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BACKGROUND: Multivariable equations are recommended by primary prevention guidelines to assess absolute risk of cardiovascular disease (CVD). However, current equations have several limitations. Therefore, we developed and validated the American Heart Association Predicting Risk of CVD EVENTs (PREVENT) equations among US adults 30 to 79 years of age without known CVD. METHODS: The derivation sample included individual-level participant data from 25 data sets (N=3281919) between 1992 and 2017. The primary outcome was CVD (atherosclerotic CVD and heart failure). Predictors included traditional risk factors (smoking status, systolic blood pressure, cholesterol, antihypertensive or statin use, and diabetes) and estimated glomerular filtration rate. Models were sex-specific, race-free, developed on the age scale, and adjusted for competing risk of nonCVD death. Analyses were conducted in each data set and meta-analyzed. Discrimination was assessed using the Harrell C-statistic. Calibration was calculated as the slope of the observed versus predicted risk by decile. Additional equations to predict each CVD subtype (atherosclerotic CVD and heart failure) and include optional predictors (urine albumin-tocreatinine ratio and hemoglobin A1c), and social deprivation index were also developed. External validation was performed in 3330085 participants from 21 additional data sets. RESULTS: Among 6612004 adults included, mean±SD age was 53±12 years, and 56% were women. Over a mean±SD follow-up of 4.8±3.1 years, there were 211515 incident total CVD events. The median C-statistics in external validation for CVD were 0.794 (interquartile interval, 0.763–0.809) in female and 0.757 (0.727–0.778) in male participants. The calibration slopes were 1.03 (interquartile interval, 0.81–1.16) and 0.94 (0.81–1.13) among female and male participants, respectively. Similar estimates for discrimination and calibration were observed for atherosclerotic CVD– and heart failure–specific models. The improvement in discrimination was small but statistically significant when urine albumin-to-creatinine ratio, hemoglobin A1c, and social deprivation index were added together to the base model to total CVD (ΔC-statistic [interquartile interval] 0.004 [0.004–0.005] and 0.005 [0.004–0.007] among female and male participants, respectively). Calibration improved significantly when the urine albumin-to-creatinine ratio was added to the base model among those with marked albuminuria (>300 mg/g; 1.05 [0.84–1.20] versus 1.39 [1.14–1.65]; P=0.01). CONCLUSIONS: PREVENT equations accurately and precisely predicted risk for incident CVD and CVD subtypes in a large, diverse, and contemporary sample of US adults by using routinely available clinical variables. [ABSTRACT FROM AUTHOR]

Cardiovascular-kidney-metabolic (CKM) syndrome is a novel construct recently defined by the American Heart Association in response to the high prevalence of metabolic and kidney disease. Epidemiological data demonstrate higher absolute risk of both atherosclerotic cardiovascular disease (CVD) and heart failure as an individual progresses from CKM stage 0 to stage 3, but optimal strategies for risk assessment need to be refined. Absolute risk assessment with the goal to match type and intensity of interventions with predicted risk and expected treatment benefit remains the cornerstone of primary prevention. Given the growing number of therapies in our armamentarium that simultaneously address all 3 CKM axes, novel risk prediction equations are needed that incorporate predictors and outcomes relevant to the CKM context. This should also include social determinants of health, which are key upstream drivers of CVD, to more equitably estimate and address risk. This scientific statement summarizes the background, rationale, and clinical implications for the newly developed sex-specific, race-free risk equations: PREVENT (AHA Predicting Risk of CVD Events). The PREVENT equations enable 10- and 30-year risk estimates for total CVD (composite of atherosclerotic CVD and heart failure), include estimated glomerular filtration rate as a predictor, and adjust for competing risk of non-CVD death among adults 30 to 79 years of age. Additional models accommodate enhanced predictive utility with the addition of CKM factors when clinically indicated for measurement (urine albumin-to-creatinine ratio and hemoglobin A1c) or social determinants of health (social deprivation index) when available. Approaches to implement risk-based prevention using PREVENT across various settings are discussed. [ABSTRACT FROM AUTHOR]

This article provides a comprehensive hemodynamic assessment of two endovascular techniques for treating cerebral aneurysms. Through finite volume simulations of pulsatile blood flow in saccular aneurysms, we evaluated hemodynamic factors under two coiling conditions with varying porosities and deformation stages to determine the most effective treatment for each case. Our analysis shows that stent and coiling treatments are more effective for aneurysms with smaller sac volumes. In particular, stent placement is found to be more effective than coiling for managing saccular aneurysms. The results indicate that stent-induced deformation effectively redirects the main blood flow, significantly lowering the risk of aneurysm rupture near the ostium. Obtained results emphasize the role of deformation and porosity in controlling wall shear stress, which is essential for understanding aneurysm progression and potential rupture risk., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

While much about the fundamental mechanisms behind the initiation and progression of Type B aortic dissection (TBAD) is still unknown, predictive models based on patient-specific fluid-structure interaction (FSI) simulations can help in risk stratification and optimal clinical decision-making. Aiming at the development of personalized treatment, FSI models can be leveraged to investigate the interplay between complex aortic flow patterns and anatomical features, while considering the deformation of the arterial wall and the dissection flap. In this study, the hemodynamics of false lumen thrombosis, a large fenestration, and the orbital orientation of the false lumen is studied through image-based FSI simulations on three TBAD patient-specific geometries. A new pipeline is developed leveraging the open-source software SimVascular and ParaView to analyze multiple patients simultaneously and to achieve large-scale parallelization in FSI results based on patients' computed tomography (CT) images. The results of this study suggest that the internal orbital orientation of the false lumen contributes to maintaining a positive luminal pressure difference Δ P T L - F L = P TL - P FL between the true lumen (TL) and the false lumen (FL), despite an impingement area in the false lumen near the entry tear. A positive and high luminal pressure difference is thought to promote TL expansion and FL compression. Moreover, it was also found that FL thrombosis at the entry tear region reduce the magnitude of the negative luminal pressure difference, which in turn may reduce FL expansion and the risk of unstable aortic growth. Finally, this FSI study suggests that the aortic wall and dissection flap stiffness determines the effects of a large fenestration in the descending thoracic aorta on the luminal pressure difference., (© 2024. The Author(s).)

We present the first-ever, fully discrete, stochastic model of triggered cardiac Ca 2+ dynamics. Using anatomically accurate subcellular cardiac myocyte geometries, we simulate the molecular players involved in Ca 2+ handling using high-resolution stochastic and explicit-particle methods at the level of an individual cardiac dyadic junction. Integrating data from multiple experimental sources, the model not only replicates the findings of traditional in silico studies and complements in vitro experimental data but also reveals new insights into the molecular mechanisms driving cardiac dysfunction under stress and disease conditions. We improve upon older, nondiscrete models using the same realistic geometry by incorporating molecular mechanisms for spontaneous, as well as triggered calcium-induced calcium release (CICR). Action potentials are used to activate L-type calcium channels (LTCC), triggering CICR through ryanodine receptors (RyRs) on the surface of the sarcoplasmic reticulum. These improvements allow for the specific focus on the couplon: the structure-function relationship between LTCC and RyR. We investigate the electrophysical effects of normal and diseased action potentials on CICR and interrogate the effects of dyadic junction deformation through detubulation and orphaning of RyR. Our work demonstrates the importance of the electrophysical integrity of the calcium release unit on CICR fidelity, giving insights into the molecular basis of heart disease. Finally, we provide a unique, detailed, molecular view of the CICR process using advanced rendering techniques. This easy-to-use model comes complete with tutorials and the necessary software for use and analysis to maximize usability and reproducibility. Our work focuses on quantifying, qualifying, and visualizing the behavior of the molecular species that underlie the function and dysfunction of subcellular cardiomyocyte systems., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Aims: Short QT syndrome type 1 (SQT1) is a genetic channelopathy caused by gain-of-function variants in human-ether-a-go-go (HERG) underlying the rapid delayed-rectifier K+ current (IKr), leading to QT-shortening, ventricular arrhythmias, and sudden cardiac death. Data on efficient pharmacotherapy for SQT1 are scarce. In patients with primary carnitine-deficiency, acquired-short QT syndrome (SQTS) has been observed and rescued by carnitine supplementation. Here, we assessed whether carnitine exerts direct beneficial (prolonging) effects on cardiac repolarization in genetic SQTS., Methods and Results: Adult wild-type (WT) and transgenic SQT1 rabbits (HERG-N588K, gain of IKr) were used. In vivo electrocardiograms (ECGs), ex vivo monophasic action potentials (APs) in Langendorff-perfused hearts, and cellular ventricular APs and ion currents were assessed at baseline and during L-Carnitine/C16-Carnitine-perfusion. Two-dimensional computer simulations were performed to assess re-entry-based ventricular tachycardia-inducibility. L-Carnitine/C16-Carnitine prolonged QT-intervals in WT and SQT1, leading to QT-normalization in SQT1. Similarly, monophasic and cellular AP duration (APD) was prolonged by L-Carnitine/C16-Carnitine in WT and SQT1. As underlying mechanisms, we identified acute effects on the main repolarizing ion currents: IKr-steady, which is pathologically increased in SQT1, was reduced by L-Carnitine/C16-Carnitine and deactivation kinetics were accelerated. Moreover, L-Carnitine/C16-Carnitine decreased IKs-steady and IK1. In silico modelling identified IKr changes as the main factor for L-Carnitine/C16-Carnitine-induced APD-prolongation. 2D simulations revealed increased sustained re-entry-based arrhythmia formation in SQT1 compared to WT, which was decreased to the WT-level when adding carnitine-induced ion current changes., Conclusion: L-Carnitine/C16-Carnitine prolong/normalize QT and whole-heart/cellular APD in SQT1 rabbits. These beneficial effects are mediated by acute effects on IKr. L-Carnitine may serve as a potential future QT-normalizing, anti-arrhythmic therapy in SQT1., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Purpose: To present a first principle-based, high-fidelity computational model for predicting full three-dimensional (3D) and time-resolved retinal microvascular hemodynamics taking into consideration the flow and deformation of individual blood cells., Methods: The computational model is a 3D fluid-structure interaction model based on combined finite volume/finite element/immersed-boundary methods. Three in silico microvascular networks are built from high-resolution in vivo motion contrast images of the superficial capillary plexus in the parafoveal region of the human retina. The maximum tissue area represented in the model is approximately 500 × 500 µm2, and vessel lumen diameters ranged from 5.5 to 25 µm covering capillaries, arterioles, and venules. Blood is modeled as a suspension of individual blood cells, namely, erythrocytes (RBC), leukocytes (WBC), and platelets in plasma. An accurate and detailed biophysical modeling of each blood cell and their flow-induced deformation is considered. A physiological, pulsatile boundary condition corresponding to an average cardiac cycle of 0.9 second is used., Results: Detailed quantitative data and analysis of 3D retinal microvascular hemodynamics are presented, and their relationship to RBC flow dynamics is illustrated. Blood velocity is shown to have temporal oscillations superimposed on the background pulsatile variation, which arise because of the way RBCs partition at vascular junctions, causing repeated clogging and unclogging of vessels. Temporal variations in RBC velocity and hematocrit are anti-correlated in a given vessel, but their time-averaged distributions are positively correlated across the network. Whole blood velocity is 65% to 85% of RBC velocity, with the discrepancy related to the formation of an RBC-free region, adjacent to the vascular endothelium and typically 0.8 to 1.8 µm thick. The 3D velocity and RBC concentration profiles are shown to be oppositely skewed with respect to each other, because of the way that RBCs "hug" the apex of each bifurcation. RBC deformation is predicted to have biphasic behavior with respect to vessel diameter, with minimal cell length for vessels approximately 7 µm in diameter. The wall shear stress (WSS) exhibits a strongly 3D distribution with local regions of high value and gradient spanning a range of 10 to 80 dyn/cm2. WSS is highest where there is faster flow, greater curvature of the vessel wall, capillary bifurcations, and at locations of RBC crowding and associated thinning of the cell-free layer., Conclusions: This study highlights the usefulness of high-fidelity cell-resolved modeling to obtain accurate and detailed 3D, time-resolved retinal hemodynamic parameters that are not readily available through noninvasive imaging approaches. The results presented are expected to complement and enhance the interpretation of in vivo data, as well as open new avenues to study retinal hemodynamics in health and disease.

Objectives: Distal stent graft-induced new entry (dSINE), a new intimal tear at the distal edge of the frozen elephant trunk (FET), is a complication of FET. Preventive measures for dSINE have not yet been established. This study aimed to clarify the mechanisms underlying the development of dSINE by simulating the mechanical environment at the distal edge of the FET., Methods: The stress field in the aortic wall after FET deployment was calculated using finite element analysis. Blood flow in the intraluminal space of the aorta and FET models was simulated using computational fluid dynamics. The simulations were conducted with various oversizing rates of FET ranging from 0 to 30% under the condition of FET with elastic recoil., Results: The elastic recoil of the FET, which caused its distal edge to push against the greater curvature of the aorta, induced a concentration of circumferential stress and increased wall shear stress (WSS) at the aorta. Elastic recoil also created a discontinuous notch on the lesser curvature of the aorta, causing flow stagnation. An increase in the oversizing rate of the FET widened the large circumferential stress area on the greater curvature and increases the maximum stress. Conversely, a decrease in the oversizing rate of the FET increased the WSS and widened the area with high WSS., Conclusions: Circumferential stress concentration due to an oversized FET and high WSS due to an undersized FET can cause a dSINE. The selection of smaller-sized FET alone might not prevent dSINE., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Mechanical circulatory support is a potential treatment for failing Fontan patients. In this study, we performed a theoretical analysis using a computational model to clarify the effects of systemic ventricular assist device (VAD) in failing Fontan patients. Cardiac chambers and vascular systems were described using the time-varying elastance model and modified Windkessel model, respectively. A VAD was simulated as a nonlinear function. In systolic and diastolic ventricular dysfunction and atrioventricular valve regurgitation models, systemic VAD increased the cardiac index and decreased the central venous pressure (CVP). However, in the high pulmonary vascular resistance model, CVP became extremely high above 15 mmHg to maintain the cardiac index when the pulmonary vascular resistance index (PVRI) was above 5 Wood units m 2 . In Fontan patients with ventricular dysfunction or atrioventricular valve regurgitation, systemic VAD efficiently improves the hemodynamics. In Fontan patients with PVRI of > 5 Wood units m 2 , systemic VAD seems ineffective., (© 2024. The Author(s).)

The waveform of ventricular action potential (AP) is a key determinant of the cardiac cycle, a marker of beating pathophysiology, and a target for anti-arrhythmic drug design. The information contained in the waveform, though, is limited to the actual dynamics of the AP under consideration. By measuring quasi-instantaneous current-voltage relationships during repolarization, I propose a three-dimensional representation of the ventricular AP which includes potential dynamic responses that the beat can show when electrically perturbed. This representation is described in the case of a numerically reconstructed ventricular AP, but it can be, at least partially, derived in real cardiomyocytes. Simulation allows to disclose the potentialities and the limitations of the approach, that can be extended to any non-cardiac AP. By reporting, at any AP time, the ion current available within the physiological membrane potential range at that time, the representation makes all together available: (1) refractory period, (2) thresholds for eliciting full or calcium-driven APs, (3) threshold for all-or-none repolarization, (4) membrane resistance during repolarization, (5) the safety of membrane repolarization. It provides further evidence of a negative membrane resistance during the late phase of ventricular AP and a quantitative estimate of repolarization reserve (RR), key determinants of repolarization dynamics., (© 2024 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Background: Macroreentry stands as the predominant mechanism of typical and atypical flutter. Despite advances in mapping, many aspects of macroreentrant atrial tachycardia remain unsolved. In this translational study, we applied principles of topology to understand the activation patterns, entrainment characteristics, and ablation responses in a large clinical macroreentrant atrial tachycardia database., Methods: Because the atrium can be topologically seen as a closed sphere with holes, we used a computational fixed spherical mesh model with a finite number of holes to induce and analyze macroreentrant atrial tachycardia. The ensuing insights were used to interpret high-density activation maps, postpacing interval-tachycardia cycle length values (difference between postpacing interval and tachycardia cycle length), and ablation response in 131 cases of typical and atypical flutter (n=106 left atrium, n=25 right atrium)., Results: Modeling of macroreentrant atrial tachycardia revealed that reentry on closed surfaces consistently manifests itself as paired rotation and that an odd number of critical boundaries is mathematically impossible. Together with mathematical confirmation by the index theorem, this led to a unifying construct that could explain the number of loops, difference between postpacing interval and tachycardia cycle length values, and ablation outcomes (termination, no change, or prolongation in tachycardia cycle length) in all 131 cases., Conclusions: Combining topology with the index theorem offers a novel and cohesive framework for understanding and managing typical and atypical flutter., Competing Interests: Dr Vandersickel, R. Van den Abeele, and S. Hendrickx have submitted a patent for description of the algorithm to find the critical boundaries automatically. The other authors report no conflicts.

The co-ordinated electrical activity of ∼2 billion cardiac cells ensures stability of the heartbeat. Indeed, the remarkably low incidence (<1%) of ventricular arrhythmias in the healthy heart is only possible when the electrical event across this syncytium is closely controlled. In contrast, the diseased myocardium is associated with increased electrophysiological heterogeneity, unstable rhythm, and increased incidence of lethal arrhythmias. But what is the link between cellular and tissue level heterogeneity? Recent research has shown the existence of considerable cellular heterogeneity even in the healthy heart, suggesting that cell-to-cell variability in electrical (e.g. action potential duration) and mechanical performance (e.g. twitch amplitude) is a normal property. This observation has been previously unappreciated because the aggregated function in the form of QT-interval and cardiac output varies <1% on a beat-to-beat basis. This article describes the underlying cellular variability that is tolerated-and perhaps needed-by different regions of the heart for normal function and indicates why this variability is not apparent in function at the chamber and organ level. Thus, in contrast to the current dominant view, this article postulates that heterogeneity is normal and potentially endows various functional benefits. This new view of how the component parts of the heart come together to function also suggests novel mechanisms for cardiac pathologies, namely that dysfunction may emerge from changes in the extent and/or nature of heterogeneity. Once understood, restoring normal forms of heterogeneity could be a novel approach to treatment., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Physics-based computer models based on numerical solutions of the governing equations generally cannot make rapid predictions, which in turn limits their applications in the clinic. To address this issue, we developed a physics-informed neural network (PINN) model that encodes the physics of a closed-loop blood circulation system embedding a left ventricle (LV). The PINN model is trained to satisfy a system of ordinary differential equations (ODEs) associated with a lumped parameter description of the circulatory system. The model predictions have a maximum error of less than 5% when compared to those obtained by solving the ODEs numerically. An inverse modeling approach using the PINN model is also developed to rapidly estimate model parameters (in ∼ 3 min) from single-beat LV pressure and volume waveforms. Using synthetic LV pressure and volume waveforms generated by the PINN model with different model parameter values, we show that the inverse modeling approach can recover the corresponding ground truth values for LV contractility indexed by the end-systolic elastance E es with a 1% error, which suggests that this parameter is unique. The estimated E es is about 58% to 284% higher for the data associated with dobutamine compared to those without, which implies that this approach can be used to estimate LV contractility using single-beat measurements. The PINN inverse modeling can potentially be used in the clinic to simultaneously estimate LV contractility and other physiological parameters from single-beat measurements., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Stent underexpansion is a significant challenge in percutaneous coronary intervention, critically impacting patient outcomes. While excimer laser coronary angioplasty (ELCA) and intravascular lithotripsy (IVL) are increasingly used to address this issue, their full impact on the integrity of drug-eluting stents remains unclear, raising concerns about their safety and efficacy., Methods: This in vitro study assessed the effects of ELCA and IVL on the structural integrity of drug-eluting stents using scanning electron microscopy. Nine stents, 5 Onyx Frontier (with durable circumferential polymer coating) and 4 Cre8 (polymer-free), were implanted in a 3-dimensional coronary artery simulator following standardized protocols. After implantation, treatments with saline-ELCA, contrast-ELCA, IVL, and high-pressure balloon dilatation were applied. A comprehensive evaluation of the stent surface was performed at 60-fold magnification., Results: Scanning electron microscopy analysis revealed significant differences in polymer damage between the techniques. High-pressure balloon dilatation and contrast-ELCA exhibited substantial polymer fragmentation and detachment compared with IVL, saline-ELCA, and conventional dilatation. High-pressure balloon dilatation demonstrated the highest incidence of polymer shaving and overcoating. No significant alterations were observed in polymer-free stents, regardless of the technique used., Conclusions: IVL and saline-ELCA applied immediately after stent implantation produce minimal polymer damage, whereas high-pressure balloon dilatation and contrast-ELCA cause significant damage to the polymer coating. The integrity of polymer-free drug-eluting stent appears stable regardless of the technique used. Further research is needed to validate these findings and explore their clinical implications., Competing Interests: Dr Rivero-Santana is a Rio Hortega Researcher at the Carlos III Health Institute (CM23/00121). Dr Jurado-Roman received speaker fees from Shockwave, Philips, Abbott, Boston Scientific, and Biotronik. In addition, Dr Jurado-Roman has served as a proctor for Philips, Abbott, Boston Scientific, and World Medica. The other authors report no conflicts.

Atherosclerosis is one of the important diseases of the circulatory system because atherosclerotic plaques cause significant disruption of blood flow. Therefore, it is very important to properly understand these processes and skillfully simulate blood flow. In our work, we consider blood flow through an abdominal aorta with iliac arteries, assuming that the right iliac artery is narrowed by an atherosclerotic lesion. Blood flow is simulated using the laminar, standard k - ω and standard k - ϵ models. The obtained results show that despite the use of identical initial conditions, the distribution of velocity flow and wall shear stress depends on the choice of flow simulation model. For the k - ϵ model, we obtain higher values of speed and wall shear stress on atherosclerotic plaque than in the other two models. The laminar and k - ω models predict larger areas where reverse blood flow occurs in the area behind the atherosclerotic lesion. This effect is associated with negative wall shear stress. These two models give very similar results. The results obtained by us, and those reported in the literature, indicate that k - ω model is the most suitable for blood flow analysis., (© 2024. The Author(s).)

This study evaluates the efficacy of annuloplasty repair as a standalone procedure for treating bileaflet mitral valve prolapse with mitral regurgitation (MR). Various flexible ring bands for MR of different severities were compared to assess their biomechanical impact and treatment outcomes. Computational beating heart models, based on the Living Heart Human Model, were utilized to simulate annuloplasty repairs. Repairs using bands of varying lengths were modeled on moderate and severe MR cases, considering bileaflet mitral valve prolapse. Key parameters, including regurgitant orifice area (ROA), prolapse severity, coaptation length, leaflet position, and deformation, were computed to compare conditions before and after implantation. Annuloplasty repairs effectively reduced the ROA in both moderate and severe MR cases, achieving complete sealing in selective instances. Additionally, annuloplasty repair corrected bileaflet prolapse, with prolapse severity decreasing as the annular size increased. Successful coaptation was indicated by the expansion of each leaflet's contact area distribution and percentage in contact with the opposing leaflet. The risk of systolic anterior motion, that may obstruct the left ventricular outflow tract, was minimized, as the anterior leaflet was directed towards the posterior position. In conclusion, annuloplasty repair alone can effectively treat MR when an appropriate band length is selected. It facilitates a significant reduction in ROA, correction of bileaflet prolapse, and improvement in leaflet coaptation. These findings have important clinical implications, potentially offering a less complex surgical treatment avenue and reducing complications in the management of MR., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Understanding cardiovascular control mediated by the autonomic system remains challenging due to its inherent complexity. Consequently, syndromes such as orthostatic intolerance continue to evoke debates regarding the underlying pathophysiological mechanisms. This study develops a comprehensive mathematical model simulating the control of the sympathetic branch of the cardiovascular system in individuals with normal and abnormal responses to the head-up-tilt test. We recruited four young women: one control, one with vasovagal syncope, one with orthostatic hypertension, and one with orthostatic hypotension, exposing them to an orthostatic head-up tilt test (HUTT) employing non-invasive methods to measure electrocardiography and continuous blood pressure. Our work encompasses a compartmental model formulated using a system of ordinary differential equations. Using heart rate as input, we predict blood pressure, flow, and volume in compartments representing the veins, arteries, heart, and the sympathetic branch of the baroreflex control system. The latter is modulated by high- and low-pressure baroreceptor afferents activated by changes in blood pressure induced by the HUTT. Sensitivity analysis, parameter subset selection, and optimization are employed to estimate patient-specific parameters associated with autonomic performance. The model has seven sensitive and identifiable parameters with significant physiological relevance that can serve as biomarkers for patient classification. Results show that the model can reproduce a spectrum of blood pressure responses successfully, fitting the trajectory displayed by the experimental data. The controller exhibits behavior that emulates the operation of the sympathetic system. These encouraging findings underscore the potential of computational methods in evaluating pathologies associated with autonomic nervous system control, warranting further exploration and novel approaches., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Maria Rodriguez-Fernandez reports financial support was provided by National Agency for Research and Innovation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The relationship between measures of stenosis and microvascular resistance is of importance due to medical decisions being based on these values. This research investigates the impact of varying microvascular resistance on fractional flow reserve (FFR) and hyperaemic stenosis resistance (hSR). Microvascular resistance is classified using hyperaemic microvascular resistance (hMR). Additionally, hMR using the upstream pressure value (hMR Pa ) has also been calculated and is compared to hMR measured conventionally. Tests were conducted at three different degrees of stenosis (quantified by percent area) in a coronary flow circuit with varying downstream resistance to simulate the microvasculature. Pressure and flow values are recorded across the stenosed section, allowing for calculation of the diagnostic indexes. Results indicate that for a constant degree of stenosis, FFR would increase with increasing microvascular resistance while hSR would remain almost constant. hMR Pa was found to approach hMR as the stenosis severity decreased, and the pressure gradient decreased. In the results shown here, with sufficiently high downstream resistance, an 84 % stenosis could produce an FFR value over 0.8. This result suggests that there is the potential for misdiagnosis of the severity of stenosis when combined with elevated microvascular resistance. Consequently, decisions on the clinical significance of a stenosis, classified by FFR, need to consider the effect of the microvascular resistance., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Accurate segmentation of medical images is critical for generating patient-specific models suitable for computational analyses, particularly in the context of transcatheter aortic valve implantation (TAVI). This study aimed to quantify the accuracy of the segmentation process from medical images of TAVI patients to understand the uncertainty in patient-specific geometries. We also quantified discrepancies between actual and CT-related diameter measurements due to artifacts and intra-observer variability. Segmentation accuracy was assessed using both synthetic phantom models and patient-specific data. The impact of voxelization and CT scanner resolution on segmentation accuracy was evaluated, while the intersection over union (IoU) metric was used to compare the consistency of different segmentation methodologies. The voxelization process introduced a marginal error (<1%) in phantom models relative to CAD models. CT scanner resolution impacted segmented model accuracy only after a 7.5-fold increase in voxel size compared to the baseline medical image. IoU analysis revealed higher segmentation accuracy for calcification (93.4 ± 3.1 %) compared to the aortic wall (85.4 ± 8.4 %) and native valve leaflets (75.5 ± 6.3 %). Discrepancies in THV diameter measurements highlighted a ∼5 % error due to metallic artifacts, with variability among observers and at different THV heights. Errors due to voxel size, segmentation methodologies and CT-related artifacts can impact the reliability of patient-specific geometries and ultimately computational predictions used to asses clinical outcomes and enhance decision-making. This study underscores the importance of accurate segmentation and its standardization for patient-specific modeling of TAVI simulations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Although the hemodynamics of cerebral aneurysms have been extensively studied using patient-specific computational fluid dynamics techniques, no specific hemodynamic factors characteristic of cerebral aneurysm development have yet been identified. We believe that one problem with previous hemodynamic studies of cerebral aneurysms has been the manner in which control groups were created for comparison with experimental groups. The purpose of this study was to determine hemodynamic factors that correlated with the development of cerebral aneurysms. The control group was established in a manner that differed from those of previous works. This allowed us to demonstrate the effectiveness of our method. We artificially removed aneurysms in the middle cerebral artery bifurcations of nine patients and reconstructed the vessel geometries before the aneurysms had occurred. Pulsatile blood flow simulations were performed using the vessel geometries ipsilateral and contralateral to the sites of aneurysm removal, and hemodynamic metrics were calculated. Use of the ipsilateral and contralateral sides as the experimental and control sites, respectively, allowed us to evaluate statistically the hemodynamic metrics between the two corresponding sites/groups. The results showed that only the normalized transverse wall shear stress (NtransWSS) was significantly higher at the MCA bifurcation ipsilateral to the site of aneurysm removal than at the contralateral bifurcation (p = 0.01). There were no significant differences in the other hemodynamic metrics between the bilateral bifurcations. Our findings imply that multi-directional disturbed wall shear stress, which is detected by the NtransWSS metric, may be one hemodynamic risk factor for the development of cerebral aneurysms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The organization of myofibers and extra cellular matrix within the myocardium plays a significant role in defining cardiac function. When pathological events occur, such as myocardial infarction (MI), this organization can become disrupted, leading to degraded pumping performance. The current study proposes a multiscale finite element (FE) framework to determine realistic fiber distributions in the left ventricle (LV). This is achieved by implementing a stress-based fiber reorientation law, which seeks to align the fibers with local traction vectors, such that contractile force and load bearing capabilities are maximized. By utilizing the total stress (passive and active), both myofibers and collagen fibers are reoriented. Simulations are conducted to predict the baseline fiber configuration in a normal LV as well as the adverse fiber reorientation that occurs due to different size MIs. The baseline model successfully captures the transmural variation of helical fiber angles within the LV wall, as well as the transverse fiber angle variation from base to apex. In the models of MI, the patterns of fiber reorientation in the infarct, border zone, and remote regions closely align with previous experimental findings, with a significant increase in fibers oriented in a left-handed helical configuration and increased dispersion in the infarct region. Furthermore, the severity of fiber reorientation and impairment of pumping performance both showed a correlation with the size of the infarct. The proposed multiscale modeling framework allows for the effective prediction of adverse remodeling and offers the potential for assessing the effectiveness of therapeutic interventions in the future. STATEMENT OF SIGNIFICANCE: The organization of muscle and collagen fibers within the heart plays a significant role in defining cardiac function. This organization can become disrupted after a heart attack, leading to degraded pumping performance. In the current study, we implemented a stress-based fiber reorientation law into a computer model of the heart, which seeks to realign the fibers such that contractile force and load bearing capabilities are maximized. The primary goal was to evaluate the effects of different sized heart attacks. We observed substantial fiber remodeling in the heart, which matched experimental observations. The proposed computational framework allows for the effective prediction of adverse remodeling and offers the potential for assessing the effectiveness of therapeutic interventions in the future., Competing Interests: Declaration of competing interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Atrial fibrillation (AF) affects millions of people in the world, causing increased morbidity and mortality. Treatment involves antiarrhythmic drugs and catheter ablation, showing high success for paroxysmal AF but challenges for persistent AF. Experimental evidence suggests reentrant waves and rotors contribute to AF substrates. Ablation procedures rely on electroanatomical maps and electrogram (EGM) signals; however, current methods used in clinical practice lack consideration for time-frequency varying EGM components. The fractional Fourier transform (FrFT) can be adopted to capture time-varying frequency components, thereby enhancing the comprehension of arrhythmogenic substrates during AF for improved ablation strategies. To this end, a FrFT-based algorithm is developed to characterize non-stationary components in EGM signals from simulated AF episodes. The proposed algorithm comprises a pre-processing step to enhance the coarser features of the EGM waveform, a windowing process for dynamic assessment of the EGM, and a FrFT order optimization stage that seeks compact signal representations in fractional Fourier domains. The resulting order is related to the rate of frequency change in the signal, making it a useful indicator for frequency-modulated components. The FrFT-based algorithm is implemented on EGM signals from AF simulations in 2D domains representing a region of the atrial tissue. Consequently, the computed optimum FrFT orders are used to build maps that are spatially correlated to the underlying propagation dynamics of the simulated AF episode. The results evince that the extreme values in the optimum orders map pinpoint the localization of fibrillatory mechanisms, generating EGM activation waveforms with varying frequency content over time., Competing Interests: Declaration of competing interest None Declared, (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The biomechanical rupture risk assessment (BRRA) of abdominal aortic aneurysms (AAA) has higher sensitivity than maximal diameter criterion (D SEX ) but its estimation is time-consuming and relies on an uncertain estimation of wall thickness. The aim of this study is to test tension-based criterion in the BRRA of AAA which removes the necessity of wall thickness measurement and should be faster. For that, we retrospectively analyzed 99 patients with intact AAA (25 females). Nineteen of them experienced a rupture later. BRRA was performed with wall tension PRRI T as a primary criterion. The ability of criterion to separate intact and ruptured AAAs at 1,3,6,9 and 12 months was estimated. Next, the receiver operating characteristics and the percentage of true negative cases for a different time to an outcome were estimated. Finally, the computational time was recorded. The results were compared to stress-based criterion PRRI and D SEX which served as a reference. All three criterions were able to discriminate between intact and ruptured AAAs up to 9 months (p < 0.05) while none of them could do for a 12 month prediction. PRRI T exhibited a significantly higher percentage of true negatives for 12 and 9 month predictions (45 % and 20 % respectively) and similar to other criteria for other prediction times. The mean computational time for estimating PRRI T was 19 h per patient compared to 67 h for PRRI. The tension- based BRRA of AAA leads to better outcomes for a 9 and 12 month prediction while the computational time drops by more than 70 % compared to PRRI., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The spleen constantly clears altered red blood cells (RBCs) from the circulation, tuning the balance between RBC formation (erythropoiesis) and removal. The retention and elimination of RBCs occur predominantly in the open circulation of the spleen, where RBCs must cross submicron-wide inter-endothelial slits (IES). Several experimental and computational studies have illustrated the role of IES in filtrating the biomechanically and morphologically altered RBCs based on a rigid wall assumption. However, these studies also reported that when the size of IES is close to the lower end of clinically observed sizes (less than 0.5 μm), an unphysiologically large pressure difference across the IES is required to drive the passage of normal RBCs, sparking debates on the feasibility of the rigid wall assumption. In this work, We propose two deformable IES models, namely the passive model and the active model, aiming to explore the impact of the deformability of IES on the filtration function of the spleen. In the passive model, we implement the worm-like string model to depict the IES's deformation as it interacts with blood plasma and allows RBC to traverse. In contrast, the active model involved regulating the IES deformation based on the local pressure surrounding the slit. To demonstrate the validity of the deformable model, we simulate the filtration of RBCs with varied size and stiffness by IES under three scenarios: (1) a single RBC traversing a single slit; (2) a suspension of RBCs traversing an array of slits, mimicking in vitro spleen-on-a-chip experiments; (3) RBC suspension passing through the 3D spleen filtration unit known as'the splenon'. Our simulation results of RBC passing through a single slit show that the deformable IES model offers more accurate predictions of the critical cell surface area to volume ratio that dictate the removal of aged RBCs from circulation compared to prior rigid-wall models. Our biophysical models of the spleen-on-a-chip indicate a hierarchy of filtration function stringency: rigid model > passive model > active model, providing a possible explanation of the filtration function of IES. We also illustrate that the biophysical model of 'the splenon' enables us to replicate the ex vivo experiments involving spleen filtration of malaria-infected RBCs. Taken together, our simulation findings indicate that the deformable IES model could serve as a mesoscopic representation of spleen filtration function closer to physiological reality, addressing questions beyond the scope of current experimental and computational models and enhancing our understanding of the fundamental flow dynamics and mechanical clearance processes within in the human spleen., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

The human aorta undergoes complex morphologic changes that mirror the evolution of disease. Finite element analysis (FEA) enables the prediction of aortic pathologic states, but the absence of a biomechanical understanding hinders the applicability of this computational tool. We incorporate geometric information from computed tomography angiography (CTA) imaging scans into FEA to predict a trajectory of future geometries for four aortic disease patients. Through defining a geometric correspondence between two patient scans separated in time, a patient-specific FEA model can recreate the deformation of the aorta between the two time points, showing that pathologic growth drives morphologic heterogeneity. FEA-derived trajectories in a shape-size geometric feature space, which plots the variance of the shape index versus the inverse square root of aortic surface area (δS vs. [Formula: see text] ), quantitatively demonstrate an increase in δS. This represents a deviation from physiologic shape changes and parallels the true geometric progression of aortic disease patients., Competing Interests: Declaration of competing interest None declared, (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Sympathetic hyperactivity via spatially dense adrenergic stimulation may create pro-arrhythmic substrates even without structural remodelling. However, the effect of sympathetic hyperactivity on arrhythmic activity, such as rotors, is unknown. Using simulations, we examined the effects of gradually increasing the spatial density of adrenergic stimulation (AS) in atrial sheets on rotors. We compared their characteristics against rotors hosted in atrial sheets with increasing spatial density of minimally conductive (MC) elements to simulate structural remodelling due to injury or disease. We generated rotors using an S1-S2 stimulation protocol. Then, we created phase maps to identify phase singularities and map their trajectory over time. We measured each rotor's duration (s), angular speed (rad/s), and spatiotemporal organization. We demonstrated that atrial sheets with increased AS spatial densities could maintain rotors longer than with MC elements (2.6 ± 0.1 s vs. 1.5 ± 0.2 s, p<0.001). Moreover, rotors have higher angular speed (70 ± 7 rads/s vs. 60 ± 15 rads/s, p<0.05) and better spatiotemporal organization (0.56 ± 0.05 vs. 0.58 ± 0.18, p<0.05) in atrial sheets with less than 25% AS elements compared to MC elements. Our findings may help elucidate electrophysiological potential alterations in atrial substrates due to sympathetic hyperactivity, particularly among individuals with autonomic derangements caused by chronic distress., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Three-dimensional Digital Subtraction Angiography (3D-DSA) is a well-established X-ray-based technique for visualizing vascular anatomy. Recently, four-dimensional DSA (4D-DSA) reconstruction algorithms have been developed to enable the visualization of volumetric contrast flow dynamics through time-series of volumes. This reconstruction problem is ill-posed mainly due to vessel overlap in the projection direction and geometric vessel foreshortening, which leads to information loss in the recorded projection images. However, knowledge about the underlying fluid dynamics can be leveraged to constrain the solution space. In our work, we implicitly include this information in a neural network-based model that is trained on a dataset of image-based blood flow simulations. The model predicts the spatially averaged contrast agent concentration for each centerline point of the vasculature over time, lowering the overall computational demand. The trained network enables the reconstruction of relative contrast agent concentrations with a mean absolute error of 0.02±0.02 and a mean absolute percentage error of 5.31±9.25 %. Moreover, the network is robust to varying degrees of vessel overlap and vessel foreshortening. Our approach demonstrates the potential of the integration of machine learning and blood flow simulations in time-resolved angiographic contrast agent concentration reconstruction., Competing Interests: Declaration of competing interest None declared., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Neovascularization has been extensively studied because of its significant role in both physiological processes and diseases. The significance of vascular microfluidic platforms lies in its essential role in recreating an in vitro environment capable of supporting cellular and tissue systems through the process of neovascularization. Biomechanical properties in a tissue engineered system use fluid flow and transport properties to recapitulate physiological systems. This enables mimicry of organ systems which can further personalized and regenerative medicine. Thus, fluid hemodynamics can be used to study these flow patterns and create a system that mimics real physiological pathways and processes. The establishment of stable flow pathways encourages endothelial cells (ECs) ECs to undergo neovascularization. Specifically, the shear stress applied in capillary beds generates the increased proliferation and differentiation of ECs to build larger microcirculatory beds., Mathematical Framework: Here, we describe a mathematical model that uses branching patterns and vessel morphology to predict hemodynamic parameters in capillary beds., Results: A retinal capillary bed is used as one-use case of our model to show how the mathematical framework can be used to determine hemodynamic parameters for any microfluidic system., Conclusion: In doing so, this tool can be altered to be used to supplement emerging research areas in neovascularization., (© 2024 John Wiley & Sons Ltd.)

Despite recent clinical and technological advancements, the cardiac arrest survival rate remains as low as 10%. To enhance patient outcomes, it is crucial to deepen the understanding of cardiopulmonary resuscitation (CPR) at a fundamental level. Currently, there is a lack of knowledge on the physiological effects of CPR, in particular on the hemodynamics in the heart and the great vessels. The design and validation of a dedicated in vitro heart simulator, capable of replicating the physiological response to CPR, holds the potential to provide valuable insights into the fluid dynamics in the heart during CPR but also to be used as a platform for the development and testing of mechanical CPR machines. The main objective of this study is to design and validate the first in vitro heart simulator that can replicate the physiological response during CPR. For that, a custom-made heart simulator is designed consisting of an elastic model of the complete heart and a controllable linear actuator. The heart model is positioned in an anatomical position, and the linear actuator compresses the model at specific rates and depths. Flow and pressure waveforms are recorded on the newly developed simulator at 60 contractions per minute and results are validated against reported in vivo data in the literature. Finally, the system's capabilities are evaluated by considering several combinations of compression rates and depths., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: The objective of this study is to validate a novel workflow for implementing patient-specific finite element (FE) simulations to virtually replicate the Transcatheter Aortic Valve Implantation (TAVI) procedure., Methods: Seven patients undergoing TAVI were enrolled. Patient-specific anatomical models were reconstructed from pre-operative computed tomography (CT) scans and subsequentially discretized, considering the native aortic leaflets and calcifications. Moreover, high-fidelity models of CoreValve Evolut R and Acurate Neo2 valves were built. To determine the most suitable material properties for the two stents, an accurate calibration process was undertaken. This involved conducting crimping simulations and fine-tuning Nitinol parameters to fit experimental force-diameter curves. Subsequently, FE simulations of TAVI procedures were conducted. To validate the reliability of the implemented implantation simulations, qualitative and quantitative comparisons with post-operative clinical data, such as angiographies and CT scans, were performed., Results: For both devices, the simulation curves closely matched the experimental data, indicating successful validation of the valves mechanical behaviour. An accurate qualitative superimposition with both angiographies and CTs was evident, proving the reliability of the simulated implantation. Furthermore, a mean percentage difference of 1,79 ± 0,93 % and 3,67 ± 2,73 % between the simulated and segmented final configurations of the stents was calculated in terms of orifice area and eccentricity, respectively., Conclusion: This study shows the successful validation of TAVI simulations in patient-specific anatomies, offering a valuable tool to optimize patients care through personalized pre-operative planning. A systematic approach for the validation is presented, laying the groundwork for enhanced predictive modeling in clinical practice., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: In electrocardiographic imaging (ECGI), selecting an optimal regularization parameter (λ) is crucial for obtaining accurate inverse electrograms. The effects of signal and geometry uncertainties on the inverse problem regularization have not been thoroughly quantified, and there is no established methodology to identify when λ is sub-optimal due to these uncertainties. This study introduces a novel approach to λ selection using Tikhonov regularization and L-curve optimization, specifically addressing the impact of electrical noise in body surface potential map (BSPM) signals and geometrical inaccuracies in the cardiac mesh., Methods: Nineteen atrial simulations (5 of regular rhythms and 14 of atrial fibrillation) ensuring variability in substrate complexity and activation patterns were used for computing the ECGI with added white Gaussian noise from 40 dB to -3dB. Cardiac mesh displacements (1-3 cm) were applied to simulate the uncertainty of atrial positioning and study its impact on the L-curve shape. The regularization parameter, the maximum curvature, and the most horizontal angle of the L-curve (β) were quantified. In addition, BSPM signals from real patients were used to validate our findings., Results: The maximum curvature of the L-curve was found to be inversely related to signal-to-noise ratio and atrial positioning errors. In contrast, the β angle is directly related to electrical noise and remains unaffected by geometrical errors. Our proposed adjustment of λ, based on the β angle, provides a more reliable ECGI solution than traditional corner-based methods. Our findings have been validated with simulations and real patient data, demonstrating practical applicability., Conclusion: Adjusting λ based on the amount of noise in the data (or on the β angle) allows finding optimal ECGI solutions than a λ purely found at the corner of the L-curve. It was observed that the relevant information in ECGI activation maps is preserved even under the presence of uncertainties when the regularization parameter is correctly selected. The proposed criteria for regularization parameter selection have the potential to enhance the accuracy and reliability of ECGI solutions., Competing Interests: Declaration of competing interest M.S. Guillem. A.M. Climent. Are co-founders of Corify Care SL. R. Molero, J. Reventós-Presmanes, A.M. Climent. And M.S. Guillem get honorary from Corify Care SL. M.S. Guillem, L. Mont is shareholders of Corify Care SL. L. Mont reports honoraria as consultant, lecturer, and Advisory Board from Boston Scientific, Abbott Medical, Johnson & Johnson, and Medtronic. He is a shareholder of Galgo Medical SL. I. Roca-Luque has received honoraria as a lecturer and consultant from Abbott and Biosense Webster., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Hypertrophic cardiomyopathy (HCM) is one of the most common genetic cardiac disorders and is characterized by different phenotypes of left ventricular hypertrophy with and without obstruction. The effects of left ventricular outflow tract (LVOT) obstruction based on different anatomies may be hemodynamically relevant and influence therapeutic decision making. Cardiovascular magnetic resonance (CMR) provides anatomical information. We aimed to identify different shapes of LVOT-obstruction using Cardiovascular Magnetic Resonance (CMR). The study consisted of two parts: An in-vivo experiment for shape analysis and in-vitro part for the assessment of its hemodynamic consequences. In-vivo a 3D depiction of the LVOT was created using a 3D multi-slice reconstruction from 2D-slices (full coverage cine stack with 7 slices and a thickness of 5-6 mm with no gap) in 125 consecutive HOCM patients (age = 64.17 +/- 12.655; female n = 42). In-vitro an analysis of the LVOT regarding shape and flow behavior was conducted. For this purpose, 2D and 4D measurements were performed on 3D printed phantoms which were based on the anatomical characteristics of the in-vivo study, retrospectively. The in-vivo study identified three main shapes named K- (28.8%), X- (51.2%) and V-shape (10.4%) and a mixed one (9.6%). By analyzing the in-vitro flow measurements every shape showed an individual flow profile in relation to the maximum velocity in cm/s. Here, the V-shape showed the highest value of velocity (max. 138.87 cm/s). The X-shape was characterized by a similar profile but with lower velocity values (max. 125.39 cm/s), whereas the K-shape had an increase of the velocity without decrease (max. 137.11 cm/s). For the first time three different shapes of LVOT-obstruction could be identified. These variants seem to affect the hemodynamics in HOCM., Competing Interests: Declarations Competing interests The authors have no relevant financial or non-financial interests to disclose., (© 2024. The Author(s).)

In the last decades, many computational models have been developed to predict soft tissue growth and remodeling (G&R). The constrained mixture theory describes fundamental mechanobiological processes in soft tissue G&R and has been widely adopted in cardiovascular models of G&R. However, even after two decades of work, large organ-scale models are rare, mainly due to high computational costs (model evaluation and memory consumption), especially in long-range simulations. We propose two strategies to adaptively integrate history variables in constrained mixture models to enable large organ-scale simulations of G&R. Both strategies exploit that the influence of deposited tissue on the current mixture decreases over time through degradation. One strategy is independent of external loading, allowing the estimation of the computational resources ahead of the simulation. The other adapts the history snapshots based on the local mechanobiological environment so that the additional integration errors can be controlled and kept negligibly small, even in G&R scenarios with severe perturbations. We analyze the adaptively integrated constrained mixture model on a tissue patch for a parameter study and show the performance under different G&R scenarios. To confirm that adaptive strategies enable large organ-scale examples, we show simulations of different hypertension conditions with a real-world example of a biventricular heart discretized with a finite element mesh. In our example, adaptive integrations sped up simulations by a factor of three and reduced memory requirements to one-sixth. The reduction of the computational costs gets even more pronounced for simulations over longer periods. Adaptive integration of the history variables allows studying more finely resolved models and longer G&R periods while computational costs are drastically reduced and largely constant in time., (© 2024 The Author(s). International Journal for Numerical Methods in Biomedical Engineering published by John Wiley & Sons Ltd.)

Background: This study seeks to quantify the effects of upper body veno-arterial extracorporeal membrane oxygenation (VA ECMO) on the anatomical distribution of oxygen delivery in the setting of hypoxic respiratory failure and provide new insights that will guide clinical use of this support strategy to bridge patients to lung transplant., Methods: Employing a patient-specific vascular geometry and a quantitative model of oxygen transport, computational simulations were performed to determine hemodynamics and oxygen delivery in the ascending and descending aorta, left and right coronary arteries, and great vessels during upper body VA ECMO support. Oxygen content in ECMO circuit blood flow was varied while considering different degrees of lung failure severity. Using lumped parameter models to dynamically apply perfusion boundary conditions, hemodynamic parameters and oxygen content were analyzed to assess the effect of ECMO supply titration., Results: The results emphasize the importance of anatomical distribution for tissue oxygen delivery in severe lung failure, with ECMO-derived flow primarily augmenting oxygen content in specific vascular beds. They also demonstrate that although cannulating the subclavian artery can enhance cerebral oxygen delivery, its ability to ensure sufficient oxygen delivery to the coronary circulation seems to be comparatively restricted., Conclusions: The oxygen delivery to a specific vascular area is primarily determined by the oxygen content in the source of perfusion. Caution is advised with upper body VA ECMO for patients with hypoxic respiratory failure and right ventricle dysfunction, due to potential coronary ischemia. Management of these patients is challenging due to disease progression and organ availability uncertainties., Competing Interests: Declaration of competing interest Hamed Moradi denies any competing interests. Raghu Seethala denies any competing interests. Elazer Edelman is the primary investigator of an educational grant to the Massachusetts Institute of Technology (MIT) from Abiomed, Inc. that investigates use of mechanical circulatory support devices. He has developed intellectual property that is licensed to Abiomed, Inc. through MIT. This work is in the related field of mechanical support but is not directly related to the submitted work. Farhad Nezami denies any competing interests. Steven Keller is a co-inventor of intellectual property with Dr. Edelman that is licensed to Abiomed, Inc. through MIT. This work is not directly related to the submitted work., (Copyright © 2024. Published by Elsevier Ltd.)

Splenic artery embolization (SAE) has become a favored alternative to splenectomy, offering a less invasive intervention for injured spleens while preserving spleen function. However, our understanding of the role that hemodynamics plays during embolization remains limited. In this study, we utilized patient-specific computational fluid dynamics (CFD) simulations to study distal and proximal embolization strategies commonly used in SAE. Detailed 3D computer models were constructed considering the descending aorta, various major visceral arteries, and the iliac arteries. Subsequently, the blood flow and pressure associated with different coil placement locations in proximal embolization were studied considering the collateral vessels. Coil induced variations in pressure fields were quantified and compared to baseline. The coil induced flow stagnation was also quantified with particle residence time. Distal embolization was modeled with Lagrangian particle tracking and the effect of particle size, release location, and timing on embolization outcome was studied. Our findings highlight the crucial role of collateral vessels in maintaining blood supply to the spleen following proximal embolization. It was demonstrated that coil location can affect distal pressure and that strategic coil placement guided by patient-specific CFD simulations can further reduce this pressure as desired. Additionally, the results point to the critical roles that particle size, release timing, and location play in distal embolization. Our study provides an early attempt to use patient-specific computer modeling for optimizing embolization strategies and ultimately improving patient outcomes during SAE procedures., Competing Interests: Declaration of competing interest The authors hereby declare that they have no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Accurate prenatal diagnosis of coarctation of the aorta (CoA) is challenging due to high false positive rate burden and poorly understood aetiology. Despite associations with abnormal blood flow dynamics, fetal arch anatomy changes and alterations in tissue properties, its underlying mechanisms remain a longstanding subject of debate hindering diagnosis in utero. This study leverages computational fluid dynamics (CFD) simulations and statistical shape modelling to investigate the interplay between fetal arch anatomy and blood flow alterations in CoA. Using cardiac magnetic resonance imaging data from 188 fetuses, including normal controls and suspected CoA cases, a statistical shape model of the fetal arch anatomy was built. From this analysis, digital twin models of false and true positive CoA cases were generated. These models were then used to perform CFD simulations of the three-dimensional fetal arch haemodynamics, considering physiological variations in arch shape and blood flow conditions across the disease spectrum. This analysis revealed that independent changes in the shape of. the arch and the balance of left-to-right ventricular output led to qualitatively similar haemodynamic alterations. Transitioning from a false to a true positive phenotype increased retrograde flow through the aortic isthmus. This resulted in the appearance of an area of low wall shear stress surrounded by high wall shear stress values at the flow split apex on the aortic posterior wall opposite the ductal insertion point. Our results suggest a distinctive haemodynamic signature in CoA characterised by the appearance of retrograde flow through the aortic isthmus and altered wall shear stress at its posterior side. The consistent link between alterations in shape and blood flow in CoA suggests the need for comprehensive anatomical and functional diagnostic approaches in CoA. This study presents an application of the digital twin approach to support the understanding of CoA mechanisms in utero and its potential for improved diagnosis before birth., Competing Interests: Declaration of competing interest None declared., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

A key strategy for increasing drug mass (DM) while maintaining good safety is to improve the drug release profile (RP). We designed a dual layer coating drug-eluting stent (DES) that exhibited smaller concentration gradients between the coating and the artery wall and significantly impacted the drug RP. However, a detailed understanding of the effects of the DES designed by our team on safety and efficacy is still lacking. The objective of this study was to provide a comprehensive multiscale computational framework that would allow us to probe the safety and efficacy of the DES we designed. This framework consisted of four coupled modules, namely (1) a mechanical stimuli module, simulating mechanical stimuli caused by percutaneous coronary intervention through a finite element analysis, (2) an inflammation module, simulating inflammation of vascular smooth muscle cells (VSMCs) induced by mechanical stimuli through an agent-based model (ABM), (3) a drug transport module, simulating drug transport through a continuum-based approach, and (4) a mitosis module, simulating VSMC mitosis through an ABM. Our results indicated that when the DM increased to two times the initial DM value, the DES we designed had higher safety and lower efficacy values than a conventional DES. When the DM increased to five times the initial DM value, the DES we designed had higher safety than a conventional DES, and negligible differences in efficacy compared with a conventional DES. In summary, the DES we designed exhibited a significant advantage in safety, but a slightly reduced efficacy compared with that of a conventional DES., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Guidewire-based pressure measurement is essential for diagnosing coronary artery disease. However, the impact of the guidewire on local hemodynamics and diagnostic outcomes is not fully understood. In this study, we propose a generalized reduced-order model (ROM) to accurately predict the trans-stenotic pressure drop in arteries. A key advantage of this model is that the viscous term does not rely on empirical parameters, making it applicable to both scenarios with and without guidewire insertion, and across varying stenosis severities. The proposed model demonstrates good accuracy compared to 3D idealized numerical models, achieving an average prediction error of 3.61% for cases without a guidewire and 4.53% for cases with a guidewire. Furthermore, when applied to a patient-specific model, it achieves comparable or better results than previously published ROMs. Finally, this ROM is employed to investigate the shifting relative importance of different components of the trans-stenotic pressure drop at various stenosis severities, and to provide further insights into the guidewire's influence on FFR measurements., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Heart Failure (HF) poses a challenge for our health systems, and early detection of Worsening HF (WHF), defined as a deterioration in symptoms and clinical and instrumental signs of HF, is vital to improving prognosis. Predicting WHF in a phase that is currently undiagnosable by physicians would enable prompt treatment of such events in patients at a higher risk of WHF. Although the role of Artificial Intelligence in cardiovascular diseases is becoming part of clinical practice, especially for diagnostic and prognostic purposes, its usage is often considered not completely reliable due to the incapacity of these models to provide a valid explanation about their output results. Physicians are often reluctant to make decisions based on unjustified results and see these models as black boxes. This study aims to develop a novel diagnostic model capable of predicting WHF while also providing an easy interpretation of the outcomes. We propose a threshold-based binary classifier built on a mathematical model derived from the Genetic Programming approach. This model clearly indicates that WHF is closely linked to creatinine, sPAP, and CAD, even though the relationship of these variables and WHF is almost complex. However, the proposed mathematical model allows for providing a 3D graphical representation, which medical staff can use to better understand the clinical situation of patients. Experiments conducted using retrospectively collected data from 519 patients treated at the HF Clinic of the University Hospital of Salerno have demonstrated the effectiveness of our model, surpassing the most commonly used machine learning algorithms. Indeed, the proposed GP-based classifier achieved a 96% average score for all considered evaluation metrics and fully supported the controls of medical staff. Our solution has the potential to impact clinical practice for HF by identifying patients at high risk of WHF and facilitating more rapid diagnosis, targeted treatment, and a reduction in hospitalizations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The Ozaki procedure is a surgical technique which avoids to implant foreign aortic valve prostheses in human heart, using the patient's own pericardium. Although this approach has well-identified benefits, it is still a topic of debate in the cardiac surgical community, which prevents its larger use to treat valve pathologies. This is linked to the actual lack of knowledge regarding the dynamics of tissue deformations and surrounding blood flow for this autograft pericardial valve. So far, there is no numerical study examining the coupling between the blood flow characteristics and the Ozaki leaflets dynamics. To fill this gap, we propose here a comprehensive comparison of various performance criteria between a healthy native valve, its pericardium-based counterpart, and a bioprosthetic solution, this is done using a three-dimensional fluid-structure interaction solver. Our findings reveal similar physiological dynamics between the valves but with the emergence of fluttering for the Ozaki leaflets and higher velocity and wall shear stress for the bioprosthetic heart valve., (© 2024. The Author(s) under exclusive licence to Biomedical Engineering Society.)

The opening and closing dynamics of the aortic valve (AV) has a strong influence on haemodynamics in the aortic root, and both play a pivotal role in maintaining normal physiological functions of the valve. The aim of this study was to establish a subject-specific fluid-structure interaction (FSI) workflow capable of simulating the motion of a tricuspid healthy valve and the surrounding haemodynamics under physiologically realistic conditions. A subject-specific aortic root was reconstructed from magnetic resonance (MR) images acquired from a healthy volunteer, whilst the valve leaflets were built using a parametric model fitted to the subject-specific aortic root geometry. The material behaviour of the leaflets was described using the isotropic hyperelastic Ogden model, and subject-specific boundary conditions were derived from 4D-flow MR imaging (4D-MRI). Strongly coupled FSI simulations were performed using a finite volume-based boundary conforming method implemented in FlowVision. Our FSI model was able to simulate the opening and closing of the AV throughout the entire cardiac cycle. Comparisons of simulation results with 4D-MRI showed a good agreement in key haemodynamic parameters, with stroke volume differing by 7.5% and the maximum jet velocity differing by less than 1%. Detailed analysis of wall shear stress (WSS) on the leaflets revealed much higher WSS on the ventricular side than the aortic side and different spatial patterns amongst the three leaflets., (© 2024 The Author(s). International Journal for Numerical Methods in Biomedical Engineering published by John Wiley & Sons Ltd.)

The article presents a semi-automatic approach to generating structured hexahedral meshes of patient-specific aortas ailed by aortic dissection. The condition manifests itself as a formation of two blood flow channels in the aorta, as a result of a tear in the inner layers of the aortic wall. Subsequently, the morphology of the aorta is greatly impacted, making the task of domain discretization highly challenging. The meshing algorithm presented herein is automatic for the individual lumina, whereas the tears require user interaction. Starting from an input (triangle) surface mesh, we construct an implicit surface representation as well as a topological skeleton, which provides a basis for the generation of a block-structure. Thereafter, the mesh generation is performed via transfinite maps. The meshes are structured and fully hexahedral, exhibit good quality and reliably match the original surface. As they are generated with computational fluid dynamics in mind, a fluid flow simulation is performed to verify their usefulness. Moreover, since the approach is based on valid block-structures, the meshes can be made very coarse (around 1000 elements for an entire aortic dissection domain), and thus promote using solvers based on the geometric multigrid method, which is typically reliant on the presence of a hierarchy of coarser meshes., (© 2024 The Author(s). International Journal for Numerical Methods in Biomedical Engineering published by John Wiley & Sons Ltd.)

Background: The exclusion/occlusion of the left atrial appendage (LAA) is a treatment option for atrial fibrillation (AF) patients who are at high risk of stroke and high risk of bleeding. As the role of the LAA is not well understood or explored, this study aims to assess its role on flow dynamics in the left atrium., Methods: Computational fluid dynamics (CFD) simulations were carried out for nine AF patients before and after LAA exclusion. The flow parameters investigated included the LA velocities, Time Averaged Wall Shear Stress (TAWSS), Oscillatory Shear Index (OSI), Relative Residence Time (RRT), and Pressure in the LA., Results: This study shows that, on average, a decrease in TAWSS (1.82 ± 1.85 Pa to 1.27 ± 0.96 Pa, p < 0.05) and a slight increase in OSI (0.16 ± 0.10 to 0.17 ± 0.10, p < 0.05), RRT (1.87 ± 1.84 Pa -1 to 2.11 ± 1.78 Pa -1 , p < 0.05), and pressure (-19.2 ± 6.8 mmHg to -15.3 ± 8.3 mmHg, p < 0.05) were observed in the LA after the exclusion of the LAA, with a decrease in low-magnitude velocities., Conclusion: The exclusion of the LAA seems to be associated with changes in LA flow dynamics. Further studies are needed to elucidate the clinical implications of these changes., (© 2024 Wiley Periodicals LLC.)

Donor vessel fractional flow reserve (FFR) usually increases following successful chronic total occlusion (CTO) percutaneous coronary intervention, as documented by pressure wires. In this case, donor vessel physiology changes were assessed using FFR derived from coronary computed tomography angiography (CCTA) and an artificial Intelligence-guided quantitative CCTA ischemia model in combination with pressure wire-based FFR., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Redo-transcatheter aortic valve replacement (TAVR) is a promising treatment for transcatheter aortic valve degeneration, becoming increasingly relevant with an aging population. In redo-TAVR, the leaflets of the initial (index) transcatheter aortic valve (TAV) are displaced vertically when the second TAV is implanted, creating a cylindrical cage that can impair coronary cannulation and flow. Preventing coronary obstruction and maintaining coronary access is essential, especially in young and low-risk patients undergoing TAVR. This study aimed to develop a new leaflet modification strategy using laser ablation to prevent coronary obstruction and facilitate coronary access after repeat TAVR., Methods: To evaluate the feasibility of the leaflet modification technique using laser ablation, the initial phase of this study involved applying a medical-grade ultraviolet laser for ablation through pericardial tissue. Following this intervention, computational fluid dynamics simulations were utilized to assess the efficacy of the resulting perforations in promoting coronary flow. These simulations played a crucial role in understanding the impact of the modifications on blood flow patterns, ensuring these changes would facilitate the restoration of coronary circulation., Results: Laser ablation of pericardium leaflets was successful, demonstrating the feasibility of creating openings in the TAV leaflets. Flow simulation results show that ablation of index valve leaflets can effectively mitigate the flow obstruction caused by sinus sequestration in redo-TAVR, with the extent of restoration dependent on the number and location of the ablated openings., Conclusions: Laser ablation could be a viable method for leaflet modification in redo-TAVR, serving as a new tool in interventional procedures., (© 2024 Wiley Periodicals LLC.)

As full-scale detailed hemodynamic simulations of the entire vasculature are not feasible, numerical analysis should be focused on specific regions of the cardiovascular system, which requires the identification of lumped parameters to represent the patient behavior outside the simulated computational domain. We present a novel technique for estimating cardiovascular model parameters using gappy Proper Orthogonal Decomposition (g-POD). A POD basis is constructed with FSI simulations for different values of the lumped model parameters, and a linear operator is applied to retain information that can be compared to the available patient measurements. Then, the POD coefficients of the reconstructed solution are computed either by projecting patient measurements or by solving a minimization problem with constraints. The POD reconstruction is then used to estimate the model parameters. In the first test case, the parameter values of a 3-element Windkessel model are approximated using artificial patient measurements, obtaining a relative error of less than 4.2%. In the second case, 4 sets of 3-element Windkessel are approximated in a patient's aorta geometry, resulting in an error of less than 8% for the flow and less than 5% for the pressure. The method shows accurate results even with noisy patient data. It automatically calculates the delay between measurements and simulations and has flexibility in the types of patient measurements that can handle (at specific points, spatial or time averaged). The method is easy to implement and can be used in simulations performed in general-purpose FSI software., (© 2024. The Author(s).)

Aneurysms are bulges of an artery, which require clinical management solutions. Due to the inherent advantages, endovascular coil filling is emerging as the treatment of choice for intracranial aneurysms (IAs). However, after successful treatment of coil embolization, there is a serious risk of recurrence. It is well known that optimal packing density will enhance treatment outcomes. The main objective of endovascular coil embolization is to achieve flow stasis by enabling significant reduction in intra-aneurysmal flow and facilitate thrombus formation. The present study numerically investigates the effect of framing coil orientation on intra-aneurysmal hemodynamics. For the purpose of analysis, actual shape of the embolic coil is used, instead of simplified ideal coil shape. Typically used details of the framing coil are resolved for the analysis. However, region above the framing coil is assumed to be filled with a porous medium. Present simulations have shown that orientation of the framing coil loop (FCL) greatly influences the intra-aneurysmal hemodynamics. The FCLs which were placed parallel to the outlets of basilar tip aneurysm (Coil A) were found to reduce intra-aneurysmal flow velocity that facilitates thrombus formation. Involving the coil for the region is modeled using a porous medium model with a packing density of 20 % . The simulations indicate that the framing coil loop (FCL) has a significant influence on the overall outcome., (© 2024. International Federation for Medical and Biological Engineering.)

The control of left ventricular assist devices (LVADs) requires sensors and/or estimators to account for the physiological state of the patient and apply advanced controllers. Sensor characteristics are a challenge when using implantable pressure sensors because they influence the quality of physiological control and the robustness of the controlled system. The objective of this work is to investigate the performance and robustness of LVAD controllers that operate based on LVAD integrated pressure sensors. Four pressure-based LVAD controllers are tested with a HeartMate 3 that has an integrated pressure sensor. Controller sensitivity as well as robustness to sensor drift and noise are evaluated based on controller response to large changes in preload and afterload. A fail-safe strategy for sensor failure used also to investigate the reliable operation of the LVAD in realistic conditions. All tested controllers are sensitive to drifting pressure signals, which can lead to unstable behavior. The results show that two controllers are robust to noise. The other two controllers show high deviation and oscillation in cardiac output even for small noise. Additionally, a noticeable difference of the controller's response between simulated and measured pressure input was observed, indicating the need for a robust controller design. Reliable operation even in the event of a sensor failure was achieved on the basis of a fail-safe control system.

Background: Low wall shear stress (WSS) is predictive of aortic aneurysm growth and rupture. Yet, estimating WSS in a clinical setting is impractical, whereas measuring aneurysm geometry is feasible. This study investigates the association between saccular aneurysm geometry of the infrarenal aorta and WSS., Methods: Starting with a nonaneurysmal, patient-specific, computational fluid dynamics model of the aorta, saccular aneurysms of varying geometry were created by incrementally increasing the neck width and sac depth from 1 cm to 4 cm. The aspect ratio (the ratio between sac depth and neck width) varied between 0.25 and 4. The peak WSS, time-averaged WSS (TAWSS), and oscillatory shear index (OSI) were measured within the aneurysm sac., Results: Decreasing the neck width from 4 cm to 1 cm decreased the peak WSS by 69% and the TAWSS by 83%. Increasing the sac depth from 1 cm to 4 cm decreased the peak WSS by 55% and the OSI by 37%. The aspect ratio was negatively correlated to peak WSS (Rs -0.85; P < 0.001)., Conclusions: In saccular aneurysms of the infrarenal aorta, a smaller neck width, deeper aneurysm sac, and larger aspect ratio are associated with lower peak WSS., (Copyright © 2024 Elsevier Inc. All rights reserved.)