Lawrence J. Mulligan

Effects of biventricular pacing and scar size in a computational model of the failing heart with left bundle branch block

OBJECTIVESnTo study the impact of biventricular pacing (BiV) and scar size on left ventricular (LV) regional and global function using a detailed finite element model of three-dimensional electromechanics in the failing canine heart.nnnBACKGROUNDnCardiac resynchronization therapy (CRT) clinical trials have demonstrated that up to 30% of patients may be classified as non-responders. The presence of a scar appears to contribute to those that do not respond to CRT. A recent study in patients with myocardial scar showed that LV dyssynchrony was the sole independent predictor of reverse remodeling, and not scar location or size.nnnMETHODSnTwo activation sequences were simulated: left bundle branch block (LBBB) and acute simultaneous BiV (with leads in the left and right ventricle) in hearts with chronic scars of various sizes. The dependence of regional function (mean fiber ejection strain, variance of fiber isovolumic strain and fraction of tissue stretched during ejection) and global function (left ventricular dP/dt(max), ejection fraction, stroke work) on scar size and pacing protocol was tested.nnnRESULTSnGlobal function and regional function averaged over the whole LV during LBBB and BiV decreased as a function of scar size. In the non-scarred regions, however, regional function was largely independent of scar size for a fixed pacing site.nnnCONCLUSIONSnThe model results suggest that uniformity of mechanical contraction in non-scarred regions in the failing heart during biventricular pacing is independent of scar size for a fixed pacing site.

Ventricular Dilation and Electrical Dyssynchrony Synergistically Increase Regional Mechanical Nonuniformity But Not Mechanical Dyssynchrony A Computational Model

Background—Heart failure (HF) in combination with mechanical dyssynchrony is associated with a high mortality rate. To quantify contractile dysfunction in patients with HF, investigators have proposed several indices of mechanical dyssynchrony, including percentile range of time to peak shortening (WTpeak), circumferential uniformity ratio estimate (CURE), and internal stretch fraction (ISF). The goal of this study was to compare the sensitivity of these indices to 4 major abnormalities responsible for cardiac dysfunction in dyssynchronous HF: dilation, negative inotropy, negative lusitropy, and dyssynchronous activation. Methods and Results—All combinations of these 4 major abnormalities were included in 3D computational models of ventricular electromechanics. Compared with a nonfailing heart model, ventricles were dilated, inotropy was reduced, twitch duration was prolonged, and activation sequence was changed from normal to left bundle branch block. In the nonfailing heart, CURE, ISF, and WTpeak were 0.97±0.004, 0.010±0.002, and 78±1 milliseconds, respectively. With dilation alone, CURE decreased 2.0±0.07%, ISF increased 58±47%, and WTpeak increased 31±3%. With dyssynchronous activation alone, CURE decreased 15±0.6%, ISF increased 14-fold (±3), and WTpeak increased 121±4%. With the combination of dilation and dyssynchronous activation, CURE decreased 23±0.8%, ISF increased 20-fold (±5), and WTpeak increased 147±5%. Conclusions—Dilation and left bundle branch block combined synergistically decreased regional cardiac function. CURE and ISF were sensitive to this combination, but WTpeak was not. CURE and ISF also reflected the relative nonuniform distribution of regional work better than WTpeak. These findings might explain why CURE and ISF are better predictors of reverse remodeling in cardiac resynchronization therapy.

Effect of transmurally heterogeneous myocyte excitation–contraction coupling on canine left ventricular electromechanics

The excitation–contraction coupling properties of cardiac myocytes isolated from different regions of the mammalian left ventricular wall have been shown to vary considerably, with uncertain effects on ventricular function. We embedded a cell‐level excitation–contraction coupling model with region‐dependent parameters within a simple finite element model of left ventricular geometry to study effects of electromechanical heterogeneity on local myocardial mechanics and global haemodynamics. This model was compared with one in which heterogeneous myocyte parameters were assigned randomly throughout the mesh while preserving the total amount of each cell subtype. The two models displayed nearly identical transmural patterns of fibre and cross‐fibre strains at end‐systole, but showed clear differences in fibre strains at earlier points during systole. Haemodynamic function, including peak left ventricular pressure, maximal rate of left ventricular pressure development and stroke volume, were essentially identical in the two models. These results suggest that in the intact ventricle heterogeneously distributed myocyte subtypes primarily impact local deformation of the myocardium, and that these effects are greatest during early systole.

Computational Modeling for Bedside Application

Advances in computer power, novel diagnostic and therapeutic medical technologies, and an increasing knowledge of pathophysiology from gene to organ systems make it increasingly feasible to apply multiscale patient-specific modeling based on proven disease mechanisms. Such models may guide and predict the response to therapy in many areas of medicine. This is an exciting and relatively new approach, for which efficient methods and computational tools are of the utmost importance. Investigators have designed patient-specific models in almost all areas of human physiology. Not only will these models be useful in clinical settings to predict and optimize the outcome from surgery and non-interventional therapy, but they will also provide pathophysiologic insights from the cellular level to the organ system level. Models, therefore, will provide insight as to why specific interventions succeed or fail.

Ventricular Dilation and Electrical Dyssynchrony Synergistically Increase Regional Mechanical Nonuniformity But Not Mechanical DyssynchronyClinical Perspective

Background—Heart failure (HF) in combination with mechanical dyssynchrony is associated with a high mortality rate. To quantify contractile dysfunction in patients with HF, investigators have proposed several indices of mechanical dyssynchrony, including percentile range of time to peak shortening (WTpeak), circumferential uniformity ratio estimate (CURE), and internal stretch fraction (ISF). The goal of this study was to compare the sensitivity of these indices to 4 major abnormalities responsible for cardiac dysfunction in dyssynchronous HF: dilation, negative inotropy, negative lusitropy, and dyssynchronous activation. Methods and Results—All combinations of these 4 major abnormalities were included in 3D computational models of ventricular electromechanics. Compared with a nonfailing heart model, ventricles were dilated, inotropy was reduced, twitch duration was prolonged, and activation sequence was changed from normal to left bundle branch block. In the nonfailing heart, CURE, ISF, and WTpeak were 0.97±0.004, 0.010±0.002, and 78±1 milliseconds, respectively. With dilation alone, CURE decreased 2.0±0.07%, ISF increased 58±47%, and WTpeak increased 31±3%. With dyssynchronous activation alone, CURE decreased 15±0.6%, ISF increased 14-fold (±3), and WTpeak increased 121±4%. With the combination of dilation and dyssynchronous activation, CURE decreased 23±0.8%, ISF increased 20-fold (±5), and WTpeak increased 147±5%. Conclusions—Dilation and left bundle branch block combined synergistically decreased regional cardiac function. CURE and ISF were sensitive to this combination, but WTpeak was not. CURE and ISF also reflected the relative nonuniform distribution of regional work better than WTpeak. These findings might explain why CURE and ISF are better predictors of reverse remodeling in cardiac resynchronization therapy.

Effect of pacing site and infarct location on regional mechanics and global hemodynamics in a model based study of heart failure

Clinical trials evaluating cardiac resynchronization therapy (CRT) have demonstrated that 30% of patients with heart failure and wide QRS do not respond to CRT (especially patients with myocardial infarcts). We have developed 3D numerical models of failing hearts, with and without chronic infarcts in different regions of the left ventricle. The hearts were coupled to a closed circulation, and the model included effects of the pericardium. The hearts were either paced at the right ventricular apex (RVA) or left ventricular free wall (LVFW). In normal and failing hearts, LV pump function was moderately better for LVFW pacing. In the normal heart model, heterogeneity of ejection strain was similar for RVA and LVFW pacing. However, in the failing heart model, LVFW pacing was associated with 44% less heterogeneity of ejection strain. This may be an important factor in the remodeling process associated with pacing.

Improvement in pump function with endocardial biventricular pacing increases with activation time at the left ventricular pacing site in failing canine hearts

Recently, attention has been focused on comparing left ventricular (LV) endocardial (ENDO) with epicardial (EPI) pacing for cardiac resynchronization therapy. However, the effects of ENDO and EPI lead placement at multiple sites have not been studied in failing hearts. We hypothesized that differences in the improvement of ventricular function due to ENDO vs. EPI pacing in dyssynchronous (DYSS) heart failure may depend on the position of the LV lead in relation to the original activation pattern. In six nonfailing and six failing dogs, electrical DYSS was created by atrioventricular sequential pacing of the right ventricular apex. ENDO was compared with EPI biventricular pacing at five LV sites. In failing hearts, increases in the maximum rate of LV pressure change (dP/dt; r = 0.64), ejection fraction (r = 0.49), and minimum dP/dt (r = 0.51), relative to DYSS, were positively correlated (P < 0.01) with activation time at the LV pacing site during ENDO but not EPI pacing. ENDO pacing at sites with longer activation delays led to greater improvements in hemodynamic parameters and was associated with an overall reduction in electrical DYSS compared with EPI pacing (P < 0.05). These findings were qualitatively similar for nonfailing hearts. Improvement in hemodynamic function increased with activation time at the LV pacing site during ENDO but not EPI pacing. At the anterolateral wall, end-systolic transmural function was greater with local ENDO compared with EPI pacing. ENDO pacing and intrinsic activation delay may have important implications for management of DYSS heart failure.

Multi-scale modeling of excitation-contraction coupling in the normal and failing heart

Here we describe new computational models of cardiac electromechanics starting from the cellular scale and building to the tissue, organ and system scales. We summarize application to human genetic diseases (LQT1 and LQT3) and to modeling of congestive heart failure.

Myofiber prestretch magnitude determines regional systolic function during ectopic activation in the tachycardia-induced failing canine heart

Electrical dyssynchrony leads to prestretch in late-activated regions and alters the sequence of mechanical contraction, although prestretch and its mechanisms are not well defined in the failing heart. We hypothesized that in heart failure, fiber prestretch magnitude increases with the amount of early-activated tissue and results in increased end-systolic strains, possibly due to length-dependent muscle properties. In five failing dog hearts with scars, three-dimensional strains were measured at the anterolateral left ventricle (LV). Prestretch magnitude was varied via ventricular pacing at increasing distances from the measurement site and was found to increase with activation time at various wall depths. At the subepicardium, prestretch magnitude positively correlated with the amount of early-activated tissue. At the subendocardium, local end-systolic strains (fiber shortening, radial wall thickening) increased proportionally to prestretch magnitude, resulting in greater mean strain values in late-activated compared with early-activated tissue. Increased fiber strains at end systole were accompanied by increases in preejection fiber strain, shortening duration, and the onset of fiber relengthening, which were all positively correlated with local activation time. In a dog-specific computational failing heart model, removal of length and velocity dependence on active fiber stress generation, both separately and together, alter the correlations between local electrical activation time and timing of fiber strains but do not primarily account for these relationships.

Computational Modeling of Heart Failure with Application to Cardiac Resynchronization Therapy

In recent years, cardiac resynchronization therapy (CRT) has become an effective and popular approach to the treatment of heart failure with a conduction disturbance, but it is unclear why 30% of patients do not respond. With improvements in computer power, diagnostic and therapeutic medical technologies, it is increasingly feasible to apply patient-specific modeling to guide and predict the response to CRT. In this chapter we discuss strategies as to how computational modeling of CRT could be used to try to predict the outcome of this therapy patient-specifically.