the plasma membrane (flexoelectricity). Electromechanical coupling in the cell's lateral wall is modeled in terms of linear constitutive equations for a flexoelectric membrane and then extended to nonlinear coupling based on the Langevin function. The Langevin function, which describes the fraction of dipoles aligned with an applied electric field, is shown to be capable of predicting the electromotility voltage displacement function. We calculate the electrical and mechanical contributions to the force balance and show that the model is consistent with experimentally measured values for electromechanical properties. The model rationalizes several experimental observations associated with outer hair cell electromotility and provides for constant surface area of the plasma membrane. The model accounts for the isometric force generated by the cell and explains the observation that the disruption of spectrin by diamide reduces force generation in the cell. We discuss the relation of this mechanism to other proposed models of outer hair cell electromotility. Our analysis suggests that rotation of membrane dipoles and the accompanying mechanical deformation may be the molecular mechanism of electromotility.     

Electromechanical coupling in cardiomyocytes from transmural layers of guinea pig left ventricle

The electrical and mechanical activity of heart ventricle cardiomyocytes is known to vary depending on the spatial location of cells in the wall, in particular, transmurally from the sub-endocardial layer to the sub-epicardial one. To investigate intracellular mechanisms of the functional heterogeneity of cardiomyocytes we developed mathematical models of the electromechanical coupling in cardiomyocytes from different transmural layers across the left ventricle (LV) wall of guinea pig. It is shown that the mechanisms of both direct linkages and feedback in the electromechanical coupling contribute to differences in both the shape and duration of action potential, and speed characteristics of contraction between isolated cardiac myocytes from the sub-endocardial and sub-epicardial layers.     

Evaluation of inotropic changes in ventricular function by NOGA mapping: comparison with echocardiography.

Assessment of left ventricular (LV) function in the catheterization laboratory is important to optimize treatment decisions and guide catheter-based local therapies. NOGA electromechanical mapping was developed to assess LV contraction during catheterization; however, quantitative analysis of its "local shortening" (LS) algorithm and direct comparison with conventional methods are lacking. We evaluated the accuracy of NOGA-based regional and global function by examining its ability to detect pharmacologically induced changes in contractility compared with echocardiography. Ten anesthetized pigs were paced to ensure a constant heart rate throughout the experiment. Electromechanical maps of the LV and short-axis echocardiograms were obtained 1) at baseline, 2) during intravenous dobutamine, and 3) after intravenous propranolol. NOGA LS and ejection fraction (EF) consistently increased under dobutamine and decreased after propranolol. NOGA LS and NOGA and echocardiography circumferential shortening correlated highly with one another (r > 0.80), as did NOGA EF with echocardiography EF (r = 0.92), although absolute values differed somewhat. Thus NOGA-based global and regional function correlates closely with echocardiography and is sensitive to changes in contractility, but, at the upper end of the scale, LV function is underestimated.     

Analyses of the Redistribution of Work following Cardiac Resynchronisation Therapy in a Patient Specific Model

Regulation of regional work is essential for efficient cardiac function. In patients with heart failure and electrical dysfunction such as left branch bundle block regional work is often depressed in the septum. Following cardiac resynchronisation therapy (CRT) this heterogeneous distribution of work can be rebalanced by altering the pattern of electrical activation. To investigate the changes in regional work in these patients and the mechanisms underpinning the improved function following CRT we have developed a personalised computational model. Simulations of electromechanical cardiac function in the model estimate the regional stress, strain and work pre- and post-CRT. These simulations predict that the increase in observed work performed by the septum following CRT is not due to an increase in the volume of myocardial tissue recruited during contraction but rather that the volume of recruited myocardium remains the same and the average peak work rate per unit volume increases. These increases in the peak average rate of work is is attributed to slower and more effective contraction in the septum, as opposed to a change in active tension. Model results predict that this improved septal work rate following CRT is a result of resistance to septal contraction provided by the LV free wall. This resistance results in septal shortening over a longer period which, in turn, allows the septum to contract while generating higher levels of active tension to produce a higher work rate.