CircAdapt Model Research Articles

Impact of myocardial phenotype on atrioventricular delay optimization at rest and during exercise: insights from a virtual patient study

Abstract Background The usefulness of atrioventricular delay (AVD) optimization in cardiac resynchronization therapy (CRT) for heart failure (HF) patients with left bundle branch block (LBBB) and reduced left ventricular ejection fraction (LVEF) is still debated. Yet, studies have not explored the role of non-electrical myocardial disease substrates in determining optimal AVD settings among patients. Purpose We first hypothesized that acute response to AVD optimization might be modulated by various myocardial disease substrates. Furthermore, we hypothesized that cardiac function is more sensitive to changes in AV coupling during exercise and that this sensitivity is also modulated by underlying myocardial disease substrates. Methods We used the CircAdapt model of the human heart and circulation to simulate different types of LV remodeling that can be found in CRT candidates. First, an LBBB-like pattern of mechanical activation was imposed by delaying LV free wall (LVFW) and interventricular septal (IVS) activation relative to right ventricular free wall activation. Then, two types of LV remodeling were simulated by LV dilation with preserved or impaired myocardial contractility, resulting in LVEF <35%. To investigate the effect of diastolic dysfunction, we increased passive myocardial stiffness of the IVS and LVFW on both substrates with LV remodeling until a mean left atrial pressure (mLAP) of 14 mmHg was reached. CRT was simulated by resynchronizing IVS and LVFW. AVD optimization was conducted by gradually reducing the paced AVD from 220 ms to 40 ms in steps of 20 ms. In each simulation, the optimal paced AVD at rest (cardiac output (CO) and heart rate (HR) of 4.2 L/min and 80 bpm, respectively) was assessed using stroke volume (SV) and mLAP which is used as a measure of LV filling pressure. To investigate the relative effect of these myocardial phenotypes during AVD optimization under exercise, CO and HR were increased step-wise. Results The gain in SV by AVD optimization was larger in the simulations with healthy myocardium than in those with hypo-contractile and stiff myocardium (Figure 1: top-row). However, mLAP was comparably decreased by AVD optimization in healthy and diseased myocardium (Figure 1: bottom row). During exercise, the optimum AVD shifted to shorter values (Figure 2: top-row), and mLAP was much more sensitive to AVD, particularly in the presence of hypo-contractile and stiff myocardium (Figure 2: bottom row). Conclusion Virtual patient simulations show that both myocardial hypocontractility and stiffness dampen the effect of AVD optimization on SV. Furthermore, simulations suggest that patients benefit more from AVD optimization during exercise than during resting conditions. These mechanistic insights may help to gain more benefit from AVD optimization for patients undergoing CRT.AVD optimization at restAVD optimization during exercise

The role of atrial pacing site in reducing filling pressures by accelerated pacing in virtual HFpEF patients

Abstract Background Patients with heart failure with preserved ejection fraction (HFpEF) and pacemakers have been shown to benefit from moderately accelerated pacing rates compared to the standard 60bpm. HFpEF patients often present with prolonged P-wave duration (PWD) and atrial fibrillation. Right atrial appendage pacing (RAAP) lengthens PWD, RA septal (RASP) has a neutral effect, while Bachmann’s bundle pacing (BBP) normalizes or shortens PWD compared to sinus rhythm. The mechanical and hemodynamic effects of atrial pacing site selection remain unknown. Aim To investigate the impact of RAAP, RASP and BBP on cardiac mechanics and hemodynamics in an established cohort of virtual HFpEF patients undergoing accelerated pacing. Method HFpEF with prolonged PWD was simulated using the validated CircAdapt computational model of the human cardiovascular system. First, left ventricular (LV) diastolic dysfunction was simulated by decreasing LV myocardial relaxation rate and compliance, such that mean left atrial (LA) pressure (mLAP) was 15mmHg. Second, PWD was prolonged by prescribing a gradual electrical activation delay from RA to LA of 140ms. We then simulated atrial pacing with three different lead positions (Fig.1, left) and gradually increased pacing rate with a constant 120-ms paced atrioventricular (AV) delay. The CircAdapt model computed regional LA strain and mLAP with RAAP, RASP, and BBP. Cardiac output (5L/min) and mean arterial pressure (92mmHg) were kept constant in all simulations. Results Simulated BBP demonstrated the most synchronous LA mechanical activation and function, characterized by uniform segmental LA strain patterns and highest LA reservoir strain (LASR) (Fig.1, middle, with colored arrows highlighting the mechanical dyssynchrony). Hemodynamically (Fig.1, right), BBP acutely decreased mLAP (-1.0mmHg) at the initial heart rate of 60bpm, while RAAP increased it (+0.3mmHg). As pacing rate accelerated, BBP reduces filling pressure (mLAP: -2.8mmHg), more than RASP (-1.8mmHg) or RAAP (-1.2mmHg) at 80bpm. At high pacing rates, RASP and RAAP adversely increase mLAP, due to the prolonged atrial contraction duration and shorter LV filling time. Conclusion Our simulations of different atrial pacing sites in virtual HFpEF patients suggest that BBP yields the most synchronous LA activation pattern and a more substantial reduction in filling pressures with accelerated atrial pacing compared to RASP. Reduction in mLAP with accelerated pacing was attenuated with RAAP. While our study concentrated on a specific paced AV interval, the favorable outcomes observed with BBP could be further improved by including different, rate-adaptive, AV protocols.Fig 1.

Parameter subset reduction for imaging-based digital twin generation of patients with left ventricular mechanical discoordination

BackgroundIntegration of a patient’s non-invasive imaging data in a digital twin (DT) of the heart can provide valuable insight into the myocardial disease substrates underlying left ventricular (LV) mechanical discoordination. However, when generating a DT, model parameters should be identifiable to obtain robust parameter estimations. In this study, we used the CircAdapt model of the human heart and circulation to find a subset of parameters which were identifiable from LV cavity volume and regional strain measurements of patients with different substrates of left bundle branch block (LBBB) and myocardial infarction (MI). To this end, we included seven patients with heart failure with reduced ejection fraction (HFrEF) and LBBB (study ID: 2018-0863, registration date: 2019–10–07), of which four were non-ischemic (LBBB-only) and three had previous MI (LBBB-MI), and six narrow QRS patients with MI (MI-only) (study ID: NL45241.041.13, registration date: 2013–11–12). Morris screening method (MSM) was applied first to find parameters which were important for LV volume, regional strain, and strain rate indices. Second, this parameter subset was iteratively reduced based on parameter identifiability and reproducibility. Parameter identifiability was based on the diaphony calculated from quasi-Monte Carlo simulations and reproducibility was based on the intraclass correlation coefficient (ICC\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${ICC}$$\\end{document}) obtained from repeated parameter estimation using dynamic multi-swarm particle swarm optimization. Goodness-of-fit was defined as the mean squared error (χ2\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${{{\\chi}}}^{{2}}$$\\end{document}) of LV myocardial strain, strain rate, and cavity volume.ResultsA subset of 270 parameters remained after MSM which produced high-quality DTs of all patients (χ2\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${{{\\chi}}}^{{2}}$$\\end{document} < 1.6), but minimum parameter reproducibility was poor (ICCmin\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${{ICC}}_{{min}}$$\\end{document} = 0.01). Iterative reduction yielded a reproducible (ICCmin\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${{ICC}}_{{min}}$$\\end{document} = 0.83) subset of 75 parameters, including cardiac output, global LV activation duration, regional mechanical activation delay, and regional LV myocardial constitutive properties. This reduced subset produced patient-resembling DTs (χ2\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${{{\\chi}}}^{{2}}$$\\end{document} < 2.2), while septal-to-lateral wall workload imbalance was higher for the LBBB-only DTs than for the MI-only DTs (p < 0.05).ConclusionsBy applying sensitivity and identifiability analysis, we successfully determined a parameter subset of the CircAdapt model which can be used to generate imaging-based DTs of patients with LV mechanical discoordination. Parameters were reproducibly estimated using particle swarm optimization, and derived LV myocardial work distribution was representative for the patient’s underlying disease substrate. This DT technology enables patient-specific substrate characterization and can potentially be used to support clinical decision making.

Mitral regurgitation in heart failure with preserved ejection fraction: The interplay of valve, ventricle, and atrium.

Mitral regurgitation (MR) is highly prevalent among patients with heart failure and preserved ejection fraction (HFpEF). Despite this combination being closely associated with unfavourable outcomes, it remains relatively understudied. This is partly due to the inherent heterogeneity of patients with HFpEF. To address this gap, dissecting HFpEF into mechanism-based phenotypes may offer a promising avenue for advancing our comprehension of these complex intertwined conditions. This review employs the validated CircAdapt model to explore the haemodynamic implications of moderate to severe MR across a well-defined spectrum of myocardial disease, characterized by impaired relaxation and reduced myocardial compliance. Both heart failure and mitral valve disease share overlapping symptomatology, primarily attributed to elevated pulmonary pressures. The intricate mechanisms contributing to these elevated pressures are multifaceted, potentially influenced by diastolic dysfunction, left atrial myopathy, and MR. Accurate evaluation of the haemodynamic and clinical impact of MR necessitates a comprehensive approach, taking into account the characteristics of both the left atrium and left ventricle, as well as their intricate interactions, which may currently be underemphasized in diagnostic practice. This holistic assessment is imperative for enhancing our understanding and refining therapeutic strategies within this patient cohort.

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.

How to assess and treat right ventricular electromechanical dyssynchrony in post-repair tetralogy of Fallot: insights from imaging, invasive studies, and computational modelling.

Right bundle branch block (RBBB) and resulting right ventricular (RV) electromechanical discoordination are thought to play a role in the disease process of subpulmonary RV dysfunction that frequently occur post-repair tetralogy of Fallot (ToF). We sought to describe this disease entity, the role of pulmonary re-valvulation, and the potential added value of RV cardiac resynchronization therapy (RV-CRT). Two patients with repaired ToF, complete RBBB, pulmonary regurgitation, and significantly decreased RV function underwent echocardiography, cardiac magnetic resonance, and an invasive study to evaluate the potential for RV-CRT as part of the management strategy. The data were used to personalize the CircAdapt model of the human heart and circulation. Resulting Digital Twins were analysed to quantify the relative effects of RV pressure and volume overload and to predict the effect of RV-CRT. Echocardiography showed components of a classic RV dyssynchrony pattern which could be reversed by RV-CRT during invasive study and resulted in acute improvement in RV systolic function. The Digital Twins confirmed a contribution of electromechanical RV dyssynchrony to RV dysfunction and suggested improvement of RV contraction efficiency after RV-CRT. The one patient who underwent successful permanent RV-CRT as part of the pulmonary re-valvulation procedure carried improvements that were in line with the predictions based on his Digital Twin. An integrative diagnostic approach to RV dysfunction, including the construction of Digital Twins may help to identify candidates for RV-CRT as part of the lifetime management of ToF and similar congenital heart lesions.

Virtual pacing of a patient's digital twin to predict left ventricular reverse remodelling after cardiac resynchronization therapy.

Identifying heart failure (HF) patients who will benefit from cardiac resynchronization therapy (CRT) remains challenging. We evaluated whether virtual pacing in a digital twin (DT) of the patient's heart could be used to predict the degree of left ventricular (LV) reverse remodelling post-CRT. Forty-five HF patients with wide QRS complex (≥130 ms) and reduced LV ejection fraction (≤35%) receiving CRT were retrospectively enrolled. Echocardiography was performed before (baseline) and 6 months after CRT implantation to obtain LV volumes and 18-segment longitudinal strain. A previously developed algorithm was used to generate 45 DTs by personalizing the CircAdapt model to each patient's baseline measurements. From each DT, baseline septal-to-lateral myocardial work difference (MWLW-S,DT) and maximum rate of LV systolic pressure rise (dP/dtmax,DT) were derived. Biventricular pacing was then simulated using patient-specific atrioventricular delay and lead location. Virtual pacing-induced changes ΔMWLW-S,DT and ΔdP/dtmax,DT were correlated with real-world LV end-systolic volume change at 6-month follow-up (ΔLVESV). The DT's baseline MWLW-S,DT and virtual pacing-induced ΔMWLW-S,DT were both significantly associated with the real patient's reverse remodelling ΔLVESV (r = -0.60, P < 0.001 and r = 0.62, P < 0.001, respectively), while correlation between ΔdP/dtmax,DT and ΔLVESV was considerably weaker (r = -0.34, P = 0.02). Our results suggest that the reduction of septal-to-lateral work imbalance by virtual pacing in the DT can predict real-world post-CRT LV reverse remodelling. This DT approach could prove to be an additional tool in selecting HF patients for CRT and has the potential to provide valuable insights in optimization of CRT delivery.

Relationship between cardiac mechanical properties and cardiac magnetic resonance imaging at rest in childhood acute lymphoblastic leukemia survivors.

The characterization of cardiac mechanical properties may contribute to better understanding of doxorubicin-induced cardiotoxicity. Our study aims to investigate the relationship between cardiac mechanical properties, T1 and T2 relaxation times and partition coefficient.Fifty childhood acute lymphoblastic leukemia survivors underwent a cardiac magnetic resonance (CMR) at rest on a 3T MRI system and included a standard ECG-gated 3(3)3(3)5 MOLLI sequence for T1 mapping and an ECG-gated T2-prepared TrueFISP sequence for T2 mapping. Partition coefficient, ejection fraction, end-diastolic volume (EDV) and end-systolic volume (ESV) were calculated. CircAdapt model was used to study cardiac mechanical performance (left ventricle stiffness (LVS), contractility (LVC) and pressure (Pmin and Pmax), cardiac work efficiency (CWE) and ventricular arterial coupling).In the whole cohort, our results showed that LVC (R2 = 69.2%, r = 0.83), Pmin (R2 = 62.9%, r = 0.79) and Pmax can be predicted by significant CMR parameters, while T1 (R2 = 23.2%, r = 0.48) and partition coefficient (R2 = 13.8%, r = 0.37) can be predicted by significant cardiac mechanical properties. In SR group LVS (R2 = 94.8%, r = 0.97), LVC (R2 = 93.7%, r = 0.96) and Pmin (R2 = 90.6%, r = 0.95) can be predicted by significant cardiac mechanical properties, while in HR + DEX group CWE (R2 = 49.8%, r = 0.70) can be predicted by significant cardiac mechanical properties. Partition coefficient (R2 = 72.6%, r = 0.85) can be predicted by significant CMR parameters in SR group.Early characterization of cardiac mechanical properties from CMR parameters has the potential to early detect doxorubicin-induced cardiotoxicity.

Mechanical and hemodynamic effects of left bundle branch area versus biventricular pacing in virtual heart failure patients with left bundle branch block

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): The Dutch Research Council (NWO) Background Left bundle branch area pacing (LBBAP) has been introduced as an alternative, more physiological pacing strategy to biventricular pacing (BiVP). LBBAP can result in selective LBB pacing (sLBBP), non-selective LBB pacing (nsLBBP), or LV septal pacing (LVSP). Direct comparison between the different pacing strategies is challenging due to the practical implications of performing multiple pacing procedures within the same patients, as well as the large heterogeneity of underlying disease in patients. Computational models can be used to perform controlled in silico experiments and to compare all possible pacing modalities under the same conditions. Aim To investigate the effects of LBBAP strategies versus BiVP on cardiac mechanics and hemodynamics in a set of well-defined virtual heart failure patients. Methods An electrophysiological model was used to calculate biventricular electrical activation maps during LBBB and the different pacing strategies. The resulting regional activation times were imposed to the well-validated CircAdapt model of the human four-chamber heart and circulation. A set of virtual patients at different stages of heart failure are then defined within the CircAdapt framework, which is achieved by decreasing the contractility of the LV myocardium, such that LVEF≤35%. The CircAdapt model is then used to compute regional ventricular strain patterns and myocardial work as well as global ventricular pump function during LBBB, BiVP and the different LBBAP modalities. Results Selective LBBP is best at restoring mechanical homogeneity in LV contraction as evidenced by simulated wall strains waveforms (Fig 1, Left). NsLBBP increases septal dyssynchrony and introduces small pre-stretch in the LVfw (1.3±0.3%). This effect is more pronounced in LVSP (2.4±1.4%). In BiVP, pre-stretch occurs only in a single LV free wall (LVfw) segment, but all septal segments display a distinct oscillatory pattern. Work load homogeneity (Fig 1, Center) was best restored in sLBBP (4.9±1.1 kPa). NsLBBP lead to reduced homogeneity (4.9±1.8 kPa). LVSP reduced this further (4.8±2.6kPa), while BiVP performed similarly (4.6±2.6kPa) to LVSP. All modalities vastly improved on the baseline LBBB (4.06±5.6 kPa). Hemodynamically (Fig 1, Right), sLBBP showed greatest improvement in LV function (LVESV:-8.1%; LVEF:+6.8%; MLAP:-16.4%; LVdp/dtmax:+12.8%), followed by nsLBBP (LVESV:-7.2%; LVEF:+6.0%; MLAP:-14.5%; LVdp/dtmax:+12.5%), LVSP (LVESV:-5.6%; LVEF:+4.6%; MLAP:-11.7%; LVdp/dtmax:+12.358%) and finally BiVP (LVESV: -4.6%; LVEF:+3.8%; MLAP:-9.3%; LVdp/dtmax:+9.8%) Conclusion We were able to simulate LBBB and subsequent pacing strategies in virtual heart failure patients. This approach allowed direct comparison of mechanical and hemodynamic effects of BiVP and LBBAP modalities without confounding variables. Our results indicate that all LBBAP modalities perform at least similar to bi-ventricular pacing regardless of mechanical viability.

Left Atrial Function in Patients with Titin Cardiomyopathy

BackgroundTruncating variants in titin (TTNtv) are the most prevalent genetic etiology of dilated cardiomyopathy (DCM). Although TTNtv has been associated with atrial fibrillation, it remains unknown whether and how left atrial (LA) function differs between patients with DCM with and without TTNtv. We aimed to determine and compare LA function in patients with DCM with and without TTNtv and to evaluate whether and how left ventricular (LV) function affects the LA using computational modeling. Methods and ResultsPatients with DCM from the Maastricht DCM registry that underwent genetic testing and cardiovascular magnetic resonance (CMR) were included in the current study. Subsequent computational modeling (CircAdapt model) was performed to identify potential LV and LA myocardial hemodynamic substrates. In total, 377 patients with DCM (n = 42 with TTNtv, n = 335 without a genetic variant) were included (median age 55 years, interquartile range [IQR] 46–62 years, 62% men). Patients with TTNtv had a larger LA volume and decreased LA strain compared with patients without a genetic variant (LA volume index 60 mLm−2 [IQR 49–83] vs 51 mLm−2 [IQR 42–64]; LA reservoir strain 24% [IQR 10–29] vs 28% [IQR 20–34]; LA booster strain 9% [IQR 4–14] vs 14% [IQR 10–17], respectively; all P < .01). Computational modeling suggests that while the observed LV dysfunction partially explains the observed LA dysfunction in the patients with TTNtv, both intrinsic LV and LA dysfunction are present in patients with and without a TTNtv. ConclusionsPatients with DCM with TTNtv have more severe LA dysfunction compared with patients without a genetic variant. Insights from computational modeling suggest that both intrinsic LV and LA dysfunction are present in patients with DCM with and without TTNtv.

Cardiac Mechanical Performance Assessment at Different Levels of Exercise in Childhood Acute Lymphoblastic Leukemia Survivors.

There is a shortage of relevant studies interested in cardiac mechanical performance. Thus, it is clinically relevant to study the impact of cancer treatments on survivors' cardiac mechanical performance to improve our knowledge. The first objective of this study is to assess survivors' cardiac mechanical performance during a cardiopulmonary exercise test (CPET) using both ventricular-arterial coupling (VAC) and cardiac work efficiency (CWE) from cardiac magnetic resonance (CMR) acquisitions. The second objective is to assess the impact of doxorubicin and dexrazoxane (DEX) treatments. A total of 63 childhood acute lymphoblastic leukemia survivors underwent a CMR at rest on a 3T magnetic resonance imaging system, followed by a CPET on ergocycle. The CircAdapt model was used to study cardiac mechanical performance. At different levels of exercise, arterial elastance, end-systolic elastance, VAC, and CWE were estimated. We observed significant differences between the different levels of exercise for both VAC ( P <0.0001) and CWE parameters ( P =0.001). No significant differences were reported between prognostic risk groups at rest and during the CPET. Nevertheless, we observed that survivors in the SR group had a VAC value slightly lower than heart rate (HR)+DEX and HR groups throughout the CPET. Moreover, survivors in the SR group had a CWE parameter slightly higher than HR+DEX and HR groups throughout the CPET. This study reveals that the combination of CPET, CMR acquisitions and CircAdapt model was sensitive enough to observe slight changes in the assessment of VAC and CWE parameters. Our study contributes to improving survivors' follow-up and detection of cardiac problems induced by doxorubicin-related cardiotoxicity.

Modelling cardiac mechanics in doxorubicin-induced cardiotoxicity following childhood acute lymphoblastic leukemia using a combination of cardiac magnetic resonance imaging, cardiopulmonary exercise testing and the CircAdapt model

Children with acute lymphoblastic leukemia (ALL) are treated with doxorubicin-based chemotherapy that can lead to cardiotoxicity which is a well-known cause of mortality. This study aims to characterize myocardial subtle changes induced by doxorubicin-related cardiotoxicity. We used the combination of cardiac magnetic resonance (CMR) imaging, cardiopulmonary exercise testing and the CircAdapt model to explore hemodynamics and intraventricular mechanisms at rest and during exercise in 53 childhood ALL survivors. A sensitivity analysis of the CircAdapt model identified the most influencing parameters on the left ventricle volume. ANOVA were performed to explore significant differences between left ventricle stiffness, contractility, and arteriovenous pressure drop, as well as survivors’ prognostic risk groups. No significant differences were observed between prognostic risk groups. The left ventricle stiffness and left ventricle contractility were non-significantly higher in survivors receiving cardioprotective agents (94.3 %), compared to those at standard and high prognostic risk (77 % and 86 %, respectively). In both left ventricle stiffness and left ventricle contractility, we observed that survivors receiving cardioprotective agents were close to the nominal value of CircAdapt (healthy reference group value is 100 %). This study allowed to improve our knowledge of potential subtle myocardial changes induced by doxorubicin-related cardiotoxicity in childhood ALL survivors. This study confirms that survivors exposed to a high cumulative dose of doxorubicin during treatments are at potential risk of myocardial changes many years after the end of their cancer, while cardio-protective agents may prevent changes in cardiac mechanical properties.

Mechanoelectric effects in healthy cardiac function and under Left Bundle Branch Block pathology

Mechanoelectric feedback (MEF) in the heart operates through several mechanisms which serve to regulate cardiac function. Stretch activated channels (SACs) in the myocyte membrane open in response to cell lengthening, while tension generation depends on stretch, shortening velocity, and calcium concentration. How all of these mechanisms interact and their effect on cardiac output is still not fully understood. We sought to gauge the acute importance of the different MEF mechanisms on heart function.An electromechanical computer model of a dog heart was constructed, using a biventricular geometry of 500K tetrahedral elements. To describe cellular behavior, we used a detailed ionic model to which a SAC model and an active tension model, dependent on stretch and shortening velocity and with calcium sensitivity, were added. Ventricular inflow and outflow were connected to the CircAdapt model of cardiovascular circulation. Pressure–volume loops and activation times were used for model validation.Simulations showed that SACs did not affect acute mechanical response, although if their trigger level was decreased sufficiently, they could cause premature excitations. The stretch dependence of tension had a modest effect in reducing the maximum stretch, and stroke volume, while shortening velocity had a much bigger effect on both. MEF served to reduce the heterogeneity in stretch while increasing tension heterogeneity. In the context of left bundle branch block, a decreased SAC trigger level could restore cardiac output by reducing the maximal stretch when compared to cardiac resynchronization therapy. MEF is an important aspect of cardiac function and could potentially mitigate activation problems.

A Lumped Two-Compartment Model for Simulation of Ventricular Pump and Tissue Mechanics in Ischemic Heart Disease.

Introduction: Computational modeling of cardiac mechanics and hemodynamics in ischemic heart disease (IHD) is important for a better understanding of the complex relations between ischemia-induced heterogeneity of myocardial tissue properties, regional tissue mechanics, and hemodynamic pump function. We validated and applied a lumped two-compartment modeling approach for IHD integrated into the CircAdapt model of the human heart and circulation. Methods: Ischemic contractile dysfunction was simulated by subdividing a left ventricular (LV) wall segment into a hypothetical contractile and noncontractile compartment, and dysfunction severity was determined by the noncontractile volume fraction (). Myocardial stiffness was determined by the zero-passive stress length ( and nonlinearity () of the passive stress-sarcomere length relation of the noncontractile compartment. Simulated end-systolic pressure volume relations (ESPVRs) for 20% acute ischemia were qualitatively compared between a two- and one-compartment simulation, and parameters of the two-compartment model were tuned to previously published canine data of regional myocardial deformation during acute and prolonged ischemia and reperfusion. In six patients with myocardial infarction (MI), the was automatically estimated using the echocardiographic LV strain and volume measurements obtained acutely and 6 months after MI. Estimated segmental values at the baseline and 6-month follow-up were compared with percentage late gadolinium enhancement (LGE) at 6-month follow-up. Results: Simulation of 20% of shifted the ESPVR rightward while moderately reducing the slope, while a one-compartment simulation caused a leftward shift with severe reduction in the slope. Through tuning of the , , and , it was found that manipulation of the alone reproduced the deformation during acute ischemia and reperfusion, while additional manipulations of and were required to reproduce deformation during prolonged ischemia and reperfusion. Out of all segments with LGE>25% at the follow-up, the majority (68%) had higher estimated at the baseline than at the follow-up. Furthermore, the baseline correlated better with percentage LGE than did at the follow-up. Conclusion: We successfully used a two-compartment model for simulation of the ventricular pump and tissue mechanics in IHD. Patient-specific optimizations using regional myocardial deformation estimated the in a small cohort of MI patients in the acute and chronic phase after MI, while estimated values closely approximated the extent of the myocardial scar at the follow-up. In future studies, this approach can facilitate deformation imaging–based estimation of myocardial tissue properties in patients with cardiovascular diseases.

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.

Strain-based characterization of electromechanical tissue properties using patient-specific simulation of dyssynchronous hearts: a pilot study

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Dutch Heart Foundation (ERA-CVD JTC2018 grant 2018T094; Dr. Dekker Program grant 2015T082 to J.L.) and the Netherlands Organisation for Scientific Research (NWO- ZonMw, VIDI grant 016.176.340 to J.L.) Background/Introduction Interpretation of regional strain patterns in patients with failing hearts is often challenging due to presence of different underlying tissue abnormalities, including electrical conduction delay and myocardial infarction (MI). Purpose To test whether an automatic strain-based computer simulation algorithm can differentiate between electrical and ischemic contractile dysfunction in patients with mechanical dyssynchrony. Methods Three heart failure patients with reduced left ventricular ejection fraction (33 ± 3%) and wide QRS (160 ± 7ms, LBBB morphology) were retrospectively included, two with and one without MI. Longitudinal strain patterns obtained in 18 myocardial segments using speckle tracking echocardiography (STE) and left ventricular (LV) volume measurements were used as an input to the patient-specific simulation algorithm, which automatically optimizes a set of global and regional myocardial tissue parameters such that the regional strain patterns and global volumes simulated by the CircAdapt model of the human heart and circulation were similar to the strains and volumes measured in the patients. As output, the patient-specific simulations revealed onset time of mechanical activation (relative to first activated segment) and relative severity of contractile dysfunction in all 18 segments. We compared predicted mechanical activation delays and segmental contractile dysfunction values with independent measurements of QRS width and transmurality of late gadolinium enhancement (LGE), respectively. Results The model was able to reproduce the dyssynchronous regional strain patterns as measured in the patients (Figure 1: representative example). In all patients, significant septal—to-lateral wall mechanical activation delays (33-55ms) were predicted (Figure 2: blue bullseye plot of same patient used for figure 1), matching the presence of electrical activation delays on the patient’s ECGs (i.e. wide QRS and LBBB morphology). Furthermore, all simulations predicted a global loss of contractile dysfunction, matching the low ejection fractions reported in those patients. The simulations of the two patients with MI predicted more severe contractile dysfunction (&amp;gt;60%) in the regions with transmural LGE (Figure 2: red bullseye plot versus gold standard LGE-MRI image of same patient used for figure 1). Conclusion This pilot study demonstrated the ability of an automatic patient-specific simulation algorithm to differentiate between electrical and ischemic myocardial disease substrates in heart failure patients with electrical conduction abnormalities with and without MI. Future studies will investigate whether this computer algorithm can improve diagnosis of patients with mechanical dyssynchrony. Abstract Figure 1 Abstract Figure 2

Evolution of right ventricular tissue abnormalities in early-stage Arrhythmogenic Cardiomyopathy: an imaging-based patient-specific modeling study

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): (NWO-ZonMw, VIDI grant 016.176.340) and Dutch Heart Foundation (2015T082) Introduction Arrhythmogenic Cardiomyopathy (AC) is an inherited cardiac disease which is characterized by life-threatening ventricular arrhythmias and progressive cardiac dysfunction. Early disease detection and risk stratification is important as geno-positive subjects with and without symptoms may suffer from sudden cardiac death. We propose a patient-specific computer modelling approach using clinical imaging data, to non-invasively quantify regional ventricular tissue abnormalities during follow-up. Purpose To non-invasively reveal the development of myocardial disease substrates underlying the regional RV deformation abnormalities in individual AC mutation carriers. Methods In 2 individuals carrying a plakophilin-2 mutation, regional longitudinal deformation patterns of the RV free wall (RVfw, Figure top row strain panels) , interventricular septum (IVS) and left ventricular free wall (LVfw) were obtained using speckle-tracking echocardiography at baseline during follow-up (4.2 and 9.9 years) and used as input for our Bayesian-based computational framework (Figure Left). This framework generates Digital Twins based on the CircAdapt model of the cardiovascular system which allows estimation of regional tissue properties and its associated uncertainties. The Digital Twins at baseline and during follow-up reveal evolution of the investigated regional tissue properties myocardial contractility, compliance, activation delay, and work. Results This framework was able to reproduce the regional deformation patterns measured at baseline and during follow-up (Figure second row strain panels). Both patients developed abnormal basal deformation patterns during follow-up. Our model revealed this was paired with an increase in heterogeneity in tissue properties. In Patient 1, heterogeneity in contractility developed (75kPa/s [p=.228] at baseline to 347kPa/s [p&amp;lt;.001] at last follow-up). No activation delay was present in this subject (p = 0.188 and p = 0.242 at baseline and at last follow-up). Heterogeneity in compliance developed from 0.11 (p=.014) to 0.49 /kPa (p=.002). Heterogeneity in work-density increased from 1927 (p&amp;lt;.001) to 5497kPa (p&amp;lt;.001). Patient 2 did not develop a contractile substrate (p=.336 and p=.104 for baseline and last follow-up) or delayed basal activation (p=.336 and p=.190 for baseline and last follow-up). Heterogeneity in compliance and work did both develop from 0.04 (p=.070) to 0.1 /kPa (p=.004) and from 865 (p=.100) to 2504kPa (p &amp;lt; 0.001), respectively. Conclusion Our patient-specific modelling approach is able to reveal individual myocardial substrates including uncertainty underlying the regional RV deformation abnormalities and allows investigation of substrate development. Early abnormalities in RV longitudinal strain are most likely caused by increased heterogeneity in tissue compliance. Future studies will investigate whether this approach can improve early detection and risk stratification in geno-positive subjects. Abstract Figure.

Pacing therapy for atrioventricular dromotropathy: a combined computational-experimental-clinical study.

AimsInvestigate haemodynamic effects, and their mechanisms, of restoring atrioventricular (AV)-coupling using pacemaker therapy in normal and failing hearts in a combined computational–experimental–clinical study.Methods and resultsComputer simulations were performed in the CircAdapt model of the normal and failing human heart and circulation. Experiments were performed in a porcine model of AV dromotropathy. In a proof-of-principle clinical study, left ventricular (LV) pressure and volume were measured in 22 heart failure (HF) patients (LV ejection fraction <35%) with prolonged PR interval (>230 ms) and narrow or non-left bundle branch block QRS complex. Computer simulations and animal studies in normal hearts showed that restoring of AV-coupling with unchanged ventricular activation sequence significantly increased LV filling, mean arterial pressure, and cardiac output by 10–15%. In computer simulations of failing hearts and in HF patients, reducing PR interval by biventricular (BiV) pacing (patients: from 300 ± 61 to 137 ± 30 ms) resulted in significant increases in LV stroke volume and stroke work (patients: 34 ± 40% and 26 ± 31%, respectively). However, worsening of ventricular dyssynchrony by using right ventricular (RV) pacing abrogated the benefit of restoring AV-coupling. In model simulations, animals and patients, the increase of LV filling and associated improvement of LV pump function coincided with both larger mitral inflow (E- and A-wave area) and reduction of diastolic mitral regurgitation.ConclusionRestoration of AV-coupling by BiV pacing in normal and failing hearts with prolonged AV conduction leads to considerable haemodynamic improvement. These results indicate that BiV or physiological pacing, but not RV pacing, may improve cardiac function in patients with HF and prolonged PR interval.

Uncertainty Quantification of Regional Cardiac Tissue Properties in Arrhythmogenic Cardiomyopathy Using Adaptive Multiple Importance Sampling.

Introduction: Computational models of the cardiovascular system are widely used to simulate cardiac (dys)function. Personalization of such models for patient-specific simulation of cardiac function remains challenging. Measurement uncertainty affects accuracy of parameter estimations. In this study, we present a methodology for patient-specific estimation and uncertainty quantification of parameters in the closed-loop CircAdapt model of the human heart and circulation using echocardiographic deformation imaging. Based on patient-specific estimated parameters we aim to reveal the mechanical substrate underlying deformation abnormalities in patients with arrhythmogenic cardiomyopathy (AC).Methods: We used adaptive multiple importance sampling to estimate the posterior distribution of regional myocardial tissue properties. This methodology is implemented in the CircAdapt cardiovascular modeling platform and applied to estimate active and passive tissue properties underlying regional deformation patterns, left ventricular volumes, and right ventricular diameter. First, we tested the accuracy of this method and its inter- and intraobserver variability using nine datasets obtained in AC patients. Second, we tested the trueness of the estimation using nine in silico generated virtual patient datasets representative for various stages of AC. Finally, we applied this method to two longitudinal series of echocardiograms of two pathogenic mutation carriers without established myocardial disease at baseline.Results: Tissue characteristics of virtual patients were accurately estimated with a highest density interval containing the true parameter value of 9% (95% CI [0–79]). Variances of estimated posterior distributions in patient data and virtual data were comparable, supporting the reliability of the patient estimations. Estimations were highly reproducible with an overlap in posterior distributions of 89.9% (95% CI [60.1–95.9]). Clinically measured deformation, ejection fraction, and end-diastolic volume were accurately simulated. In presence of worsening of deformation over time, estimated tissue properties also revealed functional deterioration.Conclusion: This method facilitates patient-specific simulation-based estimation of regional ventricular tissue properties from non-invasive imaging data, taking into account both measurement and model uncertainties. Two proof-of-principle case studies suggested that this cardiac digital twin technology enables quantitative monitoring of AC disease progression in early stages of disease.

A computationally efficient physiologically comprehensive 3D–0D closed-loop model of the heart and circulation

Computer models of cardiac electro-mechanics (EM) show promise as an effective means for the quantitative analysis of clinical data and, potentially, for predicting therapeutic responses. To realize such advanced applications methodological key challenges must be addressed. Enhanced computational efficiency and robustness is crucial to facilitate, within tractable time frames, model personalization, the simulation of prolonged observation periods under a broad range of conditions, and physiological completeness encompassing therapy-relevant mechanisms is needed to endow models with predictive capabilities beyond the mere replication of observations.Here, we introduce a universal feature-complete cardiac EM modeling framework that builds on a flexible method for coupling a 3D model of bi-ventricular EM to the physiologically comprehensive 0D CircAdapt model representing atrial mechanics and closed-loop circulation. A detailed mathematical description is given and efficiency, robustness, and accuracy of numerical scheme and solver implementation are evaluated. After parameterization and stabilization of the coupled 3D–0D model to a limit cycle under baseline conditions, the model’s ability to replicate physiological behaviors is demonstrated, by simulating the transient response to alterations in loading conditions and contractility, as induced by experimental protocols used for assessing systolic and diastolic ventricular properties. Mechanistic completeness and computational efficiency of this novel model render advanced applications geared towards predicting acute outcomes of EM therapies feasible.