Publications by authors named "Tammo Delhaas"

188 Publications

An integrated set-up for ex vivo characterisation of biaxial murine artery biomechanics under pulsatile conditions.

Sci Rep 2021 Jan 29;11(1):2671. Epub 2021 Jan 29.

Department of Biomedical Engineering, CARIM School for Cardiovascular Diseases, Maastricht University, Universiteitssingel 50, Room 3.359, 6229ER, Maastricht, The Netherlands.

Ex vivo characterisation of arterial biomechanics enables detailed discrimination of the various cellular and extracellular contributions to arterial stiffness. However, ex vivo biomechanical studies are commonly performed under quasi-static conditions, whereas dynamic biomechanical behaviour (as relevant in vivo) may differ substantially. Hence, we aim to (1) develop an integrated set-up for quasi-static and dynamic biaxial biomechanical testing, (2) quantify set-up reproducibility, and (3) illustrate the differences in measured arterial stiffness between quasi-static and dynamic conditions. Twenty-two mouse carotid arteries were mounted between glass micropipettes and kept fully vasodilated. While recording pressure, axial force (F), and inner diameter, arteries were exposed to (1) quasi-static pressure inflation from 0 to 200 mmHg; (2) 300 bpm dynamic pressure inflation (peaking at 80/120/160 mmHg); and (3) axial stretch (λ) variation at constant pressures of 10/60/100/140/200 mmHg. Measurements were performed in duplicate. Single-point pulse wave velocities (PWV; Bramwell-Hill) and axial stiffness coefficients (c = dF/dλ) were calculated at the in vivo value of λ. Within-subject coefficients of variation were ~ 20%. Dynamic PWVs were consistently higher than quasi-static PWVs (p < 0.001); c increased with increasing pressure. We demonstrated the feasibility of ex vivo biomechanical characterisation of biaxially-loaded murine carotid arteries under pulsatile conditions, and quantified reproducibility allowing for well-powered future study design.
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http://dx.doi.org/10.1038/s41598-021-81151-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846753PMC
January 2021

Second heart sound splitting as an indicator of interventricular mechanical dyssynchrony using a novel splitting detection algorithm.

Physiol Rep 2021 Jan;9(1):e14687

Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM, Maastricht, the Netherlands.

Second heart sound (S2) splitting results from nonsimultaneous closures between aortic (A2) and pulmonic valves (P2) and may be used to detect timing differences (dyssynchrony) in relaxation between right (RV) and left ventricle (LV). However, overlap of A2 and P2 and the change in heart sound morphologies have complicated detection of the S2 splitting interval. This study introduces a novel S-transform amplitude ridge tracking (START) algorithm for estimating S2 splitting interval and investigates the relationship between S2 splitting and interventricular relaxation dyssynchrony (IRD). First, the START algorithm was validated in a simulated model of heart sound. It showed small errors (<5 ms) in estimating splitting intervals from 10 to 70 ms, with A2/P2 amplitude ratios from 0.2 to 5, and signal-to-noise ratios from 10 to 30 dB. Subsequently, the START algorithm was evaluated in a porcine model employing a wide range of paced RV-LV delays. IRD was quantified by the time difference between invasively measured LV and RV pressure downslopes. Between LV pre-excitation to RV pre-excitation, mean S2 splitting interval decreased from 47 ms to 23 ms (p < .001), accompanied by a decrease in mean IRD from 8 ms to -18 ms (p < .001). S2 splitting interval was significantly correlated with IRD in each experiment (p < .001). In conclusion, the START algorithm can accurately assess S2 splitting and may serve as a useful tool to assess interventricular dyssynchrony.
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http://dx.doi.org/10.14814/phy2.14687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785055PMC
January 2021

Ratio of arterial blood pressures at borders of window surrounding systolic peak indicates patent ductus arteriosus in preterm infants.

Physiol Meas 2021 Feb 6;42(1):015005. Epub 2021 Feb 6.

Department of Biomedical Engineering, Maastricht University, Maastricht, The Netherlands. CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands. MHeNS School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.

Objective: Presence of a patent ductus arteriosus (PDA) in neonates is assessed by echocardiography. Echocardiographic assessment has disadvantages, primarily its discontinuous nature. We hypothesize that the continuously measured ratio of arterial blood pressures (ABP) at the borders of a window surrounding the systolic peak ratio discriminates non-PDA from PDA patients.

Approach: Preterm infants (gestational age <32 weeks) with and without PDA were included. Patients were divided into controls (n = 8) and PDA patients (n = 22), the latter with a subset of patients with closed PDA after three doses Ibuprofen (n = 10). For each patient, a six-hour ABP segment from 12 AM to 6 AM on the day of echocardiographic assessment patency or closure of the DA was selected. The mean ratio of the ABP values a samples before and p samples after the systolic peak (R ) was calculated for each segment. If R  < 1, the patient was predicted to have a PDA. The a and p with the least misclassifications were selected (-64 and +104 ms).

Main Results: R was significantly lower in PDA patients (median 0.95, IQR 0.06) compared to controls (median 1.05, IQR 0.10; p = 0.0024). R correctly predicted 19 out of 22 patients (86.4%) and six out of eight controls (75%). R increased after closure in nine out of 10 patients (median 1.01, IQR 0.04; p = 0. 0182).

Significance: R may discriminate preterm PDA patients from non-PDA patients and can be calculated continuously from clinical data measured during standard of care.
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http://dx.doi.org/10.1088/1361-6579/abd5aaDOI Listing
February 2021

Haemodynamic optimisation of a dialysis graft design using a global optimisation approach.

Int J Numer Method Biomed Eng 2021 Feb 9;37(2):e3423. Epub 2020 Dec 9.

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

Disturbed flow and the resulting non-physiological wall shear stress (WSS) at the graft-vein anastomosis play an important role in arteriovenous graft (AVG) patency loss. Modifying graft geometry with helical features is a popular approach to minimise the occurrence of detrimental haemodynamics and to potentially increase graft longevity. Haemodynamic optimisation of AVGs typically requires many computationally expensive computational fluid dynamics (CFD) simulations to evaluate haemodynamic performance of different graft designs. In this study, we aimed to develop a haemodynamically optimised AVG by using an efficient meta-modelling approach. A training dataset containing CFD evaluations of 103 graft designs with helical features was used to develop computationally low-cost meta-models for haemodynamic metrics related to graft dysfunction. During optimisation, the meta-models replaced CFD simulations that were otherwise needed to evaluate the haemodynamic performance of possible graft designs. After optimisation, haemodynamic performance of the optimised graft design was verified using a CFD simulation. The obtained optimised graft design contained both a helical graft centreline and helical ridge. Using the optimised design, the magnitude of flow disturbances and the size of the anastomotic areas exposed to non-physiological WSS was successfully reduced compared to a regular straight graft. Our meta-modelling approach allowed to reduce the total number of CFD model evaluations required for our design optimisation by approximately a factor 2000. The applied efficient meta-modelling technique was successful in identifying an optimal, helical graft design at relatively low computational costs. Future studies should evaluate the in vivo benefits of the developed graft design.
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http://dx.doi.org/10.1002/cnm.3423DOI Listing
February 2021

A Novel Tool for the Identification and Characterization of Repetitive Patterns in High-Density Contact Mapping of Atrial Fibrillation.

Front Physiol 2020 15;11:570118. Epub 2020 Oct 15.

Department of Physiology, Maastricht University Medical Center, Cardiovascular Research Institute Maastricht, Maastricht, Netherlands.

Introduction: Electrical contact mapping provides a detailed view of conduction patterns in the atria during atrial fibrillation (AF). Identification of repetitive wave front propagation mechanisms potentially initiating or sustaining AF might provide more insights into temporal and spatial distribution of candidate AF mechanism and identify targets for catheter ablation. We developed a novel tool based on recurrence plots to automatically identify and characterize repetitive conduction patterns in high-density contact mapping of AF.

Materials And Methods: Recurrence plots were constructed by first transforming atrial electrograms recorded by a multi-electrode array to activation-phase signals and then quantifying the degree of similarity between snapshots of the activation-phase in the electrode array. An AF cycle length dependent distance threshold was applied to discriminate between repetitive and non-repetitive snapshots. Intervals containing repetitive conduction patterns were detected in a recurrence plot as regions with a high recurrence rate. Intervals that contained similar repetitive patterns were then grouped into clusters. To demonstrate the ability to detect and quantify the incidence, duration and size of repetitive patterns, the tool was applied to left and right atrial recordings in a goat model of different duration of persistent AF [3 weeks AF (3 wkAF, = 8) and 22 weeks AF (22 wkAF, = 8)], using a 249-electrode mapping array (2.4 mm inter-electrode distance).

Results: Recurrence plots identified frequent recurrences of activation patterns in all recordings and indicated a strong correlation between recurrence plot threshold and AF cycle length. Prolonged AF duration was associated with shorter repetitive pattern duration [mean maximum duration 3 wkAF: 74 cycles, 95% confidence interval (54-94) vs. 22 wkAF: 41 cycles (21-62), = 0.03], and smaller recurrent regions within repetitive patterns [3 wkAF 1.7 cm (1.0-2.3) vs. 22 wkAF 0.5 cm (0.0-1.2), = 0.02]. Both breakthrough patterns and re-entry were identified as repetitive conduction patterns.

Conclusion: Recurrence plots provide a novel way to delineate high-density contact mapping of AF. Dominant repetitive conduction patterns were identified in a goat model of sustained AF. Application of the developed methodology using the new generation of multi-electrode catheters could identify additional targets for catheter ablation of AF.
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http://dx.doi.org/10.3389/fphys.2020.570118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593698PMC
October 2020

Complementing sparse vascular imaging data by physiological adaptation rules.

J Appl Physiol (1985) 2020 Oct 29. Epub 2020 Oct 29.

Department of Biomedical Engineering, Maastricht University, Netherlands.

Introduction: Mathematical modeling of pressure and flow waveforms in blood vessels using pulse wave propagation (PWP)-models has tremendous potential to support clinical decision-making. For a personalized model outcome, measurements of all modeled vessel radii and wall thicknesses are required. In clinical practice, however, data sets are often incomplete. To overcome this problem, we hypothesized that the adaptive capacity of vessels in response to mechanical load could be utilized to fill in the gaps of incomplete patient-specific data sets.

Methods: We implemented homeostatic feedback loops in a validated PWP model to allow adaptation of vessel geometry to maintain physiological values of wall stress and wall shear stress. To evaluate our approach, we gathered vascular MRI and ultrasound data sets of wall thicknesses and radii of central and arm arterial segments of ten healthy subjects. Reference models (i.e. termed RefModel, n=10) were simulated using complete data, whereas adapted models (AdaptModel, n=10) used data of one carotid artery segment only while the remaining geometries in this model were estimated using adaptation. We evaluated agreement between RefModel and AdaptModel geometries, as well as between pressure and flow waveforms of both models.

Results: Limits of agreement (bias±2SD of difference) between AdaptModel and RefModel radii and wall thicknesses were 0.2±2.6 mm and -140±557 μm, respectively. Pressure and flow waveform characteristics of the AdaptModel better resembled those of the RefModels as compared to the model in which the vessels were not adapted.

Conclusions: Our adaptation-based PWP-model enables personalization of vascular geometries even when not all required data is available.
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http://dx.doi.org/10.1152/japplphysiol.00250.2019DOI Listing
October 2020

Chorioamnionitis induces changes in ovine pulmonary endogenous epithelial stem/progenitor cells in utero.

Pediatr Res 2020 Oct 18. Epub 2020 Oct 18.

Department of Respiratory Medicine, Maastricht University, Maastricht, The Netherlands.

Background: Chorioamnionitis, an intrauterine infection of the placenta and fetal membranes, is a common risk factor for adverse pulmonary outcomes in premature infants including BPD, which is characterized by an arrest in alveolar development. As endogenous epithelial stem/progenitor cells are crucial for organogenesis and tissue repair, we examined whether intrauterine inflammation negatively affects these essential progenitor pools.

Methods: In an ovine chorioamnionitis model, fetuses were intra-amniotically exposed to LPS, 2d or 7d (acute inflammation) before preterm delivery at 125d of gestation, or to intra-amniotic Ureaplasma parvum for 42d (chronic inflammation). Lung function, pulmonary endogenous epithelial stem/progenitor pools, and downstream functional markers were studied.

Results: Lung function was improved in the 7d LPS and 42d Ureaplasma groups. However, intrauterine inflammation caused a loss of P63+ basal cells in proximal airways and reduced SOX-9 expression and TTF-1+ Club cells in distal airways. Attenuated type-2 cell numbers were associated with lower proliferation and reduced type-1 cell marker Aqp5 expression, indicative for impaired progenitor function. Chronic Ureaplasma infection only affected distal airways, whereas acute inflammation affected stem/progenitor populations throughout the lungs.

Conclusions: Acute and chronic prenatal inflammation improve lung function at the expense of stem/progenitor alterations that potentially disrupt normal lung development, thereby predisposing to adverse postnatal outcomes.

Impact: In this study, prenatal inflammation improved lung function at the expense of stem/progenitor alterations that potentially disrupt normal lung development, thereby predisposing to adverse postnatal outcomes.Importantly, we demonstrate that these essential alterations can already be initiated before birth. So far, stem/progenitor dysfunction has only been shown postnatally.This study indicates that clinical protocols to target the consequences of perinatal inflammatory stress for the immature lungs should be initiated as early as possible and ideally in utero. Within this context, our data suggest that interventions, which promote function or repair of endogenous stem cells in the lungs, hold great promise.
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http://dx.doi.org/10.1038/s41390-020-01204-9DOI Listing
October 2020

The Effect of Geometric Graft Modification on Arteriovenous Graft Patency in Haemodialysis Patients: A Systematic Review and Meta-Analysis.

Eur J Vasc Endovasc Surg 2020 Oct 15;60(4):568-577. Epub 2020 Aug 15.

Department of Vascular Surgery, Maastricht University Medical Centre, Maastricht, the Netherlands; CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands; European Vascular Centre Aachen-Maastricht, Maastricht, The Netherlands and Aachen, Germany. Electronic address:

Objective: Arteriovenous grafts (AVGs) are the second best option for haemodialysis access when native arteriovenous fistulae placement is not possible, because they have a lower patency owing to neointimal hyperplasia at the venous anastomosis. This review aimed to evaluate the effect of geometric graft modification to the graft-vein interface on AVG patency.

Data Sources: The MEDLINE and Embase (OvidSP) databases were systematically searched for relevant studies analysing the effect of geometrically modified AVGs on graft patency and stenosis formation (last search July 2019).

Review Methods: Data regarding AVG type, patency, and graft outlet stenosis was extracted for further evaluation. Data were pooled in a random effects model to estimate the relative risk of graft occlusion within one year. Follow up, number of patients, and relevant patient characteristics were extracted for the quality assessment of the included studies using Newcastle-Ottawa Scale and Cochrane Risk of Bias Tool. The quality of the evidence was determined according to the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) system.

Results: Search strategies produced 2772 hits, of which eight articles met predetermined inclusion criteria. Overall, the included articles had low to moderate risk of bias. In total, 414 expanded polytetrafluoroethylene AVGs (232 geometrically modified and 182 standard) were analysed, comprising two modified AVG types: a prosthetic cuff design (Venaflo®) and grafts with a Tyrell vein patch. Overall, modified grafts did not show a statistically significantly higher one year primary (relative risk [RR] 0.86, 95% confidence interval [CI] 95% 0.64-1.16; GRADE: "low to very low") or secondary patency (RR 0.57, 95% CI 0.32-1.02; GRADE: "low to very low") when compared with standard AVGs. Analysis of prosthetic cuffed grafts (112 patients) separately demonstrated a statistically significantly higher one year primary (RR 0.75, 95% CI 0.61-0.91) and one year secondary patency (RR 0.47, 95% CI 0.30-0.75) compared with standard grafts (92 patients). The results on stenosis formation were inconclusive and inadmissible to quantitative analyses.

Conclusion: The meta-analysis showed that a prosthetic cuff design significantly improves AVG patency, while a venous cuff does not. Although the heterogeneity and low number of available studies limit the strength of the results, this review shows the potential of grafts with geometric modification to the graft-vein anastomosis and should stimulate further clinical and fundamental research on improving graft geometry to improve graft patency.
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http://dx.doi.org/10.1016/j.ejvs.2020.06.023DOI Listing
October 2020

Heart rate and blood pressure dependence of aortic distensibility in rats: comparison of measured and calculated pulse wave velocity.

J Hypertens 2021 Jan;39(1):117-126

Department of Biomedical Sciences, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, New South Wales, Australia.

Objectives: When assessing arterial stiffness, heart rate (HR) and blood pressure (BP) are potential confounders. It appears that the HR/BP dependences of pulse wave velocity (PWV) and distensibility are different, even though both assess arterial stiffness. This study aims to compare aortic PWV as measured using pulse transit time (PWVTT) and as calculated from distensibility (PWVdist) at the same measurement site and propose a solution to the disparity in dependences of PWVTT and PWVdist.

Methods: Adult anaesthetized rats (n = 24) were randomly paced at HRs 300-500 bpm, at 50 bpm steps. At each step, aortic PWVTT (two pressure-tip catheters) and PWVdist (pressure-tip catheter and ultrasound wall-tracking; abdominal aorta) were measured simultaneously while BP was varied pharmacologically.

Results: HR dependence of PWVdist paradoxically decreased at higher levels of BP. In addition, BP dependence of PWVdist was much larger than that of PWVTT. These discrepancies are explained in that standard PWVdist uses an approximate derivative of pressure to diameter, which overestimates PWV with increasing pulse pressure (PP). In vivo, PP decreases as HR increases, potentially causing a PWVdist decrease with HR. Estimating the full pressure-diameter curve for each HR corrected for this effect by enabling calculation of the true derivative at diastolic BP. This correction yielded a PWVdist that shows HR and BP dependences similar to those of PWVTT. As expected, BP dependence of all PWV metrics was much larger than HR dependence.

Conclusion: Measured and calculated PWV have different dependences on HR and BP. These differences are, at least in part, because of approximations made in using systolic and diastolic values to calculate distensibility.
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http://dx.doi.org/10.1097/HJH.0000000000002608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752216PMC
January 2021

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

Decreased endothelial glycocalyx thickness is an early predictor of mortality in sepsis.

Anaesth Intensive Care 2020 May 2;48(3):221-228. Epub 2020 Jun 2.

Department of Intensive Care Medicine, Maastricht University Medical Center, the Netherlands.

Microcirculatory alterations play an important role in the early phase of sepsis. Shedding of the endothelial glycocalyx is regarded as a central pathophysiological mechanism causing microvascular dysfunction, contributing to multiple organ failure and death in sepsis. The objective of this study was to investigate whether endothelial glycocalyx thickness at an early stage in septic patients relates to clinical outcome. We measured the perfused boundary region (PBR), which is inversely proportional to glycocalyx thickness, of sublingual microvessels (5-25 µm) using sidestream dark field imaging. The PBR in 21 patients with sepsis was measured within 24 h of admission to the intensive care unit (ICU). In addition, we determined plasma markers of microcirculatory dysfunction and studied their correlation with PBR and mortality. Endothelial glycocalyx thickness in sepsis was significantly lower for non-survivors as compared with survivors, indicated by a higher PBR of 1.97 [1.85, 2.19]µm compared with 1.76 [1.59, 1.97] µm, =0.03. Admission PBR was associated with hospital mortality with an area under the curve of 0.778 based on the receiver operating characteristic curve. Furthermore, PBR correlated positively with angiopoietin-2 (rho=0.532, =0.03), indicative of impaired barrier function. PBR did not correlate with Acute Physiology and Chronic Health Evaluation IV (APACHE IV), Sequential Organ Failure Assessment score (SOFA score), lactate, syndecan-1, angiopoietin-1 or heparin-binding protein. An increased PBR within the first 24 h after ICU admission is associated with mortality in sepsis. Further research should be aimed at the pathophysiological importance of glycocalyx shedding in the development of multi-organ failure and at therapies attempting to preserve glycocalyx integrity.
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http://dx.doi.org/10.1177/0310057X20916471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328096PMC
May 2020

An audit of uncertainty in multi-scale cardiac electrophysiology models.

Philos Trans A Math Phys Eng Sci 2020 Jun 25;378(2173):20190335. Epub 2020 May 25.

Universitade Federal de Juiz de Fora, Juiz de Fora, Brazil.

Models of electrical activation and recovery in cardiac cells and tissue have become valuable research tools, and are beginning to be used in safety-critical applications including guidance for clinical procedures and for drug safety assessment. As a consequence, there is an urgent need for a more detailed and quantitative understanding of the ways that uncertainty and variability influence model predictions. In this paper, we review the sources of uncertainty in these models at different spatial scales, discuss how uncertainties are communicated across scales, and begin to assess their relative importance. We conclude by highlighting important challenges that continue to face the cardiac modelling community, identifying open questions, and making recommendations for future studies. 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.2019.0335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287340PMC
June 2020

Considering discrepancy when calibrating a mechanistic electrophysiology model.

Philos Trans A Math Phys Eng Sci 2020 Jun 25;378(2173):20190349. Epub 2020 May 25.

School of Mathematics and Statistics, University of Sheffield, Sheffield, UK.

Uncertainty quantification (UQ) is a vital step in using mathematical models and simulations to take decisions. The field of cardiac simulation has begun to explore and adopt UQ methods to characterize uncertainty in model inputs and how that propagates through to outputs or predictions; examples of this can be seen in the papers of this issue. In this review and perspective piece, we draw attention to an important and under-addressed source of uncertainty in our predictions-that of uncertainty in the model structure or the equations themselves. The difference between imperfect models and reality is termed , and we are often uncertain as to the size and consequences of this discrepancy. Here, we provide two examples of the consequences of discrepancy when calibrating models at the ion channel and action potential scales. Furthermore, we attempt to account for this discrepancy when calibrating and validating an ion channel model using different methods, based on modelling the discrepancy using Gaussian processes and autoregressive-moving-average models, then highlight the advantages and shortcomings of each approach. Finally, suggestions and lines of enquiry for future work are provided. 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.2019.0349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287333PMC
June 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

Adenosine usage during AF ablation in Europe and selected long-term findings from the ESC-EHRA EORP Atrial Fibrillation Ablation Long-Term registry.

J Interv Card Electrophysiol 2020 Apr 30. Epub 2020 Apr 30.

Department of Cardiology, Maastricht University Medical Center, PO Box 5800, 6202 AZ, Maastricht, The Netherlands.

Background: Adenosine can be used to reveal dormant pulmonary vein (PV) conduction after PV isolation (PVI). This study presents a subanalysis of real-world 1-year follow-up data from the ESC-EHRA EORP Atrial Fibrillation (AF) Ablation Long-Term registry to analyze the usage of adenosine during PVI treatment in terms of rhythm outcome and safety.

Methods: The registry consists of 104 participating centers in 27 countries within the European Society of Cardiology. The registry data was split into an adenosine group (AG) and no-adenosine group (NAG). Procedure characteristics and patient outcome were compared.

Results: Adenosine was administered in 10.8% of the 3591 PVI patients included in the registry. Spain, the Netherlands, and Italy included the majority of adenosine cases (48.8%). Adenosine was applied more often in combination with open irrigation radiofrequency (RF) energy (74.7%) and less often in combination with nonirrigated RF energy (1.6%). After 1 year, a higher percentage of the AG was free from AF compared with the NAG (68.9% vs 59.1%, p < 0.001). Adenosine was associated with better rhythm outcome in RF ablation procedures, but not in cryo-ablation procedures (freedom from AF: RF: AG: 70.9%, NAG: 58.1%, p < 0.001, cryo: AG: 63.9%, NAG: 63.8%, p = 0.991).

Conclusions: The use of adenosine was associated with a better rhythm outcome after 1 year follow-up and seems more useful in patients treated with RF energy compared with patients treated with cryo energy. Given the improved rhythm outcome at 1-year follow-up, it seems reasonable to encourage the use of adenosine during RF AF ablation.
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http://dx.doi.org/10.1007/s10840-020-00744-8DOI Listing
April 2020

Ten-year follow-up after endocardial point-by-point cryoablation for paroxysmal atrial fibrillation.

Acta Cardiol 2020 May 1:1-6. Epub 2020 May 1.

Department of Cardiology, Maastricht University Medical Center Maastricht, Maastricht, The Netherlands.

Since many years catheter ablation is widely used for the treatment of atrial fibrillation (AF), however, long-term follow-up data of ablation techniques are rare. This study presents a 10-year follow-up period in patients treated for paroxysmal AF (PAF) with point-by-point pulmonary vein isolation (PVI) using cryothermal energy (cryoPVI). The main objective is to investigate whether cryoPVI is able to create durable PVI. All consecutive patients with PAF who underwent a point-by-point cryoPVI were included. Information from the index procedure, anti-arrhythmic drug (AAD) use, recurrence of arrhythmias and re-ablation, was retrospectively analysed. Re-ablations were specifically evaluated for reconnection of PVs. Seventy-three patients were included. Five (7%) were lost to follow-up and 55/73 (75%) reached 10-year follow-up (median follow-up duration: 11.3 years [10.0-12.4]). Thirteen (18%) did not reach 10-years follow-up (mean follow-up duration: 4.4 ± 3.3 years). All targeted PVs were successfully isolated during the index procedure. Only 10/68 patients (15%) kept sinus rhythm (SR) without the use of AAD or a re-ablation. Re-ablations were performed in 47/68 patients (69%). Reconnection was seen in 81% of the PVs. Ostial point-by-point cryoPVI has the ability to provide acute electrical isolation of arrhythmogenic PVs based on abolition of all PV potentials, but fails in long-term isolation and prevention of AF-recurrence in most patients.
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http://dx.doi.org/10.1080/00015385.2020.1756087DOI Listing
May 2020

The standardized 12-lead fetal electrocardiogram of the healthy fetus in mid-pregnancy: A cross-sectional study.

PLoS One 2020 30;15(4):e0232606. Epub 2020 Apr 30.

Department of Electrical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands.

Introduction: The examination of the fetal heart in mid-pregnancy is by ultrasound examination. The quality of the examination is highly dependent on the skill of the sonographer, fetal position and maternal body mass index. An additional tool that is less dependent on human experience and interpretation is desirable. The fetal electrocardiogram (ECG) could fulfill this purpose. We aimed to show the feasibility of recording a standardized fetal ECG in mid-pregnancy and explored its possibility to detect congenital heart disease (CHD).

Materials And Methods: Women older than 18 years of age with an uneventful pregnancy, carrying a healthy singleton fetus with a gestational age between 18 and 24 weeks were included. A fetal ECG was performed via electrodes on the maternal abdomen. After removal of interferences, a vectorcardiogram was constructed. Based on the ultrasound assessment of the fetal orientation, the vectorcardiogram was rotated to standardize for fetal orientation and converted into a 12-lead ECG. Median ECG waveforms for each lead were calculated.

Results: 328 fetal ECGs were recorded. 281 were available for analysis. The calculated median ECG waveform showed the electrical heart axis oriented to the right and inferiorly i.e. a negative QRS deflection in lead I and a positive deflection in lead aVF. The two CHD cases show ECG abnormalities when compared to the mean ECG of the healthy cohort.

Discussion: We have presented a method for estimating a standardized 12-lead fetal ECG. In mid-pregnancy, the median electrical heart axis is right inferiorly oriented in healthy fetuses. Future research should focus on fetuses with congenital heart disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0232606PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7192482PMC
July 2020

Pre-operative Patient Specific Flow Predictions to Improve Haemodialysis Arteriovenous Fistula Maturation (Shunt Simulation Study): A Randomised Controlled Trial.

Eur J Vasc Endovasc Surg 2020 Jul 25;60(1):98-106. Epub 2020 Apr 25.

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

Objective: An arteriovenous fistula (AVF) needs to mature before it becomes suitable to cannulate for haemodialysis treatment. Maturation importantly depends on the post-operative flow increase. Unfortunately, 20-40% of AVFs fail to mature (FTM). A patient specific computational model that predicts immediate post-operative flow was developed, and it was hypothesised that providing information from this model for planning of fistula creation might reduce FTM rates.

Methods: A multicentre, randomised controlled trial in nine Dutch hospitals was conducted in which patients with renal failure who were referred for AVF creation, were recruited. Patients were randomly assigned (1:1) to the control or computer simulation group. Both groups underwent a work up, with physical and duplex ultrasonography (DUS) examination. In the simulation group the data from the DUS examination were used for model simulations, and based on the immediate post-operative flow prediction, the ideal AVF configuration was recommended. The primary endpoint was AVF maturation defined as an AVF flow ≥500 mL/min and a vein inner diameter of ≥4 mm six weeks post-operatively. The secondary endpoint was model performance (i.e. comparisons between measured and predicted flows, and (multivariable) regression analysis for maturation probability with accompanying area under the receiver operator characteristic curve [AUC]).

Results: A total of 236 patients were randomly assigned (116 in the control and 120 in the simulation group), of whom 205 (100 and 105 respectively) were analysed for the primary endpoint. There was no difference in FTM rates between the groups (29% and 32% respectively). Immediate post-operative flow prediction had an OR of 1.15 (1.06-1.26; p < .001) per 100 mL/min for maturation, and the accompanying AUC was 0.67 (0.59-0.75).

Conclusion: Providing pre-operative patient specific flow simulations during surgical planning does not result in improved maturation rates. Further study is needed to improve the predictive power of these simulations in order to render the computational model an adjunct to surgical planning.
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http://dx.doi.org/10.1016/j.ejvs.2020.03.005DOI Listing
July 2020

The 'Digital Twin' to enable the vision of precision cardiology.

Eur Heart J 2020 Dec;41(48):4556-4564

Department of Biomedical Engineering, Division of Imaging Sciences and Biomedical Engineering, King's College London, London, UK.

Providing therapies tailored to each patient is the vision of precision medicine, enabled by the increasing ability to capture extensive data about individual patients. In this position paper, we argue that the second enabling pillar towards this vision is the increasing power of computers and algorithms to learn, reason, and build the 'digital twin' of a patient. Computational models are boosting the capacity to draw diagnosis and prognosis, and future treatments will be tailored not only to current health status and data, but also to an accurate projection of the pathways to restore health by model predictions. The early steps of the digital twin in the area of cardiovascular medicine are reviewed in this article, together with a discussion of the challenges and opportunities ahead. We emphasize the synergies between mechanistic and statistical models in accelerating cardiovascular research and enabling the vision of precision medicine.
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http://dx.doi.org/10.1093/eurheartj/ehaa159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774470PMC
December 2020

Improving Prediction of Favourable Outcome After 6 Months in Patients with Severe Traumatic Brain Injury Using Physiological Cerebral Parameters in a Multivariable Logistic Regression Model.

Neurocrit Care 2020 10;33(2):542-551

MHeNS School for Mental Health and Neuroscience, Maastricht University, PO Box 616, 6200 MD, Maastricht, The Netherlands.

Background/objective: Current severe traumatic brain injury (TBI) outcome prediction models calculate the chance of unfavourable outcome after 6 months based on parameters measured at admission. We aimed to improve current models with the addition of continuously measured neuromonitoring data within the first 24 h after intensive care unit neuromonitoring.

Methods: Forty-five severe TBI patients with intracranial pressure/cerebral perfusion pressure monitoring from two teaching hospitals covering the period May 2012 to January 2019 were analysed. Fourteen high-frequency physiological parameters were selected over multiple time periods after the start of neuromonitoring (0-6 h, 0-12 h, 0-18 h, 0-24 h). Besides systemic physiological parameters and extended Corticosteroid Randomisation after Significant Head Injury (CRASH) score, we added estimates of (dynamic) cerebral volume, cerebral compliance and cerebrovascular pressure reactivity indices to the model. A logistic regression model was trained for each time period on selected parameters to predict outcome after 6 months. The parameters were selected using forward feature selection. Each model was validated by leave-one-out cross-validation.

Results: A logistic regression model using CRASH as the sole parameter resulted in an area under the curve (AUC) of 0.76. For each time period, an increased AUC was found using up to 5 additional parameters. The highest AUC (0.90) was found for the 0-6 h period using 5 parameters that describe mean arterial blood pressure and physiological cerebral indices.

Conclusions: Current TBI outcome prediction models can be improved by the addition of neuromonitoring bedside parameters measured continuously within the first 24 h after the start of neuromonitoring. As these factors might be modifiable by treatment during the admission, testing in a larger (multicenter) data set is warranted.
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http://dx.doi.org/10.1007/s12028-020-00930-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505885PMC
October 2020

Percutaneous Device Closure of Congenital Isolated Ventricular Septal Defects: A Single-Center Retrospective Database Study Amongst 412 Cases.

Pediatr Cardiol 2020 Mar 13;41(3):591-598. Epub 2020 Feb 13.

Cardiovascular Research Institute Maastricht CARIM, Maastricht University, Maastricht, The Netherlands.

To identify suitable cases and reduce failure/complication rates for percutaneous ventricular septal defect (VSD) closure, we aimed to (1) study causes of device failure and (2) compare outcomes with different VSD types and devices in a high-volume single center with limited resources. Retrospective data of 412 elective percutaneous VSD closure of isolated congenital VSDs between 2003 and 2017 were analyzed. Out of 412, 363 were successfully implanted, in 30 device implantation failed, and in 19 the procedure was abandoned. Outcome was assessed using echocardiography, electrocardiography, and catheterization data (before procedure, immediately after and during follow-up). Logistic regression analyses were performed to assess effects of age, VSD type, and device type and size on procedural outcome. Median [interquartile range] age and body surface area were 6.6 [4.1-10.9] years and 0.7 [0.5-1.0] m, respectively. Device failure was not associated with age (p = 0.08), type of VSD (p = 0.5), device type (p = 0.2), or device size (p = 0.1). Device failure occurred in 7.6% of patients. As device type is not related to failure rate and device failure and complication risk was not associated with age, it is justifiable to use financially beneficial ductal devices in VSD position and to consider closure of VSD with device in clinically indicated children.
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http://dx.doi.org/10.1007/s00246-020-02315-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170976PMC
March 2020

Improving long QT syndrome diagnosis by a polynomial-based T-wave morphology characterization.

Heart Rhythm 2020 05 7;17(5 Pt A):752-758. Epub 2020 Jan 7.

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

Background: Diagnosing long QT syndrome (LQTS) remains challenging because of a considerable overlap in QT interval between patients with LQTS and healthy subjects. Characterizing T-wave morphology might improve LQTS diagnosis.

Objective: The purpose of this study was to improve LQTS diagnosis by combining new polynomial-based T-wave morphology parameters with the corrected QT interval (QTc), age, and sex in a model.

Methods: A retrospective cohort consisting of 333 patients with LQTS and 345 genotype-negative family members was used in this study. For each patient, a linear combination of the first 2 Hermite-Gauss (HG) polynomials was fitted to the STT segments of an average complex of all precordial leads and limb leads I and II. The weight coefficients as well as the error of the best fit were used to characterize T-wave morphology. Subjects were classified as patients with LQTS or controls by clinical QTc cutoffs and 3 support vector machine models fed with different features. An external cohort consisting of 72 patients and 45 controls was finally used to check the robustness of the models.

Results: Baseline QTc cutoffs were specific but had low sensitivity in diagnosing LQTS. The model with T-wave morphology features, QTc, age, and sex had the best overall accuracy (84%), followed by a model with QTc, age, and sex (79%). The model with T-wave morphology features especially performed better in LQTS type 3 patients (69%).

Conclusion: T-wave morphologies can be characterized by fitting a linear combination of the first 2 Hermite-Gauss polynomials. Adding T-wave morphology characterization to age, sex, and QTc in a support vector machine model improves LQTS diagnosis.
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http://dx.doi.org/10.1016/j.hrthm.2019.12.020DOI Listing
May 2020

Natural Vascular Remodelling After Arteriovenous Fistula Creation in Dialysis Patients With and Without Previous Ipsilateral Vascular Access.

Eur J Vasc Endovasc Surg 2020 02 3;59(2):277-287. Epub 2020 Jan 3.

Department of Vascular Surgery, Maastricht University Medical Centre+, Maastricht, the Netherlands.

Objective: The aim of the study was to observe the natural haemodynamic changes after arteriovenous fistula (AVF) creation in haemodialysis patients with and without a previous ipsilateral vascular access.

Methods: This was a retrospective, single centre cohort study. Patient demographics were registered and pre- and post-operative vessel ultrasound examinations were performed at regular follow up intervals. Arteriovenous fistula outcomes in terms of vessel diameter and access flow enhancement were determined for radiocephalic, brachiocephalic, and brachiobasilic AVFs.

Results: In total, 331 patients (median age 66 years, 60% male) with 366 new autologous AVFs were studied, of whom 112 patients had a previous ipsilateral vascular access (VA). Patients with a previous ipsilateral VA had a statistically significantly greater pre-operative brachial artery diameter (4.4 mm) and flow (106 mL/min), and basilic vein diameter (4.9 mm), compared with patients without a previous ipsilateral VA (4.0 mm, 54 mL/min, and 4.3 mm, respectively). For all AVF configurations these differences gradually disappeared over three months after AVF creation. The haemodynamic changes reached a plateau at three months, and were statistically significantly accelerated in patients with a previous ipsilateral VA. There were no differences in primary failure or high flow complications between both groups.

Conclusion: Arteriovenous fistulae show haemodynamic and remodelling changes up to three months post-operatively. Previous ipsilateral VAs may initiate vessel preconditioning, and accelerate the observed haemodynamic changes after AVF creation. However, this preconditioning does not result in a beneficial or detrimental effect on VA function.
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http://dx.doi.org/10.1016/j.ejvs.2019.10.010DOI Listing
February 2020

Computational Modelling Based Recommendation on Optimal Dialysis Needle Positioning and Dialysis Flow in Patients With Arteriovenous Grafts.

Eur J Vasc Endovasc Surg 2020 02 26;59(2):288-294. Epub 2019 Dec 26.

Department of Vascular Surgery, Maastricht University Medical Centre, Maastricht, the Netherlands. Electronic address:

Objective: Arteriovenous grafts (AVGs) typically lose patency within two years of creation due to venous neointimal hyperplasia, which is initiated by disturbed haemodynamics after AVG surgery. Haemodialysis needle flow can further disturb haemodynamics and thus impact AVG longevity. In this computational study it was assessed how dialysis flow and venous needle positioning impacts flow at the graft-vein anastomosis. Furthermore, it was studied how negative effects of dialysis needle flow could be mitigated.

Methods: Non-physiological wall shear stress and disturbed blood flow were assessed in an AVG model with and without dialysis needle flow. Needle distance to the venous anastomosis was set to 6.5, 10.0, or 13.5 cm, whereas dialysis needle flow was set to 200, 300 or 400 mL/min. Intraluminal needle tip depth was varied between superficial, central, or deep. The detrimental effects of dialysis needle flow were summarised by a haemodynamic score (HS), ranging from 0 (minimal) to 5 (severe).

Results: Dialysis needle flow resulted in increased disturbed flow and/or non-physiological wall shear stress in the venous peri-anastomotic region. Increasing cannulation distance from 6.5 to 13.5 cm reduced the HS by a factor 4.0, whereas a central rather than a deep or superficial needle tip depth reduced the HS by a maximum factor of 1.9. Lowering dialysis flow from 400 to 200 mL/min reduced the HS by a factor 7.4.

Conclusion: Haemodialysis needle flow, cannulation location, and needle tip depth considerably increase the amount of disturbed flow and non-physiological wall shear stress in the venous anastomotic region of AVGs. Negative effects of haemodialysis needle flow could be minimised by more upstream cannulation, by lower dialysis flow and by ensuring a central needle tip depth. Since disturbed haemodynamics are associated with neointimal hyperplasia development, optimising dialysis flow and needle positioning during haemodialysis could play an important role in maintaining AVG patency.
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http://dx.doi.org/10.1016/j.ejvs.2019.08.013DOI Listing
February 2020

Variability of Microcirculatory Measurements in Critically Ill Patients.

Shock 2020 07;54(1):9-14

Department of Biochemistry, Maastricht University, Maastricht, the Netherlands.

Introduction: Monitoring the microcirculation may be helpful in guiding resuscitation in patients with circulatory shock. Sublingual side-stream dark field imaging cameras allow for noninvasive, bedside evaluation of the microcirculation, although their use in clinical practice has not yet been validated. The GlycoCheck system automatically analyzes images to determine glycocalyx thickness, red blood cell filling percentage, and vessel density. Although GlycoCheck has been used to study microcirculation in critically ill patients, little is known about the reproducibility of measurements in this population.

Materials And Methods: A total of 60 critically ill patients were studied. Three consecutive microcirculation measurements were performed with the GlycoCheck system in 40 of these patients by one of two experienced observers. Twenty patients were assessed by both observers. Intra- and interobserver variability were assessed using intraclass correlation coefficients (ICCs).

Results: ICCs of single measurements were poor for glycocalyx thickness and good for filling percentage and vessel density. Reproducibility could be substantially increased for all parameters when three consecutive measurements were performed and averaged.

Discussion: GlycoCheck can be used to study microcirculation. However, to obtain reliable results three consecutive measurements should be performed and averaged. The variation of the measurements currently hampers the clinical application in individual patients.
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http://dx.doi.org/10.1097/SHK.0000000000001470DOI Listing
July 2020

Computational study on the haemodynamic and mechanical performance of electrospun polyurethane dialysis grafts.

Biomech Model Mechanobiol 2020 Apr 2;19(2):713-722. Epub 2019 Nov 2.

Department of Biomedical Engineering, CARIM School for Cardiovascular Diseases, Maastricht University, Universiteitssingel 50, 6223ER, Maastricht, The Netherlands.

Compliance mismatch between an arteriovenous dialysis graft (AVG) and the connected vein is believed to result in disturbed haemodynamics around the graft-vein anastomosis and increased mechanical loading of the vein. Both phenomena are associated with neointimal hyperplasia development, which is the main reason for AVG patency loss. In this study, we use a patient-specific fluid structure interaction AVG model to assess whether AVG haemodynamics and mechanical loading can be optimised by using novel electrospun polyurethane (ePU) grafts, since their compliance can be better tuned to match that of the native veins, compared to gold standard, expanded polytetrafluoroethylene (ePTFE) grafts. It was observed that the magnitude of flow disturbances in the vein and the size of anastomotic areas exposed to highly oscillatory shear ([Formula: see text]) and very high wall shear stress ([Formula: see text]) were largest for the ePTFE graft. Median strain and von Mises stress in the vein were similar for both graft types, whereas highest stress and strain were observed in the anastomosis of the ePU graft. Since haemodynamics were most favourable for the ePU graft simulation, AVG longevity might be improved by the use of ePU grafts.
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http://dx.doi.org/10.1007/s10237-019-01242-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7105427PMC
April 2020

Head orientation and electrode placement potentially influence fetal scalp ECG waveform.

PLoS One 2019 10;14(10):e0223282. Epub 2019 Oct 10.

Department of BioMedical Engineering, Maastricht University Medical Center, Maastricht, the Netherlands.

Background: Fetal monitoring based on electrocardiographic (ECG) morphology is obtained from a single unipolar fetal scalp electrode. Ideally, it should be obtained from multiple leads, as ECG waveform depends on alignment between electrode and electrical heart axis. This alignment is unknown in fetuses. Besides, fetuses are surrounded by conductive media, which may influence ECG waveform. We explored the influence of electrode position and head orientation on ECG waveforms of unipolar and bipolar scalp ECGs recorded in air and in conductive medium.

Methods: We recorded ECGs in one adult subject at five different scalp positions in five different head orientations both in dry and immersed conditions. The ratio between T-amplitude and QRS-amplitude (T/QRS ratio) of unipolar and bipolar scalp ECGs was determined and compared between all conditions.

Results: In the dry condition, we observed in the unipolar leads little to no difference between different electrode positions (maximal T/QRS difference 0.00-0.01) and minor differences between head orientations (0.02-0.03), whereas bipolar leads showed no recognizable ECG signal at all. During the immersed condition, we found variation in the unipolar leads, both between electrode positions (maximal T/QRS difference 0.02-0.05) and between head orientations (0.03-0.06). Bipolar leads showed different ECG signals in contrasting head orientations.

Conclusions: Both unipolar and bipolar scalp lead-derived ECG waveforms are influenced by electrode position and head orientation when the subject is submerged in a conductive medium. Fetal monitoring based on single scalp lead ECG waveform might be suboptimal, as it lacks correction for fetal head orientation and electrode position.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0223282PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6786568PMC
March 2020

A Metamodeling Approach for Instant Severity Assessment and Uncertainty Quantification of Iliac Artery Stenoses.

J Biomech Eng 2019 Aug 1. Epub 2019 Aug 1.

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

Complex models of blood flow in stenosed arteries can be used to patient-specifically predict outcome metrics, thereby supporting the physicians in decision making processes. However, these models are time consuming which limits the feasibility of output uncertainty quantification. Accurate surrogates (metamodels) might be the solution. In this study, we aim to demonstrate the feasibility of a generalized polynomial chaos expansion (gPCE)-based metamodel to predict a clinically relevant output metric and to quantify output uncertainty. As an example, a metamodel was constructed from a 2D CFD model that was shown to be able to estimate translesional pressure drops in iliac artery stenoses (-0.9±12.7mmHg, R2=0.81). The metamodel was constructed from a virtual database using the adaptive gPCE method. The constructed metamodel was then applied to 25 stenosed iliac arteries to predict the patient-specific pressure drop and to perform uncertainty quantification. Comparing predicted pressure drops of the metamodel and in vivo measured pressure drops, the mean bias (-0.2±13.7mmHg) and the coefficient of determination (R2=0.80) were as good as of the original 2D model. Uncertainty quantification results of the 2D and metamodel were comparable. Estimation of the uncertainty interval using the original 2D model took 14 days, whereas the result of the metamodel was instantly available. In conclusion, it is feasible to quantify the uncertainty of the output metric and perform sensitivity analysis instantly using a metamodel. Future studies should investigate the possibility to construct a metamodel of more complex problems.
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http://dx.doi.org/10.1115/1.4044502DOI Listing
August 2019

Why -aVF can be used in STAN as a proxy for scalp electrode-derived signal; reply to comments by Kjellmer et al.

PLoS One 2019 22;14(8):e0221220. Epub 2019 Aug 22.

Department of Biomedical Engineering, Maastricht University, Maastricht, the Netherlands.

The conclusion of our recent paper that performance of the STAN device in clinical practice is potentially limited by high false-negative and high false-positive STAN-event rates and loss of ST waveform assessment capacity during severe hypoxemia, evoked comments by Kjellmer, Lindecrantz and Rosén. These comments can be summarized as follows: 1) STAN analysis is based on a unipolar lead but the authors used a negative aVF lead, and they did not validate this methodology; 2) The fetuses used in the study were too young to display the signals that the authors were trying to detect. In response to these comments we now provide both a theoretical and an experimental underpinning of our approach. In an in vivo experiment in human we placed several electrodes over the head (simulating different places of a scalp electrode), simultaneously recorded Einthoven lead I and II, and constructed -aVF from these two frontal leads. Irrespective of scalp electrode placement, the correlation between any of unipolar scalp electrode-derived signals and constructed-aVF was excellent (≥ 0.92). In response to the second comment we refer to a study which demonstrated that umbilical cord occlusion resulted in rapid increase in T/QRS ratio that coincided with initial hypertension and bradycardia at all gestational ages which were tested from 0.6-0.8 gestation. The animals of our study were in this gestational range and, hence, our experimental setup can be used to assess STAN's quality to detect fetal hypoxia. In conclusion, we have clearly demonstrated the appropriateness of using-aVF as a proxy for a scalp electrode-derived signal in STAN in these preterm lambs. Investigation why STAN could not detect relevant ST-changes and instead produced erroneous alarms in our experimental setup is hampered by the fact that the exact STAN algorithm (signal processing and analysis) is not in the public domain.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0221220PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6705853PMC
February 2020

The Role of One-Dimensional Model-Generated Inter-Subject Variations in Systemic Properties on Wall Shear Stress Indices of Intracranial Aneurysms.

IEEE Trans Biomed Eng 2020 04 15;67(4):1030-1039. Epub 2019 Jul 15.

Variations in systemic properties of the arterial tree, such as aging-induced vessel stiffness, can alter the shape of pressure and flow waveforms. As a consequence, the hemodynamics around a cerebral aneurysm change, and therefore, also the corresponding in- and outlet boundary conditions (BCs) used for three-dimensional (3D) calculations of hemodynamic indices. In this study, we investigate the effects of variations in systemic properties on wall shear stress (WSS) indices of a cerebral aneurysm. We created a virtual patient database by varying systemic properties within physiological ranges. BCs for 3D-CFD simulations were derived using a pulse wave propagation model for each realization of the virtual database. WSS indices were derived from the 3D simulations and their variabilities quantified. Variations in BCs, caused by changes in systemic properties, yielded variabilities in the WSS indices that were of the same order of magnitude as differences in these WSS indices between ruptured and unruptured aneurysms. Sensitivity analysis showed that the systemic properties impacted both in- and outlet BCs simultaneously and altered the WSS indices. We conclude that the influence of variations in patient-specific systemic properties on WSS indices should be evaluated when using WSS indices in multidisciplinary rupture prediction models.
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http://dx.doi.org/10.1109/TBME.2019.2928416DOI Listing
April 2020