Publications by authors named "Joost Lumens"

74 Publications

Artificial Intelligence and Transcatheter Interventions for Structural Heart Disease: A glance at the (near) future.

Trends Cardiovasc Med 2021 Feb 10. Epub 2021 Feb 10.

Department of Cardiology, Thoraxcenter, Erasmus Medical Center, Rotterdam, the Netherlands. Electronic address:

With innovations in therapeutic technologies and changes in population demographics, transcatheter interventions for structural heart disease have become the preferred treatment and will keep growing. Yet, a thorough clinical selection and efficient pathway from diagnosis to treatment and follow-up are mandatory. In this review we reflect on how artificial intelligence may help to improve patient selection, pre-procedural planning, procedure execution and follow-up so to establish efficient and high quality health care in an increasing number of patients.
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http://dx.doi.org/10.1016/j.tcm.2021.02.002DOI Listing
February 2021

A roadmap to nationwide monitoring of Cardiovascular Implantable Electronic Devices in Greece: staying safe in the era of COVID-19 pandemic.

Hellenic J Cardiol 2020 Sep 15. Epub 2020 Sep 15.

Department of Biomedical Engineering, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands.

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http://dx.doi.org/10.1016/j.hjc.2020.09.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491421PMC
September 2020

Investigating myocardial work as a CRT response predictor is not a waste of work.

Eur Heart J 2020 Oct;41(39):3824-3826

Departments of Physiology and Biomedical Engineering, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands.

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http://dx.doi.org/10.1093/eurheartj/ehaa677DOI Listing
October 2020

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

Am J Physiol Heart Circ Physiol 2020 09 31;319(3):H519-H530. Epub 2020 Jul 31.

Department of Biomedical Engineering, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.

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 β-adrenergic stimulation (β-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 β-ARS and initial sarcomere lengths. The model reproduced force-frequency, quick-release, and isotonic contraction experiments, validating the bidirectional electromechanical interactions. An increase in β-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 β-ARS and stretch on calcium and force. Stretch mostly contributed to increased force amplitude and β-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. 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.
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http://dx.doi.org/10.1152/ajpheart.00275.2020DOI Listing
September 2020

Parameter subset reduction for patient-specific modelling of arrhythmogenic cardiomyopathy-related mutation carriers in the CircAdapt model.

Philos Trans A Math Phys Eng Sci 2020 Jun 25;378(2173):20190347. Epub 2020 May 25.

Department of Biomedical Engineering, Maastricht University CARIM School for Cardiovascular Diseases, Maastricht, Limburg, The Netherlands.

Arrhythmogenic cardiomyopathy (AC) is an inherited cardiac disease, clinically characterized by life-threatening ventricular arrhythmias and progressive cardiac dysfunction. Patient-specific computational models could help understand the disease progression and may help in clinical decision-making. We propose an inverse modelling approach using the CircAdapt model to estimate patient-specific regional abnormalities in tissue properties in AC subjects. However, the number of parameters ( = 110) and their complex interactions make personalized parameter estimation challenging. The goal of this study is to develop a framework for parameter reduction and estimation combining Morris screening, quasi-Monte Carlo (qMC) simulations and particle swarm optimization (PSO). This framework identifies the best subset of tissue properties based on clinical measurements allowing patient-specific identification of right ventricular tissue abnormalities. We applied this framework on 15 AC genotype-positive subjects with varying degrees of myocardial disease. Cohort studies have shown that atypical regional right ventricular (RV) deformation patterns reveal an early-stage AC disease. The CircAdapt model of cardiovascular mechanics and haemodynamics has already demonstrated its ability to capture typical deformation patterns of AC subjects. We, therefore, use clinically measured cardiac deformation patterns to estimate model parameters describing myocardial disease substrates underlying these AC-related RV deformation abnormalities. Morris screening reduced the subset to 48 parameters. qMC and PSO further reduced the subset to a final selection of 16 parameters, including regional tissue contractility, passive stiffness, activation delay and wall reference area. This article is part of the theme issue 'Uncertainty quantification in cardiac and cardiovascular modelling and simulation'.
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http://dx.doi.org/10.1098/rsta.2019.0347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287326PMC
June 2020

The ESC Working Group on e-Cardiology.

Eur Heart J 2021 Jan;42(2):143-144

Department of Biomedical Engineering, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands.

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http://dx.doi.org/10.1093/eurheartj/ehaa401DOI Listing
January 2021

Does the Right Go Wrong During Cardiac Resynchronization Therapy?

JACC Cardiovasc Imaging 2020 Jul 18;13(7):1485-1488. Epub 2020 Mar 18.

Department of Physiology, CARIM School for Cardiovascular Diseases, Maastricht University Medical Center, Maastricht, the Netherlands.

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http://dx.doi.org/10.1016/j.jcmg.2020.01.009DOI Listing
July 2020

Cardiomyocyte calcium handling in health and disease: Insights from in vitro and in silico studies.

Prog Biophys Mol Biol 2020 11 15;157:54-75. Epub 2020 Mar 15.

Department of Cardiology, CARIM School for Cardiovascular Diseases, Maastricht University, the Netherlands. Electronic address:

Calcium (Ca) plays a central role in cardiomyocyte excitation-contraction coupling. To ensure an optimal electrical impulse propagation and cardiac contraction, Ca levels are regulated by a variety of Ca-handling proteins. In turn, Ca modulates numerous electrophysiological processes. Accordingly, Ca-handling abnormalities can promote cardiac arrhythmias via various mechanisms, including the promotion of afterdepolarizations, ion-channel modulation and structural remodeling. In the last 30 years, significant improvements have been made in the computational modeling of cardiomyocyte Ca handling under physiological and pathological conditions. However, numerous questions involving the Ca-dependent regulation of different macromolecular complexes, cross-talk between Ca-dependent regulatory pathways operating over a wide range of time scales, and bidirectional interactions between electrophysiology and mechanics remain to be addressed by in vitro and in silico studies. A better understanding of disease-specific Ca-dependent proarrhythmic mechanisms may facilitate the development of improved therapeutic strategies. In this review, we describe the fundamental mechanisms of cardiomyocyte Ca handling in health and disease, and provide an overview of currently available computational models for cardiomyocyte Ca handling. Finally, we discuss important uncertainties and open questions about cardiomyocyte Ca handling and highlight how synergy between in vitro and in silico studies may help to answer several of these issues.
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http://dx.doi.org/10.1016/j.pbiomolbio.2020.02.008DOI Listing
November 2020

Impact of paced left ventricular dyssynchrony on left ventricular reverse remodeling after cardiac resynchronization therapy.

J Cardiovasc Electrophysiol 2020 02 15;31(2):494-502. Epub 2020 Jan 15.

Division of Cardiology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.

Introduction: We investigated whether pacing-induced electrical dyssynchrony at the time of cardiac resynchronization therapy (CRT) device implantation was associated with chronic CRT response.

Methods And Results: We included a total of 69 consecutive heart failure patients who received a CRT device. Left (LVp-RVs) and right (RVp-LVs) pacing-induced interlead delays were measured intraoperatively and used to determine if there was paced left ventricular (LV) dyssynchrony, defined as present when LVp-RVs is larger than RVp-LVs. CRT response was defined as a reduction in LV end-systolic volume ≥15%, 6 months after implantation. Paced left ventricular dyssynchrony (PLVD) was associated with ischemic cardiomyopathy (ICM) (χ : 8; P = .005) but not with QRS morphology nor with pacing lead positions. In a univariate analysis, PLVD (odds ratio [OR], 6.53; 95% confidence interval [CI], 2.2-18.9; P = .001), atypical left bundle branch block (LBBB) (OR, 3.3; 95% CI, 1.2-9.4; P = .022), and ICM (OR, 5.2; 95% CI, 1.6-17; P = .006) were associated with nonresponse. In a multivariate analysis, both PLVD (OR, 9.74; 95% CI, 2.8-33.9; P < .0001) and atypical LBBB (OR, 5.6; 95% CI, 1.5-20.3; P = .009) were independently associated with nonresponse. Adding PLVD to a model based on QRS morphology provided a significant and meaningful incremental value to predict LV reverse remodeling after CRT (χ to enter: 8; P < .005). Computer simulations corroborate these findings by showing that, while intrinsic electrical dyssynchrony is a prerequisite, the level of pacing-induced dyssynchrony modulates acute CRT response.

Conclusion: In addition to the intrinsic electrical substrate, PLVD is strongly associated with less LV reverse remodeling, demonstrating that measuring the electrical substrate during pacing has additional value for prediction of CRT response in an already well-selected patient population.
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http://dx.doi.org/10.1111/jce.14330DOI Listing
February 2020

Impact of abrupt versus gradual correction of mitral and tricuspid regurgitation: a modelling study.

EuroIntervention 2019 Nov;15(10):902-911

CARIM School for Cardiovascular Diseases, Maastricht University Medical Center, Maastricht, the Netherlands.

Aims: Correction of mitral and/or tricuspid regurgitation (MR, TR) frequently leads to poor outcomes in the days following intervention. We sought to understand how abrupt correction of MR and TR affects ventricular load and to investigate if gradual correction is beneficial.

Methods And Results: MR and TR were simulated using the CircAdapt cardiovascular system model with effective regurgitant orifice (ERO) areas of 0.5 cm2 and 0.7 cm2. Ventricular and atrial contractility reductions to 40% of normal and pulmonary hypertension were simulated. Abrupt and gradual ERO closure were simulated with homeostatic regulation of blood pressure and volume. Abrupt correction of MR increased left and right ventricular fibre stress by 40% and 15%, respectively, whereas TR correction increased left and right ventricular fibre stress by 26% and 19%, respectively. This spike was followed by a rapid drop in fibre stress. Myocardial dysfunction prolonged the spike but reduced its amplitude. Right ventricular fibre stress increased more with pulmonary hypertension and TR. Gradual correction demonstrated no spike in tissue load.

Conclusions: Simulations demonstrated that abrupt ERO closure creates a transient increase in ventricular load that is prolonged by worsened myocardial condition and exacerbated by pulmonary hypertension. Gradual closure of the ERO abolishes this spike and merits clinical investigation.
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http://dx.doi.org/10.4244/EIJ-D-19-00598DOI Listing
November 2019

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

PLoS Comput Biol 2019 07 15;15(7):e1007173. Epub 2019 Jul 15.

Department of Biomedical Engineering, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, Netherlands.

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.
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http://dx.doi.org/10.1371/journal.pcbi.1007173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6677326PMC
July 2019

Value of Speckle Tracking-Based Deformation Analysis in Screening Relatives of Patients With Asymptomatic Dilated Cardiomyopathy.

JACC Cardiovasc Imaging 2020 02 12;13(2 Pt 2):549-558. Epub 2019 Jun 12.

Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, the Netherlands. Electronic address:

Objectives: This study sought to investigate the prevalence of systolic dysfunction using global longitudinal strain (GLS) and its prognostic value in relatives of dilated cardiomyopathy (DCM) patients that had normal left ventricular ejection fraction (LVEF).

Background: DCM relatives are advised to undergo cardiac assessment including echocardiography, irrespective of the genetic status of the index patient. Even though LVEF is normal, the question remains whether this indicates absence of disease or simply normal cardiac volumes. GLS may provide additional information regarding (sub)clinical cardiac abnormalities and thus allow earlier disease detection.

Methods: A total of 251 DCM relatives and 251 control subjects with a normal LVEF (≥55%) were screened. Automated software measured the GLS on echocardiographic 2-, 3-, and 4-chamber views. The cutoff value for abnormal strain was >-21.5. Median follow-up was 40 months (interquartile range: 5 to 80 months). Primary outcome was the combination of death and cardiac hospitalization.

Results: A total of 120 relatives and 83 control subjects showed abnormal GLS (48% vs. 33%, respectively; p < 0.001). Abnormal GLS was independently associated with DCM relatives and cardiovascular risk factors, rather than genetic mutations. Subjects with abnormal GLS had more frequent cardiac hospitalizations and a higher mortality as compared with subjects with normal GLS (hazard ratio: 3.29; 95% confidence interval: 1.58 to 6.87; p = 0.001). Additionally, follow-up LVEF was measured in a subset of relatives, and it decreased significantly in those with abnormal as compared with normal GLS (p = 0.006).

Conclusions: Relatives of DCM patients had a significantly higher prevalence of systolic dysfunction detected by GLS despite normal LVEF compared with control subjects, independent of age, sex, comorbidities, and genotype. Abnormal GLS was associated with LVEF deterioration, cardiac hospitalization, and death.
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http://dx.doi.org/10.1016/j.jcmg.2019.02.032DOI Listing
February 2020

Augmentation index is not a proxy for wave reflection magnitude: mechanistic analysis using a computational model.

J Appl Physiol (1985) 2019 08 30;127(2):491-500. Epub 2019 May 30.

CARIM School for Cardiovascular Diseases, Maastricht University, The Netherlands.

The augmentation index (AIx) is deemed to capture the deleterious effect on left ventricular (LV) work of increased wave reflection associated with stiffer arteries. However, its validity as a proxy for wave reflection magnitude has been questioned. We hypothesized that, in addition to increased wave reflection due to increased pulse wave velocity, LV myocardial shortening velocity influences AIx. Using a computational model of the circulation, we investigated the isolated and combined influences of myocardial shortening velocity and arterial stiffness on AIx. Aortic blood pressure waveforms were characterized using AIx and the reflected wave pressure amplitude (, obtained using wave separation analysis). Our reference simulation (normal and arterial stiffness) was characterized by an AIx of 21%. A realistic reduction in caused AIx to increase from 21 to 42%. An arterial stiffness increase, characterized by a relevant 1.0 m/s increase in carotid-femoral pulse wave velocity, caused AIx to increase from 21 to 41%. Combining the reduced and increased arterial stiffness resulted in an AIx of 54%. In a multistep parametric analysis, both and arterial stiffness were about equal determinants of AIx, whereas was only determined by arterial stiffness. Furthermore, the relation between increased AIx and LV stroke work was only ≈50% explained by an increase in arterial stiffness, the other factor being . The , on the other hand, related less ambiguously to LV stroke work. We conclude that the AIx reflects both cardiac and vascular properties and should not be considered an exclusively vascular parameter. We used a state-of-the-art computational model to mechanistically investigate the validity of the augmentation index (AIx) as a proxy for (changes in) wave reflection. In contrary to current belief, we found that LV contraction velocity influences AIx as much as increased arterial stiffness, and increased AIx does not necessarily relate to an increase in LV stroke work. Wave reflection magnitude derived from considering pressure, as well as flow, does qualify as a determinant of LV stroke work.
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http://dx.doi.org/10.1152/japplphysiol.00769.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6711407PMC
August 2019

Opposing Wall Pushing and Stretching: Response to Cardiac Resynchronization Therapy Requires Electrical Delay and Viability.

JACC Cardiovasc Imaging 2019 12 13;12(12):2414-2416. Epub 2019 Mar 13.

Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, the Netherlands.

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http://dx.doi.org/10.1016/j.jcmg.2019.01.013DOI Listing
December 2019

The Left and Right Ventricles Respond Differently to Variation of Pacing Delays in Cardiac Resynchronization Therapy: A Combined Experimental- Computational Approach.

Front Physiol 2019 1;10:17. Epub 2019 Feb 1.

Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, Netherlands.

Timing of atrial, right (RV), and left ventricular (LV) stimulation in cardiac resynchronization therapy (CRT) is known to affect electrical activation and pump function of the LV. In this study, we used computer simulations, with input from animal experiments, to investigate the effect of varying pacing delays on both LV and RV electrical dyssynchrony and contractile function. A pacing protocol was performed in dogs with atrioventricular block ( = 6), using 100 different combinations of atrial (A)-LV and A-RV pacing delays. Regional LV and RV electrical activation times were measured using 112 electrodes and LV and RV pressures were measured with catheter-tip micromanometers. Contractile response to a pacing delay was defined as relative change of the maximum rate of LV and RV pressure rise (dP/dt) compared to RV pacing with an A-RV delay of 125 ms. The pacing protocol was simulated in the CircAdapt model of cardiovascular system dynamics, using the experimentally acquired electrical mapping data as input. Ventricular electrical activation changed with changes in the amount of LV or RV pre-excitation. The resulting changes in dP/dt differed markedly between the LV and RV. Pacing the LV 10-50 ms before the RV led to the largest increases in LV dP/dt. In contrast, RV dP/dt was highest with RV pre-excitation and decreased up to 33% with LV pre-excitation. These opposite patterns of changes in RV and LV dP/dt were reproduced by the simulations. The simulations extended these observations by showing that changes in steady-state biventricular cardiac output differed from changes in both LV and RV dP/dt. The model allowed to explain the discrepant changes in dP/dt and cardiac output by coupling between atria and ventricles as well as between the ventricles. The LV and the RV respond in a opposite manner to variation in the amount of LV or RV pre-excitation. Computer simulations capture LV and RV behavior during pacing delay variation and may be used in the design of new CRT optimization studies.
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http://dx.doi.org/10.3389/fphys.2019.00017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367498PMC
February 2019

AntagomiR-103 and -107 Treatment Affects Cardiac Function and Metabolism.

Mol Ther Nucleic Acids 2019 Mar 22;14:424-437. Epub 2018 Dec 22.

CARIM School for Cardiovascular Diseases, Department of Cardiology, Maastricht University, 6229 ER Maastricht, the Netherlands. Electronic address:

MicroRNA-103/107 regulate systemic glucose metabolism and insulin sensitivity. For this reason, inhibitory strategies for these microRNAs are currently being tested in clinical trials. Given the high metabolic demands of the heart and the abundant cardiac expression of miR-103/107, we questioned whether antagomiR-mediated inhibition of miR-103/107 in C57BL/6J mice impacts on cardiac function. Notably, fractional shortening decreased after 6 weeks of antagomiR-103 and -107 treatment. This was paralleled by a prolonged systolic radial and circumferential time to peak and by a decreased global strain rate. Histology and electron microscopy showed reduced cardiomyocyte area and decreased mitochondrial volume and mitochondrial cristae density following antagomiR-103 and -107. In line, antagomiR-103 and -107 treatment decreased mitochondrial OXPHOS complexes' protein levels compared to scrambled, as assessed by mass spectrometry-based label-free quantitative proteomics. MiR-103/107 inhibition in primary cardiomyocytes did not affect glycolysis rates, but it decreased mitochondrial reserve capacity, reduced mitochondrial membrane potential, and altered mitochondrial network morphology, as assessed by live-cell imaging. Our data indicate that antagomiR-103 and -107 decrease cardiac function, cardiomyocyte size, and mitochondrial oxidative capacity in the absence of pathological stimuli. These data raise concern about the possible cardiac implications of the systemic use of antagomiR-103 and -107 in the clinical setting, and careful cardiac phenotyping within ongoing trials is highly recommended.
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http://dx.doi.org/10.1016/j.omtn.2018.12.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365487PMC
March 2019

Relative Impact of Right Ventricular Electromechanical Dyssynchrony Versus Pulmonary Regurgitation on Right Ventricular Dysfunction and Exercise Intolerance in Patients After Repair of Tetralogy of Fallot.

J Am Heart Assoc 2019 01;8(2):e010903

1 Division of Cardiology Labatt Family Heart Centre and Department of Paediatrics Hospital for Sick Children and University of Toronto Toronto Ontario Canada.

Background The relative impact of right ventricular ( RV ) electromechanical dyssynchrony versus pulmonary regurgitation ( PR ) on exercise capacity and RV function after tetralogy of Fallot repair is unknown. We aimed to delineate the relative effects of these factors on RV function and exercise capacity. Methods and Results We retrospectively analyzed 81 children with tetralogy of Fallot repair using multivariable regression. Predictor parameters were electrocardiographic QRS duration reflecting electromechanical dyssynchrony and PR severity by cardiac magnetic resonance. The outcome parameters were exercise capacity (percentage predicted peak oxygen consumption) and cardiac magnetic resonance ejection fraction (RV ejection fraction). To understand the relative effects of RV dyssynchrony versus PR on exercise capacity and RV function, virtual patient simulations were performed using a closed-loop cardiovascular system model (CircAdapt), covering a wide spectrum of disease severity. Eighty-one patients with tetralogy of Fallot repair (median [interquartile range { IQR} ] age, 14.48 [11.55-15.91] years) were analyzed. All had prolonged QRS duration (median [IQR], 144 [123-152] ms), at least moderate PR (median [IQR], 40% [29%-48%]), reduced exercise capacity (median [IQR], 79% [68%-92%] predicted peak oxygen consumption), and reduced RV ejection fraction (median [IQR], 48% [44%-52%]). Longer QRS duration, more than PR , was associated with lower oxygen consumption and lower RV ejection fraction. In a multivariable regression analysis, oxygen consumption decreased with both increasing QRS duration and PR severity. CircAdapt modeling showed that RV dyssynchrony exerts a stronger limiting effect on exercise capacity and on RV ejection fraction than does PR , regardless of contractile function. Conclusions In both patient data and computer simulations, RV dyssynchrony, more than PR , appears to be associated with reduced exercise capacity and RV systolic dysfunction in patients after TOF repair.
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http://dx.doi.org/10.1161/JAHA.118.010903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6497336PMC
January 2019

Pathophysiology of the right ventricle and of the pulmonary circulation in pulmonary hypertension: an update.

Eur Respir J 2019 01 24;53(1). Epub 2019 Jan 24.

Dept of Cardiology, Erasme University Hospital, Brussels, Belgium.

The function of the right ventricle determines the fate of patients with pulmonary hypertension. Since right heart failure is the consequence of increased afterload, a full physiological description of the cardiopulmonary unit consisting of both the right ventricle and pulmonary vascular system is required to interpret clinical data correctly. Here, we provide such a description of the unit and its components, including the functional interactions between the right ventricle and its load. This physiological description is used to provide a framework for the interpretation of right heart catheterisation data as well as imaging data of the right ventricle obtained by echocardiography or magnetic resonance imaging. Finally, an update is provided on the latest insights in the pathobiology of right ventricular failure, including key pathways of molecular adaptation of the pressure overloaded right ventricle. Based on these outcomes, future directions for research are proposed.
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http://dx.doi.org/10.1183/13993003.01900-2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6351344PMC
January 2019

Uniqueness of local myocardial strain patterns with respect to activation time and contractility of the failing heart: a computational study.

Biomed Eng Online 2018 Dec 5;17(1):182. Epub 2018 Dec 5.

Department of Biomedical Engineering, CARIM School for Cardiovascular Diseases, Maastricht University Medical Center, Maastricht, The Netherlands.

Background: Myocardial deformation measured by strain is used to detect electro-mechanical abnormalities in cardiac tissue. Estimation of myocardial properties from regional strain patterns when multiple pathologies are present is therefore a promising application of computer modelling. However, if different tissue properties lead to indistinguishable strain patterns ('degeneracy'), the applicability of any such method will be limited. We investigated whether estimation of local activation time (AT) and contractility from myocardial strain patterns is theoretically possible.

Methods: For four different global cardiac pathologies local myocardial strain patterns for 1025 combinations of AT and contractility were simulated with a computational model (CircAdapt). For each strain pattern, a cohort of similar patterns was found within estimated measurement error using the sum of least-squared differences. Cohort members came from (1) the same pathology only, and (2) all four pathologies. Uncertainty was calculated as accuracy and precision of cohort members in parameter space. Connectedness within the cohorts was also studied.

Results: We found that cohorts drawn from one pathology had parameters with adjacent values although their distribution was neither constant nor symmetrical. In comparison cohorts drawn from four pathologies had disconnected components with drastically different parameter values and accuracy and precision values up to three times higher.

Conclusions: Global pathology must be known when extracting AT and contractility from strain patterns, otherwise degeneracy occurs causing unacceptable uncertainty in derived parameters.
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http://dx.doi.org/10.1186/s12938-018-0614-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6280493PMC
December 2018

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

Europace 2018 Nov;20(suppl_3):iii87-iii93

Department of Biomedical Engineering, CARIM School for Cardiovascular Diseases, Maastricht University Medical Center, Maastricht University, Universiteitssingel 50., P.O. Box 616, ER Maastricht, The Netherlands.

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.
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http://dx.doi.org/10.1093/europace/euy230DOI Listing
November 2018

Computational models in cardiology.

Nat Rev Cardiol 2019 02;16(2):100-111

Department of Biomedical Engineering and the Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD, USA.

The treatment of individual patients in cardiology practice increasingly relies on advanced imaging, genetic screening and devices. As the amount of imaging and other diagnostic data increases, paralleled by the greater capacity to personalize treatment, the difficulty of using the full array of measurements of a patient to determine an optimal treatment seems also to be paradoxically increasing. Computational models are progressively addressing this issue by providing a common framework for integrating multiple data sets from individual patients. These models, which are based on physiology and physics rather than on population statistics, enable computational simulations to reveal diagnostic information that would have otherwise remained concealed and to predict treatment outcomes for individual patients. The inherent need for patient-specific models in cardiology is clear and is driving the rapid development of tools and techniques for creating personalized methods to guide pharmaceutical therapy, deployment of devices and surgical interventions.
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http://dx.doi.org/10.1038/s41569-018-0104-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6556062PMC
February 2019

Adding Speckle-Tracking Echocardiography to Visual Assessment of Systolic Wall Motion Abnormalities Improves the Detection of Myocardial Infarction.

J Am Soc Echocardiogr 2019 01 17;32(1):65-73. Epub 2018 Oct 17.

Department of Cardiology, Maastricht University Medical Center, Maastricht, the Netherlands; Department of Radiology and Nuclear Medicine, Maastricht University Medical Center, Maastricht, the Netherlands; CARIM School for Cardiovascular Diseases, Maastricht University Medical Center, Maastricht, the Netherlands.

Background: The aim of this study was to investigate whether speckle-tracking echocardiography (STE) improves the detection of myocardial infarction (MI) over visual assessment of systolic wall motion abnormalities (SWMAs) using delayed enhancement cardiac magnetic resonance imaging as a reference.

Methods: Transthoracic echocardiography was performed in 95 patients with first ST segment elevation MI 110 days (interquartile range, 97-171 days) after MI and in 48 healthy control subjects. Two experienced observers independently assessed SWMAs. Separately, longitudinal peak negative, peak systolic, end-systolic, global strain, and strain rate were measured and averaged for the American Heart Association-recommended coronary artery perfusion territories. Receiver operating characteristic analysis was used to determine a single optimal cutoff value for each strain parameter. The diagnostic accuracy of an algorithm combining visual assessment and STE was evaluated.

Results: Median infarct size and transmurality were 15% (interquartile range, 7%-24%) and 64% (interquartile range, 46%-78%), respectively. Sensitivity, specificity, and accuracy of visual assessment to detect MI were 74% (95% CI, 63%-82%), 85% (95% CI, 72%-93%), and 78% (95% CI, 70%-84%), respectively. Among the strain parameters, SR had the highest diagnostic accuracy (area under the curve, 0.88; 95% CI, 0.83-0.94; cutoff value, -0.97 sec). The combination with STE improved sensitivity compared with visual assessment alone (94%; 95% CI, 86%-97%; P < .001), minimally affecting specificity (79%; 95% CI, 65%-89%; P = .607). Overall accuracy improved to 89% (95% CI, 82%-93%; P = .011). Multivariate analysis accounting for age and sex demonstrated that SR was independently associated with MI (odds ratio, 2.0; 95% CI, 1.6-2.7).

Conclusions: The sensitivity and diagnostic accuracy of visually detecting chronic MI by assessing SWMAs are moderate but substantially improve when adding STE.
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http://dx.doi.org/10.1016/j.echo.2018.09.007DOI Listing
January 2019

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

PLoS One 2018 4;13(10):e0204642. Epub 2018 Oct 4.

Department of Biomedical Engineering, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0204642PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6171862PMC
March 2019

Systolic Stretch Characterizes the Electromechanical Substrate Responsive to Cardiac Resynchronization Therapy.

JACC Cardiovasc Imaging 2019 09 12;12(9):1741-1752. Epub 2018 Sep 12.

CARIM School for Cardiovascular Diseases, Maastricht University Medical Center, Maastricht, the Netherlands; L'Institut de Rythmologie et Modélisation Cardiaque (IHU-LIRYC), Université de Bordeaux, Pessac, France.

Objectives: In this study, the authors tested the hypotheses that the systolic stretch index (SSI) developed by computer modeling and applied using echocardiographic strain imaging may characterize the electromechanical substrate predictive of outcome following cardiac resynchronization therapy (CRT). They included patients with QRS width 120 to 149 ms or non-left bundle branch block (LBBB), where clinical uncertainty for CRT exists. They further tested the hypothesis that global longitudinal strain (GLS) has additional prognostic value.

Background: Response to CRT is variable. Guidelines favor patient selection by electrocardiographic LBBB with QRS width ≥150 ms.

Methods: The authors studied 442 patients enrolled in the Adaptive CRT 94-site randomized trial with New York Heart Association functional class III-IV heart failure, ejection fraction ≤35%, and QRS ≥120 ms. A novel computer program semiautomatically calculated the SSI from strain curves as the sum of posterolateral prestretch percent before aortic valve opening and the septal rebound stretch percent during ejection. The primary endpoint was hospitalization for heart failure (HF) or death, and the secondary endpoint was death over 2 years after CRT.

Results: In all patients, high longitudinal SSI (≥ group median of 3.1%) was significantly associated with freedom from the primary endpoint of HF hospitalization or death (hazard ratio [HR] for low SSI: 2.17; 95% confidence interval [CI]: 1.45 to 3.24, p < 0.001) and secondary endpoint of death (HR for low SSI: 4.06; 95% CI: 1.95 to 8.45, p < 0.001). Among the 203 patients with QRS 120 to 149 ms or non-LBBB, those with high longitudinal SSI (≥ group median of 2.6%) had significantly fewer HF hospitalizations or deaths (HR for low SSI: 2.08; 95% CI: 1.27 to 3.41, p = 0.004) and longer survival (HR for low SSI: 5.08; 95% CI: 1.94 to 13.31, p < 0.001), similar to patients with LBBB ≥150 ms. SSI by circumferential strain had similar associations with clinical outcomes, and GLS was additive to SSI in predicting clinical events (p = 0.001).

Conclusions: Systolic stretch by strain imaging characterized the myocardial substrate associated with favorable CRT response, including in the important patient subgroup with QRS width 120 to 149 ms or non-LBBB. GLS had additive prognostic value.
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http://dx.doi.org/10.1016/j.jcmg.2018.07.013DOI Listing
September 2019

Electrical Substrates Driving Response to Cardiac Resynchronization Therapy: A Combined Clinical-Computational Evaluation.

Circ Arrhythm Electrophysiol 2018 04;11(4):e005647

Electrophysiology and Heart Modeling Institute (LIRYC), Bordeaux University, Pessac, France (P.R.H., S.P., M.S., P.R., M.H., J.L., P.B.). Cardiac Electrophysiology and Cardiac Stimulation Team, Bordeaux University Hospital, Pessac, France (P.R.H., S.P., M.S., P.R., M.H., J.L., P.B.). Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, the Netherlands (P.R.H., M.S., J.W., F.W.P., T.D., J.L.).

Background: The predictive value of interventricular versus intraventricular dyssynchrony for response to cardiac resynchronization therapy (CRT) remains unclear. We investigated the relative importance of both ventricular electrical substrate components for left ventricular (LV) hemodynamic function.

Methods And Results: First, we used the cardiovascular computational model CircAdapt to characterize the isolated effect of intrinsic interventricular and intraventricular activation on CRT response (ΔLVdP/dt). Simulated ΔLVdP/dt (range: 1.3%-26.5%) increased considerably with increasing interventricular dyssynchrony. In contrast, the isolated effect of intraventricular dyssynchrony in either the LV or right ventricle was limited (ΔLVdP/dt range: 12.3%-18.3% and 14.1%-15.7%, respectively). Effects of activation during biventricular pacing on ΔLVdP/dt were small. Second, electrocardiographic imaging-derived activation characteristics of 51 CRT candidates were used to personalize ventricular activation in CircAdapt. The individualized models were subsequently used to assess the accuracy of ΔLVdP/dt prediction based on the electrical data. The model-predicted ΔLVdP/dt was close to the actual value in patients with left bundle branch block (measured-simulated: 2.7±9.0%) when only intrinsic interventricular dyssynchrony was personalized. Among patients without left bundle branch block, ΔLVdP/dt was systematically overpredicted by CircAdapt (measured-simulated: 9.2±7.1%). Adding intraventricular activation to the model did not improve the accuracy of the response prediction.

Conclusions: Computer simulations revealed that intrinsic interventricular dyssynchrony is the dominant component of the electrical substrate driving the response to CRT. Intrinsic intraventricular dyssynchrony and any dyssynchrony during biventricular pacing play a minor role in this respect. This may facilitate patient-specific modeling for prediction of CRT response.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01270646.
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http://dx.doi.org/10.1161/CIRCEP.117.005647DOI Listing
April 2018

The Prognostic Value of Right Ventricular Deformation Imaging in Early Arrhythmogenic Right Ventricular Cardiomyopathy.

JACC Cardiovasc Imaging 2019 03 14;12(3):446-455. Epub 2018 Mar 14.

Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, the Netherlands. Electronic address:

Objectives: The aim of this study was to investigate the prognostic value of echocardiographic deformation imaging in arrhythmogenic right ventricular cardiomyopathy (ARVC) to optimize family screening protocols.

Background: ARVC is characterized by variable disease expressivity among family members, which complicates family screening protocols. Previous reports have shown that echocardiographic deformation imaging detects abnormal right ventricular (RV) deformation in the absence of established disease expression in ARVC.

Methods: First-degree relatives of patients with ARVC were evaluated according to 2010 task force criteria, including RV deformation imaging (n = 128). Relatives fulfilling structural task force criteria were excluded for further analysis. At baseline, deformation patterns of the subtricuspid region were scored as type I (normal deformation), type II (delayed onset, decreased systolic peak, and post-systolic shortening), or type III (systolic stretching and large post-systolic shortening). The final study population comprised relatives who underwent a second evaluation during follow-up. Disease progression was defined as the development of a new 2010 task force criterion during follow-up that was absent at baseline.

Results: Sixty-five relatives underwent a second evaluation after a mean follow-up period of 3.7 ± 2.1 years. At baseline, 28 relatives (43%) had normal deformation (type I), and 37 relatives (57%) had abnormal deformation (type II or III) in the subtricuspid region. Disease progression occurred in 4% of the relatives with normal deformation at baseline and in 43% of the relatives with abnormal deformation at baseline (p < 0.001). Positive and negative predictive values of abnormal deformation were, respectively, 43% (95% confidence interval: 27% to 61%) and 96% (95% confidence interval: 82% to 100%).

Conclusions: Normal RV deformation in the subtricuspid region is associated with absence of disease progression during nearly 4-year follow-up in relatives of patients with ARVC. Abnormal RV deformation seems to precede the established signs of ARVC. RV deformation imaging may potentially play an important role in ARVC family screening protocols.
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http://dx.doi.org/10.1016/j.jcmg.2018.01.012DOI Listing
March 2019

Clinical Applications of Patient-Specific Models: The Case for a Simple Approach.

J Cardiovasc Transl Res 2018 04 16;11(2):71-79. Epub 2018 Feb 16.

Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, The Netherlands.

Over the past several decades, increasingly sophisticated models of the heart have provided important insights into cardiac physiology and are increasingly used to predict the impact of diseases and therapies on the heart. In an era of personalized medicine, many envision patient-specific computational models as a powerful tool for personalizing therapy. Yet the complexity of current models poses important challenges, including identifying model parameters and completing calculations quickly enough for routine clinical use. We propose that early clinical successes are likely to arise from an alternative approach: relatively simple, fast, phenomenologic models with a small number of parameters that can be easily (and automatically) customized. We discuss examples of simple yet foundational models that have already made a tremendous impact on clinical education and practice, and make the case that reducing rather than increasing model complexity may be the key to realizing the promise of patient-specific modeling for clinical applications.
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http://dx.doi.org/10.1007/s12265-018-9787-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5910244PMC
April 2018

LBBB and High Afterload: A Dangerous Liaison?

JACC Cardiovasc Imaging 2019 06 17;12(6):978-980. Epub 2018 Jan 17.

Departments of Physiology and Biomedical Engineering, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands.

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http://dx.doi.org/10.1016/j.jcmg.2017.12.002DOI Listing
June 2019

Combining computer modelling and cardiac imaging to understand right ventricular pump function.

Cardiovasc Res 2017 Oct;113(12):1486-1498

CARIM School for Cardiovascular Diseases, Maastricht University Medical Center, Maastricht, The Netherlands.

Right ventricular (RV) dysfunction is a strong predictor of outcome in heart failure and is a key determinant of exercise capacity. Despite these crucial findings, the RV remains understudied in the clinical, experimental, and computer modelling literature. This review outlines how recent advances in using computer modelling and cardiac imaging synergistically help to understand RV function in health and disease. We begin by highlighting the complexity of interactions that make modelling the RV both challenging and necessary, and then summarize the multiscale modelling approaches used to date to simulate RV pump function in the context of these interactions. We go on to demonstrate how these modelling approaches in combination with cardiac imaging have improved understanding of RV pump function in pulmonary arterial hypertension, arrhythmogenic right ventricular cardiomyopathy, dyssynchronous heart failure and cardiac resynchronization therapy, hypoplastic left heart syndrome, and repaired tetralogy of Fallot. We conclude with a perspective on key issues to be addressed by computational models of the RV in the near future.
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http://dx.doi.org/10.1093/cvr/cvx154DOI Listing
October 2017