Translating myosin-binding protein C and titin abnormalities to whole-heart function using a novel calcium-contraction coupling model.

Mutations in cardiac myosin-binding protein C (cMyBP-C) or titin may respectively lead to hypertrophic (HCM) or dilated (DCM) cardiomyopathies. The mechanisms leading to these phenotypes remain unclear because of the challenge of translating cellular abnormalities to whole-heart and system function. We developed and validated a novel computer model of calcium-contraction coupling incorporating the role of cMyBP-C and titin based on the key assumptions: 1) tension in the thick filament promotes cross-bridge attachment mechanochemically, 2) with increasing titin tension, more myosin heads are unlocked for attachment, and 3) cMyBP-C suppresses cross-bridge attachment. Simulated stationary calcium-tension curves, isotonic and isometric contractions, and quick release agreed with experimental data. The model predicted that a loss of cMyBP-C function decreases the steepness of the calcium-tension curve, and that more compliant titin decreases the level of passive and active tension and its dependency on sarcomere length. Integrating this cellular model in the CircAdapt model of the human heart and circulation showed that a loss of cMyBP-C function resulted in HCM-like hemodynamics with higher left ventricular end-diastolic pressures and smaller volumes. More compliant titin led to higher diastolic pressures and ventricular dilation, suggesting DCM-like hemodynamics. The novel model of calcium-contraction coupling incorporates the role of cMyBP-C and titin. Its coupling to whole-heart mechanics translates changes in cellular calcium-contraction coupling to changes in cardiac pump and circulatory function and identifies potential mechanisms by which cMyBP-C and titin abnormalities may develop into HCM and DCM phenotypes. This modeling platform may help identify distinct mechanisms underlying clinical phenotypes in cardiac diseases.

Differentiating the effects of ß-adrenergic stimulation and stretch on calcium and force dynamics using a novel electromechanical cardiomyocyte model.

Cardiac electrophysiology and mechanics are strongly interconnected. Calcium is crucial in this complex interplay through its role in cellular electrophysiology and sarcomere contraction. We aim to differentiate the effects of acute ß-adrenergic stimulation (ß-ARS) and cardiomyocyte stretch (increased sarcomere length) on calcium-transient dynamics and force generation, using a novel computational model of cardiac electromechanics. We implemented a bidirectional coupling between the O'Hara-Rudy model of human ventricular electrophysiology and the MechChem model of sarcomere mechanics through the buffering of calcium by troponin. The coupled model was validated using experimental data from large mammals or human samples. Calcium transient and force were simulated for various degrees of ß-ARS and initial sarcomere lengths. The model reproduced force-frequency, quick-release, and isotonic contraction experiments, validating the bidirectional electromechanical interactions. An increase in ß-ARS increased the amplitudes of force (augmented inotropy) and calcium transient, and shortened both force and calcium-transient duration (lusitropy). An increase in sarcomere length increased force amplitude even more, but decreased calcium-transient amplitude and increased both force and calcium-transient duration. Finally, a gradient in relaxation along the thin filament may explain the nonmonotonic decay in cytosolic calcium observed with high tension. Using a novel coupled human electromechanical model, we identified differential effects of ß-ARS and stretch on calcium and force. Stretch mostly contributed to increased force amplitude and ß-ARS to the reduction of calcium and force duration. We showed that their combination, rather than individual contributions, is key to ensure force generation, rapid relaxation, and low diastolic calcium levels.NEW & NOTEWORTHY This work identifies the contribution of electrical and mechanical alterations to regulation of calcium and force under exercise-like conditions using a novel human electromechanical model integrating ventricular electrophysiology and sarcomere mechanics. By better understanding their individual and combined effects, this can uncover arrhythmogenic mechanisms in exercise-like situations. This publicly available model is a crucial step toward understanding the complex interplay between cardiac electrophysiology and mechanics to improve arrhythmia risk prediction and treatment.

Large vessels as a tree of transmission lines incorporated in the CircAdapt whole-heart model: A computational tool to examine heart-vessel interaction.

We developed a whole-circulation computational model by integrating a transmission line (TL) model describing vascular wave transmission into the established CircAdapt platform of whole-heart mechanics. In the present paper, we verify the numerical framework of our TL model by benchmark comparison to a previously validated pulse wave propagation (PWP) model. Additionally, we showcase the integrated CircAdapt-TL model, which now includes the heart as well as extensive arterial and venous trees with terminal impedances. We present CircAdapt-TL haemodynamics simulations of: 1) a systemic normotensive situation and 2) a systemic hypertensive situation. In the TL-PWP benchmark comparison we found good agreement regarding pressure and flow waveforms (relative errors ≤ 2.9% for pressure, and ≤ 5.6% for flow). CircAdapt-TL simulations reproduced the typically observed haemodynamic changes with hypertension, expressed by increases in mean and pulsatile blood pressures, and increased arterial pulse wave velocity. We observed a change in the timing of pressure augmentation (defined as a late-systolic boost in aortic pressure) from occurring after time of peak systolic pressure in the normotensive situation, to occurring prior to time of peak pressure in the hypertensive situation. The pressure augmentation could not be observed when the systemic circulation was lumped into a (non-linear) three-element windkessel model, instead of using our TL model. Wave intensity analysis at the carotid artery indicated earlier arrival of reflected waves with hypertension as compared to normotension, in good qualitative agreement with findings in patients. In conclusion, we successfully embedded a TL model as a vascular module into the CircAdapt platform. The integrated CircAdapt-TL model allows detailed studies on mechanistic studies on heart-vessel interaction.

Linking cross-bridge cycling kinetics to response to cardiac resynchronization therapy: a multiscale modelling study.

AIMS: Cardiac resynchronization therapy (CRT) is currently the most widely used treatment for heart failure patients with left bundle branch block (LBBB). In recent years, the presence of septal rebound stretch (SRS) has been found to be a positive indicator for CRT response although the mechanism is unknown. METHODS AND RESULTS: In an attempt to understand the relation between cellular mechanics and global pump function in CRT patients, we utilize the CircAdapt closed-loop cardiovascular system model in combination with the MechChem model of cardiac sarcomere contraction. Left bundle branch block has been simulated with increasing delay in left ventricular free wall and septal wall activation. In addition to the electrical dyssynchrony, myocardial mechanical function was diminished by decreasing the cross-bridge cycling rate. Our results have shown that a decrease in the cross-bridge cycling rate in addition to LBBB resulted in a decrease in SRS with a concomitant decreased response to resynchronization. CONCLUSIONS: The results of our multiscale modelling study suggest that, while greater SRS during systole clearly indicates electrical dyssynchrony, it also predicts mechanical viability and healthy cross-bridge cycling rates in the myocardium. Hence, SRS positively indicates response to CRT.

Mechano-chemical Interactions in Cardiac Sarcomere Contraction: A Computational Modeling Study.

We developed a model of cardiac sarcomere contraction to study the calcium-tension relationship in cardiac muscle. Calcium mediates cardiac contraction through its interactions with troponin (Tn) and subsequently tropomyosin molecules. Experimental studies have shown that a slight increase in intracellular calcium concentration leads to a rapid increase in sarcomeric tension. Though it is widely accepted that the rapid increase is not possible without the concept of cooperativity, the mechanism is debated. We use the hypothesis that there exists a base level of cooperativity intrinsic to the thin filament that is boosted by mechanical tension, i.e. a high level of mechanical tension in the thin filament impedes the unbinding of calcium from Tn. To test these hypotheses, we developed a computational model in which a set of three parameters and inputs of calcium concentration and sarcomere length result in output tension. Tension as simulated appeared in good agreement with experimentally measured tension. Our results support the hypothesis that high tension in the thin filament impedes Tn deactivation by increasing the energy required to detach calcium from the Tn. Given this hypothesis, the model predicted that the areas with highest tension, i.e. closest to the Z-disk end of the single overlap region, show the largest concentration of active Tn's.

Modeling Fatty Acid Transfer from Artery to Cardiomyocyte.

Despite the importance of oxidation of blood-borne long-chain fatty acids (Fa) in the cardiomyocytes for contractile energy of the heart, the mechanisms underlying the transfer of Fa from the coronary plasma to the cardiomyocyte is still incompletely understood. To obtain detailed insight into this transfer process, we designed a novel model of Fa transfer dynamics from coronary plasma through the endothelial cells and interstitium to the cardiomyocyte, applying standard physicochemical principles on diffusion and on the chemical equilibrium of Fa binding to carrier proteins Cp, like albumin in plasma and interstitium and Fatty Acid-Binding Proteins within endothelium and cardiomyocytes. Applying these principles, the present model strongly suggests that in the heart, binding and release of Fa to and from Cp in the aqueous border zones on both sides of the cell membranes form the major hindrance to Fa transfer. Although often considered, the membrane itself appears not to be a significant hindrance to diffusion of Fa. Proteins, residing in the cellular membrane, may facilitate transfer of Fa between Cp and membrane. The model is suited to simulate multiple tracer dilution experiments performed on isolated rabbit hearts administrating albumin and Fa as tracer substances into the coronary arterial perfusion line. Using parameter values on myocardial ultrastructure and physicochemical properties of Fa and Cp as reported in literature, simulated washout curves appear to be similar to the experimentally determined ones. We conclude therefore that the model is realistic and, hence, can be considered as a useful tool to better understand Fa transfer by evaluation of experimentally determined tracer washout curves.

Fast Simulation of Mechanical Heterogeneity in the Electrically Asynchronous Heart Using the MultiPatch Module.

Cardiac electrical asynchrony occurs as a result of cardiac pacing or conduction disorders such as left bundle-branch block (LBBB). Electrically asynchronous activation causes myocardial contraction heterogeneity that can be detrimental for cardiac function. Computational models provide a tool for understanding pathological consequences of dyssynchronous contraction. Simulations of mechanical dyssynchrony within the heart are typically performed using the finite element method, whose computational intensity may present an obstacle to clinical deployment of patient-specific models. We present an alternative based on the CircAdapt lumped-parameter model of the heart and circulatory system, called the MultiPatch module. Cardiac walls are subdivided into an arbitrary number of patches of homogeneous tissue. Tissue properties and activation time can differ between patches. All patches within a wall share a common wall tension and curvature. Consequently, spatial location within the wall is not required to calculate deformation in a patch. We test the hypothesis that activation time is more important than tissue location for determining mechanical deformation in asynchronous hearts. We perform simulations representing an experimental study of myocardial deformation induced by ventricular pacing, and a patient with LBBB and heart failure using endocardial recordings of electrical activation, wall volumes, and end-diastolic volumes. Direct comparison between simulated and experimental strain patterns shows both qualitative and quantitative agreement between model fibre strain and experimental circumferential strain in terms of shortening and rebound stretch during ejection. Local myofibre strain in the patient simulation shows qualitative agreement with circumferential strain patterns observed in the patient using tagged MRI. We conclude that the MultiPatch module produces realistic regional deformation patterns in the asynchronous heart and that activation time is more important than tissue location within a wall for determining myocardial deformation. The CircAdapt model is therefore capable of fast and realistic simulations of dyssynchronous myocardial deformation embedded within the closed-loop cardiovascular system.

Assessment and comparison of left ventricular shear in normal and situs inversus totalis hearts by means of magnetic resonance tagging.

Situs inversus totalis (SIT) is characterized by complete mirroring of gross cardiac anatomy and position combined with an incompletely mirrored myofiber arrangement, being normal at the apex but inverted at the base of the left ventricle (LV). This study relates myocardial structure to mechanical function by analyzing and comparing myocardial deformation patterns of normal and SIT subjects, focusing especially on circumferential-radial shear. In nine control and nine SIT normotensive human subjects, myocardial deformation was assessed from magnetic resonance tagging (MRT) image sequences of five LV short-axis slices. During ejection, no significant difference in either circumferential shortening (εcc) or its axial gradient (Δεcc) is found between corresponding LV levels in control and SIT hearts. Circumferential-radial shear (εcr) has a clear linear trend from apex-to-base in controls, while in SIT it hovers close to zero at all levels. Torsion as well as axial change in εcr (Δεcr) is as in controls in apical sections of SIT hearts but deviates significantly towards the base, changing sign close to the LV equator. Interindividual variability in torsion and Δεcr values is higher in SIT than in controls. Apex-to-base trends of torsion and Δεcr in SIT, changing sign near the LV equator, further substantiate a structural transition in myofiber arrangement close to the LV equator itself. Invariance of εcc and Δεcc patterns between controls and SIT subjects shows that normal LV pump function is achieved in SIT despite partial mirroring of myocardial structure leading to torsional and shear patterns that are far from normality.

Control of whole heart geometry by intramyocardial mechano-feedback: a model study.

Geometry of the heart adapts to mechanical load, imposed by pressures and volumes of the cavities. We regarded preservation of cardiac geometry as a homeostatic control system. The control loop was simulated by a chain of models, starting with geometry of the cardiac walls, sequentially simulating circulation hemodynamics, myofiber stress and strain in the walls, transfer of mechano-sensed signals to structural changes of the myocardium, and finalized by calculation of resulting changes in cardiac wall geometry. Instead of modeling detailed mechano-transductive pathways and their interconnections, we used principles of control theory to find optimal transfer functions, representing the overall biological responses to mechanical signals. As biological responses we regarded tissue mass, extent of contractile myocyte structure and extent of the extra-cellular matrix. Mechano-structural stimulus-response characteristics were considered to be the same for atrial and ventricular tissue. Simulation of adaptation to self-generated hemodynamic load rendered physiologic geometry of all cardiac cavities automatically. Adaptation of geometry to chronic hypertension and volume load appeared also physiologic. Different combinations of mechano-sensors satisfied the condition that control of geometry is stable. Thus, we expect that for various species, evolution may have selected different solutions for mechano-adaptation.

Myocardial perfusion and flow reserve in the asynchronous heart: mechanistic insight from a computational model.

The tight coupling between myocardial oxygen demand and supply has been recognized for decades, but it remains controversial whether this coupling persists under asynchronous activation, such as during left bundle branch block (LBBB). Furthermore, it is unclear whether the amount of local cardiac wall growth, following longer-lasting asynchronous activation, can explain differences in myocardial perfusion distribution between subjects. For a better understanding of these matters, we built upon our existing modeling framework for cardiac mechanics-to-perfusion coupling by incorporating coronary autoregulation. Regional coronary flow was regulated with a vasodilator signal based on regional demand, as estimated from regional fiber stress-strain area. Volume of left ventricular wall segments was adapted with chronic asynchronous activation toward a homogeneous distribution of myocardial oxygen demand per tissue weight. Modeling results show that 1) both myocardial oxygen demand and supply are decreased in early activated regions and increased in late-activated regions; 2) but that regional hyperemic flow remains unaffected; while 3) regional myocardial flow reserve (the ratio of hyperemic to resting myocardial flow) decreases with increases in absolute regional myocardial oxygen demand as well as with decreases in wall thickness. These findings suggest that septal hypoperfusion in LBBB represents an autoregulatory response to reduced myocardial oxygen demand. Furthermore, oxygen demand-driven remodeling of wall mass can explain asymmetric hypertrophy and the related homogenization of myocardial perfusion and flow reserve. Finally, the inconsistent observations of myocardial perfusion distribution can primarily be explained by the degree of dyssynchrony, the degree of asymmetric hypertrophy, and the imaging modality used.NEW & NOTEWORTHY This versatile modeling framework couples myocardial oxygen demand to oxygen supply and myocardial growth, enabling simulation of resting and hyperemic myocardial flow during acute and chronic asynchronous ventricular activation. Model-based findings suggest that reported inconsistencies in myocardial perfusion and flow reserve responses with asynchronous ventricular activation between patients can primarily be explained by the degree of dyssynchrony and wall mass remodeling, which together determine the heterogeneity in regional oxygen demand and, hence, supply with autoregulation.

Increased Chamber Resting Tone Is a Key Determinant of Left Ventricular Diastolic Dysfunction.

BACKGROUND: Twitch-independent tension has been demonstrated in cardiomyocytes, but its role in heart failure (HF) is unclear. We aimed to address twitch-independent tension as a source of diastolic dysfunction by isolating the effects of chamber resting tone (RT) from impaired relaxation and stiffness. METHODS: We invasively monitored pressure-volume data during cardiopulmonary exercise in 20 patients with hypertrophic cardiomyopathy, 17 control subjects, and 35 patients with HF with preserved ejection fraction. To measure RT, we developed a new method to fit continuous pressure-volume measurements, and first validated it in a computational model of loss of cMyBP-C (myosin binding protein-C). RESULTS: In hypertrophic cardiomyopathy, RT (estimated marginal mean [95% CI]) was 3.4 (0.4-6.4) mm Hg, increasing to 18.5 (15.5-21.5) mm Hg with exercise (P<0.001). At peak exercise, RT was responsible for 64% (53%-76%) of end-diastolic pressure, whereas incomplete relaxation and stiffness accounted for the rest. RT correlated with the levels of NT-proBNP (N-terminal pro-B-type natriuretic peptide; R=0.57; P=0.02) and with pulmonary wedge pressure but following different slopes at rest and during exercise (R2=0.49; P<0.001). In controls, RT was 0.0 mm Hg and 1.2 (0.3-2.8) mm Hg in HF with preserved ejection fraction patients and was also exacerbated by exercise. In silico, RT increased in parallel to the loss of cMyBP-C function and correlated with twitch-independent myofilament tension (R=0.997). CONCLUSIONS: Augmented RT is the major cause of LV diastolic chamber dysfunction in hypertrophic cardiomyopathy and HF with preserved ejection fraction. RT transients determine diastolic pressures, pulmonary pressures, and functional capacity to a greater extent than relaxation and stiffness abnormalities. These findings support antimyosin agents for treating HF.

Atrial septostomy benefits severe pulmonary hypertension patients by increase of left ventricular preload reserve.

At present, it is unknown why patients suffering from severe pulmonary hypertension (PH) benefit from atrial septostomy (AS). Suggested mechanisms include enhanced filling of the left ventricle, reduction of right ventricular preload, increased oxygen availability in the peripheral tissue, or a combination. A multiscale computational model of the cardiovascular system was used to assess the effects of AS in PH. Our model simulates beat-to-beat dynamics of the four cardiac chambers with valves and the systemic and pulmonary circulations, including an atrial septal defect (ASD). Oxygen saturation was computed for each model compartment. The acute effect of AS on systemic flow and oxygen delivery in PH was assessed by a series of simulations with combinations of different ASD diameters, pulmonary flows, and degrees of PH. In addition, blood pressures at rest and during exercise were compared between circulations with PH before and after AS. If PH did not result in a right atrial pressure exceeding the left one, AS caused a left-to-right shunt flow that resulted in decreased oxygenation and a further increase of right ventricular pump load. Only in the case of severe PH a right-to-left shunt flow occurred during exercise, which improved left ventricular preload reserve and maintained blood pressure but did not improve oxygenation. AS only improves symptoms of right heart failure in patients with severe PH if net right-to-left shunt flow occurs during exercise. This flow enhances left ventricular filling, allows blood pressure maintenance, but does not increase oxygen availability in the peripheral tissue.

A Closed-Loop Modeling Framework for Cardiac-to-Coronary Coupling.

The mechanisms by which cardiac mechanics effect coronary perfusion (cardiac-to-coronary coupling) remain incompletely understood. Several coronary models have been proposed to deepen our understanding of coronary hemodynamics, but possibilities for in-depth studies on cardiac-to-coronary coupling are limited as mechanical properties like myocardial stress and strain are most often neglected. To overcome this limitation, a mathematical model of coronary mechanics and hemodynamics was implemented in the previously published multi-scale CircAdapt model of the closed-loop cardiovascular system. The coronary model consisted of a relatively simple one-dimensional network of the major conduit arteries and veins as well as a lumped parameter model with three transmural layers for the microcirculation. Intramyocardial pressure was assumed to arise from transmission of ventricular cavity pressure into the myocardial wall as well as myocardial stiffness, based on global pump mechanics and local myofiber mechanics. Model-predicted waveforms of global epicardial flow velocity, as well as of intramyocardial flow and diameter were qualitatively and quantitatively compared with reported data. Versatility of the model was demonstrated in a case study of aortic valve stenosis. The reference simulation correctly described the phasic pattern of coronary flow velocity, arterial flow impediment, and intramyocardial differences in coronary flow and diameter. Predicted retrograde flow during early systole in aortic valve stenosis was in agreement with measurements obtained in patients. In conclusion, we presented a powerful multi-scale modeling framework that enables realistic simulation of coronary mechanics and hemodynamics. This modeling framework can be used as a research platform for in-depth studies of cardiac-to-coronary coupling, enabling study of the effect of abnormal myocardial tissue properties on coronary hemodynamics.

Intra-cardiac transfer of fatty acids from capillary to cardiomyocyte.

Blood-borne fatty acids (Fa) are important substrates for energy conversion in the mammalian heart. After release from plasma albumin, Fa traverse the endothelium and the interstitial compartment to cross the sarcolemma prior to oxidation in the cardiomyocytal mitochondria. The aims of the present study were to elucidate the site with lowest Fa permeability (i.e., highest Fa resistance) in the overall Fa trajectory from capillary to cardiomyocyte and the relative contribution of unbound Fa (detach pathway, characterized by the dissociation time constant τAlbFa) and albumin-bound Fa (contact pathway, characterized by the membrane reaction rate parameter dAlb) in delivering Fa to the cellular membranes. In this study, an extensive set of 34 multiple indicator dilution experiments with radiolabeled albumin and palmitate on isolated rabbit hearts was analysed by means of a previously developed mathematical model of Fa transfer dynamics. In these experiments, the ratio of the concentration of palmitate to albumin was set at 0.91. The analysis shows that total cardiac Fa permeability, Ptot, is indeed related to the albumin concentration in the extracellular compartment as predicted by the mathematical model. The analysis also reveals that the lowest permeability may reside in the boundary zones containing albumin in the microvascular and interstitial compartment. However, the permeability of the endothelial cytoplasm, Pec, may influence overall Fa permeability, Ptot, as well. The model analysis predicts that the most likely value of τAlbFa ranges from about 200 to 400 ms. In case τAlbFa is fast, i.e., about 200 ms, the extracellular contact pathway appears to be of minor importance in delivering Fa to the cell membrane. If Fa dissociation from albumin is slower, e.g. τAlbFa equals 400 ms, the contribution of the contact pathway may vary from minimal (dAlb≤5 nm) to substantial (dAlb about 100 nm). In the latter case, the permeability of the endothelial cytoplasm varies from infinite (no hindrance) to low (substantial hindrance) to keep the overall Fa flux at a fixed level. Definitive estimation of the impact of endothelial permeability on Ptot and the precise contribution of the contact pathway to overall transfer of Fa in boundary zones containing albumin requires adequate physicochemical experimentation to delineate the true value of, among others, τAlbFa, under physiologically relevant circumstances. Our analysis also implies that concentration differences of unbound Fa are the driving force of intra-cardiac Fa transfer; an active, energy requiring transport mechanism is not necessarily involved. Membrane-associated proteins may facilitate Fa transfer in the boundary zones containing albumin by modulating the membrane reaction rate parameter, dAlb, and, hence, the contribution of the contact pathway to intra-cardiac Fa transfer.

Complementing sparse vascular imaging data by physiological adaptation rules.

Mathematical modeling of pressure and flow waveforms in blood vessels using pulse wave propagation (PWP) models has tremendous potential to support clinical decision making. For a personalized model outcome, measurements of all modeled vessel radii and wall thicknesses are required. In clinical practice, however, data sets are often incomplete. To overcome this problem, we hypothesized that the adaptive capacity of vessels in response to mechanical load could be utilized to fill in the gaps of incomplete patient-specific data sets. We implemented homeostatic feedback loops in a validated PWP model to allow adaptation of vessel geometry to maintain physiological values of wall stress and wall shear stress. To evaluate our approach, we gathered vascular MRI and ultrasound data sets of wall thicknesses and radii of central and arm arterial segments of 10 healthy subjects. Reference models (i.e., termed RefModel, n = 10) were simulated using complete data, whereas adapted models (AdaptModel, n = 10) used data of one carotid artery segment only, and the remaining geometries in this model were estimated using adaptation. We evaluated agreement between RefModel and AdaptModel geometries, as well as that between pressure and flow waveforms of both models. Limits of agreement (bias ± 2 SD of difference) between AdaptModel and RefModel radii and wall thicknesses were 0.2 ± 2.6 mm and -140 ± 557 µm, respectively. Pressure and flow waveform characteristics of the AdaptModel better resembled those of the RefModels as compared with the model in which the vessels were not adapted. Our adaptation-based PWP model enables personalization of vascular geometries even when not all required data are available.NEW & NOTEWORTHY To benefit personalized pulse wave propagation (PWP) modeling, we propose a novel method that, instead of relying on extensive data sets on vascular geometries, incorporates physiological adaptation rules. The developed vascular adaptation model adequately predicted arterial radius and wall thickness compared with ultrasound and MRI estimates, obtained in humans. Our approach could be used as a tool to facilitate personalized modeling, notably in case of missing data, as routinely found in clinical settings.

Left ventricular underfilling and not septal bulging dominates abnormal left ventricular filling hemodynamics in chronic thromboembolic pulmonary hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH) is associated with abnormal left ventricular (LV) filling hemodynamics [mitral early passive filling wave velocity/late active filling wave velocity (E/A) < 1]. Pulmonary endarterectomy (PEA) acutely reduces pulmonary vascular resistance, resulting in an increase of mitral E/A. The abolishment of leftward septal bulging and an increase in right ventricular (RV) output are thought to be responsible for the increase of mitral E/A. In this study, we quantified the separate effects of leftward septal bulging and RV output on LV hemodynamics. In 39 CTEPH patients who underwent PEA, transmitral flow velocities and RV hemodynamic data were obtained pre- and postoperatively. A mathematical model describing the mechanics of ventricular interaction was fitted to the preoperative average values of cardiac output (CO; 4.4 l/min), mean pulmonary artery pressure (mPAP; 50 mmHg), mitral E/A (0.74), and mean left atrial pressure (mLAP; 9.8 mmHg). Starting from this preoperative reference state with leftward septal bulging, PEA was simulated by changing mPAP and CO to average postoperative values (28 mmHg and 5.7 l/min, respectively). Simulated and postoperatively measured data on E/A (1.27 vs. 1.48), mLAP (12.6 vs. 11.5 mmHg), and septal curvature (both rightward) were consistent. When an exclusive decrease of mPAP was simulated, mitral E/A increased 26%, mLAP decreased 16%, and septal curvature became rightward. When an exclusive increase of CO was simulated, mitral E/A increased 53% and mLAP increased 62%, whereas leftward septal bulging persisted. Thus, our simulations suggest that the increase of mitral E/A with PEA is caused two-thirds by an increase of RV output and one-third by the abolishment of leftward septal bulging.

Right ventricular free wall pacing improves cardiac pump function in severe pulmonary arterial hypertension: a computer simulation analysis.

In pulmonary arterial hypertension (PAH), duration of myofiber shortening is prolonged in the right ventricular (RV) free wall (RVfw) compared with that in the interventricular septum and left ventricular free wall. This interventricular mechanical asynchrony eventually leads to right heart failure. We investigated by computer simulation whether, in PAH, early RVfw pacing may improve interventricular mechanical synchrony and, hence, cardiac pump function. A mathematical model of the human heart and circulation was used to simulate left ventricular and RV pump mechanics and myofiber mechanics. First, we simulated cardiovascular mechanics of a healthy adult at rest. Size and mass of heart and blood vessels were adapted so that mechanical tissue load was normalized. Second, compensated PAH was simulated by increasing mean pulmonary artery pressure to 32 mmHg while applying load adaptation. Third, decompensated PAH was simulated by increasing mean pulmonary artery pressure further to 79 mmHg without further adaptation. Finally, early RVfw pacing was simulated in severely decompensated PAH. Time courses of circumferential strain in the ventricular walls as simulated were similar to the ones measured in healthy subjects (uniform strain patterns) and in PAH patients (prolonged RVfw shortening). When simulating pacing in decompensated PAH, RV pump function was best upon 40-ms RVfw preexcitation, as evidenced by maximal decrease of RV end-diastolic volume, reduced RVfw myofiber work, and most homogeneous distribution of workload over the ventricular walls. Thus our simulations indicate that, in decompensated PAH, RVfw pacing may improve RV pump function and may homogenize workload over the ventricular walls.

Left ventricular apical torsion and architecture are not inverted in situs inversus totalis.

Occasionally, individuals have a complete, mirror-image reversal of their internal organ position, called situs inversus totalis (SIT). Whereas gross anatomy is mirror-imaged in SIT, this might not be the case for the internal architecture of organs, e.g. the myofiber pattern in the left cardiac ventricle. We performed a Magnetic Resonance Tagging study in nine controls and in eight subjects with SIT to assess the deformation pattern in the apical half of the LV wall. It appeared that both groups had the same LV apical deformation pattern. This implies that not only the superficial LV apical layers in SIT follow a normal, not inverted pattern, but the deeper layers as well. Apparently, the embryonic L/R controlling genetic pathway does determine situs-specific gross anatomy morphogenesis but it is not the only factor regulating fiber architecture within the apical part of the LV wall. We propose that mechanical forces generated in the not-inverted molecular structure of the basic right-handed helical contractile components of the sarcomere play a role in shaping the LV apex.

High tension in sarcomeres hinders myocardial relaxation: A computational study.

Experiments have shown that the relaxation phase of cardiac sarcomeres during an isometric twitch is prolonged in muscles that reached a higher peak tension. However, the mechanism is not completely understood. We hypothesize that the binding of calcium to troponin is enhanced by the tension in the thin filament, thus contributing to the prolongation of contraction upon higher peak tension generation. To test this hypothesis, we developed a computational model of sarcomere mechanics that incorporates tension-dependence of calcium binding. The model was used to simulate isometric twitch experiments with time dependency in the form of a two-state cross-bridge cycle model and a transient intracellular calcium concentration. In the simulations, peak isometric twitch tension appeared to increase linearly by 51.1 KPa with sarcomere length from 1.9 µm to 2.2 µm. Experiments showed an increase of 47.3 KPa over the same range of sarcomere lengths. The duration of the twitch also increased with both sarcomere length and peak intracellular calcium concentration, likely to be induced by the inherently coupled increase of the peak tension in the thin filament. In the model simulations, the time to 50% relaxation (tR50) increased over the range of sarcomere lengths from 1.9 µm to 2.2 µm by 0.11s, comparable to the increased duration of 0.12s shown in experiments. Model simulated tR50 increased by 0.12s over the range of peak intracellular calcium concentrations from 0.87 µM to 1.45 µM. Our simulation results suggest that the prolongation of contraction at higher tension is a result of the tighter binding of Ca2+ to troponin in areas under higher tension, thus delaying the deactivation of the troponin.

Calculation of effective VV interval facilitates optimization of AV delay and VV interval in cardiac resynchronization therapy.

BACKGROUND: In hearts with left bundle branch block (LBBB), both atrioventricular (AV) delay and interventricular (VV) interval determine left ventricular (LV) pump function in cardiac resynchronization therapy (CRT). The optimal combination of AV delay and VV interval currently is determined by extensive hemodynamic testing. OBJECTIVES: The purpose of this study was to investigate whether the effective VV interval (VV(eff)) can be used to optimize AV delay and VV interval. METHODS: In eight canine hearts with chronic LBBB, LV pacing was performed at various AV delays as well as biventricular pacing at multiple AV delays and VV intervals. LV pump function was assessed from LVdP/dt(max) and stroke volume (conductance catheter). Interventricular asynchrony was calculated from the timing difference between upslope of LV and RV pressure curves. VV(eff) was defined as the time delay between activation of the RV apex and LV lateral wall, irrespective of the source of RV activation (RV pacing or intrinsic conduction). VV(eff) was determined from pacemaker settings and surface ECGs recorded during biventricular pacing at various AV delays (positive values denote LV preexcitation). RESULTS: For all animals, the relationship between VV(eff) and LVdP/dt(max) as well as LV stroke work was parabolic. Maximal improvement in LVdP/dt(max) was similar during LV pacing, simultaneous biventricular pacing, and sequential biventricular pacing and was obtained at similar values of VV(eff). VV(eff) was strongly correlated with interventricular asynchrony (R = 0.97 +/- 0.03). Optimum LVdP/dt(max) occurred at VV(eff) ranging from -24 to 12 ms (mean -6 +/- 13 ms). For each experiment, the optimal VV(eff) was virtually equal to the value halfway between its minimum (during LV pacing at short AV delay) and maximum (during LBBB) value (R = 0.91). CONCLUSION: Use of VV(eff) facilitates determination of the best combination of AV delay and VV interval during biventricular pacing. For each individual heart, VV(eff), resulting in optimum LV pump function, can be estimated using surface ECGs recorded during biventricular pacing.